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Section editor
	Travis Zack, MD, PhD University of California San Francisco San Francisco, CA, USA LinkedIn

Note: there is significant overlap between regimens for gastric cancer and esophageal cancer, if you can't find the regimen you're looking for here, please try the esophageal cancer page. If you still can't find it, it is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page.

Note: this page contains regimens which were not tested in biomarker-specific populations. The following links will take you to biomarker-specific subpages:

Regimens for HER2 positive gastric cancer are here.

71 regimens on this page 108 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

2022: Lordick et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed
- 2016: Smyth et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Okines et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Jackson et al. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Cunningham & Oliveira. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2007: Cunningham. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2005: Cunningham et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of gastric cancer PubMed
2019: Stjepanovic et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
2019: Muro et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS PubMed

ESMO/ESSO/ESTRO

2013: Waddell et al. Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

French Intergroup

2018: Zaanan et al. Gastric cancer: French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO) PubMed

NCCN

NCCN Guidelines - Gastric Cancer
- 2022: Ajani et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. PubMed
- 2016: Ajani et al. Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology. PubMed
- 2013: Ajani et al. Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines. PubMed
- 2010: Ajani et al. Gastric cancer. PubMed
- 2006: Ajani et al. Gastric Cancer Clinical Practice Guidelines. PubMed
- 2003: Ajani et al. Gastric cancer. Clinical practice guidelines in oncology. PubMed

Perioperative therapy

This section contains protocols with a pre-planned neoadjuvant (preoperative) and adjuvant (postoperative) component.

Capecitabine & Cisplatin (CX)

CX: Cisplatin, Xeloda (Capecitabine)
XP: Xeloda (Capecitabine), Platinol (Cisplatin)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (KEYNOTE-585)	2017-ongoing	Phase 3 (C)	1a. Perioperative CX & Pembrolizumab 1b. Perioperative CF & Pembrolizumab 1c. Perioperative FLOT & Pembrolizumab	To be determined

Neoadjuvant

Chemotherapy

Cisplatin (Platinol) 80 mg/m² IV once on day 1
Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycle for 3 cycles

Definitive

Local therapy

Surgical resection

Adjuvant

Chemotherapy

Cisplatin (Platinol) 80 mg/m² IV once on day 1
Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycle for 3 cycles

References

KEYNOTE-585: contains dosing details on CT.gov NCT03221426

Cisplatin & Fluorouracil (CF)

CF: Cisplatin & Fluorouracil
FP: Fluorouracil & Platinol (Cisplatin)

Protocol variant #1, 80/4000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (KEYNOTE-585)	2017-ongoing	Phase 3 (C)	1a. Perioperative CX & Pembrolizumab 1b. Perioperative CF & Pembrolizumab 1c. Perioperative FLOT & Pembrolizumab	To be determined

Chemotherapy, neoadjuvant CF portion (cycles 1 to 3)

Cisplatin (Platinol) 80 mg/m² IV once on day 1
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

21-day cycle for 3 cycles

Local therapy, definitive portion

Surgical resection

Chemotherapy, adjuvant CF portion (cycles 4 to 6)

Cisplatin (Platinol) 80 mg/m² IV once on day 1
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

21-day cycle for 3 cycles

Protocol variant #2, 100/4000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ychou et al. 2011 (ACCORD 07)	1995-2003	Phase 3 (E-esc)	Surgery alone	Superior OS (primary endpoint) OS60: 38% vs 24% (HR 0.69, 95% CI 0.50-0.95)

Note: ACCORD 07 included patients with lower esophageal malignancy as well (25% gastric, 11% lower esophagus, and 64% GE junction).

Chemotherapy, neoadjuvant CF portion

Cisplatin (Platinol) 100 mg/m² IV over 60 minutes once on day 1
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

28-day cycle for 2 to 3 cycles

Local therapy, definitive portion

Surgical resection

Chemotherapy, adjuvant CF portion

Cisplatin (Platinol) 100 mg/m² IV over 60 minutes once on day 28
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

28-day cycle for 3 to 4 cycles, for a total of 6 cycles

References

ACCORD 07: Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P; FNCLCC; FFCD. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. link to original article contains dosing details in abstract PubMed NCT00002883
KEYNOTE-585: contains dosing details on CT.gov NCT03221426

ECF

ECF: Epirubicin, Cisplatin, Fluorouracil

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2006 (MAGIC)	1994-2002	Phase 3 (E-esc)	Surgery alone	Superior OS (primary endpoint) OS60: 36% vs 23% (HR 0.75, 95% CI 0.60-0.93)
Cats et al. 2018 (CRITICS)	2007-2015	Phase 3 (C)	1a. ECF/CX & RT 1b. ECX/CX & RT 1c. EOF/CX & RT 1d. EOX/CX & RT	Did not meet primary endpoint of OS Median OS: 43 vs 37 mo (HR 1.01, 95% CI 0.84-1.22)
Reynolds et al. 2023 (Neo-AEGIS)	2013-01-24 to 2020-12-23	Phase 3 (C)	CP & RT, then surgery	Did not meet primary endpoint of OS

Note: MAGIC included patients with lower esophageal malignancy as well (74% gastric, 14.8% lower esophagus, and 11.2% GE junction). CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction. In CRITICS, only patients with trouble swallowing pills were assigned to this treatment arm.

Neoadjuvant

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Cisplatin (Platinol) 60 mg/m² IV once on day 1
Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m²)

Supportive therapy

MAGIC, suggested as thrombosis prophylaxis:
- Warfarin (Coumadin) 1 mg PO once per day

21-day cycle for 3 cycles, followed by:

Definitive

Local therapy

MAGIC: Surgical resection is performed 3 to 6 weeks after the completion of cycle 3
CRITICS: Surgery with a D1+ lymph node resection

Followed in 6 to 12 weeks by:

Adjuvant

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Cisplatin (Platinol) 60 mg/m² IV once on day 1
Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m²)

Supportive therapy

MAGIC, suggested as thrombosis prophylaxis:
- Warfarin (Coumadin) 1 mg PO once per day

21-day cycle for 3 cycles

References

MAGIC: Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. link to original article contains dosing details in abstract PubMed NCT00002615
CRITICS: Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. link to original article contains dosing details in manuscript PubMed NCT00407186
Neo-AEGIS: Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. Epub 2023 Sep 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01726452

ECX

ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cats et al. 2018 (CRITICS)	2007-2015	Phase 3 (C)	1a. ECF/CX & RT 1b. ECX/CX & RT 1c. EOF/CX & RT 1d. EOX/CX & RT	Did not meet primary endpoint of OS Median OS: 43 vs 37 mo (HR 1.01, 95% CI 0.84-1.22)
Reynolds et al. 2023 (Neo-AEGIS)	2013-01-24 to 2020-12-23	Phase 3 (C)	CP & RT, then surgery	Did not meet primary endpoint of OS

Note: CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction

Neoadjuvant

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Cisplatin (Platinol) 60 mg/m² IV once on day 1
Capecitabine (Xeloda) by the following study-specific criteria:
- Neo-AEGIS: 625 mg/m² PO twice per day on days 1 to 21
- CRITICS: 1000 mg/m² PO twice per day on days 1 to 14

21-day cycle for 3 cycles, followed by:

Definitive

Local therapy

Surgery with a D1+ lymph node resection

Adjuvant

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Cisplatin (Platinol) 60 mg/m² IV once on day 1
Capecitabine (Xeloda) by the following study-specific criteria:
- Neo-AEGIS: 625 mg/m² PO twice per day on days 1 to 21
- CRITICS: 1000 mg/m² PO twice per day on days 1 to 14

21-day cycle for 3 cycles

References

CRITICS: Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. link to original article contains dosing details in manuscript PubMed NCT00407186
Neo-AEGIS: Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. Epub 2023 Sep 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01726452

EOF

EOF: Epirubicin, Oxaliplatin, Fluourouracil

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cats et al. 2018 (CRITICS)	2007-2015	Phase 3 (C)	1a. ECF/CX & RT 1b. ECX/CX & RT 1c. EOF/CX & RT 1d. EOX/CX & RT	Did not meet primary endpoint of OS Median OS: 43 vs 37 mo (HR 1.01, 95% CI 0.84-1.22)
Reynolds et al. 2023 (Neo-AEGIS)	2013-01-24 to 2020-12-23	Phase 3 (C)	CP & RT, then surgery	Did not meet primary endpoint of OS

Note: CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction. Only patients with trouble swallowing pills were assigned to this treatment arm.

Neoadjuvant

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m²)

21-day cycle for 3 cycles, followed by:

Definitive

Local therapy

Surgery with a D1+ lymph node resection

Adjuvant

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m²)

21-day cycle for 3 cycles

References

CRITICS: Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. link to original article contains dosing details in manuscript PubMed NCT00407186
Neo-AEGIS: Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. Epub 2023 Sep 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01726452

EOX

EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cats et al. 2018 (CRITICS)	2007-2015	Phase 3 (C)	1a. ECF/CX & RT 1b. ECX/CX & RT 1c. EOF/CX & RT 1d. EOX/CX & RT	Did not meet primary endpoint of OS Median OS: 43 vs 37 mo (HR 1.01, 95% CI 0.84-1.22)
Reynolds et al. 2023 (Neo-AEGIS)	2013-01-24 to 2020-12-23	Phase 3 (C)	CP & RT, then surgery	Did not meet primary endpoint of OS

Note: CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction

Neoadjuvant

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
Capecitabine (Xeloda) 625 mg/m² PO twice per day on days 1 to 21

21-day cycle for 3 cycles, followed by:

Definitive

Local therapy

Surgery with a D1+ lymph node resection

Adjuvant

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
Capecitabine (Xeloda) 625 mg/m² PO twice per day on days 1 to 21

21-day cycle for 3 cycles

References

CRITICS: Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. link to original article contains dosing details in manuscript PubMed NCT00407186
Neo-AEGIS: Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. Epub 2023 Sep 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01726452

FLOT

FLOT: Fluorouracil, Leucovorin, Oxaliplatin, Taxotere (Docetaxel)

Protocol variant #1, 3 + 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (KEYNOTE-585)	2017-ongoing	Phase 3 (C)	1a. Perioperative CX & Pembrolizumab 1b. Perioperative CF & Pembrolizumab 1c. Perioperative FLOT & Pembrolizumab	To be determined

Chemotherapy, neoadjuvant FLOT portion (cycles 1 to 3)

Fluorouracil (5-FU) 2600 mg/m² IV continuous infusion over 24 hours, started on day 1
Leucovorin (Folinic acid) as follows:
- Cycle 1: 200 mg/m² IV once per day on days 1 & 15
- Cycle 2: 200 mg/m² IV once on day 8
- Cycle 3: 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
Docetaxel (Taxotere) 50 mg/m² IV once on day 1

21-day cycle for 3 cycles

Local therapy, definitive portion

Surgery

Chemotherapy, adjuvant FLOT portion (cycles 4 to 6)

Fluorouracil (5-FU) 2600 mg/m² IV continuous infusion over 24 hours, started on day 1
Leucovorin (Folinic acid) as follows:
- Cycle 1: 200 mg/m² IV once per day on days 1 & 15
- Cycle 2: 200 mg/m² IV once on day 8
- Cycle 3: 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
Docetaxel (Taxotere) 50 mg/m² IV once on day 1

21-day cycle for 3 cycles

Protocol variant #2, 4 + 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Al-Batran et al. 2016 (FLOT4-AIO)	2010-2015	Phase 2/3 (E-switch-ic)	1a. Perioperative ECF 1b. Perioperative ECX	Superior OS¹ (primary endpoint) Median OS: 50 vs 35 mo (HR 0.77, 95% CI 0.63-0.94)

¹Reported efficacy is based on the 2019 update.

Chemotherapy, neoadjuvant FLOT portion (cycles 1 to 4)

Fluorouracil (5-FU) 2600 mg/m² IV continuous infusion over 24 hours, started on day 1
Leucovorin (Folinic acid) 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
Docetaxel (Taxotere) 50 mg/m² IV once on day 1

14-day cycle for 4 cycles

Local therapy, definitive portion

Surgery

Chemotherapy, adjuvant FLOT portion (cycles 5 to 8)

Fluorouracil (5-FU) 2600 mg/m² IV continuous infusion over 24 hours, started on day 1
Leucovorin (Folinic acid) 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
Docetaxel (Taxotere) 50 mg/m² IV once on day 1

14-day cycle for 4 cycles

References

FLOT4-AIO: Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. link to original article PubMed NCT01216644
1. Update: Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, von Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Weniger J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Jäger E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957. Epub 2019 Apr 11. link to original article PubMed
KEYNOTE-585: contains dosing details on CT.gov NCT03221426
MATTERHORN: NCT04592913
RAMSES: NCT02661971

mFOLFOX6

mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yu et al. 2022 (FOCUS_gastric)	2011-2016	Phase 3 (C)	Perioperative SOX	Non-inferior OS36 (primary endpoint) OS36: 67.8% vs 75.2%

Neoadjuvant

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

21-day cycle for 2 to 4 cycles, followed by:

Definitive

Local therapy

Gastrectomy with at least D2 dissection

Adjuvant

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

21-day cycle for 2 to 4 cycles

References

FOCUS_gastric: Yu J, Gao Y, Chen L, Wu D, Shen Q, Zhao Z, Liu W, Yang H, Zhang Q, Wang X, Hu P, Zheng Z, Wang X, Liu H, Xu Z, Yan Z, Wu Y, Jin M, Zhang Q, Liu X, Zhu K, Shou C. Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2022 Feb 1;5(2):e220426. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01364376

SOX

SOX: S-1 & OXaliplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yu et al. 2022 (FOCUS_gastric)	2011-2016	Phase 3 (E-switch-ic)	Perioperative mFOLFOX6	Non-inferior OS36 (primary endpoint) OS36: 75.2% vs 67.8%
Wang et al. 2024 (RESONANCE)	2012-09-01 to 2019-07-01	Phase 3 (E-switch-ic)	Adjuvant SOX	Seems to have superior DFS36 (primary endpoint) DFS36: 61.7% vs 53.8%

Neoadjuvant

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 14
- Between 1.25 m² and 1.5 m²: 50 mg PO twice per day on days 1 to 14
- 1.5 m² or more: 60 mg PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1

21-day cycle for 2 to 4 cycles, followed by:

Definitive

Local therapy

Gastrectomy with at least D2 dissection

Adjuvant

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 14
- Between 1.25 m² and 1.5 m²: 50 mg PO twice per day on days 1 to 14
- 1.5 m² or more: 60 mg PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1

21-day cycle for 2 to 4 cycles

References

RESOLVE_gastric: Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, Wang X, Wu A, Li G, Su X, Xiao G, Cui M, Wu D, Chen L, Wu X, Zhou Y, Zhang L, Dang C, He Y, Zhang Z, Sun Y, Li Y, Chen H, Bai Y, Qi C, Yu P, Zhu G, Suo J, Jia B, Li L, Huang C, Li F, Ye Y, Xu H, Wang X, Yuan Y, E JY, Ying X, Yao C, Shen L, Ji J; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021 Aug;22(8):1081-1092. Epub 2021 Jul 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. link to original article PubMed NCT01534546
FOCUS_gastric: Yu J, Gao Y, Chen L, Wu D, Shen Q, Zhao Z, Liu W, Yang H, Zhang Q, Wang X, Hu P, Zheng Z, Wang X, Liu H, Xu Z, Yan Z, Wu Y, Jin M, Zhang Q, Liu X, Zhu K, Shou C. Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2022 Feb 1;5(2):e220426. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01364376
RESONANCE: Wang X, Lu C, Wei B, Li S, Li Z, Xue Y, Ye Y, Zhang Z, Sun Y, Liang H, Li K, Zhu L, Zheng Z, Zhou Y, He Y, Li F, Wang X, Liang P, Huang H, Li G, Shen X, Ji J, Tang Y, Xu Z, Chen L; RESONANCE study group. Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial. J Hematol Oncol. 2024 Apr 8;17(1):17. link to original article link to PMC article contains dosing details in supplement PubMed NCT01583361

Neoadjuvant chemotherapy

DOS

DOS: Docetaxel, Oxaliplatin, S-1

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kang et al. 2021 (PRODIGY)	2012-2017	Phase 3 (E-esc)	No neoadjuvant therapy	Seems to have superior PFS (primary endpoint) PFS36: 66% vs 60% (aHR 0.70, 95% CI 0.52-0.95)

Chemotherapy

Docetaxel (Taxotere) 50 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 100 mg/m² IV once on day 1
S-1 40 mg/m² PO twice per day on days 1 to 14

21-day cycle for 3 cycles

Subsequent treatment

Surgery, then adjuvant S-1

References

PRODIGY: Kang YK, Yook JH, Park YK, Lee JS, Kim YW, Kim JY, Ryu MH, Rha SY, Chung IJ, Kim IH, Oh SC, Park YS, Son T, Jung MR, Heo MH, Kim HK, Park C, Yoo CH, Choi JH, Zang DY, Jang YJ, Sul JY, Kim JG, Kim BS, Beom SH, Cho SH, Ryu SW, Kook MC, Ryoo BY, Kim HK, Yoo MW, Lee NS, Lee SH, Kim G, Lee Y, Lee JH, Noh SH. PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer. J Clin Oncol. 2021 Sep 10;39(26):2903-2913. Epub 2021 Jun 16. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01515748

ECF

ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (TOPGEAR)	2009-ongoing	Phase 3 (C)	1a. ECF/5-FU & RT 1b. ECX/Capecitabine & RT 1c. EOX/Capecitabine & RT 1d. FLOT/Capecitabine & RT	TBD if different primary endpoint of OS

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Cisplatin (Platinol) 60 mg/m² IV once on day 1
Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m²)

21-day cycle for 3 cycles

References

TOPGEAR: NCT01924819

Adjuvant therapy

CapeOx

CapeOX: Capecitabine & OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bang et al. 2012 (CLASSIC)	2006-2009	Phase 3 (E-esc)	Surgery alone	Superior DFS36 (primary endpoint) DFS36: 74% vs 59% (HR 0.56, 95% CI 0.44-0.72) Superior OS¹ (secondary endpoint) OS60: 78% vs 69% (HR 0.66, 95% CI 0.51-0.85)
Zhang et al. 2021 (RESOLVE_gastric)	2012-2017	Phase 3 (C)	1. Perioperative SOX	Seems to have inferior DFS36
Zhang et al. 2021 (RESOLVE_gastric)	2012-2017	Phase 3 (C)	2. Adjuvant SOX	Non-inferior DFS36

¹Reported efficacy for CLASSIC is based on the 2014 update.
Note: RESOLVE should not be confused for the trial by the same name in pancreatic cancer.

Preceding treatment

Gastrectomy with D2 dissection

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycle for 8 cycles

References

CLASSIC: Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH; CLASSIC trial investigators. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012 Jan 28;379(9813):315-21. Epub 2012 Jan 7. link to original article contains dosing details in abstract PubMed NCT00411229
1. Update: Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W, Lee JI, Shin DB, Ji J, Chen JS, Lim Y, Ha S, Bang YJ; CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1389-96. Epub 2014 Oct 15. link to original article PubMed
RESOLVE_gastric: Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, Wang X, Wu A, Li G, Su X, Xiao G, Cui M, Wu D, Chen L, Wu X, Zhou Y, Zhang L, Dang C, He Y, Zhang Z, Sun Y, Li Y, Chen H, Bai Y, Qi C, Yu P, Zhu G, Suo J, Jia B, Li L, Huang C, Li F, Ye Y, Xu H, Wang X, Yuan Y, E JY, Ying X, Yao C, Shen L, Ji J; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021 Aug;22(8):1081-1092. Epub 2021 Jul 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. link to original article contains dosing details in abstract PubMed NCT01534546

Carboplatin & Docetaxel

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bamias et al. 2010	2002-2005	Phase 3 (C)	DCb & RT	Did not meet primary endpoint of OS

Note: the original protocol was for cisplatin & docetaxel but was changed due to excess CINV. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Preceding treatment

Surgery

Chemotherapy

Carboplatin (Paraplatin) AUC 5 IV once on day 1
Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for 6 cycles

References

Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, Samantas E, Christodoulou Ch, Pentheroudakis G, Pectasides D, Dimopoulos MA, Fountzilas G. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol. 2010 May;65(6):1009-21. Epub 2010 Feb 4. link to original article contains dosing details in abstract PubMed

Capecitabine & Cisplatin (CX)

CX: Cisplatin, Xeloda (Capecitabine)
XP: Xeloda (Capecitabine), Platinol (Cisplatin)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2011 (ARTIST_gastric)	2004-2008	Phase 3 (C)	XP/Capecitabine & RT	Might have inferior DFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This trial should not be confused for the one by the same name in colorectal cancer.

Preceding treatment

R0 gastrectomy and at least D2 dissection

Chemotherapy

Cisplatin (Platinol) 60 mg/m² IV once on day 1
Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycle for 6 cycles

References

ARTIST: Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, Lim HY, Choi MG, Sohn TS, Noh JH, Bae JM, Ahn YC, Sohn I, Jung SH, Park CK, Kim KM, Kang WK. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012 Jan 20;30(3):268-73. Epub 2011 Dec 19. link to original article contains dosing details in manuscript PubMed NCT00323830
1. Update: Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, Sohn I, Jung SH, Choi MG, Lee JH, Bae JM, Kim S, Kim ST, Park JO, Park YS, Lim HY, Kang WK. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: Final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015 Oct 1;33(28):3130-6. Epub 2015 Jan 5. link to original article PubMed

Cisplatin & S-1

SP: S-1 & Platinol (Cisplatin)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2018 (POST)	2010-2013	Phase 3 (C)	DS	Did not meet primary endpoint of DFS36

Preceding treatment

Surgery

Chemotherapy

Cisplatin (Platinol) 60 mg/m² IV once on day 1
S-1 35 mg/m² PO twice per day on days 1 to 14

21-day cycle for 8 cycles

References

POST: Lee CK, Jung M, Kim HS, Jung I, Shin DB, Kang SY, Zang DY, Kim KH, Lee MH, Kim BS, Lee KH, Cheong JH, Hyung WJ, Noh SH, Chung HC, Rha SY. S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial. Cancer Res Treat. 2019 Jan;51(1):1-11. Epub 2018 Feb 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01283217

Docetaxel & S-1

DS: Docetaxel & S-1

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2018 (POST)	2010-2013	Phase 3 (E-switch-ic)	SP	Did not meet primary endpoint of DFS36

Preceding treatment

Surgery

Chemotherapy

Docetaxel (Taxotere) 35 mg/m² IV once per day on days 1 & 8
S-1 35 mg/m² PO twice per day on days 1 to 14

21-day cycle for 8 cycles

Regimen variant #2, 40/80

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshida et al. 2019 (JACCRO GC-07)	2013-2017	Phase 3 (E-esc)	S-1	Superior RFS36 (primary endpoint) RFS36: 66% vs 50% (HR 0.632, 99.99% CI 0.40-0.998) Superior OS¹ (secondary endpoint) OS36: 77.7% vs 71.2% (HR 0.74, 95% CI 0.60-0.925)

¹Reported efficacy is based on the 2021 update.
Note: this dosing was for BSA less than 1.25 mg/m².

Preceding treatment

Surgery

Chemotherapy

Docetaxel (Taxotere) as follows:
- Cycles 2 to 7: 40 mg/m² IV once on day 1
S-1 as follows:
- Cycles 1 to 7: 40 mg/m² PO twice per day on days 1 to 14
- Cycles 8 to 12: 40 mg/m² PO twice per day on days 1 to 28

21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)

Regimen variant #3, 40/100

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshida et al. 2019 (JACCRO GC-07)	2013-2017	Phase 3 (E-esc)	S-1	Superior RFS36 (primary endpoint) RFS36: 66% vs 50% (HR 0.632, 99.99% CI 0.40-0.998) Superior OS¹ (secondary endpoint) OS36: 77.7% vs 71.2% (HR 0.74, 95% CI 0.60-0.925)

¹Reported efficacy is based on the 2021 update.
Note: this dosing was for BSA between 1.25 to 1.5 mg/m².

Preceding treatment

Surgery

Chemotherapy

Docetaxel (Taxotere) as follows:
- Cycles 2 to 7: 40 mg/m² IV once on day 1
S-1 as follows:
- Cycles 1 to 7: 50 mg/m² PO twice per day on days 1 to 14
- Cycles 8 to 12: 50 mg/m² PO twice per day on days 1 to 28

21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)

Regimen variant #4, 40/120

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshida et al. 2019 (JACCRO GC-07)	2013-2017	Phase 3 (E-esc)	S-1	Superior RFS36 (primary endpoint) RFS36: 66% vs 50% (HR 0.632, 99.99% CI 0.40-0.998) Superior OS¹ (secondary endpoint) OS36: 77.7% vs 71.2% (HR 0.74, 95% CI 0.60-0.925)

¹Reported efficacy is based on the 2021 update.
Note: this dosing was for BSA greater than 1.5 mg/m².

Preceding treatment

Surgery

Chemotherapy

Docetaxel (Taxotere) as follows:
- Cycles 2 to 7: 40 mg/m² IV once on day 1
S-1 as follows:
- Cycles 1 to 7: 60 mg/m² PO twice per day on days 1 to 14
- Cycles 8 to 12: 60 mg/m² PO twice per day on days 1 to 28

21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)

References

POST: Lee CK, Jung M, Kim HS, Jung I, Shin DB, Kang SY, Zang DY, Kim KH, Lee MH, Kim BS, Lee KH, Cheong JH, Hyung WJ, Noh SH, Chung HC, Rha SY. S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial. Cancer Res Treat. 2019 Jan;51(1):1-11. Epub 2018 Feb 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01283217
JACCRO GC-07: Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019 May 20;37(15):1296-1304. Epub 2019 Mar 29. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN000010337
1. Update: Kakeji Y, Yoshida K, Kodera Y, Kochi M, Sano T, Ichikawa W, Lee SW, Shibahara K, Shikano T, Kataoka M, Ishiguro A, Ojima H, Sakai Y, Musha N, Takase T, Kimura T, Takeuchi M, Fujii M. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer. 2022 Jan;25(1):188-196. Epub 2021 Aug 5. link to original article PubMed

FP/Capecitabine & RT

FP/Capecitabine & RT: Fluorouracil & Platinol (Cisplatin) alternating with Capecitabine & Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence
Lee et al. 2006	NR	Phase 2

Note: In contrast to the primary reference, some guidelines list this regimen without FP cycles 1, 3, 4, 5. Dosage of Capecitabine (Xeloda) was listed as 625 to 825 mg/m² PO twice per day on days 1 to 5 or 1 to 7 while radiation is being given.

Preceding treatment

Surgery, 3 weeks prior

Chemotherapy

Cisplatin (Platinol) as follows:
- Cycles 1, 3, 4, 5: 60 mg/m² IV once on day 1
Fluorouracil (5-FU) as follows:
- Cycles 1, 3, 4, 5: 1000 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m²)
Capecitabine (Xeloda) as follows:
- Cycle 2 (chemoradiation): 825 mg/m² PO twice per day on days 1 to 35

Radiotherapy

Concurrent radiation therapy during cycle 2: 180 cGy fractions x 25 fractions (total dose of 4500 cGy)

21-day course, then 9-week course, then 21-day cycle for 3 cycles

References

Lee HS, Choi Y, Hur WJ, Kim HJ, Kwon HC, Kim SH, Kim JS, Lee JH, Jung GJ, Kim MC. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006 Jan 28;12(4):603-7. link to original article contains dosing details in manuscript link to PMC article PubMed

FULV

FULV: 5-FU & LeucoVorin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bajetta et al. 2014 (ITACA-S)	2005-2009	Phase 3 (C)	FOLFIRI, then Cisplatin & Docetaxel	Did not meet primary endpoint of DFS

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1 & 2, then 600 mg/m² IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m²)
Leucovorin (Folinic acid) 100 mg/m² IV over 2 hours once per day on days 1 & 2

14-day cycle for 9 cycles

References

ITACA-S: Bajetta E, Floriani I, Di Bartolomeo M, Labianca R, Falcone A, Di Costanzo F, Comella G, Amadori D, Pinto C, Carlomagno C, Nitti D, Daniele B, Mini E, Poli D, Santoro A, Mosconi S, Casaretti R, Boni C, Pinotti G, Bidoli P, Landi L, Rosati G, Ravaioli A, Cantore M, Di Fabio F, Aitini E, Marchet A; ITACA-S (Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach Trial) Study Group. Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol. 2014 Jul;25(7):1373-1378. Epub 2014 Apr 12. link to original article contains dosing details in manuscript PubMed NCT01640782

FULV/FULV & RT

FULV/FULV & RT: FluoroUracil & LeucoVorin alternating with FluoroUracil, LeucoVorin, Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Macdonald et al. 2001 (INT-0116)	1991-1998	Phase 3 (E-esc)	Surgery alone	Superior OS (primary endpoint)
Fuchs et al. 2017 (CALGB 80101)	2002-2009	Phase 3 (C)	ECF/FULV & RT	Did not meet primary endpoint of OS

Treatment is to start 20 to 40 days after surgery. Note: Study included patients with GE junction malignancy as well (20% GE junction) and included patients with a performance status of 2.

Preceding treatment

INT-0116: Surgery with R0 resection (10% underwent D2 dissection, 36% underwent D1 dissection and 54% underwent D0 dissection)
CALGB 80101: Surgery

Chemotherapy

Fluorouracil (5-FU) as follows:
- Cycles 1, 3, 4: 425 mg/m² IV bolus once per day on days 1 to 5
- Cycle 2 (chemoradiation): 400 mg/m² IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
Leucovorin (Folinic acid) as follows:
- Cycles 1, 3, 4: 20 mg/m² IV bolus once per day on days 1 to 5
- Cycle 2 (chemoradiation): 20 mg/m² IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy

Radiotherapy

Concurrent radiation therapy during cycle 2: 180 cGy x 25 fractions (total of 4500 cGy)

28-day course, then 9-week course, then 28-day cycle for 2 cycles

References

INT-0116: Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. link to original article contains dosing details in abstract PubMed
1. Update: Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. link to original article link to PMC article PubMed
CALGB 80101: Fuchs CS, Niedzwiecki D, Mamon HJ, Tepper JE, Ye X, Swanson RS, Enzinger PC, Haller DG, Dragovich T, Alberts SR, Bjarnason GA, Willett CG, Gunderson LL, Goldberg RM, Venook AP, Ilson D, O'Reilly E, Ciombor K, Berg DJ, Meyerhardt J, Mayer RJ. Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance). J Clin Oncol. 2017 Nov 10;35(32):3671-3677. Epub 2017 Oct 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00052910

S-1 monotherapy

Regimen variant #1, 21-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tsuburaya et al. 2014 (SAMIT)	2004-2009	Phase 3 (C)	1. Paclitaxel, then S-1 2. Paclitaxel, then UFT	Did not meet primary endpoint of DFS
Tsuburaya et al. 2014 (SAMIT)	2004-2009	Phase 3 (C)	3. UFT	Superior DFS DFS36: 58.2% vs 53% (HR 0.81, 95% CI 0.70-0.93)

Preceding treatment

R0 or R1 gastrectomy with at least D2 dissection, within 2 to 8 weeks

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) 80 mg/m² PO twice per day on days 1 to 14

21-day cycle for 16 cycles (1 year)

Regimen variant #2, 42-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sakuramoto et al. 2007 (ACTS-GC)	2001-2004	Phase 3 (E-esc)	Observation	Superior OS¹ (primary endpoint) OS60: 72% vs 61% (HR 0.67, 95% CI 0.54-0.83)
Yoshikawa et al. 2019 (OPAS-1)	2012-2017	Phase 3 (C)	S-1 x 6 mo	Inconclusive whether non-inferior RFS
Park et al. 2020 (ARTIST 2)	2013-2018	Phase 3 (C)	1. SOX	Seems to have inferior DFS
Park et al. 2020 (ARTIST 2)	2013-2018	Phase 3 (C)	2. SOXRT	Might have inferior DFS

¹Reported efficacy for ACTS-GC is based on the 2011 update.

Eligibility criteria

ACTS-GC & ARTIST 2: Stage II or III gastric cancer
OPAS-1: Stage II gastric cancer

Preceding treatment

R0 gastrectomy with at least D2 dissection, within 6 weeks

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
- Between 1.25 and 1.5 m²: 50 mg PO twice per day on days 1 to 28
- 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycle for 8 cycles (1 year)

References

ACTS-GC: Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007 Nov 1;357(18):1810-20. Erratum in: N Engl J Med. 2008 May 1;358(18):1977. link to original article contains dosing details in manuscript PubMed NCT00152217
1. Update: Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. link to original article PubMed
SAMIT: Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. link to original article contains dosing details in manuscript PubMed UMIN C000000082
OPAS-1: Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Fukushima N, Hato S, Choda Y, Yabusaki H, Yoshida K, Ito S, Takeno A, Yasuda T, Kawachi Y, Katayama H, Fukuda H, Boku N, Sano T, Sasako M. Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104[OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial. Lancet Gastroenterol Hepatol. 2019 Mar;4(3):208-216. Epub 2019 Jan 22. Erratum in: Lancet Gastroenterol Hepatol. 2019 Apr;4(4):e3. link to original article PubMed UMIN000007306
1. Update: Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Nomura T, Hato S, Choda Y, Yabusaki H, Yoshida K, Misawa K, Masuzawa T, Tsuda M, Kawachi Y, Katayama H, Fukuda H, Kurokawa Y, Boku N, Sano T, Sasako M. 5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer. Gastric Cancer. 2024 Jan;27(1):155-163. Epub 2023 Nov 21. link to original article PubMed
JACCRO GC-07: Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019 May 20;37(15):1296-1304. Epub 2019 Mar 29. link to original article link to PMC article PubMed UMIN000010337
1. Update: Kakeji Y, Yoshida K, Kodera Y, Kochi M, Sano T, Ichikawa W, Lee SW, Shibahara K, Shikano T, Kataoka M, Ishiguro A, Ojima H, Sakai Y, Musha N, Takase T, Kimura T, Takeuchi M, Fujii M. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer. 2022 Jan;25(1):188-196. Epub 2021 Aug 5. link to original article PubMed
ARTIST 2: Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH, Shin DB, Yu JI, Kim KM, An JY, Choi MG, Lee JH, Kim S, Hong JY, Park JO, Park YS, Lim HY, Bae JM, Kang WK; ARTIST 2 investigators. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021 Mar;32(3):368-374. Epub 2020 Dec 3. link to original article contains dosing details in abstract PubMed NCT01761461
HKIT-GC: NCT00216034

SOX

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wang et al. 2024 (RESONANCE)	2012-09-01 to 2019-07-01	Phase 3 (C)	Perioperative SOX	Seems to have inferior DFS36
Park et al. 2020 (ARTIST 2)	2013-2018	Phase 3 (E-esc)	1. S-1	Seems to have superior DFS (primary endpoint) DFS36: 74.3% vs 64.8% (HR 0.69, 95% CI 0.41-0.99)
Park et al. 2020 (ARTIST 2)	2013-2018	Phase 3 (E-esc)	2. SOXRT	Did not meet primary endpoint of DFS

Preceding treatment

R0 or R1 gastrectomy with at least D2 dissection

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 14
- Between 1.25 and 1.5 m²: 50 mg PO twice per day on days 1 to 14
- 1.5 m² or more: 60 mg PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1

21-day cycle for up to 8 cycles (6 months)

References

ARTIST 2: Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH, Shin DB, Yu JI, Kim KM, An JY, Choi MG, Lee JH, Kim S, Hong JY, Park JO, Park YS, Lim HY, Bae JM, Kang WK; ARTIST 2 investigators. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021 Mar;32(3):368-374. Epub 2020 Dec 3. link to original article contains dosing details in manuscript PubMed NCT01761461
TOTTG030103: Zhao Q, Lian C, Huo Z, Li M, Liu Y, Fan L, Tan B, Zhao X, Zhang Z, Wang D, Liu Y, Guo H, Yang P, Tian Y, Li Y. The efficacy and safety of neoadjuvant chemotherapy on patients with advanced gastric cancer: A multicenter randomized clinical trial. Cancer Med. 2020 Aug;9(16):5731-5745. Epub 2020 Jun 24. link to original article link to PMC article PubMed NCT01516944
RESONANCE: Wang X, Lu C, Wei B, Li S, Li Z, Xue Y, Ye Y, Zhang Z, Sun Y, Liang H, Li K, Zhu L, Zheng Z, Zhou Y, He Y, Li F, Wang X, Liang P, Huang H, Li G, Shen X, Ji J, Tang Y, Xu Z, Chen L; RESONANCE study group. Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial. J Hematol Oncol. 2024 Apr 8;17(1):17. link to original article link to PMC article contains dosing details in supplement PubMed NCT01583361

UFT monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nakajima et al. 2007 (NSAS-GC)	1997-2001	Phase 3 (E-esc)	Observation	Superior OS (primary endpoint) OS60: 86% vs 73% (HR 0.48, 95% CI 0.26-0.89)

Preceding treatment

Gastrectomy, with complete (R0) D2 dissection

Chemotherapy

Tegafur and uracil (UFT) 360 mg/m² PO once per day

16-month course

References

NSAS-GC: Nakajima T, Kinoshita T, Nashimoto A, Sairenji M, Yamaguchi T, Sakamoto J, Fujiya T, Inada T, Sasako M, Ohashi Y; National Surgical Adjuvant Study of Gastric Cancer Group. Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg. 2007 Dec;94(12):1468-76. link to original article contains dosing details in abstract PubMed NCT00152243
SAMIT: Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. link to original article PubMed UMIN C000000082

Metastatic or locally advanced disease, first-line

Capecitabine monotherapy

X: Xeloda (Capecitabine)

Regimen variant #1, 2000 mg/m²/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hwang et al. 2017 (SMC 2010-04-118)	2010-2014	Phase 3 (C)	XELOX	Did not meet primary endpoint of OS
Lee et al. 2023 (KCSG ST13-10)	2014-02 to 2019-01	Phase 3 (C)	1a. mFOLFOX6 1b. CapeOx 1c. Cisplatin & S-1 1d. CX	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Eligibility criteria

KCSG ST13-10: CrCl at least 60 mL/min

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycles

Regimen variant #2, 2500 mg/m²/day

Study	Dates of enrollment	Evidence
Hong et al. 2004	NR	Phase 2

Eligibility criteria

Karnofsky status of at least 70%

Chemotherapy

Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for up to 6 cycles

References

Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep;15(9):1344-7. link to original article contains dosing details in manuscript PubMed
SMC 2010-04-118: Hwang IG, Ji JH, Kang JH, Lee HR, Lee HY, Chi KC, Park SW, Lee SJ, Kim ST, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017 May;8(3):170-175. Epub 2017 Jan 21. link to original article contains dosing details in abstract PubMed NCT01470742
KCSG ST13-10: Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS. A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10). Cancer Res Treat. 2022 Oct;55(4):1250-1260. Epub 2023 May 25. link to original article contains dosing details in manuscript PubMed NCT02114359

Capecitabine & Cisplatin (CX)

CX: Cisplatin, Xeloda (Capecitabine)
XP: Xeloda (Capecitabine), Platinol (Cisplatin)

Regimen variant #1, 6 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ohtsu et al. 2011 (AVAGAST)	2007-09 to 2008-12	Phase 3 (C)	CX & Bevacizumab	Did not meet primary endpoint of OS
Shen et al. 2014 (AVATAR)	2009-03-25 to 2010-07-12	Phase 3 (C)	CX & Bevacizumab	Did not meet primary endpoint of OS
Lu et al. 2018 (PAC-C)	2009-2014	Phase 3 (C)	Capecitabine & Paclitaxel	Did not meet primary endpoint of PFS

Note: The following studies included patients with GE junction malignancy as well:

AVAGAST patients: 86% gastric and 14% GE junction. 5.4% of patients had an ECOG PS of 2.

Chemotherapy

Cisplatin (Platinol) 80 mg/m² IV over 2 hours once on day 1
Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Supportive therapy

Some protocols: "Hyperhydration" for cisplatin

21-day cycle for 6 cycles

Subsequent treatment

AVAGAST & AVATAR: Capecitabine maintenance

Regimen variant #2, 8 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kim et al. 2014 (SMC 2008-12-019)	2009-2012	Phase 3 (C)	CX & Simvastatin	Did not meet primary endpoint of PFS

Note: The following studies included patients with GE junction malignancy as well:

SMC 2008-12-019 patients: 79% gastric, 16% GE junction and 5% unknown

Chemotherapy

Cisplatin (Platinol) 80 mg/m² IV once on day 1
Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycle for 8 cycles

Subsequent treatment

Capecitabine maintenance

Regimen variant #3, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kang et al. 2009 (ML17032)	2003-2005	Phase 3 (E-switch-ic)	CF	Non-inferior PFS (primary endpoint) Median PFS: 5.6 vs 5 mo (HR 0.81, 95% CI 0.63-1.04)
Lordick et al. 2013 (EXPAND)	2008-2010	Phase 3 (C)	CX & Cetuximab	Did not meet primary endpoint of PFS
Fuchs et al. 2019 (RAINFALL)	2015-01-28 to 2016-09-16	Phase 3 (C)	CX & Ramucirumab	Did not meet primary endpoint of PFS¹

¹while the primary analysis of RAINFALL showed that this arm seemed to have inferior PFS, independent central review did not confirm this finding.
The following studies included patients with GE junction malignancy as well:

EXPAND patients: 83% gastric, 5% GE junction and 16% unknown

Chemotherapy

Cisplatin (Platinol) 80 mg/m² IV over 2 hours once on day 1
Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
- Alternate dosing in EXPAND: 1000 mg/m² PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)

Supportive therapy

Some protocols: "Hyperhydration" for cisplatin

21-day cycles

References

ML17032: Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org NCT02563054
AVAGAST: Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. link to original article contains dosing details in manuscript PubMed NCT00548548
EXPAND: Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. link to original article contains dosing details in manuscript PubMed NCT00678535
AVATAR: Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, Xu R, Chen L, Liu Y, Yu S, Bu L, Piao Y. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015 Jan;18(1):168-76. Epub 2014 Feb 21. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00887822
SMC 2008-12-019: Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. link to original article contains dosing details in manuscript PubMed NCT01099085
PAC-C: Lu Z, Zhang X, Liu W, Liu T, Hu B, Li W, Fan Q, Xu J, Xu N, Bai Y, Pan Y, Xu Q, Bai W, Xia L, Gao Y, Wang W, Shu Y, Shen L. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018 Sep;21(5):782-791. Epub 2018 Feb 27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01015339
RAINFALL: Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):420-435. Epub 2019 Feb 1. Erratum in: Lancet Oncol. 2019 May;20(5):e242. link to original article contains dosing details in abstract PubMed NCT02314117

Capecitabine & Cisplatin (CX) & Pembrolizumab

CX & Pembrolizumab: Cisplatin, Xeloda (Capecitabine), Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shitara et al. 2020 (KEYNOTE-062)	2015-2017	Phase 3 (E-esc)	1a. CF 1b. CX	Might have superior OS¹ (co-primary endpoint) Median OS: 12.5 vs 11.1 mo (HR 0.85, 95% CI 0.70-1.03)
Shitara et al. 2020 (KEYNOTE-062)	2015-2017	Phase 3 (E-esc)	2. Pembrolizumab	Not reported

¹Reported efficacy is for patients with CPS of 1 or greater.
Note: KEYNOTE-062 included patients with GEJ malignancy.

Biomarker eligibility criteria

PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Cisplatin (Platinol) 80 mg/m² IV once on day 1

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

References

KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02494583

CapeOx

CapeOX: Capecitabine & OXaliplatin

Regimen variant #1, 750/78

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hall et al. 2021 (GO2)	2014-2017	Phase 3 (E-de-esc)	1. CapeOx; 1000/104	Not reported
Hall et al. 2021 (GO2)	2014-2017	Phase 3 (E-de-esc)	2. CapeOx; 1250/130	Non-inferior PFS (primary endpoint) (HR 1.10, 95% CI 0.90-1.33)

Chemotherapy

Capecitabine (Xeloda) 375 mg/m² PO twice per day
Oxaliplatin (Eloxatin) 78 mg/m² IV once on day 1

21-day cycles

Regimen variant #2, 1000/104

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hall et al. 2021 (GO2)	2014-2017	Phase 3 (E-de-esc)	1. CapeOx; 750/78	Not reported
Hall et al. 2021 (GO2)	2014-2017	Phase 3 (E-de-esc)	2. CapeOx; 1250/130	Non-inferior PFS (primary endpoint) (HR 1.09, 95% CI 0.89-1.32)

Chemotherapy

Capecitabine (Xeloda) 500 mg/m² PO twice per day
Oxaliplatin (Eloxatin) 104 mg/m² IV once on day 1

21-day cycles

Regimen variant #3, 1250/130

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hall et al. 2021 (GO2)	2014-2017	Phase 3 (C)	1. CapeOx; 750/78 2. CapeOx; 1000/104	Non-inferior PFS

Chemotherapy

Capecitabine (Xeloda) 625 mg/m² PO twice per day
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycles

Regimen variant #4, 1700/130

Study	Dates of enrollment	Evidence
Jatoi et al. 2006	2002-2004	Phase 2

Chemotherapy

Capecitabine (Xeloda) 850 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycles

Regimen variant #5, 2000/130

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moehler et al. 2020 (JAVELIN Gastric 100)	2015-2017	Phase 3 (C)	1a. CapeOx-Avelumab 1b. FOLFOX6-Avelumab 1c. mFOLFOX6-Avelumab	Did not meet primary endpoint of OS
Awaiting publication (ARMANI)	2016-2019	Phase 3 (C)	1a. CapeOx x 3 mo, then Paclitaxel & Ramucirumab 1b. FOLFOX4 x 3 mo, then Paclitaxel & Ramucirumab 1c. mFOLFOX6 x 3 mo, then Paclitaxel & Ramucirumab	TBD if different primary endpoint of PFS
Kang et al. 2022 (ATTRACTION-4)	2017-03-23 to 2018-05-10	Phase 3 (C)	1a. CapeOx & Nivolumab 1b. SOX & Nivolumab	Inferior PFS
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04	Phase 3 (C)	1a. CapeOx & Nivolumab 1b. mFOLFOX6 & Nivolumab	Inferior OS
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04	Phase 3 (C)	2. Ipilimumab & Nivolumab	Not reported
Awaiting publication (BGB-A317-305)	2018-ongoing	Phase 3 (C)	1a. CapeOx & Tislelizumab 1b. CF & Tislelizumab	TBD if different primary endpoint of OS
Rha et al. 2023 (KEYNOTE-859)	2018-11-08 to 2021-06-11	Phase 3 (C)	1a. CapeOx & Pembrolizumab 1b. CF & Pembrolizumab	Inferior OS

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycles

Regimen variant #6, 2000/130, limited oxaliplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhu et al. 2022 (EXELOX)	2015-2020	Phase 3 (E-de-esc)	EOX	Non-inferior PFS (primary endpoint) Median PFS: 5 vs 5.5 mo (HR 0.989, 95% CI 0.81-1.20)
Shah et al. 2023 (GLOW_gastric)	2018-11-28 to 2022-02-18	Phase 3 (C)	CapeOx & Zolbetuximab	Seems to have inferior OS (secondary endpoint) Inferior PFS (primary endpoint)

Note: GLOW should not be confused by the trial of the same name in CLL. In GLOW, continuation of capecitabine past cycle 8 was at the investigator's discretion.

Biomarker eligibility criteria

GLOW_gastric: CLDN18.2 positive

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) as follows:
- Cycles 1 up to 8: 130 mg/m² IV once on day 1

21-day cycles

References

Jatoi A, Murphy BR, Foster NR, Nikcevich DA, Alberts SR, Knost JA, Fitch TR, Rowland KM Jr; North Central Cancer Treatment Group. Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group. Ann Oncol. 2006 Jan;17(1):29-34. Epub 2005 Nov 22. link to original article contains dosing details in abstract PubMed
JAVELIN Gastric 100: Moehler M, Dvorkin M, Boku N, Özgüroğlu M, Ryu MH, Muntean AS, Lonardi S, Nechaeva M, Bragagnoli AC, Coşkun HS, Cubillo Gracian A, Takano T, Wong R, Safran H, Vaccaro GM, Wainberg ZA, Silver MR, Xiong H, Hong J, Taieb J, Bang YJ. Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100. J Clin Oncol. 2021 Mar 20;39(9):966-977. Epub 2020 Nov 16. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02625610
CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02872116
1. Update: Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. link to original article link to PMC article PubMed
2. HRQoL analysis: Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. link to original article link to PMC article PubMed
GO2: Hall PS, Swinson D, Cairns DA, Waters JS, Petty R, Allmark C, Ruddock S, Falk S, Wadsley J, Roy R, Tillett T, Nicoll J, Cummins S, Mano J, Grumett S, Stokes Z, Kamposioras KV, Chatterjee A, Garcia A, Waddell T, Guptal K, Maisey N, Khan M, Dent J, Lord S, Crossley A, Katona E, Marshall H, Grabsch HI, Velikova G, Ow PL, Handforth C, Howard H, Seymour MT; GO2 Trial Investigators. Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Jun 1;7(6):869-877. Erratum in: JAMA Oncol. 2021 Aug 1;7(8):1249. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN44687907
ATTRACTION-4: Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):234-247. Epub 2022 Jan 11. link to original article contains dosing details in abstract PubMed NCT02746796
EXELOX: Zhu XD, Huang MZ, Wang YS, Feng WJ, Chen ZY, He YF, Zhang XW, Liu X, Wang CC, Zhang W, Ying JE, Wu J, Yang L, Qin YR, Luo JF, Zhao XY, Li WH, Zhang Z, Qiu LX, Geng QR, Zou JL, Zhang JY, Zheng H, Song XF, Wu SS, Zhang CY, Gong Z, Liu QQ, Wang XF, Xu Q, Wang Q, Ji JM, Zhao J, Guo WJ. XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX). Cancer Commun (Lond). 2022 Apr;42(4):314-326. Epub 2022 Feb 25. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02395640
GLOW_gastric: Shah MA, Shitara K, Ajani JA, Bang YJ, Enzinger P, Ilson D, Lordick F, Van Cutsem E, Gallego Plazas J, Huang J, Shen L, Oh SC, Sunpaweravong P, Soo Hoo HF, Turk HM, Oh M, Park JW, Moran D, Bhattacharya P, Arozullah A, Xu RH. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023 Aug;29(8):2133-2141. Epub 2023 Jul 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03653507
KEYNOTE-859: Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. link to original article contains dosing details in abstract PubMed NCT03675737
ARMANI: NCT02934464
BGB-A317-305: contains dosing details on CT.gov NCT03777657
ORIENT-16: NCT03745170

CapeOx & Nivolumab

CapeOx & Nivolumab: Capecitabine, OXaliplatin, Nivolumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kang et al. 2022 (ATTRACTION-4)	2017-03-23 to 2018-05-10	Phase 3 (E-esc)	1a. CapeOx 1b. SOX	Superior PFS (co-primary endpoint) Median PFS: 10.45 vs 8.3 mo (HR 0.68, 98.51% CI 0.51-0.90) Did not meet co-primary endpoint of OS Median OS: 17.45 vs 17.15 mo (HR 0.90, 95% CI 0.75-1.08)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04	Phase 3 (E-RT-esc)	1a. CapeOx 1b. mFOLFOX6	Superior OS¹ (co-primary endpoint) Median OS: 14.4 vs 11.1 mo (HR 0.70, 95% CI 0.61-0.81)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04	Phase 3 (E-RT-esc)	2. Ipilimumab & Nivolumab	Not reported

¹Reported efficacy and MCBS score are for the group with PD-L1 CPS of 5 or more; reported efficacy is based on the 2022 update.

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

Immunotherapy

Nivolumab (Opdivo) 360 mg IV once on day 1

21-day cycles

References

CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02872116
1. Update: Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. link to original article link to PMC article PubMed
2. HRQoL analysis: Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. link to original article link to PMC article PubMed
ATTRACTION-4: Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):234-247. Epub 2022 Jan 11. link to original article contains dosing details in abstract PubMed NCT02746796

CapeOx & Pembrolizumab

CapeOx & Pembrolizumab: Capecitabine, OXaliplatin, Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rha et al. 2023 (KEYNOTE-859)	2018-11-08 to 2021-06-11	Phase 3 (E-RT-esc)	1a. CF 1b. CapeOx	Superior OS (primary endpoint) Median OS: 12.9 vs 11.5 mo (HR 0.78, 95% CI 0.70-0.87)

KEYNOTE-859 included patients with GEJ malignancy

Biomarker eligibility criteria

PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles

References

KEYNOTE-859: Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. link to original article contains dosing details in abstract PubMed NCT03675737

Carboplatin & Paclitaxel (CP)

Regimen

Study	Dates of enrollment	Evidence
Philip et al. 1997	NR in abstract	Phase 2
Gadgeel et al. 2003	1996-2000	Phase 2

Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6. Philip et al. included patients with locally advanced metastatic or recurrent esophageal or gastric cancer. Gadgeel et al. study showed an ORR of 35%.

Chemotherapy

Carboplatin (Paraplatin) AUC 5 IV once on day 1, given second
Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycles

References

Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. contains dosing details in abstract PubMed
Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, Philip PA. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003 Feb;26(1):37-41. link to original article contains dosing details in abstract PubMed

Cisplatin & Docetaxel (DC)

DC: Docetaxel, Cisplatin
TC: Taxotere (Docetaxel), Cisplatin

Regimen variant #1, 75/75

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Roth et al. 2007	1999-2003	Randomized Phase 2 (E-de-esc)	1. ECF	Not reported
Roth et al. 2007	1999-2003	Randomized Phase 2 (E-de-esc)	2. TCF	Might have inferior ORR

Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m² to 75 mg/m² based on high incidence of febrile neutropenia.

Chemotherapy

Cisplatin (Platinol) 75 mg/m² IV over 4 hours once on day 1
Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Supportive therapy

3 liters per day "hyperhydration"
Dexamethasone (Decadron) 8 mg PO given 12 hours & 6 hours prior to docetaxel, then 8 mg PO twice per day for 4 days after docetaxel
5-HT3 antagonist for emesis prophylaxis
Growth factor support allowed, such as with Filgrastim (Neupogen)

21-day cycle for up to 8 cycles

Regimen variant #2, 75/85

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ajani et al. 2005 (V-325)	1998-1999	Randomized Phase 2 (C)	DCF	Seems to have inferior ORR

Note: patients had 100% adenocarcinoma histology (32% esophagogastric junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70.

Chemotherapy

Cisplatin (Platinol) 75 mg/m² IV over 1 to 3 hours once on day 1
Docetaxel (Taxotere) 85 mg/m² IV over 60 minutes once on day 1

Supportive therapy

Dexamethasone (Decadron) 8 mg PO the night before chemotherapy, the morning of day 1, 1 hour before chemotherapy, the night of day 1, the morning of day 2, and the evening of day 2 (total dose per cycle: 48 mg)
Dexamethasone (Decadron) 20 mg IV prior to cisplatin and 8 hours after cisplatin
Ondansetron (Zofran) 8 mg IV prior to cisplatin, 4 hours after cisplatin, and 8 hours after cisplatin
"Hydration was administered in a standard manner"

21-day cycles

References

V-325: Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. link to original article contains dosing details in manuscript PubMed
Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. link to original article contains dosing details in manuscript PubMed

Cisplatin & Fluorouracil (CF)

CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol (Cisplatin)

Regimen variant #1, 60/5000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2009a	2000-2004	Phase 3 (C)	Fluorouracil & Heptaplatin (FH)	Equivalent OS

Note: this is reported to be an equivalence study but the statistical analysis does not provide details on the definition of equivalence.

Chemotherapy

Cisplatin (Platinol) 60 mg/m² IV over 60 minutes once on day 1, given first
Fluorouracil (5-FU) 1000 mg/m² IV over 12 hours once per day on days 1 to 5, given second

28-day cycles

Regimen variant #2, 80/4000 x 8

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ajani et al. 2017 (DIGEST)	2011-2014	Phase 3 (C)	CS	Did not meet primary endpoint of OS

Chemotherapy

Cisplatin (Platinol) 80 mg/m² IV over 1 to 3 hours once on day 1, given first
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 4000 mg/m²)

Supportive therapy

Some protocols: "Hyperhydration" for cisplatin

21-day cycle for 8 cycles

Regimen variant #3, 80/4000, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kang et al. 2009 (ML17032)	2003-2005	Phase 3 (C)	CX	Non-inferior PFS
Shitara et al. 2020 (KEYNOTE-062)	2015-2017	Phase 3 (C)	1a. CF & Pembrolizumab 1b. CX & Pembrolizumab	Might have inferior OS
Shitara et al. 2020 (KEYNOTE-062)	2015-2017	Phase 3 (C)	2. Pembrolizumab	Non-inferior OS
Awaiting publication (BGB-A317-305)	2018-ongoing	Phase 3 (C)	1a. CapeOx & Tislelizumab 1b. CF & Tislelizumab	TBD if different primary endpoint of OS
Rha et al. 2023 (KEYNOTE-859)	2018-11-08 to 2021-06-11	Phase 3 (C)	1a. CapeOx & Pembrolizumab 1b. CF & Pembrolizumab	Inferior OS

Chemotherapy

Cisplatin (Platinol) 80 mg/m² IV over 1 to 3 hours once on day 1, given first
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 4000 mg/m²)

Supportive therapy

Some protocols: "Hyperhydration" for cisplatin

21-day cycles

Regimen variant #4, 100/4000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Duffour et al. 2006 (FFCD 9404)	1995-1998	Phase 3 (C)	FLP	Inconclusive whether non-inferior ORR

Chemotherapy

Cisplatin (Platinol) 100 mg/m² IV over 60 minutes once on either day 1 or 2
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

28-day cycles

Regimen variant #5, 100/4000, split-dose cisplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ohtsu et al. 2003 (JCOG 9205)	1992-1997	Phase 3 (E-esc)	1. Fluorouracil	Did not meet primary endpoint of OS
Ohtsu et al. 2003 (JCOG 9205)	1992-1997	Phase 3 (E-esc)	2. UFTM	Did not meet primary endpoint of OS

Note: this study included patients with ECOG PS of 2 (9.6%)

Chemotherapy

Cisplatin (Platinol) 20 mg/m² IV over 30 minutes once per day on days 1 to 5
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

28-day cycle for up to 6 cycles

Regimen variant #6, 100/5000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Van Cutsem et al. 2006 (TAX 325)	1999-2003	Phase 3 (C)	DCF	Seems to have inferior OS
Dank et al. 2008	2000-2002	Phase 3 (C)	IF	Might have inferior TTP
Ajani et al. 2010 (FLAGS)	2005-2007	Phase 3 (C)	CS	Did not meet primary endpoint of OS

Note: TAX 325 patients had 100% adenocarcinoma histology (22% Esophagogastric junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70. Dank et al patients had 100% adenocarcinoma histology (20% Esophagogastric junction, 80% gastric origin). 96% with metastatic disease. 1% with Karnofsky PS of 70.

Chemotherapy

Cisplatin (Platinol) 100 mg/m² IV over 1 to 3 hours once on day 1, given first
Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 5000 mg/m²)

Supportive therapy

As described in Dank et al. 2008:
"Hyperhydration" for 2 to 3 days with each infusion
Ondansetron (Zofran) IV for antiemetic prophylaxis
Dexamethasone (Decadron) IV for antiemetic prophylaxis, then PO for 2 to 3 days
Metoclopramide (Reglan) for antiemetic prophylaxis
Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/μL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection
Atropine (Atropen) prn cholinergic symptoms
Loperamide (Imodium) prn delayed diarrhea

28-day cycles

References

JCOG 9205: Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; JCOG. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. link to original article contains dosing details in manuscript PubMed
FFCD 9404: Duffour J, Bouché O, Rougier P, Milan C, Bedenne L, Seitz JF, Buecher B, Legoux JL, Ducreux M, Vetter D, Raoul JL, François E, Ychou M. Safety of cisplatin combined with continuous 5-FU versus bolus 5-FU and leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised trial). Anticancer Res. 2006 Sep-Oct;26(5B):3877-83. link to original article contains dosing details in manuscript PubMed
TAX 325: Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. link to original article contains dosing details in manuscript PubMed
Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. link to original article contains dosing details in manuscript PubMed
ML17032: Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. link to original article contains dosing details in manuscript PubMed NCT02563054
Lee KH, Hyun MS, Kim HK, Jin HM, Yang J, Song HS, Do YR, Ryoo HM, Chung JS, Zang DY, Lim HY, Jin JY, Yim CY, Park HS, Kim JS, Sohn CH, Lee SN. Randomized, multicenter, phase III trial of heptaplatin 1-hour infusion and 5-fluorouracil combination chemotherapy comparing with cisplatin and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer. Cancer Res Treat. 2009 Mar;41(1):12-8. Epub 2009 Mar 31. link to original article link to PMC article contains dosing details in manuscript PubMed
FLAGS: Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. link to original article contains dosing details in abstract PubMed NCT00400179
AVAGAST: Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. link to original article contains dosing details in manuscript PubMed NCT00548548
DIGEST: Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. link to original article contains dosing details in manuscript PubMed NCT01285557
KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. link to original article link to PMC article PubMed NCT02494583
KEYNOTE-859: Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. link to original article contains dosing details in abstract PubMed NCT03675737
BGB-A317-305: contains dosing details on CT.gov NCT03777657

Cisplatin & Fluorouracil (CF) & Pembrolizumab

CF & Pembrolizumab: Cisplatin, Fluorouracil, Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shitara et al. 2020 (KEYNOTE-062)	2015-2017	Phase 3 (E-esc)	1a. CF 1b. CX	Might have superior OS (co-primary endpoint) Median OS: 12.5 vs 11.1 mo (HR 0.85, 95% CI 0.70-1.03)
Shitara et al. 2020 (KEYNOTE-062)	2015-2017	Phase 3 (E-esc)	2. Pembrolizumab	Not reported
Rha et al. 2023 (KEYNOTE-859)	2018-11-08 to 2021-06-11	Phase 3 (E-RT-esc)	1a. CF 1b. CapeOx	Superior OS (primary endpoint) Median OS: 12.9 vs 11.5 mo (HR 0.78, 95% CI 0.70-0.87)

KEYNOTE-062 & KEYNOTE-859 included patients with GEJ malignancy

Biomarker eligibility criteria

PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test

Chemotherapy

Cisplatin (Platinol) 80 mg/m² IV once on day 1
Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles

References

KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. link to original article link to PMC article PubMed NCT02494583
KEYNOTE-859: Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. link to original article contains dosing details in abstract PubMed NCT03675737

Cisplatin & S-1

CS: Cisplatin & S-1
SP: S-1 & Platinol (Cisplatin)

Regimen variant #1, q3wk ("SP3")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ryu et al. 2015 (SOS)	2009-2012	Phase 3 (E-switch-ic)	Cisplatin & S-1; SP5	Seems to have superior PFS (primary endpoint) Median PFS: 5.5 vs 4.9 mo (HR 0.82, 95% CI 0.68-0.99)
Lee et al. 2020 (SOPP)	2012-2014	Phase 3 (C)	SOX	Non-inferior PFS

Chemotherapy

Cisplatin (Platinol) 60 mg/m² IV once on day 1
Tegafur, gimeracil, oteracil (S-1) 40 mg/m² PO twice per day on days 1 to 14

21-day cycles

Regimen variant #2, q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ajani et al. 2010 (FLAGS)	2005-2007	Phase 3 (E-switch-ic)	CF	Did not meet primary endpoint of OS
Ajani et al. 2017 (DIGEST)	2011-2014	Phase 3 (E-switch-ic)	CF	Did not meet primary endpoint of OS

Note: This was an experimental arm of a study where the primary endpoint was not met. Included because CS has been shown to be superior in comparison to other regimens (see above).

Chemotherapy

Cisplatin (Platinol) 75 mg/m² IV over 1 to 3 hours once on day 1
Tegafur, gimeracil, oteracil (S-1) 25 mg/m² PO twice per day on days 1 to 21

28-day cycles

Regimen variant #3, q5wk ("SP5")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Koizumi et al. 2008 (SPIRITS)	2002-2004	Phase 3 (E-esc)	S-1	Seems to have superior OS (primary endpoint) Median OS: 13 vs 11 mo (HR 0.77, 95% CI 0.61-0.98)
Fujitani et al. 2016 (REGATTA)	2008-2013	Non-randomized part of phase 3 RCT
Ryu et al. 2015 (SOS)	2009-2012	Phase 3 (C)	Cisplatin & S-1; SP3	Seems to have inferior PFS
Yamada et al. 2014 (G-SOX)	2010-01 to 2011-10	Phase 3 (C)	SOX	Non-inferior PFS
Ishigami et al. 2018 (PHOENIX-GC)	2011-2013	Phase 3 (C)	IV/IP Paclitaxel & S-1	Might have inferior OS
Yamada et al. 2019 (JCOG1013)	2012-2016	Phase 3 (C)	Cisplatin, Docetaxel, S-1	Did not meet primary endpoint of OS
Kang et al. 2020 (SOLAR)	2015-01-28 to 2016-12-05	Phase 3 (C)	Oxaliplatin & TAS-118	Seems to have inferior PFS

Note: in REGATTA, there was no difference in outcome amongst patients who did or did not undergo surgery. SPIRITS trial included patients with ECOG PS of 2 (3% of patients).

Eligibility criteria

REGATTA: presence of a single non-curable factor (ex: hepatic, peritoneal, and para-aortic mets), see link for further details
PHEONIX-GC: patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details

Preceding treatment

REGATTA: Non-laparoscopic gastrectomy with D1 lymphadenectomy versus no surgery; chemotherapy began within 8 weeks of surgery

Chemotherapy

Cisplatin (Platinol) 60 mg/m² IV once on day 8
Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 21
- Between 1.25 m² and 1.5 m²: 50 mg PO twice per day on days 1 to 21
- 1.5 m² or more: 60 mg PO twice per day on days 1 to 21

35-day cycles

References

SPIRITS: Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. link to original article contains dosing details in manuscript PubMed NCT00150670
FLAGS: Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. link to original article contains dosing details in abstract PubMed NCT00400179
G-SOX: Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015 Jan;26(1):141-8. Epub 2014 Oct 14. link to original article contains dosing details in abstract PubMed JapicCTI-101021
SOS: Ryu MH, Baba E, Lee KH, Park YI, Boku N, Hyodo I, Nam BH, Esaki T, Yoo C, Ryoo BY, Song EK, Cho SH, Kang WK, Yang SH, Zang DY, Shin DB, Park SR, Shinozaki K, Takano T, Kang YK; SOS study investigators. Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS). Ann Oncol. 2015 Oct;26(10):2097-101. Epub 2015 Jul 27. link to original article contains dosing details in abstract PubMed NCT00915382
REGATTA: Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, Iwasaki Y, Hyung WJ, Takagane A, Park DJ, Yoshikawa T, Hahn S, Nakamura K, Park CH, Kurokawa Y, Bang YJ, Park BJ, Sasako M, Tsujinaka T; REGATTA study investigators. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016 Mar;17(3):309-18. Epub 2016 Jan 26. link to original article contains dosing details in manuscript PubMed UMIN000001012
DIGEST: Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. link to original article contains dosing details in manuscript PubMed NCT01285557
PHOENIX-GC: Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. link to original article contains dosing details in manuscript PubMed UMIN000005930
JCOG1013: Yamada Y, Boku N, Mizusawa J, Iwasa S, Kadowaki S, Nakayama N, Azuma M, Sakamoto T, Shitara K, Tamura T, Chin K, Hata H, Nakamori M, Hara H, Yasui H, Katayama H, Fukuda H, Yoshikawa T, Sasako M, Terashima M. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 Jul;4(7):501-510. Epub 2019 May 14. link to original article contains dosing details in abstract PubMed UMIN000007652
SOPP: Lee KW, Chung IJ, Ryu MH, Park YI, Nam BH, Oh HS, Lee KH, Han HS, Seo BG, Jo JC, Lee HR, Kim JW, Park SR, Cho SH, Kang YK; SOPP study investigators. Multicenter phase III trial of S-1 and cisplatin versus S-1 and oxaliplatin combination chemotherapy for first-line treatment of advanced gastric cancer (SOPP trial). Gastric Cancer. 2021 Jan;24(1):156-167. Epub 2020 Jun 28. link to original article contains dosing details in abstract PubMed NCT01671449
SOLAR: Kang YK, Chin K, Chung HC, Kadowaki S, Oh SC, Nakayama N, Lee KW, Hara H, Chung IJ, Tsuda M, Park SH, Hosaka H, Hironaka S, Miyata Y, Ryu MH, Baba H, Hyodo I, Bang YJ, Boku N. S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Aug;21(8):1045-1056. Epub 2020 Jul 16. link to original article contains dosing details in abstract PubMed NCT02322593

CLF

CLF: Cisplatin, Leucovorin, Fluorouracil
FLP: Fluorouracil, Leucovorin, Platinol (Cisplatin)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Al-Batran et al. 2008	2003-2006	Phase 3 (C)	FLO	Might have inferior PFS

Note: In contrast to the original reference, some guidelines list 5-FU as being given every 2 weeks rather than the schedule below. Patients had 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric).

Chemotherapy

Cisplatin (Platinol) 50 mg/m² IV over 2 hours once per day on days 1, 15, 29, 43
Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once per day on days 1, 15, 29, 43
Fluorouracil (5-FU) 2000 mg/m² IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m²)

Supportive therapy

Up to 3 liters normal saline as hydration with cisplatin
Antiemetic medications per "local protocols"

8-week cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bouché et al. 2004 (FFCD 9803)	1999-2001	Randomized Phase 2 (E-esc)	1. LV5FU2 2. LV5FU2 & Irinotecan	Not powered to draw conclusions

Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used.

Chemotherapy

Cisplatin (Platinol) 50 mg/m² IV over 60 minutes once on either day 1 or 2
Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once on day 1
Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1200 mg/m² IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m²)

Supportive therapy

1 liter hydration over 3 hours before and after cisplatin
5-HT3 antagonist IV prior to cisplatin
Methylprednisolone (Solumedrol) 120 mg IV 10 minutes prior to cisplatin
Oral antiemetics and corticosteroids from days 2 to 5

14-day cycle for at least 4 cycles

References

FFCD 9803: Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. link to original article contains dosing details in manuscript PubMed
Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. link to original article contains dosing details in manuscript PubMed

DCF

DCF: Docetaxel, Cisplatin, Fluorouracil
TCF: Taxotere (Docetaxel), Cisplatin, Fluorouracil

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ajani et al. 2005 (V-325)	1998-1999	Randomized Phase 2 (E-esc)	DC	Seems to have superior ORR
Van Cutsem et al. 2006 (TAX 325)	1999-2003	Phase 3 (E-RT-esc)	CF	Seems to have superior OS (secondary endpoint) Superior TTP (primary endpoint)

Note: In contrast to the original references, some guidelines list each cycle as lasting 28 days. V-325 patients had 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70. TAX 325 patients had 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS score of 70.

Chemotherapy

Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1
Cisplatin (Platinol) 75 mg/m² IV over 1 to 3 hours once on day 1
Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m²)

Supportive therapy

(varied depending on reference):
Dexamethasone (Decadron) 8 mg PO once the night before chemotherapy, then 8 mg PO once on day 1; 1 hour prior to chemotherapy, then 8 mg PO twice per day until day 2 (total dose per cycle: 48 mg)
Dexamethasone (Decadron) 20 mg IV prior to cisplatin and 8 hours after cisplatin
Ondansetron (Zofran) 8 mg IV prior to cisplatin, 4 hours after cisplatin, and 8 hours after cisplatin
"Hydration (was) administered in a standard manner"

21-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Roth et al. 2007	1999-2003	Randomized Phase 2 (E-esc)	1. ECF	Not reported
Roth et al. 2007	1999-2003	Randomized Phase 2 (E-esc)	2. TC	Might have superior ORR (primary endpoint)

Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m² to 75 mg/m² based on high incidence of febrile neutropenia.

Chemotherapy

Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1
Cisplatin (Platinol) 75 mg/m² IV over 4 hours once on day 1
Fluorouracil (5-FU) 300 mg/m²/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m²)

Supportive therapy

3 liters per day "hyperhydration"
Dexamethasone (Decadron) 8 mg PO given 12 hours & 6 hours prior to docetaxel, then 8 mg PO twice per day for 4 days after docetaxel
5-HT3 antagonist for emesis prophylaxis
Growth factor support allowed, such as with Filgrastim (Neupogen)

21-day cycle for up to 8 cycles

References

V-325: Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. link to original article contains dosing details in manuscript PubMed
TAX 325: Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. link to original article contains dosing details in manuscript PubMed
Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. link to original article contains dosing details in manuscript PubMed

mDCF

mDCF: modified Docetaxel, Cisplatin, Fluorouracil

Regimen variant #1, 60/60/3000, 4-day 5-FU infusion

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wang et al. 2015 (DOCET L 02195)	2008-2010	Phase 3 (E-esc)	CF	Seems to have superior OS (secondary endpoint) Median OS: 10.2 vs 8.5 mo (HR 0.71, 95% CI 0.52-0.97)

Chemotherapy

Docetaxel (Taxotere) 60 mg/m² IV once on day 1
Cisplatin (Platinol) 60 mg/m² IV once on day 1
Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m²)

21-day cycles

Regimen variant #2, 60/60/3000, 5-day 5-FU infusion

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wang et al. 2015 (DOCET L 02195)	2008-2010	Phase 3 (E-esc)	CF	Seems to have superior OS (secondary endpoint) Median OS: 10.2 vs 8.5 mo (HR 0.71, 95% CI 0.52-0.97)

Chemotherapy

Docetaxel (Taxotere) 60 mg/m² IV once on day 1
Cisplatin (Platinol) 60 mg/m² IV once on day 1
Fluorouracil (5-FU) 600 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3000 mg/m²)

21-day cycles

References

DOCET L 02195: Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S, Dai G, Xu J, Liu Y, Fan N, Shu Y, Ba Y, Ma D, Qin S, Zheng L, Chen W, Shen L. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer. 2016 Jan;19(1):234-44. Epub 2015 Jan 21. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00811447

mDCF & Bevacizumab

mDCF & Bevacizumab: modified Docetaxel, Cisplatin, Fluorouracil & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence
Shah et al. 2010 (MSK 06-096)	2006-2008	Phase 2

Note: patients had 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy. Unlike most DCF regimens that we are aware of, this one includes leucovorin.

Chemotherapy

Docetaxel (Taxotere) 40 mg/m² IV over 60 minutes once on day 1
Cisplatin (Platinol) 40 mg/m² IV over 1 to 3 hours once on day 3
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1200 mg/m²/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m²)

Targeted therapy

Bevacizumab (Avastin) 10 mg/kg IV once on day 1

Supportive therapy

"Standard premedication and delayed emesis regimens"

14-day cycles

References

MSK 06-096: Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00390416

Docetaxel & S-1

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Koizumi et al. 2013 (START_gastric)	2005-2008	Phase 3 (E-esc)	S-1	Seems to have superior OS (primary endpoint) Median OS: 12.5 vs 10.8 mo (HR 0.84, 95% CI 0.71-0.99)

Chemotherapy

Docetaxel (Taxotere) 40 mg/m² IV once on day 1
Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 14
- Between 1.25 m² and 1.5 m²: 50 mg PO twice per day on days 1 to 14
- 1.5 m² or more: 60 mg PO twice per day on days 1 to 14

21-day cycles

References

START: Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO; KCSG. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00287768

ECF

ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Findlay et al. 1994	1988-1992	Phase 2
Webb et al. 1997	1992-1995	Randomized (E-switch-ic)	FAMTX	Superior OS
Ross et al. 2002	1995-1998	Phase 3 (C)	MCF	Seems to have non-inferior OS
Roth et al. 2007	1999-2003	Randomized Phase 2 (C)	1. TC 2. TCF	Not reported
Cunningham et al. 2008 (REAL-2)	2000-2005	Phase 3 (C)	1. ECX	Non-inferior OS
			2. EOF	Non-inferior OS
			3. EOX	Seems to have inferior OS

Note: Findlay et al. patients all had metastatic gastric cancer. Ross et al. patients had adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer. Roth et al. patients all had metastatic gastric cancer. REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV bolus once on day 1
Cisplatin (Platinol) 60 mg/m² IV over 4 hours once on day 1
Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m²)

Supportive therapy

(varied depending on reference):
3 liters per day "hyperhydration"
5-HT3 antagonist for emesis prophylaxis
Growth factor support allowed, such as with Filgrastim (Neupogen)
Ross et al. 2002 & Cunningham et al. 2008 used Warfarin (Coumadin) 1 mg PO once per day for catheter thrombosis prophylaxis

21-day cycle for up to 8 cycles

References

Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson V, Nash A, Sacks N, Ford H, Carter R, Hill A. A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol. 1994 Sep;5(7):609-16. link to original article contains dosing details in manuscript PubMed
Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997 Jan;15(1):261-7. link to original article contains dosing details in manuscript PubMed
1. Update: Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Hickish T. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer. 1999 Apr;80(1-2):269-72. link to original article link to PMC article PubMed
Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. link to original article contains dosing details in manuscript PubMed
Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. link to original article contains dosing details in manuscript PubMed
REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article contains dosing details in manuscript PubMed ISRCTN51678883

ECX

ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)
ECC: Epirubicin, Cisplatin, Capecitabine

Regimen variant #1, continuous capecitabine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2008 (REAL-2)	2000-2005	Phase 3 (E-RT-switch-ic)	1. ECF	Non-inferior OS (primary endpoint)
Cunningham et al. 2008 (REAL-2)	2000-2005	Phase 3 (E-RT-switch-ic)	2. EOF 3. EOX	Non-inferior OS (primary endpoint)
Catenacci et al. 2017 (RILOMET-1)	2012-2014	Randomized Phase 2 (C)	ECX & Rilotumumab	Superior OS (primary endpoint) Median OS: 10.7 vs 8.8 mo (HR 0.75, 95% CI 0.61-0.91)

Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2. RILOMET-1 patients had unresectable or metastatic MET-positive gastric or gastro-esophageal junction cancer. ~80% gastric, 20% GE junction and 10% distal esophageal.

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Cisplatin (Platinol) 60 mg/m² IV once on day 1
Capecitabine (Xeloda) 625 mg/m² PO twice per day

21-day cycle for up to 8 cycles (REAL-2) or 10 cycles (RILOMET-1)

Regimen variant #2, intermittent capecitabine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Konings et al. 2010	2005-2009	Randomized Phase 2 (C)	ECC & Pravastatin	Did not meet primary endpoint of PFS6

Note: 6.6% of patients had an ECOG PS of 2

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV bolus once on day 1, given first
Cisplatin (Platinol) 60 mg/m² IV over 3 hours once on day 1, given second
Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycle for up to 6 cycles

References

REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article contains dosing details in manuscript PubMed ISRCTN51678883
Konings IR, van der Gaast A, van der Wijk LJ, de Jongh FE, Eskens FA, Sleijfer S. The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial. Eur J Cancer. 2010 Dec;46(18):3200-4. Epub 2010 Aug 18. link to original article contains dosing details in manuscript PubMed
RILOMET-1: Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe M, De Vita F, Turkington C, Tang R, Ang A, Zhang Y, Hoang T, Sidhu R, Cunningham D. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1467-1482. Epub 2017 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01697072

EOF

EOF: Epirubicin, Oxaliplatin, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2008 (REAL-2)	2000-2005	Phase 3 (E-switch-ic)	1. ECF 2. ECX	Non-inferior OS (primary endpoint)
Cunningham et al. 2008 (REAL-2)	2000-2005	Phase 3 (E-switch-ic)	3. EOX	Non-inferior OS (primary endpoint)

Note: patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV bolus once on day 1
Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1
Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m²)

Supportive therapy

Warfarin (Coumadin) 1 mg PO once per day for catheter thrombosis prophylaxis

21-day cycle for up to 8 cycles

References

REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article contains dosing details in manuscript PubMed ISRCTN51678883

EOX

EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)
EOC: Epirubicin, Oxaliplatin, Capecitabine

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2008 (REAL-2)	2000-2005	Phase 3 (E-RT-switch-ic)	1. ECF	Seems to have superior OS (secondary endpoint) Median OS: 11.2 vs 9.9 mo (HR 0.80, 95% CI 0.66-0.97)
			2. ECX	Non-inferior OS (primary endpoint)
			3. EOF	Non-inferior OS (primary endpoint)
Waddell et al. 2013 (REAL3)	2008-2011	Phase 3 (C)	mEOC+P	Superior OS Median OS: 11.3 vs 8.3 mo (HR 0.73, 95% CI 0.57-0.93)

Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2. REAL3 patients had 99% adenocarcinoma, 1% undifferentiated histology. 39% esophagus, 31% gastroesophageal junction, 30% gastric. 6% ECOF PS of 2. 89% metastatic disease.

Chemotherapy

Epirubicin (Ellence) 50 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1
Capecitabine (Xeloda) 625 mg/m² PO twice per day on days 1 to 21

21-day cycle for up to 8 cycles

Regimen variant #2, with maintenance capecitabine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhu et al. 2022 (EXELOX)	2015-2020	Phase 3 (C)	CapeOx	Non-inferior PFS

Chemotherapy

Epirubicin (Ellence) as follows:
- Cycles 1 up to 8: 50 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) as follows:
- Cycles 1 up to 8: 130 mg/m² IV over 2 hours once on day 1
Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org ISRCTN51678883
REAL3: Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, Wotherspoon A, Saffery C, Middleton G, Wadsley J, Ferry D, Mansoor W, Crosby T, Coxon F, Smith D, Waters J, Iveson T, Falk S, Slater S, Peckitt C, Barbachano Y. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):481-9. Epub 2013 Apr 15. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00824785
EXELOX: Zhu XD, Huang MZ, Wang YS, Feng WJ, Chen ZY, He YF, Zhang XW, Liu X, Wang CC, Zhang W, Ying JE, Wu J, Yang L, Qin YR, Luo JF, Zhao XY, Li WH, Zhang Z, Qiu LX, Geng QR, Zou JL, Zhang JY, Zheng H, Song XF, Wu SS, Zhang CY, Gong Z, Liu QQ, Wang XF, Xu Q, Wang Q, Ji JM, Zhao J, Guo WJ. XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX). Cancer Commun (Lond). 2022 Apr;42(4):314-326. Epub 2022 Feb 25. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02395640

Fluorouracil monotherapy

Regimen variant #1, CI

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ohtsu et al. 2003 (JCOG 9205)	1992-1997	Phase 3 (C)	1. FP	Did not meet primary endpoint of OS
Ohtsu et al. 2003 (JCOG 9205)	1992-1997	Phase 3 (C)	2. UFTM	Did not meet primary endpoint of OS
Boku et al. 2009 (JCOG 9912)	2000-2006	Phase 3 (C)	1. Cisplatin & Irinotecan	Might have inferior OS
Boku et al. 2009 (JCOG 9912)	2000-2006	Phase 3 (C)	2. S-1	Non-inferior OS
Shirao et al. 2013 (JCOG 0106)	2002-2007	Phase 3 (C)	MF	Did not meet primary endpoint of OS50%

Note: JCOG 9205 included patients with PFS of 2 (9.6%)

Chemotherapy

Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

28-day cycles

Regimen variant #2, intermittent, BSA-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cullinan et al. 1985	NR	Phase 3 (E-de-esc)	1. FA 2. FAM	Did not meet primary endpoint of OS

Note: This was an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.

Chemotherapy

Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 to 5

28-day cycle for 2 cycles, then 35-day cycles

Regimen variant #3, intermittent, weight-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kolarić et al. 1986	NR	Phase 3 (C)	Epirubicin & Fluorouracil	Seems to have inferior DOR

Chemotherapy

Fluorouracil (5-FU) 12 mg/kg IV once per day on days 1 to 5

21- to 28-day cycles

Regimen variant #4, PVI

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tebbutt et al. 2002	1994-2001	Phase 3 (C)	5-FU & Mitomycin	Did not meet primary endpoint of ORR

Chemotherapy

Fluorouracil (5-FU) 300 mg/m²/day IV continuous infusion

Up to 24-week course

References

Cullinan SA, Moertel CG, Fleming TR, Rubin JR, Krook JE, Everson LK, Windschitl HE, Twito DI, Marschke RF, Foley JF, Pfeifle DM, Barlow JF. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA. 1985 Apr 12;253(14):2061-7. link to original article PubMed
Kolarić K, Potrebica V, Stanovnik M. Controlled phase III clinical study of 4-epi-doxorubicin + 5-fluorouracil versus 5-fluorouracil alone in metastatic gastric and rectosigmoid cancer. Oncology. 1986;43(2):73-7. link to original article contains dosing details in abstract PubMed
Tebbutt NC, Norman A, Cunningham D, Iveson T, Seymour M, Hickish T, Harper P, Maisey N, Mochlinski K, Prior Y, Hill M. A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil (5-FU) with PVI 5-FU plus mitomycin C in patients with inoperable oesophago-gastric cancer. Ann Oncol. 2002 Oct;13(10):1568-75. link to original article contains dosing details in manuscript PubMed
JCOG 9205: Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; JCOG. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. link to original article contains dosing details in manuscript PubMed
JCOG 9912: Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. link to original article contains dosing details in abstract PubMed NCT00142350
JCOG 0106: Shirao K, Boku N, Yamada Y, Yamaguchi K, Doi T, Goto M, Nasu J, Denda T, Hamamoto Y, Takashima A, Fukuda H, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Randomized Phase III study of 5-fluorouracil continuous infusion vs sequential methotrexate and 5-fluorouracil therapy in far advanced gastric cancer with peritoneal metastasis (JCOG0106). Jpn J Clin Oncol. 2013 Oct;43(10):972-80. Epub 2013 Sep 7. link to original article contains dosing details in manuscript PubMed NCT00149201

Fluorouracil & Heptaplatin (FH)

FH: Fluorouracil & Heptaplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2009a	2000-2004	Phase 3 (E-switch-ic)	CF	Equivalent OS (primary endpoint) Median OS: 7.3 vs 7.9 mo

Note: this is reported to be an equivalence study but the statistical analysis does not provide details on the definition of equivalence.

Chemotherapy

Fluorouracil (5-FU) 1000 mg/m² IV over 12 hours once per day on days 1 to 5, given second
Heptaplatin (SunPla) 400 mg/m² IV over 60 minutes once on day 1, given first

28-day cycles

References

Lee KH, Hyun MS, Kim HK, Jin HM, Yang J, Song HS, Do YR, Ryoo HM, Chung JS, Zang DY, Lim HY, Jin JY, Yim CY, Park HS, Kim JS, Sohn CH, Lee SN. Randomized, multicenter, phase III trial of heptaplatin 1-hour infusion and 5-fluorouracil combination chemotherapy comparing with cisplatin and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer. Cancer Res Treat. 2009 Mar;41(1):12-8. Epub 2009 Mar 31. link to original article link to PMC article contains dosing details in manuscript PubMed

Fluorouracil, Folinic acid, Mitomycin

Regimen

Study	Dates of enrollment	Evidence
Hofheinz et al. 2002	1998-2000	Phase 2, fewer than 20 pts in this subgroup

Chemotherapy

Fluorouracil (5-FU) 2600 mg/m² IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 15,600 mg/m²)
Leucovorin (Folinic acid) 500 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
Mitomycin (Mutamycin) 10 mg/m² IV once per day on days 1 & 22

56-day cycle for 2 cycles

References

Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: a phase II study. Onkologie. 2002 Jun;25(3):255-60. link to original article contains dosing details in abstract PubMed

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan
IF: Irinotecan & 5-Fluorouracil

Regimen variant #1, 6 out of 7 weeks ("AIO regimen")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dank et al. 2008	2000-2002	Phase 3 (E-switch-ic)	CF	Might have superior TTP (primary endpoint)

Note: patients had 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric origin). 96% with metastatic disease.

Chemotherapy

Fluorouracil (5-FU) 2000 mg/m² IV continuous infusion over 22 hours, started on days 1, 8, 15, 22, 29, 36, given third (total dose per cycle: 12,000 mg/m²)
Leucovorin (Folinic acid) 500 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given second
Irinotecan (Camptosar) 80 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, given first

Supportive therapy

Ondansetron (Zofran) for antiemetic prophylaxis
Dexamethasone (Decadron) for antiemetic prophylaxis
Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/μL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection
Atropine (Atropen) prn cholinergic symptoms
Loperamide (Imodium) prn delayed diarrhea

7-week cycles

Regimen variant #2, LV5FU2 & Irinotecan (200/1600/180)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bouché et al. 2004 (FFCD 9803)	1999-2001	Randomized Phase 2 (E-esc)	1. LV5FU2 2. LV5FU2 & Cisplatin	Not powered to draw conclusions

Note: patients had 100% adenocarcinoma (70% gastric origin, 30% cardia). The primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more typical schedule was used.

Chemotherapy

Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once on day 1
Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1200 mg/m² IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m²)
Irinotecan (Camptosar) 180 mg/m² IV over 90 minutes once on day 1

14-day cycle for at least 4 cycles

Regimen variant #3, 400/2800/180

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Guimbaud et al. 2014 (FFCD 03-07)	2005-2008	Phase 3 (E-switch-ic)	ECX	Superior TTF (primary endpoint) Median TTF: 5.08 vs 4.24 mo (HR 0.77, 95% CI 0.63-0.93)

Chemotherapy

Leucovorin (Folinic acid) 400 mg/m² IV over 2 hours once on day 1
Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m²)
Irinotecan (Camptosar) 180 mg/m² IV over 90 minutes once on day 1

14-day cycles

References

FFCD 9803: Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. link to original article contains dosing details in manuscript PubMed
Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. link to original article contains dosing details in manuscript PubMed
FFCD 03-07: Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, André T, Gornet JM, Aparicio T, Nguyen S, Azzedine A, Etienne PL, Boucher E, Rebischung C, Hammel P, Rougier P, Bedenne L, Bouché O. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol. 2014 Nov 1;32(31):3520-6. Epub 2014 Oct 6. Erratum in: J Clin Oncol. 2015 Apr 20;33(12):1416. link to original article contains dosing details in manuscript PubMed NCT00374036

mFOLFOX6

mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen variant #1, limited duration

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shah et al. 2021 (GAMMA-1)	2015-2019	Phase 3 (C)	mFOLFOX6 & Andecaliximab	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycle for 12 cycles

Subsequent treatment

FULV maintenance

Regimen variant #2, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04	Phase 3 (C)	1a. CapeOx & Nivolumab 1b. mFOLFOX6 & Nivolumab	Inferior OS
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04	Phase 3 (C)	2. Ipilimumab & Nivolumab	Not reported
Shitara et al. 2023 (SPOTLIGHT)	2018-06-21 to 2022-04-01	Phase 3 (C)	mFOLFOX6 & Zolbetuximab	Inferior PFS (primary endpoint) Inferior OS (secondary endpoint)

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Biomarker eligibility criteria

SPOTLIGHT: CLDN18.2 positive

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycles

References

GAMMA-1: Shah MA, Bodoky G, Starodub A, Cunningham D, Yip D, Wainberg ZA, Bendell J, Thai D, He J, Bhargava P, Ajani JA. Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1). J Clin Oncol. 2021 Mar 20;39(9):990-1000. Epub 2021 Feb 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02545504
CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02872116
1. Update: Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. link to original article link to PMC article PubMed
2. HRQoL analysis: Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. link to original article link to PMC article PubMed
SPOTLIGHT: Shitara K, Lordick F, Bang YJ, Enzinger P, Ilson D, Shah MA, Van Cutsem E, Xu RH, Aprile G, Xu J, Chao J, Pazo-Cid R, Kang YK, Yang J, Moran D, Bhattacharya P, Arozullah A, Park JW, Oh M, Ajani JA. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023 May 20;401(10389):1655-1668. Epub 2023 Apr 15. Erratum in: Lancet. 2023 Jul 22;402(10398):290. link to original article PubMed NCT03504397

mFOLFOX6 (L-Leucovorin)

mFOLFOX6: modified L-FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shah et al. 2021 (GAMMA-1)	2015-2019	Phase 3 (C)	mFOLFOX6 & Andecaliximab	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Levoleucovorin (Fusilev) 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycle for 12 cycles

Subsequent treatment

FULV maintenance

References

GAMMA-1: Shah MA, Bodoky G, Starodub A, Cunningham D, Yip D, Wainberg ZA, Bendell J, Thai D, He J, Bhargava P, Ajani JA. Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1). J Clin Oncol. 2021 Mar 20;39(9):990-1000. Epub 2021 Feb 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02545504
ARMANI: NCT02934464

mFOLFOX6 & Nivolumab

mFOLFOX6 & Nivolumab: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Nivolumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04	Phase 3 (E-RT-esc)	1a. CapeOx 1b. mFOLFOX6	Superior OS¹ (co-primary endpoint) Median OS: 14.4 vs 11.1 mo (HR 0.70, 95% CI 0.61-0.81)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04	Phase 3 (E-RT-esc)	2. Ipilimumab & Nivolumab	Not reported

¹Reported efficacy and MCBS score are for the group with PD-L1 CPS of 5 or more; reported efficacy is based on the 2022 update.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

Immunotherapy

Nivolumab (Opdivo) 240 mg IV once on day 1

14-day cycles

References

CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02872116
1. Update: Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. link to original article link to PMC article PubMed
2. HRQoL analysis: Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. link to original article link to PMC article PubMed

FULV

FULV: 5-FU & LeucoVorin

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bouché et al. 2004 (FFCD 9803)	1999-2001	Randomized Phase 2 (E-de-esc)	1. LV5FU2 & Cisplatin 2. LV5FU2 & Irinotecan	Not powered to draw conclusions

Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more typical schedule was used. Patients had 100% adenocarcinoma histology (70% gastric origin, 30% cardia).

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1200 mg/m² IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m²)
Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once on day 1

14-day cycle for at least 4 cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2023 (KCSG ST13-10)	2014-02 to 2019-01	Phase 3 (C)	1a. mFOLFOX6 1b. CapeOx 1c. Cisplatin & S-1 1d. CX	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 46 hours, started on day 1
Leucovorin (Folinic acid) 100 mg/m² IV once on day 1

14-day cycles

References

FFCD 9803: Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. link to original article contains dosing details in manuscript PubMed
KCSG ST13-10: Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS. A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10). Cancer Res Treat. 2022 Oct;55(4):1250-1260. Epub 2023 May 25. link to original article contains dosing details in manuscript PubMed NCT02114359

FULV (L-Leucovorin)

FULV: 5-FU & Levo-LeucoVorin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nakajima et al. 2020 (JCOG1108)	2013-2017	Phase 2/3 (C)	FLTAX	Did not meet primary endpoint of OS

Chemotherapy

Fluorouracil (5-FU) 600 mg/m² IV bolus once per day on days 1, 8, 15, 22, 29, 36, given second, 60 minutes after levoleucovorin
Levoleucovorin (Fusilev) 250 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given first

8-week cycles

References

JCOG1108: Nakajima TE, Yamaguchi K, Boku N, Hyodo I, Mizusawa J, Hara H, Nishina T, Sakamoto T, Shitara K, Shinozaki K, Katayama H, Nakamura S, Muro K, Terashima M. Randomized phase II/III study of 5-fluorouracil/l-leucovorin versus 5-fluorouracil/l-leucovorin plus paclitaxel administered to patients with severe peritoneal metastases of gastric cancer (JCOG1108/WJOG7312G). Gastric Cancer. 2020 Jul;23(4):677-688. Epub 2020 Feb 8. link to original article contains dosing details in manuscript PubMed UMIN000010949

Irinotecan monotherapy

Regimen

Study	Dates of enrollment	Evidence
Enzinger et al. 2005	1997-12 to 2000-08	Phase 2

Note: In contrast to the primary references, some guidelines list a dosing schedule of 125 mg/m² IV once per day on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when irinotecan is used as a single-agent, a tri-weekly schedule may be preferable." This study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GEJ and 33% distal esophagus). The results showed a 14% response rate and 53% disease control rate.

Chemotherapy

Irinotecan (Camptosar) 125 mg/m² IV over 90 minutes once per day on days 1, 8, 15, 22

42-day cycles

References

Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. link to original article PubMed

OLF

OLF: Oxaliplatin, Leucovorin, Fluorouracil
FLO: Fluorouracil, Leucovorin, Oxaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Al-Batran et al. 2008	2003-2006	Phase 3 (E-switch-ic)	FLP	Might have superior PFS (primary endpoint) Median PFS: 5.8 vs 3.9 mo

Note: Patients had 100% adenocarcinoma histology (20% esophagogastric junction, 80% gastric).

Chemotherapy

Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once per day on days 1, 15, 29, 43
Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once per day on days 1, 15, 29, 43
Fluorouracil (5-FU) 2600 mg/m² IV continuous infusion over 24 hours, started on days 1, 15, 29, 43 (total dose per cycle: 10,400 mg/m²)

Supportive therapy

Antiemetic medications per "local protocols"

8-week cycles

References

Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. link to original article contains dosing details in manuscript PubMed

Paclitaxel & S-1

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ishigami et al. 2018 (PHOENIX-GC)	2011-2013	Phase 3 (E-switch-ooc)	Cisplatin & S-1	Might have superior OS Median OS: 17.7 vs 15.2 mo (HR 0.72, 95% CI 0.49-1.04)

Note: Inclusion criteria for PHOENIX-GC included patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details

Chemotherapy

Paclitaxel (Taxol) 50 mg/m² IV once per day on days 1 and 8
Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 14
- Between 1.25 to 1.5 m²: 50 mg PO twice per day on days 1 to 14
- More than 1.5 m²: 60 mg PO twice per day on days 1 to 14
Paclitaxel (Taxol) 20 mg/m² IP once per day over 1 hour on days 1 and 8

Supportive therapy

500 mL of normal saline was given prior to intraperitoneal paclitaxel

35-day cycles

References

PHOENIX-GC: Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. link to original article contains dosing details in manuscript PubMed UMIN000005930

Pembrolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shitara et al. 2020 (KEYNOTE-062)	2015-2017	Phase 3 (E-switch-ooc)	1a. CF 1b. CX	Non-inferior OS¹ (co-primary endpoint)
Shitara et al. 2020 (KEYNOTE-062)	2015-2017	Phase 3 (E-switch-ooc)	2a. CF & Pembrolizumab 2b. CX & Pembrolizumab	Not reported

¹Reported efficacy is for patients with PD-L1 CPS score of 1 or more. Improved OS was seen in patients with PD-L1 CPS score of 10 or more (HR: 0.62) but was not tested per analysis plan.
KEYNOTE-062 included patients with GEJ malignancy.

Biomarker eligibility criteria

PD-L1 CPS score of 1 or more

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

References

KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. link to original article link to PMC article contains dosing details in abstract PubMed NCT02494583

S-1 monotherapy

Regimen variant #1, BSA-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Boku et al. 2009 (JCOG 9912)	2000-2006	Phase 3 (E-switch-ic)	1. Cisplatin & Irinotecan	Not reported
Boku et al. 2009 (JCOG 9912)	2000-2006	Phase 3 (E-switch-ic)	2. 5-FU	Non-inferior OS (primary endpoint)

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) 40 mg/m² PO twice per day on days 1 to 28

42-day cycles

Regimen variant #2, weight-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Koizumi et al. 2008 (SPIRITS)	2002-2004	Phase 3 (C)	Cisplatin & S-1	Seems to have inferior OS
Narahara et al. 2011 (TOP-002)	2004-06 to 2005-11	Phase 3 (C)	IRIS	Did not meet primary endpoint of OS
Koizumi et al. 2013 (START_gastric)	2005-2008	Phase 3 (C)	Docetaxel & S-1	Seems to have inferior OS
Yoshino et al. 2016 (JFMC36-0701)	2007-2010	Phase 3 (C)	Lentinan & S-1	Did not meet primary endpoint of OS

Note: there is another trial named START in NSCLC.

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
- Between 1.25 and 1.5 m²: 50 mg PO twice per day on days 1 to 28
- 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycles

Regimen variant #3, 14 of 21 days

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2023 (KCSG ST13-10)	2014-02 to 2019-01	Phase 3 (C)	1a. mFOLFOX6 1b. CapeOx 1c. Cisplatin & S-1 1d. CX	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) by the following renal function-based criteria:
- CrCl 60 mL/min or more: 40 mg/m² PO twice per day on days 1 to 14
- CrCl less than 60 mL/min: 30 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

SPIRITS: Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. link to original article contains dosing details in manuscript PubMed NCT00150670
JCOG 9912: Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. link to original article contains dosing details in abstract PubMed NCT00142350
TOP-002: Narahara H, Iishi H, Imamura H, Tsuburaya A, Chin K, Imamoto H, Esaki T, Furukawa H, Hamada C, Sakata Y. Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002). Gastric Cancer. 2011 Mar;14(1):72-80. Epub 2011 Feb 23. link to original article link to PMC article contains dosing details in manuscript PubMed JapicCTI-050083
START: Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO; KCSG. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00287768
JFMC36-0701: Yoshino S, Nishikawa K, Morita S, Takahashi T, Sakata K, Nagao J, Nemoto H, Murakami N, Matsuda T, Hasegawa H, Shimizu R, Yoshikawa T, Osanai H, Imano M, Naitoh H, Tanaka A, Tajiri T, Gochi A, Suzuki M, Sakamoto J, Saji S, Oka M. Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). Eur J Cancer. 2016 Sep;65:164-71. Epub 2016 Aug 5. link to original article PubMed UMIN000000574
KCSG ST13-10: Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS. A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10). Cancer Res Treat. 2022 Oct;55(4):1250-1260. Epub 2023 May 25. link to original article contains dosing details in manuscript PubMed NCT02114359
RESCUE-GC: NCT02867839

UFTM

UFTM: UFT (Tegafur and uracil) & Mitomycin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ohtsu et al. 2003 (JCOG 9205)	1992-1997	Phase 3 (E-esc)	1. Fluorouracil	Did not meet primary endpoint of OS
Ohtsu et al. 2003 (JCOG 9205)	1992-1997	Phase 3 (E-esc)	2. FP	Did not meet primary endpoint of OS

Note: this arm of the study was terminated early, in 1995. Study included patients with PFS of 2 (9.6%). Mitomycin was interrupted for 1 month after patients received a total cumulative dose of 60 mg.

Chemotherapy

Tegafur and uracil (UFT) 187.5 mg/m² PO twice per day
Mitomycin (Mutamycin) 5 mg/m² IV once on day 1

7-day cycles (see note)

References

JCOG 9205: Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; JCOG. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. link to original article contains dosing details in manuscript PubMed

Maintenance after first-line therapy

Capecitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence
Ohtsu et al. 2011 (AVAGAST)	2007-09 to 2008-12	Non-randomized part of phase 3 RCT
Kim et al. 2014 (SMC 2008-12-019)	2009-2012	Non-randomized part of phase 3 RCT

Note: AVAGAST patients had 86% gastric and 14% GEJ. 5.4% of patients had an ECOG PS of 2. SMC 2008-12-019 patients had 79% gastric, 5% GEJ, and 16% unknown. 2% of patients had an ECOG PS of 2.

Preceding treatment

AVAGAST: First-line CX x 6
SMC 2008-12-019: First-line CX x 8

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

AVAGAST: Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. link to original article contains dosing details in manuscript PubMed NCT00548548
SMC 2008-12-019: Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. link to original article contains dosing details in manuscript PubMed NCT01099085

Metastatic or locally advanced disease, subsequent lines of therapy

Docetaxel monotherapy

Regimen variant #1, 60 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kang et al. 2012 (SMC 2008-08-055)	2008-2010	Phase 3 (E-esc)	Best supportive care	Superior OS (primary endpoint) Median OS: 5.3 vs 3.8 mo (HR 0.66, 95% CI 0.485-0.89)

Chemotherapy

Docetaxel (Taxotere) 60 mg/m² IV once on day 1

21-day cycles

Regimen variant #2, 75 mg/m² x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ford et al. 2013 (COUGAR-02)	2008-2012	Phase 3 (E-esc)	Best supportive care	Superior OS (primary endpoint) Median OS: 5.2 vs 3.6 mo (HR 0.67, 95% CI 0.49-0.92)

Chemotherapy

Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

21-day cycle for up to 6 cycles

References

SMC 2008-08-055: Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. link to original article contains dosing details in abstract PubMed NCT00821990
PEP0206: Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. link to original article PubMed NCT00813072
COUGAR-02: Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. link to original article contains dosing details in abstract PubMed NCT00978549
INTEGRATEIIb: NCT04879368

Fluorouracil, Folinic acid, Mitomycin

Regimen

Study	Dates of enrollment	Evidence
Hofheinz et al. 2002	1998-2000	Phase 2, fewer than 20 pts in this subgroup

Chemotherapy

Fluorouracil (5-FU) 2600 mg/m² IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 15,600 mg/m²)
Leucovorin (Folinic acid) 500 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
Mitomycin (Mutamycin) 10 mg/m² IV once per day on days 1 & 22

56-day cycle for 2 cycles

References

Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: a phase II study. Onkologie. 2002 Jun;25(3):255-60. link to original article contains dosing details in abstract PubMed

Irinotecan monotherapy

Regimen variant #1, 125 mg/m², 4 weeks out of 6

Study	Dates of enrollment	Evidence
Enzinger et al. 2005	1997-12 to 2000-08	Phase 2

Note: In contrast to the primary references, some guidelines list a dosing schedule of 125 mg/m² IV once per day on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when irinotecan is used as a single-agent, a tri-weekly schedule may be preferable." This study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GE junction and 33% distal esophagus), and showed a 14% response rate and 53% disease control rate.

Chemotherapy

Irinotecan (Camptosar) 125 mg/m² IV over 90 minutes once per day on days 1, 8, 15, 22

42-day cycles

Regimen variant #2, 150 mg/m² q2wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hironaka et al. 2013 (WJOG 4007)	2007-2010	Phase 3 (E-switch-ic)	Paclitaxel	Did not meet primary endpoint of OS
Nishikawa et al. 2015 (TRICS)	2007-2011	Phase 3 (C)	Cisplatin & Irinotecan	Did not meet primary endpoint of OS
Kang et al. 2012 (SMC 2008-08-055)	2008-2010	Phase 3 (E-esc)	Best supportive care	Superior OS (primary endpoint) Median OS: 5.3 vs 3.8 mo (HR 0.66, 95% CI 0.485-0.89)
Higuchi et al. 2014 (BIRIP)	2008-2011	Phase 3 (C)	Cisplatin & Irinotecan	Seems to have inferior PFS
Tanabe et al. 2015 (JACCRO GC-05)	2008-2011	Phase 3 (C)	Irinotecan & S-1	Did not meet primary endpoint of OS
Bang et al. 2018 (JAVELIN Gastric 300)	2015-2017	Phase 3 (C)	Avelumab	Did not meet primary endpoint of OS

Note: WJOG 4007 had 3.7% patients with an ECOG PS of 2

Chemotherapy

Irinotecan (Camptosar) 150 mg/m² IV once on day 1

14-day cycles

Regimen variant #3, 300 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Roy et al. 2013 (PEP0206)	2008-2010	Randomized Phase 2 (C)	1. Docetaxel 2. Irinotecan liposomal	Did not meet primary endpoint of ORR

Note: this study included patients with GE junction malignancy (77% gastric, 23% GE junction) and included patients with ECOG PS of 2

Chemotherapy

Irinotecan (Camptosar) 300 mg/m² IV over 90 minutes once on day 1

21-day cycles

Regimen variant #4, 350 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Thuss-Patience et al. 2011	2002-2006	Phase 3 (E-esc)	Best supportive care	Seems to have superior OS Median OS: 4 vs 2.4 mo (HR 0.48, 95% CI 0.25-0.92)

Note: Thuss-Patience et al. 2011 included patients with GE junction malignancy (~58% gastric, 43% GE junction) and included patients with ECOG PS of 2.

Chemotherapy

Irinotecan (Camptosar) as follows:
- Cycle 1: 250 mg/m² (maximum dose of 500 mg) IV over 30 minutes once on day 1
- Cycles 2 to 10 (depending on toxicity): 350 mg/m² IV over 30 minutes once on day 1

Supportive therapy

Atropine (Atropen) 0.25 mg SC once on day 1, given prior to irinotecan
5-HT3 antagonist
Dexamethasone (Decadron)

21-day cycle for up to 10 cycles

References

Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. link to original article PubMed
Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. link to original article contains dosing details in manuscript PubMed NCT00144378
SMC 2008-08-055: Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. link to original article PubMed NCT00821990
PEP0206: Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. link to original article PubMed NCT00813072
WJOG 4007: Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. link to original artile contains dosing details in abstract PubMed UMIN000001252
BIRIP: Higuchi K, Tanabe S, Shimada K, Hosaka H, Sasaki E, Nakayama N, Takeda Y, Moriwaki T, Amagai K, Sekikawa T, Sakuyama T, Kanda T, Sasaki T, Azuma M, Takahashi F, Takeuchi M, Koizumi W; Tokyo Cooperative Oncology Group. Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial). Eur J Cancer. 2014 May;50(8):1437-45. Epub 2014 Feb 20. link to original article contains dosing details in abstract PubMed UMIN000001028
TRICS: Nishikawa K, Fujitani K, Inagaki H, Akamaru Y, Tokunaga S, Takagi M, Tamura S, Sugimoto N, Shigematsu T, Yoshikawa T, Ishiguro T, Nakamura M, Morita S, Miyashita Y, Tsuburaya A, Sakamoto J, Tsujinaka T. Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial. Eur J Cancer. 2015 May;51(7):808-16. Epub 2015 Mar 18. link to original article contains dosing details in abstract PubMed UMIN000002571
JACCRO GC-05: Tanabe K, Fujii M, Nishikawa K, Kunisaki C, Tsuji A, Matsuhashi N, Takagane A, Ohno T, Kawase T, Kochi M, Yoshida K, Kakeji Y, Ichikawa W, Chin K, Terashima M, Takeuchi M, Nakajima T; JACCRO. Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05). Ann Oncol. 2015 Sep;26(9):1916-22. Epub 2015 Jun 24. link to original article PubMed NCT00639327
JAVELIN Gastric 300: Bang YJ, Yanez Ruiz E, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, Al-Batran SE, Park SH, Lichinitser M, Boku N, Moehler MH, Hong J, Xiong H, Hallwachs R, Conti I, Taieb J. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018 Oct 1;29(10):2052-2060. link to original article link to PMC article contains dosing details in abstract PubMed NCT02625623
INTEGRATEIIb: NCT04879368

Irinotecan liposomal monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Roy et al. 2013 (PEP0206)	2008-2010	Randomized Phase 2 (E-switch-ic)	1. Docetaxel 2. Irinotecan	Did not meet primary endpoint of ORR

Chemotherapy

Irinotecan liposome (Onivyde) 120 mg/m² IV over 90 minutes once on day 1

21-day cycles

References

PEP0206: Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00813072

Irinotecan & Mitomycin

Regimen

Study	Dates of enrollment	Evidence
Bamias et al. 2003a	1999-07 to 2001-02	Phase 2

Note: Patients had advanced gastric and colorectal cancers.

Prior treatment criteria

5-fluorouracil-based chemotherapy

Chemotherapy

Irinotecan (Camptosar) 125 mg/m² IV once on day 1
Mitomycin (Mutamycin) 5 mg/m² IV once on day 1

14-day cycles

References

Bamias A, Papamichael D, Syrigos K, Pavlidis N. Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother. 2003 Jun;15(3):275-81. link to original article contains dosing details in abstract PubMed

Nivolumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Janjigian et al. 2018 (CheckMate 032_UGI)	2013-2015	Phase 1/2
Kang et al. 2017 (ATTRACTION-2)	2014-2016	Phase 3 (E-esc)	Placebo	Superior OS¹ (primary endpoint) Median OS: 5.3 vs 4.1 mo (HR 0.62, 95% CI 0.50-0.75)

¹Reported efficacy for ATTRACTION-2 is based on the 2021 update.
Note: ATTRACTION-2 included patients with GE junction malignancy (82.6% gastric, 8.5% GE junction) and 12.3% of patients had a PD-L1 CPS score of at least 1

Immunotherapy

Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycles

References

ATTRACTION-2: Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. link to original article contains dosing details in manuscript PubMed NCT02267343
1. Subgroup analysis: Kato K, Satoh T, Muro K, Yoshikawa T, Tamura T, Hamamoto Y, Chin K, Minashi K, Tsuda M, Yamaguchi K, Machida N, Esaki T, Goto M, Komatsu Y, Nakajima TE, Sugimoto N, Yoshida K, Oki E, Nishina T, Tsuji A, Fujii H, Kunieda K, Saitoh S, Omuro Y, Azuma M, Iwamoto Y, Taku K, Fushida S, Chen LT, Kang YK, Boku N. A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2). Gastric Cancer. 2019 Mar;22(2):344-354. Epub 2018 Dec 1. link to original article link to original article PubMed
2. Update: Chen LT, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Sameshima H, Kang YK, Boku N. A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data. Gastric Cancer. 2020 May;23(3):510-519. Epub 2019 Dec 20. link to original article link to PMC article PubMed
3. Update: Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Nishiyama T, Chen LT, Kang YK. Nivolumab in previously treated advanced gastric cancer (ATTRACTION-2): 3-year update and outcome of treatment beyond progression with nivolumab. Gastric Cancer. 2021 Jul;24(4):946-958. Epub 2021 Mar 20. link to original article link to PMC article PubMed
CheckMate 032_UGI: Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, de Braud F, Chau I, Harbison CT, Dorange C, Tschaika M, Le DT. CheckMate 032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol. 2018 Oct 1;36(28):2836-2844. Epub 2018 Aug 15. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01928394

Paclitaxel monotherapy

Regimen variant #1, 70 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2018 (KCSG ST10-01)	2011-2015	Phase 3 (C)	Irinotecan	Inconclusive whether non-inferior PFS

Chemotherapy

Paclitaxel (Taxol) 70 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 80 mg/m² weekly

Study	Dates of enrollment	Evidence
Kodera et al. 2007 (CCOG0302)	2003-2006	Phase 2

Chemotherapy

Paclitaxel (Taxol) 80 mg/m² IV once on day 1

7-day cycles

Regimen variant #3, 80 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hironaka et al. 2006	2002-2004	Non-randomized
Hironaka et al. 2013 (WJOG 4007)	2007-2010	Phase 3 (E-switch-ic)	Irinotecan	Did not meet primary endpoint of OS Median OS: 9.5 vs 8.4 mo (HR 0.88, 95% CI 0.67-1.16)
Wilke et al. 2014 (RAINBOW)	2010-2012	Phase 3 (C)	Paclitaxel & Ramucirumab	Seems to have inferior OS
Lorenzen et al. 2020 (RADPAC)	2011-2015	Phase 3 (C)	Everolimus & Paclitaxel	Did not meet primary endpoint of OS
Shitara et al. 2017 (ABSOLUTE)	2013-2015	Phase 3 (C)	1. nab-Paclitaxel weekly	Non-inferior OS
Shitara et al. 2017 (ABSOLUTE)	2013-2015	Phase 3 (C)	2. nab-Paclitaxel q3wk	Might have superior OS
Bang et al. 2017 (GOLD)	2013-2016	Phase 3 (C)	Olaparib & Paclitaxel	Might have inferior OS
Shitara et al. 2018 (KEYNOTE-061)	2015-06-04 to 2016-07-26	Phase 3 (C)	Pembrolizumab	Seems to have inferior OS¹
Bang et al. 2018 (JAVELIN Gastric 300)	2015-2017	Phase 3 (C)	Avelumab	Did not meet primary endpoint of OS
Chung et al. 2021 (KEYNOTE-063)	2017-02-16 to 2018-03-12	Phase 3 (C)	Pembrolizumab	Seems to have superior PFS (co-primary endpoint) Median PFS: 4 vs 2 mo (HR 0.62, 95% CI 0.40-0.96) Did not meet co-primary endpoint of OS
Xu et al. 2021 (RAINBOW-Asia)	2017-2020	Phase 3 (C)	Paclitaxel & Ramucirumab	Seems to have inferior PFS

¹Reported efficacy is based on the 2021 update, for the CPS at least 1 group.
Note: RAINBOW included patients with GE junction malignancy (79% gastric, 21% GE junction). Satoh et al. patients had 98.5% gastric, 1.5% other. WJOG 4007 had 3.7% patients with a PFS of 2.

Prior treatment criteria

RAINBOW: documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline

Chemotherapy

Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15

28-day cycles

Regimen variant #4, 175 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kang et al. 2018 (DREAM)	2013-2015	Phase 3 (C)	DHP-107	Non-inferior PFS

Chemotherapy

Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycles

References

Hironaka S, Zenda S, Boku N, Fukutomi A, Yoshino T, Onozawa Y. Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer. 2006;9(1):14-8. link to original article contains dosing details in manuscript PubMed
CCOG0302: Kodera Y, Ito S, Mochizuki Y, Fujitake S, Koshikawa K, Kanyama Y, Matsui T, Kojima H, Takase T, Ohashi N, Fujiwara M, Sakamoto J, Akimasa N; Chubu Clinical Cancer Group. A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric cancer (CCOG0302 study). Anticancer Res. 2007 Jul-Aug;27(4C):2667-71. link to original article contains dosing details in abstract PubMed
WJOG 4007: Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. link to original artile contains dosing details in abstract PubMed UMIN000001252
RAINBOW: Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. Epub 2014 Sep 17. link to original article contains dosing details in manuscript PubMed NCT01170663
1. PRO analysis: Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim TY, Cunningham D, Rougier P, Muro K, Liepa AM, Chandrawansa K, Emig M, Ohtsu A, Wilke H. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016 Apr;27(4):673-9. Epub 2016 Jan 7. link to original article link to PMC article PubMed
ABSOLUTE: Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. Epub 2017 Jan 19. link to original article contains dosing details in abstract PubMed JapicCTI-132059
GOLD: Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, Shen L, Qin S, Xu N, Im SA, Locker G, Rowe P, Shi X, Hodgson D, Liu YZ, Boku N. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1637-1651. Epub 2017 Nov 2. link to original article PubMed NCT01924533
DREAM: Kang YK, Ryu MH, Park SH, Kim JG, Kim JW, Cho SH, Park YI, Park SR, Rha SY, Kang MJ, Cho JY, Kang SY, Roh SY, Ryoo BY, Nam BH, Jo YW, Yoon KE, Oh SC. Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus IV paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann Oncol. 2018 May 1;29(5):1220-1226. link to original article contains dosing details in abstract PubMed NCT01839773
KEYNOTE-061: Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo MD, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. Epub 2018 Jun 4. link to original article contains dosing details in manuscript PubMed NCT02370498
1. Update: Fuchs CS, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Van Cutsem E, Elme A, Thuss-Patience P, Chau I, Ohtsu A, Bhagia P, Wang A, Shih CS, Shitara K. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2022 Jan;25(1):197-206. Epub 2021 Sep 1. link to original article link to PMC article PubMed
KCSG ST10-01: Lee KW, Maeng CH, Kim TY, Zang DY, Kim YH, Hwang IG, Oh SC, Chung JS, Song HS, Kim JW, Jeong SJ, Cho JY. A phase III study to compare the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer who failed in first-line therapy (KCSG ST10-01). Oncologist. 2019 Jan;24(1):18-e24. Epub 2018 Aug 20. link to original article contains dosing details in abstract link to PMC article PubMed NCT01224652
JAVELIN Gastric 300: Bang YJ, Yanez Ruiz E, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, Al-Batran SE, Park SH, Lichinitser M, Boku N, Moehler MH, Hong J, Xiong H, Hallwachs R, Conti I, Taieb J. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018 Oct 1;29(10):2052-2060. link to original article link to PMC article contains dosing details in abstract PubMed NCT02625623
RADPAC: Lorenzen S, Knorrenschild JR, Pauligk C, Hegewisch-Becker S, Seraphin J, Thuss-Patience P, Kopp HG, Dechow T, Vogel A, Luley KB, Pink D, Stahl M, Kullmann F, Hebart H, Siveke J, Egger M, Homann N, Probst S, Goetze TO, Al-Batran SE. Phase III randomized, double-blind study of paclitaxel with and without everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC). Int J Cancer. 2020 Nov 1;147(9):2493-2502. Epub 2020 May 7. link to original article contains dosing details in abstract PubMed NCT01248403
RAINBOW-Asia: Xu RH, Zhang Y, Pan H, Feng J, Zhang T, Liu T, Qin Y, Qin S, Yin X, Liu B, Ba Y, Yang N, Voon PJ, Tanasanvimon S, Zhou C, Zhang WL, Shen L. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Dec;6(12):1015-1024. Epub 2021 Oct 6. link to original article contains dosing details in abstract PubMed NCT02898077
KEYNOTE-063: Chung HC, Kang YK, Chen Z, Bai Y, Wan Ishak WZ, Shim BY, Park YL, Koo DH, Lu J, Xu J, Chon HJ, Bai LY, Zeng S, Yuan Y, Chen YY, Gu K, Zhong WY, Kuang S, Shih CS, Qin SK. Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients. Cancer. 2022 Mar 1;128(5):995-1003. Epub 2021 Dec 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03019588
INTEGRATEIIb: NCT04879368

nab-Paclitaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shitara et al. 2017 (ABSOLUTE)	2013-2015	Phase 3 (E-switch-ic)	1. Paclitaxel; weekly	Non-inferior OS (primary endpoint) Median OS: 11.1 vs 10.9 mo (HR 0.97, 97.5% CI 0.76-1.23)
Shitara et al. 2017 (ABSOLUTE)	2013-2015	Phase 3 (E-switch-ic)	2. nab-Paclitaxel; q3wk	Not reported

Chemotherapy

Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

ABSOLUTE: Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. Epub 2017 Jan 19. link to original article contains dosing details in abstract PubMed JapicCTI-132059

Paclitaxel & Ramucirumab

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wilke et al. 2014 (RAINBOW)	2010-2012	Phase 3 (E-RT-esc)	Paclitaxel	Seems to have superior OS (primary endpoint) Median OS: 9.6 vs 7.4 mo (HR 0.81, 95% CI 0.68-0.96)
Xu et al. 2021 (RAINBOW-Asia)	2017-2020	Phase 3 (E-esc)	Paclitaxel	Seems to have superior PFS (co-primary endpoint) Median PFS: 4.1 vs 3.15 mo (HR 0.77, 95% CI 0.61-0.955)

Note: RAINBOW included patients with GE junction malignancy (79% gastric, 21% GE junction).

Prior treatment criteria

RAINBOW: documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline

Targeted therapy

Ramucirumab (Cyramza) 8 mg/kg IV over 60 minutes once per day on days 1 & 15, given first

Chemotherapy

Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, given second

28-day cycles

References

RAINBOW: Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. Epub 2014 Sep 17. link to original article contains dosing details in manuscript PubMed NCT01170663
1. PRO analysis: Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim TY, Cunningham D, Rougier P, Muro K, Liepa AM, Chandrawansa K, Emig M, Ohtsu A, Wilke H. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016 Apr;27(4):673-9. Epub 2016 Jan 7. link to original article link to PMC article PubMed
RAINBOW-Asia: Xu RH, Zhang Y, Pan H, Feng J, Zhang T, Liu T, Qin Y, Qin S, Yin X, Liu B, Ba Y, Yang N, Voon PJ, Tanasanvimon S, Zhou C, Zhang WL, Shen L. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Dec;6(12):1015-1024. Epub 2021 Oct 6. link to original article contains dosing details in abstract PubMed NCT02898077
RAMIRIS: NCT03081143

Pembrolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fuchs et al. 2018 (KEYNOTE-059)	2015-03-02 to 2016-05-26	Phase 2 (RT)		ORR: 12% (95% CI 8-16)
Shitara et al. 2018 (KEYNOTE-061)	2015-06-04 to 2016-07-26	Phase 3 (E-switch-ooc)	Paclitaxel	Seems to have superior OS¹ (co-primary endpoint) Median OS: 9.1 vs 8.3 mo (HR 0.81, 95% CI 0.66-1.00)

¹Reported efficacy is based on the 2021 update, for the CPS at least 1 group.

Note: Both studies included patients with GE junction malignancy:

KEYNOTE-059: 48.3% gastric, 51.4% GE junction and 57.1% of patients had a PD-L1 CPS score of at least 1
KEYNOTE-061: 68.8% gastric, 31.2% GE junction and 66% of all patients receiving pembrolizumab had a PD-L1 CPS score of at least 1

Biomarker eligibility criteria

PD-L1 (combined positive score > 1%) as determined by an FDA-approved test.

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles (2 years)

References

KEYNOTE-059: Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018 May 10;4(5):e180013. Epub 2018 May 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02335411
KEYNOTE-061: Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo MD, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. Epub 2018 Jun 4. link to original article contains dosing details in manuscript PubMed NCT02370498
1. Update: Fuchs CS, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Van Cutsem E, Elme A, Thuss-Patience P, Chau I, Ohtsu A, Bhagia P, Wang A, Shih CS, Shitara K. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2022 Jan;25(1):197-206. Epub 2021 Sep 1. link to original article link to PMC article PubMed

Ramucirumab monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fuchs et al. 2013 (REGARD)	2009-2012	Phase 3 (E-RT-esc)	Placebo	Seems to have superior OS (primary endpoint) Median OS: 5.2 vs 3.8 mo (HR 0.78, 95% CI 0.60-0.998)

Note: this study included patients with GE junction malignancy (75% gastric, 25% GE junction).

Prior treatment criteria

REGARD: Disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment

Targeted therapy

Ramucirumab (Cyramza) 8 mg/kg IV over 60 minutes once on day 1

14-day cycles

References

REGARD: Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3. link to original article contains dosing details in manuscript PubMed NCT00917384

Regorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pavlakis et al. 2016 (INTEGRATE)	2012-2014	Randomized Phase 2 (E-esc)	Placebo	Superior PFS (primary endpoint) Median PFS: 2.6 vs 0.9 mo (HR 0.40, 95% CI 0.28-0.59)

Note: INTEGRATE included patients with GEJ malignancy: 62% stomach or other, 38% GEJ

Targeted therapy

Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21

28-day cycles

References

INTEGRATE: Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, Bang YJ, Alcindor T, O'Callaghan CJ, Burnell MJ, Tebbutt NC, Rha SY, Lee J, Cho JY, Lipton LR, Wong M, Strickland A, Kim JW, Zalcberg JR, Simes J, Goldstein D. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II trial. J Clin Oncol. 2016 Aug 10;34(23):2728-35. Epub 2016 Jun 20. link to original article contains dosing details in manuscript link to PMC article PubMed ANZCTR12612000239864

Trifluridine and tipiracil monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shitara et al. 2018 (TAGS)	2016-2018	Phase 3 (E-RT-esc)	Placebo	Superior OS (primary endpoint) Median OS: 5.7 vs 3.6 mo (HR 0.69, 95% CI 0.56-0.85)

Chemotherapy

Trifluridine and tipiracil (Lonsurf) 35 mg/m² PO twice per day on days 1 to 5, 8 to 12

28-day cycles

References

TAGS: Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov 1;19(11):1437-48. Epub 2018 Oct 18. link to original article contains dosing details in abstract PubMed NCT02500043
INTEGRATEIIb: NCT04879368

@@ Line 14: / Line 14: @@
 {{TOC limit|limit=3}}
 =Guidelines=
-'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any article published 5+ years ago to be for historical purposes, only.'''
+'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
 ==[http://www.esmo.org/ ESMO]==
 *'''2022:''' Lordick et al. [https://doi.org/10.1016/j.annonc.2022.07.004 Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/35914639/ PubMed]
@@ Line 30: / Line 30: @@
 ==French Intergroup==
 *'''2018:''' Zaanan et al. [https://doi.org/10.1016/j.dld.2018.04.025 Gastric cancer: French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO)] [https://pubmed.ncbi.nlm.nih.gov/29886081/ PubMed]
-==[https://www.nccn.org/ NCCN]==
+==NCCN==
-*[https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf NCCN Guidelines - Gastric Cancer]
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434 NCCN Guidelines - Gastric Cancer]
+**'''2022:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2022.0008 Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/35130500/ PubMed]
-*'''2022:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2022.0008 Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/35130500/ PubMed]
+**'''2016:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2016.0137 Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/27697982/ PubMed]
-*'''2016:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2016.0137 Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/27697982/ PubMed]
+**'''2013:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2013.0070 Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines.] [https://pubmed.ncbi.nlm.nih.gov/23667204/ PubMed]
-*'''2013:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2013.0070 Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines.] [https://pubmed.ncbi.nlm.nih.gov/23667204/ PubMed]
+**'''2010:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2010.0030 Gastric cancer.] [https://pubmed.ncbi.nlm.nih.gov/20410333/ PubMed]
-*'''2010:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2010.0030 Gastric cancer.] [https://pubmed.ncbi.nlm.nih.gov/20410333/ PubMed]
+**'''2006:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2006.0030 Gastric Cancer Clinical Practice Guidelines.] [https://pubmed.ncbi.nlm.nih.gov/16569388/ PubMed]
-*'''2006:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2006.0030 Gastric Cancer Clinical Practice Guidelines.] [https://pubmed.ncbi.nlm.nih.gov/16569388/ PubMed]
+**'''2003:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2003.0005 Gastric cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19764148/ PubMed]
-*'''2003:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2003.0005 Gastric cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19764148/ PubMed]
 =Perioperative therapy=
@@ Line 56: / Line 55: @@
 |2017-ongoing
 | style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Pembrolizumab_666|Perioperative CX & Pembrolizumab]]<br>2. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab_666|Perioperative CF & Pembrolizumab]]<br>3. [[#FLOT_.26_Pembrolizumab_666|FLOT & Pembrolizumab]]
+|1a. Perioperative [[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Pembrolizumab_666| CX & Pembrolizumab]]<br>1b. Perioperative [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab_666|CF & Pembrolizumab]]<br>1c. Perioperative [[#FLOT_.26_Pembrolizumab_666|FLOT & Pembrolizumab]]
 | style="background-color:#d3d3d3" |To be determined
 |-
@@ Line 99: / Line 98: @@
 |2017-ongoing
 | style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Pembrolizumab_666|Perioperative CX & Pembrolizumab]]<br>2. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab_666|Perioperative CF & Pembrolizumab]]<br>3. [[#FLOT_.26_Pembrolizumab_666|FLOT & Pembrolizumab]]
+|1a. Perioperative [[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Pembrolizumab_666| CX & Pembrolizumab]]<br>1b. Perioperative [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab_666|CF & Pembrolizumab]]<br>1c. Perioperative [[#FLOT_.26_Pembrolizumab_666|FLOT & Pembrolizumab]]
 | style="background-color:#d3d3d3" |To be determined
 |-
@@ Line 150: / Line 149: @@
 ===References===
-#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P; FNCLCC; FFCD. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. [https://doi.org/10.1200/jco.2010.33.0597 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21444866/ PubMed] [https://clinicaltrials.gov/study/NCT00002883 NCT00002883]
+#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P; FNCLCC; FFCD. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. [https://doi.org/10.1200/jco.2010.33.0597 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21444866/ PubMed] [https://clinicaltrials.gov/study/NCT00002883 NCT00002883]
 #'''KEYNOTE-585:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03221426 NCT03221426]
 ==ECF {{#subobject:f0281c|Regimen=1}}==
@@ Line 192: / Line 191: @@
 *[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 *[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
 ====Supportive therapy====
 *MAGIC, suggested as thrombosis prophylaxis:
@@ Line 212: / Line 211: @@
 *[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 *[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
 ====Supportive therapy====
 *MAGIC, suggested as thrombosis prophylaxis:
@@ Line 395: / Line 394: @@
 |2017-ongoing
 | style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Pembrolizumab_666|Perioperative CX & Pembrolizumab]]<br>2. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab_666|Perioperative CF & Pembrolizumab]]<br>3. [[#FLOT_.26_Pembrolizumab_666|FLOT & Pembrolizumab]]
+|1a. Perioperative [[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Pembrolizumab_666| CX & Pembrolizumab]]<br>1b. Perioperative [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab_666|CF & Pembrolizumab]]<br>1c. Perioperative [[#FLOT_.26_Pembrolizumab_666|FLOT & Pembrolizumab]]
 | style="background-color:#d3d3d3" |To be determined
 |-
@@ Line 437: / Line 436: @@
 |2010-2015
 | style="background-color:#1a9851" |Phase 2/3 (E-switch-ic)
-|1a. [[#ECF|Perioperative ECF]]<br>1b. [[#ECX|Perioperative ECX]]
+|1a. Perioperative [[#ECF|ECF]]<br>1b. Perioperative [[#ECX|ECX]]
 | style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 50 vs 35 mo<br>(HR 0.77, 95% CI 0.63-0.94)
 |-
@@ Line 465: / Line 464: @@
 #'''MATTERHORN:''' [https://clinicaltrials.gov/study/NCT04592913 NCT04592913]
 #'''RAMSES:''' [https://clinicaltrials.gov/study/NCT02661971 NCT02661971]
-==SOX {{#subobject:ecig8a|Regimen=1}}==
+==mFOLFOX6 {{#subobject:nvig8a|Regimen=1}}==
-SOX: '''<u>S</u>'''-1 & '''<u>OX</u>'''aliplatin
+mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 <div class="toccolours" style="background-color:#c8a2c8">
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
@@ Line 477: / Line 476: @@
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8886520/ Yu et al. 2022 (FOCUS<sub>gastric</sub>)]
 |2011-2016
-|style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|style="background-color:#1a9851" |Phase 3 (C)
-|[[#mFOLFOX6_888|Perioperative mFOLFOX6]]
+|Perioperative [[#SOX|SOX]]
-| style="background-color:#eeee01" |Non-inferior OS36 (primary endpoint)<br>OS36: 75.2% vs 67.8%
+| style="background-color:#eeee01" |Non-inferior OS36 (primary endpoint)<br>OS36: 67.8% vs 75.2%
 |-
 |}
 <div class="toccolours" style="background-color:#eeeeee">
-===Neoadjuvant {{#subobject:5guz13|Variant=1}}===
+===Neoadjuvant {{#subobject:5h28c3|Variant=1}}===
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
 '''21-day cycle for 2 to 4 cycles, followed by:'''
 </div></div><br>
@@ Line 504: / Line 501: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
 '''21-day cycle for 2 to 4 cycles'''
 </div></div></div>
 ===References===
-#'''RESOLVE<sub>gastric</sub>:''' Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, Wang X, Wu A, Li G, Su X, Xiao G, Cui M, Wu D, Chen L, Wu X, Zhou Y, Zhang L, Dang C, He Y, Zhang Z, Sun Y, Li Y, Chen H, Bai Y, Qi C, Yu P, Zhu G, Suo J, Jia B, Li L, Huang C, Li F, Ye Y, Xu H, Wang X, Yuan Y, E JY, Ying X, Yao C, Shen L, Ji J; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021 Aug;22(8):1081-1092. Epub 2021 Jul 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. [https://doi.org/10.1016/s1470-2045(21)00297-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34252374/ PubMed] [https://clinicaltrials.gov/study/NCT01534546 NCT01534546]
 #'''FOCUS<sub>gastric</sub>:''' Yu J, Gao Y, Chen L, Wu D, Shen Q, Zhao Z, Liu W, Yang H, Zhang Q, Wang X, Hu P, Zheng Z, Wang X, Liu H, Xu Z, Yan Z, Wu Y, Jin M, Zhang Q, Liu X, Zhu K, Shou C. Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2022 Feb 1;5(2):e220426. [https://doi.org/10.1001/jamanetworkopen.2022.0426 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8886520/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35226081/ PubMed] [https://clinicaltrials.gov/study/NCT01364376 NCT01364376]
+==SOX {{#subobject:ecig8a|Regimen=1}}==
-=Neoadjuvant chemotherapy=
+SOX: '''<u>S</u>'''-1 & '''<u>OX</u>'''aliplatin
-==DOS {{#subobject:a2ug18|Regimen=1}}==
+<div class="toccolours" style="background-color:#c8a2c8">
-DOS: '''<u>D</u>'''ocetaxel, '''<u>O</u>'''xaliplatin, '''<u>S</u>'''-1
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:gu1503|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
@@ Line 527: / Line 518: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425847/ Kang et al. 2021 (PRODIGY)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8886520/ Yu et al. 2022 (FOCUS<sub>gastric</sub>)]
-|2012-2017
+|2011-2016
-| style="background-color:#1a9851" |Phase 3 (E-esc)
+|style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[Gastric_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
+|Perioperative [[#mFOLFOX6|mFOLFOX6]]
-| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>PFS36: 66% vs 60%<br>(aHR 0.70, 95% CI 0.52-0.95)
+| style="background-color:#eeee01" |Non-inferior OS36 (primary endpoint)<br>OS36: 75.2% vs 67.8%
+|-
+|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc11003079/ Wang et al. 2024 (RESONANCE)]
+|2012-09-01 to 2019-07-01
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|Adjuvant [[#SOX_2|SOX]]
+| style="background-color:#91cf60" |Seems to have superior DFS36 (primary endpoint)<br>DFS36: 61.7% vs 53.8%
 |-
 |}
+<div class="toccolours" style="background-color:#eeeeee">
+===Neoadjuvant {{#subobject:5guz13|Variant=1}}===
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
-*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+**Between 1.25 m<sup>2</sup> and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
-'''21-day cycle for 3 cycles'''
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
-</div>
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-<div class="toccolours" style="background-color:#cbd5e7">
+'''21-day cycle for 2 to 4 cycles, followed by:'''
-====Subsequent treatment====
+</div></div><br>
-*[[Surgery#Gastrectomy|Surgery]], then adjuvant [[#S-1_monotherapy|S-1]]
+<div class="toccolours" style="background-color:#eeeeee">
-</div></div>
+===Definitive===
-===References===
+<div class="toccolours" style="background-color:#b3e2cd">
-#'''PRODIGY:''' Kang YK, Yook JH, Park YK, Lee JS, Kim YW, Kim JY, Ryu MH, Rha SY, Chung IJ, Kim IH, Oh SC, Park YS, Son T, Jung MR, Heo MH, Kim HK, Park C, Yoo CH, Choi JH, Zang DY, Jang YJ, Sul JY, Kim JG, Kim BS, Beom SH, Cho SH, Ryu SW, Kook MC, Ryoo BY, Kim HK, Yoo MW, Lee NS, Lee SH, Kim G, Lee Y, Lee JH, Noh SH. PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer. J Clin Oncol. 2021 Sep 10;39(26):2903-2913. Epub 2021 Jun 16. [https://doi.org/10.1200/jco.20.02914 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425847/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34133211/ PubMed] [https://clinicaltrials.gov/study/NCT01515748 NCT01515748]
+====Local therapy====
-==ECF {{#subobject:f0281c|Regimen=1}}==
+*[[Surgery#Gastrectomy|Gastrectomy]] with at least D2 dissection
-ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+</div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:66f602|Variant=1}}===
+===Adjuvant===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.clinicaltrials.gov/study/NCT01924819 Awaiting publication (TOPGEAR)]
-|2009-ongoing
-| style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#ECF.2FFluorouracil_.26_RT_666|ECF/5-FU & RT]]<br>1b. [[#ECX.2FCapecitabine_.26_RT|ECX/Capecitabine & RT]]<br>1c. [[#EOX.2FCapecitabine_.26_RT|EOX/Capecitabine & RT]]<br>1d. [[#FLOT.2FCapecitabine_.26_RT|FLOT/Capecitabine & RT]]
-|TBD if different primary endpoint of OS
-|-
-|}
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+**Between 1.25 m<sup>2</sup> and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
-'''21-day cycle for 3 cycles'''
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
-</div></div>
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+'''21-day cycle for 2 to 4 cycles'''
+</div></div></div>
 ===References===
-#'''TOPGEAR:''' [https://clinicaltrials.gov/study/NCT01924819 NCT01924819]
+#'''RESOLVE<sub>gastric</sub>:''' Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, Wang X, Wu A, Li G, Su X, Xiao G, Cui M, Wu D, Chen L, Wu X, Zhou Y, Zhang L, Dang C, He Y, Zhang Z, Sun Y, Li Y, Chen H, Bai Y, Qi C, Yu P, Zhu G, Suo J, Jia B, Li L, Huang C, Li F, Ye Y, Xu H, Wang X, Yuan Y, E JY, Ying X, Yao C, Shen L, Ji J; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021 Aug;22(8):1081-1092. Epub 2021 Jul 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. [https://doi.org/10.1016/s1470-2045(21)00297-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34252374/ PubMed] [https://clinicaltrials.gov/study/NCT01534546 NCT01534546]
-=Adjuvant therapy=
+#'''FOCUS<sub>gastric</sub>:''' Yu J, Gao Y, Chen L, Wu D, Shen Q, Zhao Z, Liu W, Yang H, Zhang Q, Wang X, Hu P, Zheng Z, Wang X, Liu H, Xu Z, Yan Z, Wu Y, Jin M, Zhang Q, Liu X, Zhu K, Shou C. Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2022 Feb 1;5(2):e220426. [https://doi.org/10.1001/jamanetworkopen.2022.0426 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8886520/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35226081/ PubMed] [https://clinicaltrials.gov/study/NCT01364376 NCT01364376]
-==CapeOx {{#subobject:cf9acc|Regimen=1}}==
+#'''RESONANCE:''' Wang X, Lu C, Wei B, Li S, Li Z, Xue Y, Ye Y, Zhang Z, Sun Y, Liang H, Li K, Zhu L, Zheng Z, Zhou Y, He Y, Li F, Wang X, Liang P, Huang H, Li G, Shen X, Ji J, Tang Y, Xu Z, Chen L; RESONANCE study group. Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial. J Hematol Oncol. 2024 Apr 8;17(1):17. [https://doi.org/10.1186/s13045-024-01536-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc11003079/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/38589926/ PubMed] [https://clinicaltrials.gov/study/NCT01583361 NCT01583361]
-CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin
+=Neoadjuvant chemotherapy=
+==DOS {{#subobject:a2ug18|Regimen=1}}==
+DOS: '''<u>D</u>'''ocetaxel, '''<u>O</u>'''xaliplatin, '''<u>S</u>'''-1
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1ef938|Variant=1}}===
+===Regimen {{#subobject:gu1503|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
@@ Line 586: / Line 577: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S0140-6736(11)61873-4 Bang et al. 2012 (CLASSIC)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425847/ Kang et al. 2021 (PRODIGY)]
-|2006-2009
+|2012-2017
 | style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Gastric_cancer_-_null_regimens#Observation|Surgery alone]]
+|[[Gastric_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
-| style="background-color:#1a9850" |Superior DFS36 (primary endpoint)<br>DFS36: 74% vs 59%<br>(HR 0.56, 95% CI 0.44-0.72)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS60: 78% vs 69%<br>(HR 0.66, 95% CI 0.51-0.85)
+| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>PFS36: 66% vs 60%<br>(aHR 0.70, 95% CI 0.52-0.95)
-|-
-|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00297-7 Zhang et al. 2021 (RESOLVE<sub>gastric</sub>)]
-|rowspan=2|2012-2017
-|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#SOX|Perioperative SOX]]
-| style="background-color:#fc8d59" |Seems to have inferior DFS36
-|-
-|2. [[#SOX_2|Adjuvant SOX]]
-| style="background-color:#eeee01" |Non-inferior DFS36
 |-
 |}
-''<sup>1</sup>Reported efficacy for CLASSIC is based on the 2014 update.''<br>
-''Note: RESOLVE should not be confused for the trial by the same name in pancreatic cancer.''
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*[[Surgery#Gastrectomy|Gastrectomy]] with D2 dissection
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 8 cycles'''
+*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+'''21-day cycle for 3 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Gastrectomy|Surgery]], then adjuvant [[#S-1_monotherapy|S-1]]
 </div></div>
 ===References===
-#'''CLASSIC:''' Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH; CLASSIC trial investigators. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012 Jan 28;379(9813):315-21. Epub 2012 Jan 7. [https://doi.org/10.1016/S0140-6736(11)61873-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22226517/ PubMed] [https://clinicaltrials.gov/study/NCT00411229 NCT00411229]
+#'''PRODIGY:''' Kang YK, Yook JH, Park YK, Lee JS, Kim YW, Kim JY, Ryu MH, Rha SY, Chung IJ, Kim IH, Oh SC, Park YS, Son T, Jung MR, Heo MH, Kim HK, Park C, Yoo CH, Choi JH, Zang DY, Jang YJ, Sul JY, Kim JG, Kim BS, Beom SH, Cho SH, Ryu SW, Kook MC, Ryoo BY, Kim HK, Yoo MW, Lee NS, Lee SH, Kim G, Lee Y, Lee JH, Noh SH. PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer. J Clin Oncol. 2021 Sep 10;39(26):2903-2913. Epub 2021 Jun 16. [https://doi.org/10.1200/jco.20.02914 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425847/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34133211/ PubMed] [https://clinicaltrials.gov/study/NCT01515748 NCT01515748]
-##'''Update:''' Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W, Lee JI, Shin DB, Ji J, Chen JS, Lim Y, Ha S, Bang YJ; CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1389-96. Epub 2014 Oct 15. [https://doi.org/10.1016/S1470-2045(14)70473-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25439693/ PubMed]
+==ECF {{#subobject:f0281c|Regimen=1}}==
-#'''RESOLVE<sub>gastric</sub>:''' Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, Wang X, Wu A, Li G, Su X, Xiao G, Cui M, Wu D, Chen L, Wu X, Zhou Y, Zhang L, Dang C, He Y, Zhang Z, Sun Y, Li Y, Chen H, Bai Y, Qi C, Yu P, Zhu G, Suo J, Jia B, Li L, Huang C, Li F, Ye Y, Xu H, Wang X, Yuan Y, E JY, Ying X, Yao C, Shen L, Ji J; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021 Aug;22(8):1081-1092. Epub 2021 Jul 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. [https://doi.org/10.1016/s1470-2045(21)00297-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34252374/ PubMed] [https://clinicaltrials.gov/study/NCT01534546 NCT01534546]
+ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-==Carboplatin & Docetaxel {{#subobject:7263b8|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:cd8hbq|Variant=1}}===
+===Regimen {{#subobject:66f602|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 628: / Line 608: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1007/s00280-010-1256-6 Bamias et al. 2010]
+|[https://www.clinicaltrials.gov/study/NCT01924819 Awaiting publication (TOPGEAR)]
-|2002-2005
+|2009-ongoing
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Carboplatin.2C_Docetaxel.2C_RT_999|Carboplatin, Docetaxel, RT]]
+|1a. [[#ECF.2FFluorouracil_.26_RT_666|ECF/5-FU & RT]]<br>1b. [[#ECX.2FCapecitabine_.26_RT|ECX/Capecitabine & RT]]<br>1c. [[#EOX.2FCapecitabine_.26_RT|EOX/Capecitabine & RT]]<br>1d. [[#FLOT.2FCapecitabine_.26_RT|FLOT/Capecitabine & RT]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of OS
 |-
 |}
-''Note: the original protocol was for cisplatin & docetaxel but was changed due to excess CINV. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*[[Surgery#Gastrectomy|Surgery]]
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
-*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 6 cycles'''
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+'''21-day cycle for 3 cycles'''
 </div></div>
 ===References===
-#Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, Samantas E, Christodoulou Ch, Pentheroudakis G, Pectasides D, Dimopoulos MA, Fountzilas G. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol. 2010 May;65(6):1009-21. Epub 2010 Feb 4. [https://doi.org/10.1007/s00280-010-1256-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20130877/ PubMed]
+#'''TOPGEAR:''' [https://clinicaltrials.gov/study/NCT01924819 NCT01924819]
-==Capecitabine & Cisplatin (CX) {{#subobject:4896bc|Regimen=1}}==
+=Adjuvant therapy=
-CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+==CapeOx {{#subobject:cf9acc|Regimen=1}}==
-<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)
+CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:877085|Variant=1}}===
+===Regimen {{#subobject:1ef938|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 660: / Line 637: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2011.39.1953 Lee et al. 2011 (ARTIST<sub>gastric</sub>)]
+|[https://doi.org/10.1016/S0140-6736(11)61873-4 Bang et al. 2012 (CLASSIC)]
-|2004-2008
+|2006-2009
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[#Capecitabine_.26_Cisplatin_.28CX.29_2|XP]], then [[#Radiation_therapy_888|RT]], then [[#Capecitabine_.26_Cisplatin_.28CX.29_2|XP]]
+|[[Gastric_cancer_-_null_regimens#Observation|Surgery alone]]
-| style="background-color:#fee08b" |Might have inferior DFS
+| style="background-color:#1a9850" |Superior DFS36 (primary endpoint)<br>DFS36: 74% vs 59%<br>(HR 0.56, 95% CI 0.44-0.72)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS60: 78% vs 69%<br>(HR 0.66, 95% CI 0.51-0.85)
 |-
-|}
+|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00297-7 Zhang et al. 2021 (RESOLVE<sub>gastric</sub>)]
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This trial should not be confused for the one by the same name in colorectal cancer.''
+|rowspan=2|2012-2017
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
+|1. Perioperative [[#SOX|SOX]]
+| style="background-color:#fc8d59" |Seems to have inferior DFS36
+|-
+|2. Adjuvant [[#SOX_2|SOX]]
+| style="background-color:#eeee01" |Non-inferior DFS36
+|-
+|}
+''<sup>1</sup>Reported efficacy for CLASSIC is based on the 2014 update.''<br>
+''Note: RESOLVE should not be confused for the trial by the same name in pancreatic cancer.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*R0 [[Surgery#Gastrectomy|gastrectomy]] and at least D2 dissection
+*[[Surgery#Gastrectomy|Gastrectomy]] with D2 dissection
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycle for 6 cycles'''
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycle for 8 cycles'''
 </div></div>
 ===References===
-#'''ARTIST:''' Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, Lim HY, Choi MG, Sohn TS, Noh JH, Bae JM, Ahn YC, Sohn I, Jung SH, Park CK, Kim KM, Kang WK. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012 Jan 20;30(3):268-73. Epub 2011 Dec 19. [https://doi.org/10.1200/jco.2011.39.1953 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22184384/ PubMed] [https://clinicaltrials.gov/study/NCT00323830 NCT00323830]
+#'''CLASSIC:''' Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH; CLASSIC trial investigators. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012 Jan 28;379(9813):315-21. Epub 2012 Jan 7. [https://doi.org/10.1016/S0140-6736(11)61873-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22226517/ PubMed] [https://clinicaltrials.gov/study/NCT00411229 NCT00411229]
-##'''Update:''' Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, Sohn I, Jung SH, Choi MG, Lee JH, Bae JM, Kim S, Kim ST, Park JO, Park YS, Lim HY, Kang WK. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: Final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015 Oct 1;33(28):3130-6. Epub 2015 Jan 5. [https://doi.org/10.1200/jco.2014.58.3930 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25559811/ PubMed]
+##'''Update:''' Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W, Lee JI, Shin DB, Ji J, Chen JS, Lim Y, Ha S, Bang YJ; CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1389-96. Epub 2014 Oct 15. [https://doi.org/10.1016/S1470-2045(14)70473-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25439693/ PubMed]
-==Docetaxel & S-1 {{#subobject:a22c2a|Regimen=1}}==
+#'''RESOLVE<sub>gastric</sub>:''' Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, Wang X, Wu A, Li G, Su X, Xiao G, Cui M, Wu D, Chen L, Wu X, Zhou Y, Zhang L, Dang C, He Y, Zhang Z, Sun Y, Li Y, Chen H, Bai Y, Qi C, Yu P, Zhu G, Suo J, Jia B, Li L, Huang C, Li F, Ye Y, Xu H, Wang X, Yuan Y, E JY, Ying X, Yao C, Shen L, Ji J; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021 Aug;22(8):1081-1092. Epub 2021 Jul 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. [https://doi.org/10.1016/s1470-2045(21)00297-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34252374/ PubMed] [https://clinicaltrials.gov/study/NCT01534546 NCT01534546]
-DS: '''<u>D</u>'''ocetaxel & '''<u>S</u>'''-1
+==Carboplatin & Docetaxel {{#subobject:7263b8|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:82ca03|Variant=1}}===
+===Regimen {{#subobject:cd8hbq|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
@@ Line 692: / Line 679: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6333977/ Lee et al. 2018 (POST)]
+|[https://doi.org/10.1007/s00280-010-1256-6 Bamias et al. 2010]
-|2010-2013
+|2002-2005
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_S-1_888|SP]]
+|[[#Carboplatin_.26_Docetaxel_.28DCb.29_.26_RT_999|DCb & RT]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
 |}
+''Note: the original protocol was for cisplatin & docetaxel but was changed due to excess CINV. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
@@ Line 704: / Line 693: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8
+*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
-*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] 35 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 8 cycles'''
+'''21-day cycle for 6 cycles'''
-</div></div><br>
+</div></div>
+===References===
+#Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, Samantas E, Christodoulou Ch, Pentheroudakis G, Pectasides D, Dimopoulos MA, Fountzilas G. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol. 2010 May;65(6):1009-21. Epub 2010 Feb 4. [https://doi.org/10.1007/s00280-010-1256-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20130877/ PubMed]
+==Capecitabine & Cisplatin (CX) {{#subobject:4896bc|Regimen=1}}==
+CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2 {{#subobject:82ca03|Variant=1}}===
+===Regimen {{#subobject:877085|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
@@ Line 717: / Line 711: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6524985/ Yoshida et al. 2019 (JACCRO GC-07)]
+|[https://doi.org/10.1200/jco.2011.39.1953 Lee et al. 2011 (ARTIST<sub>gastric</sub>)]
-|2013-2017
+|2004-2008
-| style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#S-1 monotherapy_2|S-1]]
+|[[#Capecitabine_.26_Cisplatin_.28CX.29.2FCapecitabine_.26_RT_333|XP/Capecitabine & RT]]
-| style="background-color:#1a9850" |Superior RFS36 (primary endpoint)<br>RFS36: 66% vs 50%<br>(HR 0.632, 99.99% CI 0.40-0.998)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS36: 77.7% vs 71.2%<br>(HR 0.74, 95% CI 0.60-0.925)
+| style="background-color:#fee08b" |Might have inferior DFS
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2021 update.''
+''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This trial should not be confused for the one by the same name in colorectal cancer.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[Surgery#Gastrectomy|Surgery]]
+*R0 [[Surgery#Gastrectomy|gastrectomy]] and at least D2 dissection
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Docetaxel (Taxotere)]] as follows:
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
-**Cycles 1 to 7: 40 mg/m<sup>2</sup> IV once on day 1
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] as follows:
+'''21-day cycle for 6 cycles'''
-**Cycles 1 to 7: 80 to 120 mg/m<sup>2</sup> PO on days 1 to 14
-**Cycles 8 to 11: 80 to 120 mg/m<sup>2</sup> PO on days 1 to 28
-'''21-day course, then 42-day cycle for 10 cycles'''
 </div></div>
 ===References===
-#'''POST:''' Lee CK, Jung M, Kim HS, Jung I, Shin DB, Kang SY, Zang DY, Kim KH, Lee MH, Kim BS, Lee KH, Cheong JH, Hyung WJ, Noh SH, Chung HC, Rha SY. S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial. Cancer Res Treat. 2019 Jan;51(1):1-11. Epub 2018 Feb 5. [https://doi.org/10.4143/crt.2018.028 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6333977/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29397659/ PubMed] [https://clinicaltrials.gov/study/NCT01283217 NCT01283217]
+#'''ARTIST:''' Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, Lim HY, Choi MG, Sohn TS, Noh JH, Bae JM, Ahn YC, Sohn I, Jung SH, Park CK, Kim KM, Kang WK. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012 Jan 20;30(3):268-73. Epub 2011 Dec 19. [https://doi.org/10.1200/jco.2011.39.1953 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22184384/ PubMed] [https://clinicaltrials.gov/study/NCT00323830 NCT00323830]
-<!-- #'''Abstract:''' Kodera Y, Yoshida K, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Nakamura M, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matssuyama J, Yamada M, Ito Y, Takeuchi M, Fujii M; JACCRO. A randomized phase III study comparing S-1 plus docetaxel with S-1 alone as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer (JACCRO GC-07 trial). 2019 American Society of Clinical Oncology annual meeting. DOI: 10.1200/JCO.2018.36.15_suppl.4007 36, no. 15_suppl (May 20, 2018) 4007-4007. [https://doi.org/10.1200/JCO.2018.36.15_suppl.4007 link to abstract] -->
+##'''Update:''' Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, Sohn I, Jung SH, Choi MG, Lee JH, Bae JM, Kim S, Kim ST, Park JO, Park YS, Lim HY, Kang WK. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: Final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015 Oct 1;33(28):3130-6. Epub 2015 Jan 5. [https://doi.org/10.1200/jco.2014.58.3930 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25559811/ PubMed]
-#'''JACCRO GC-07:''' Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019 May 20;37(15):1296-1304. Epub 2019 Mar 29. [https://doi.org/10.1200/jco.18.01138 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6524985/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30925125/ PubMed] UMIN000010337
+==Cisplatin & S-1 {{#subobject:s3bc2a|Regimen=1}}==
-##'''Update:''' Kakeji Y, Yoshida K, Kodera Y, Kochi M, Sano T, Ichikawa W, Lee SW, Shibahara K, Shikano T, Kataoka M, Ishiguro A, Ojima H, Sakai Y, Musha N, Takase T, Kimura T, Takeuchi M, Fujii M. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer. 2022 Jan;25(1):188-196. Epub 2021 Aug 5. [https://doi.org/10.1007/s10120-021-01224-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34351555/ PubMed]
+SP: '''<u>S</u>'''-1 & '''<u>P</u>'''latinol (Cisplatin)
-==FP/Capecitabine & RT {{#subobject:778727|Regimen=1}}==
-FP/Capecitabine & RT: '''<u>F</u>'''luorouracil & '''<u>P</u>'''latinol (Cisplatin) alternating with Capecitabine & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:20ea7f|Variant=1}}===
+===Regimen {{#subobject:bc3203|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 20%" |Study
-!style="width: 33%"|Dates of enrollment
+! style="width: 20%" |Dates of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
+! style="width: 20%" |Comparator
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066094/ Lee et al. 2006]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|NR
-| style="background-color:#91cf61" |Phase 2
 |-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6333977/ Lee et al. 2018 (POST)]
+|2010-2013
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Docetaxel_.26_S-1|DS]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
 |}
-''Note: In contrast to the primary reference, some guidelines list this regimen without FP cycles 1, 3, 4, 5. Dosage of [[Capecitabine (Xeloda)]] was listed as 625 to 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5 or 1 to 7 while radiation is being given.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[Surgery#Gastrectomy|Surgery]], 3 weeks prior
+*[[Surgery#Gastrectomy|Surgery]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] as follows:
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
-**Cycles 1, 3, 4, 5: 60 mg/m<sup>2</sup> IV once on day 1
+*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] 35 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Fluorouracil (5-FU)]] as follows:
+'''21-day cycle for 8 cycles'''
-**Cycles 1, 3, 4, 5: 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m<sup>2</sup>)
-*[[Capecitabine (Xeloda)]] as follows:
-**Cycle 2 (chemoradiation): 825 mg/m<sup>2</sup> PO twice per day on days 1 to 35
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] during cycle 2: 1.8 Gy fractions x 25 fractions (total dose of 45 Gy)
-'''21-day course, then 9-week course, then 21-day cycle for 3 cycles'''
 </div></div>
 ===References===
-#Lee HS, Choi Y, Hur WJ, Kim HJ, Kwon HC, Kim SH, Kim JS, Lee JH, Jung GJ, Kim MC. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006 Jan 28;12(4):603-7. [http://www.wjgnet.com/1007-9327/full/v12/i4/603.htm link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/16489675/ PubMed]
+#'''POST:''' Lee CK, Jung M, Kim HS, Jung I, Shin DB, Kang SY, Zang DY, Kim KH, Lee MH, Kim BS, Lee KH, Cheong JH, Hyung WJ, Noh SH, Chung HC, Rha SY. S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial. Cancer Res Treat. 2019 Jan;51(1):1-11. Epub 2018 Feb 5. [https://doi.org/10.4143/crt.2018.028 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6333977/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29397659/ PubMed] [https://clinicaltrials.gov/study/NCT01283217 NCT01283217]
-==FULV {{#subobject:5bbh1e|Regimen=1}}==
+==Docetaxel & S-1 {{#subobject:a22c2a|Regimen=1}}==
-FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin
+DS: '''<u>D</u>'''ocetaxel & '''<u>S</u>'''-1
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1tzi01|Variant=1}}===
+===Regimen variant #1 {{#subobject:82ca03|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
@@ Line 787: / Line 772: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdu146 Bajetta et al. 2014 (ITACA-S)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6333977/ Lee et al. 2018 (POST)]
-|2005-2009
+|2010-2013
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#FOLFIRI_999|FOLFIRI]], then [[#Cisplatin_.26_Docetaxel_.28DC.29_999|Cisplatin & Docetaxel]]
+|[[#Cisplatin_.26_S-1|SP]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
-|-
 |}
 <div class="toccolours" style="background-color:#cbd5e8">
@@ Line 800: / Line 784: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
+*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Leucovorin (Folinic acid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
+*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] 35 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''14-day cycle for 9 cycles'''
+'''21-day cycle for 8 cycles'''
-</div></div>
+</div></div><br>
-===References===
-#'''ITACA-S:''' Bajetta E, Floriani I, Di Bartolomeo M, Labianca R, Falcone A, Di Costanzo F, Comella G, Amadori D, Pinto C, Carlomagno C, Nitti D, Daniele B, Mini E, Poli D, Santoro A, Mosconi S, Casaretti R, Boni C, Pinotti G, Bidoli P, Landi L, Rosati G, Ravaioli A, Cantore M, Di Fabio F, Aitini E, Marchet A; ITACA-S (Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach Trial) Study Group. Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol. 2014 Jul;25(7):1373-1378. Epub 2014 Apr 12. [https://doi.org/10.1093/annonc/mdu146 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24728035/ PubMed] [https://clinicaltrials.gov/study/NCT01640782 NCT01640782]
-==FULV & RT {{#subobject:2cd29|Regimen=1}}==
-FULV & RT: '''<u>F</u>'''luoro'''<u>U</u>'''racil, '''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:dfd3ec|Variant=1}}===
+===Regimen variant #2, 40/80 {{#subobject:82ca03|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
@@ Line 817: / Line 797: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6524985/ Yoshida et al. 2019 (JACCRO GC-07)]
-|1991-1998
+|2013-2017
 | style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Gastric_cancer_-_null_regimens#Observation|Surgery alone]]
+|[[#S-1 monotherapy_2|S-1]]
-| style="background-color:#1a9850" |Superior OS (primary endpoint)
+| style="background-color:#1a9850" |Superior RFS36 (primary endpoint)<br>RFS36: 66% vs 50%<br>(HR 0.632, 99.99% CI 0.40-0.998)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS36: 77.7% vs 71.2%<br>(HR 0.74, 95% CI 0.60-0.925)
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678342/ Fuchs et al. 2017 (CALGB 80101)]
+|}
-|2002-2009
+''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br>
-| style="background-color:#1a9851" |Phase 3 (C)
+''Note: this dosing was for BSA less than 1.25 mg/m<sup>2</sup>.''
-|[[#ECF.2FFULV_.26_RT_999|ECF/FULV & RT]]
+<div class="toccolours" style="background-color:#cbd5e8">
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+====Preceding treatment====
-|-
+*[[Surgery#Gastrectomy|Surgery]]
-|}
-''Treatment is to start 20 to 40 days after surgery.''
-''Note: Study included patients with GE junction malignancy as well (20% GE junction) and included patients with a performance status of 2.''
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*INT-0116: [[Surgery#Gastrectomy|Surgery]] with R0 resection (10% underwent D2 dissection, 36% underwent D1 dissection and 54% underwent D0 dissection)
-*CALGB 80101: [[Surgery#Gastrectomy|Surgery]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Fluorouracil (5-FU)]] as follows:
+*[[Docetaxel (Taxotere)]] as follows:
-**Cycles 1, 3, 4: 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**Cycles 2 to 7: 40 mg/m<sup>2</sup> IV once on day 1
-**Cycle 2 (chemoradiation): 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
+*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] as follows:
-*[[Leucovorin (Folinic acid)]] as follows:
+**Cycles 1 to 7: 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-**Cycles 1, 3, 4: 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**Cycles 8 to 12: 40 mg/m<sup>2</sup> PO twice per day on days 1 to 28
-**Cycle 2 (chemoradiation): 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
+'''21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)'''
-====Radiotherapy====
+</div></div><br>
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] during cycle 2: 180 cGy x 25 fractions (total of 45 Gy)
-'''28-day course, then 9-week course, then 28-day cycle for 2 cycles'''
-</div></div>
-===References===
-#'''INT-0116:''' Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [https://doi.org/10.1056/NEJMoa010187 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11547741/ PubMed]
-##'''Update:''' Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. [https://doi.org/10.1200/JCO.2011.36.7136 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517071/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22585691/ PubMed]
-#'''CALGB 80101:''' Fuchs CS, Niedzwiecki D, Mamon HJ, Tepper JE, Ye X, Swanson RS, Enzinger PC, Haller DG, Dragovich T, Alberts SR, Bjarnason GA, Willett CG, Gunderson LL, Goldberg RM, Venook AP, Ilson D, O'Reilly E, Ciombor K, Berg DJ, Meyerhardt J, Mayer RJ. Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance). J Clin Oncol. 2017 Nov 10;35(32):3671-3677. Epub 2017 Oct 4. [https://doi.org/10.1200/JCO.2017.74.2130 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678342/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28976791/ PubMed] [https://clinicaltrials.gov/study/NCT00052910 NCT00052910]
-==S-1 monotherapy {{#subobject:ec10ef|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 21-day cycles {{#subobject:5dbc53|Variant=1}}===
+===Regimen variant #3, 40/100 {{#subobject:821003|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
@@ Line 863: / Line 828: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1016/S1470-2045(14)70025-7 Tsuburaya et al. 2014 (SAMIT)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6524985/ Yoshida et al. 2019 (JACCRO GC-07)]
-| rowspan="2" |2004-2009
+|2013-2017
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|1. [[#Paclitaxel_monotherapy_999|Paclitaxel]], then [[#S-1_monotherapy|S-1]]<br>2. [[#Paclitaxel_monotherapy_999|Paclitaxel]], then [[#UFT_monotherapy_999|UFT]]
+|[[#S-1 monotherapy_2|S-1]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+| style="background-color:#1a9850" |Superior RFS36 (primary endpoint)<br>RFS36: 66% vs 50%<br>(HR 0.632, 99.99% CI 0.40-0.998)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS36: 77.7% vs 71.2%<br>(HR 0.74, 95% CI 0.60-0.925)
-|-
-|3. [[#UFT_monotherapy_999|UFT]]
-| style="background-color:#1a9850" |Superior DFS<br>DFS36: 58.2% vs 53%<br>(HR 0.81, 95% CI 0.70-0.93)
 |-
 |}
+''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br>
+''Note: this dosing was for BSA between 1.25 to 1.5 mg/m<sup>2</sup>.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*R0 or R1 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection, within 2 to 8 weeks
+*[[Surgery#Gastrectomy|Surgery]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] 80 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Docetaxel (Taxotere)]] as follows:
-'''21-day cycle for 16 cycles (1 year)'''
+**Cycles 2 to 7: 40 mg/m<sup>2</sup> IV once on day 1
+*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] as follows:
+**Cycles 1 to 7: 50 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+**Cycles 8 to 12: 50 mg/m<sup>2</sup> PO twice per day on days 1 to 28
+'''21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 42-day cycles {{#subobject:0ee98c|Variant=1}}===
+===Regimen variant #4, 40/120 {{#subobject:82ca2b|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
@@ Line 891: / Line 859: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa072252 Sakuramoto et al. 2007 (ACTS-GC)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6524985/ Yoshida et al. 2019 (JACCRO GC-07)]
-|2001-2004
+|2013-2017
 | style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Gastric_cancer_-_null_regimens#Observation|Observation]]
+|[[#S-1 monotherapy_2|S-1]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>OS60: 72% vs 61%<br>(HR 0.67, 95% CI 0.54-0.83)
+| style="background-color:#1a9850" |Superior RFS36 (primary endpoint)<br>RFS36: 66% vs 50%<br>(HR 0.632, 99.99% CI 0.40-0.998)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS36: 77.7% vs 71.2%<br>(HR 0.74, 95% CI 0.60-0.925)
-|-
-|[https://doi.org/10.1016/S2468-1253(18)30383-2 Yoshikawa et al. 2019 (OPAS-1)]
-|2012-2017
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#S-1_monotherapy|S-1]] x 6 mo
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS
-|-
-|rowspan=2|[https://doi.org/10.1016/j.annonc.2020.11.017 Park et al. 2020 (ARTIST 2)]
-|rowspan=2|2013-2018
-|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#SOX|SOX]]
-| style="background-color:#fc8d59" |Seems to have inferior DFS
-|-
-|2. [[#SOX_.26_RT_888|SOXRT]]
-| style="background-color:#fee08b" |Might have inferior DFS
 |-
 |}
-''<sup>1</sup>Reported efficacy for ACTS-GC is based on the 2011 update.''
+''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br>
+''Note: this dosing was for BSA greater than 1.5 mg/m<sup>2</sup>.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*R0 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection, within 6 weeks
+*[[Surgery#Gastrectomy|Surgery]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+*[[Docetaxel (Taxotere)]] as follows:
-**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28
+**Cycles 2 to 7: 40 mg/m<sup>2</sup> IV once on day 1
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28
+*[[Tegafur, gimeracil, oteracil (S-1)|S-1]] as follows:
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28
+**Cycles 1 to 7: 60 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''42-day cycle for 8 cycles (1 year)'''
+**Cycles 8 to 12: 60 mg/m<sup>2</sup> PO twice per day on days 1 to 28
+'''21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)'''
 </div></div>
 ===References===
-#'''ACTS-GC:''' Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007 Nov 1;357(18):1810-20. Erratum in: N Engl J Med. 2008 May 1;358(18):1977. [https://doi.org/10.1056/NEJMoa072252 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17978289/ PubMed] [https://clinicaltrials.gov/study/NCT00152217 NCT00152217]
+#'''POST:''' Lee CK, Jung M, Kim HS, Jung I, Shin DB, Kang SY, Zang DY, Kim KH, Lee MH, Kim BS, Lee KH, Cheong JH, Hyung WJ, Noh SH, Chung HC, Rha SY. S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial. Cancer Res Treat. 2019 Jan;51(1):1-11. Epub 2018 Feb 5. [https://doi.org/10.4143/crt.2018.028 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6333977/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29397659/ PubMed] [https://clinicaltrials.gov/study/NCT01283217 NCT01283217]
-##'''Update:''' Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. [https://doi.org/10.1200/JCO.2011.36.5908 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22010012/ PubMed]
+<!-- #'''Abstract:''' Kodera Y, Yoshida K, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Nakamura M, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matssuyama J, Yamada M, Ito Y, Takeuchi M, Fujii M; JACCRO. A randomized phase III study comparing S-1 plus docetaxel with S-1 alone as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer (JACCRO GC-07 trial). 2019 American Society of Clinical Oncology annual meeting. DOI: 10.1200/JCO.2018.36.15_suppl.4007 36, no. 15_suppl (May 20, 2018) 4007-4007. [https://doi.org/10.1200/JCO.2018.36.15_suppl.4007 link to abstract] -->
-#'''SAMIT:''' Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. [https://doi.org/10.1016/S1470-2045(14)70025-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24954805/ PubMed] UMIN C000000082
+#'''JACCRO GC-07:''' Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019 May 20;37(15):1296-1304. Epub 2019 Mar 29. [https://doi.org/10.1200/jco.18.01138 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6524985/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30925125/ PubMed] UMIN000010337
-#'''OPAS-1:''' Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Fukushima N, Hato S, Choda Y, Yabusaki H, Yoshida K, Ito S, Takeno A, Yasuda T, Kawachi Y, Katayama H, Fukuda H, Boku N, Sano T, Sasako M. Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104[OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial. Lancet Gastroenterol Hepatol. 2019 Mar;4(3):208-216. Epub 2019 Jan 22. Erratum in: Lancet Gastroenterol Hepatol. 2019 Apr;4(4):e3. [https://doi.org/10.1016/S2468-1253(18)30383-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30679107/ PubMed] UMIN000007306
-#'''JACCRO GC-07:''' Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019 May 20;37(15):1296-1304. Epub 2019 Mar 29. [https://doi.org/10.1200/jco.18.01138 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6524985/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30925125/ PubMed] UMIN000010337
 ##'''Update:''' Kakeji Y, Yoshida K, Kodera Y, Kochi M, Sano T, Ichikawa W, Lee SW, Shibahara K, Shikano T, Kataoka M, Ishiguro A, Ojima H, Sakai Y, Musha N, Takase T, Kimura T, Takeuchi M, Fujii M. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer. 2022 Jan;25(1):188-196. Epub 2021 Aug 5. [https://doi.org/10.1007/s10120-021-01224-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34351555/ PubMed]
-#'''ARTIST 2:''' Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH, Shin DB, Yu JI, Kim KM, An JY, Choi MG, Lee JH, Kim S, Hong JY, Park JO, Park YS, Lim HY, Bae JM, Kang WK; ARTIST 2 investigators. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021 Mar;32(3):368-374. Epub 2020 Dec 3. [https://doi.org/10.1016/j.annonc.2020.11.017 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33278599/ PubMed] [https://clinicaltrials.gov/study/NCT01761461 NCT01761461]
-#'''HKIT-GC:''' [https://clinicaltrials.gov/study/NCT00216034 NCT00216034]
+==FP/Capecitabine & RT {{#subobject:778727|Regimen=1}}==
-==SOX {{#subobject:ecig8a|Regimen=1}}==
+FP/Capecitabine & RT: '''<u>F</u>'''luorouracil & '''<u>P</u>'''latinol (Cisplatin) alternating with Capecitabine & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:5guz13|Variant=1}}===
+===Regimen {{#subobject:20ea7f|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 20%" |Study
+!style="width: 33%"|Study
-! style="width: 20%" |Dates of enrollment
+!style="width: 33%"|Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[https://doi.org/10.1016/j.annonc.2020.11.017 Park et al. 2020 (ARTIST 2)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066094/ Lee et al. 2006]
-|rowspan=2|2013-2018
+|NR
-|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#91cf61" |Phase 2
-|1. [[#S-1_monotherapy|S-1]]
-| style="background-color:#91cf60" |Seems to have superior DFS (primary endpoint)<br>DFS36: 74.3% vs 64.8%<br>(HR 0.69, 95% CI 0.41-0.99)
 |-
-|2. [[#SOX_.26_RT_888|SOXRT]]
+|}
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+''Note: In contrast to the primary reference, some guidelines list this regimen without FP cycles 1, 3, 4, 5. Dosage of [[Capecitabine (Xeloda)]] was listed as 625 to 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5 or 1 to 7 while radiation is being given.''
-|-
-|}
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*R0 or R1 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection
+*[[Surgery#Gastrectomy|Surgery]], 3 weeks prior
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+*[[Cisplatin (Platinol)]] as follows:
-**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
+**Cycles 1, 3, 4, 5: 60 mg/m<sup>2</sup> IV once on day 1
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
+*[[Fluorouracil (5-FU)]] as follows:
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
+**Cycles 1, 3, 4, 5: 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Capecitabine (Xeloda)]] as follows:
-'''21-day cycle for up to 8 cycles (6 months)'''
+**Cycle 2 (chemoradiation): 825 mg/m<sup>2</sup> PO twice per day on days 1 to 35
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] during cycle 2: 180 cGy fractions x 25 fractions (total dose of 4500 cGy)
+'''21-day course, then 9-week course, then 21-day cycle for 3 cycles'''
 </div></div>
 ===References===
-#'''ARTIST 2:''' Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH, Shin DB, Yu JI, Kim KM, An JY, Choi MG, Lee JH, Kim S, Hong JY, Park JO, Park YS, Lim HY, Bae JM, Kang WK; ARTIST 2 investigators. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021 Mar;32(3):368-374. Epub 2020 Dec 3. [https://doi.org/10.1016/j.annonc.2020.11.017 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33278599/ PubMed] [https://clinicaltrials.gov/study/NCT01761461 NCT01761461]
+#Lee HS, Choi Y, Hur WJ, Kim HJ, Kwon HC, Kim SH, Kim JS, Lee JH, Jung GJ, Kim MC. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006 Jan 28;12(4):603-7. [http://www.wjgnet.com/1007-9327/full/v12/i4/603.htm link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/16489675/ PubMed]
-#'''TOTTG030103:''' Zhao Q, Lian C, Huo Z, Li M, Liu Y, Fan L, Tan B, Zhao X, Zhang Z, Wang D, Liu Y, Guo H, Yang P, Tian Y, Li Y. The efficacy and safety of neoadjuvant chemotherapy on patients with advanced gastric cancer: A multicenter randomized clinical trial. Cancer Med. 2020 Aug;9(16):5731-5745. Epub 2020 Jun 24. [https://doi.org/10.1002/cam4.3224 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7433829/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32583567/ PubMed] [https://clinicaltrials.gov/study/NCT01516944 NCT01516944]
+==FULV {{#subobject:5bbh1e|Regimen=1}}==
+FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin
-=Metastatic or locally advanced disease, first-line=
-==Capecitabine monotherapy {{#subobject:a9eb0b|Regimen=1}}==
-X: '''<u>X</u>'''eloda (Capecitabine)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 2000 mg/m<sup>2</sup>/day {{#subobject:b6ba4c|Variant=1}}===
+===Regimen {{#subobject:1tzi01|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 984: / Line 931: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/j.jgo.2017.01.002 Hwang et al. 2017 (SMC 2010-04-118)]
+|[https://doi.org/10.1093/annonc/mdu146 Bajetta et al. 2014 (ITACA-S)]
-|2010-2014
+|2005-2009
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#CapeOx_2|XELOX]]
+|[[#FOLFIRI_999|FOLFIRI]], then [[#Cisplatin_.26_Docetaxel_.28DC.29_999|Cisplatin & Docetaxel]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://doi.org/10.4143/crt.2023.333 Lee et al. 2023 (KCSG ST13-10)]
+|}
-|2014-02 to 2019-01
+<div class="toccolours" style="background-color:#cbd5e8">
-|style="background-color:#1a9851" |Phase 3 (C)
+====Preceding treatment====
-|1a. [[#mFOLFOX6|mFOLFOX6]]<br>1b. [[#CapeOx_2|CapeOx]]<br>1c. [[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br>1d. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
+*[[Surgery#Gastrectomy|Surgery]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
-<div class="toccolours" style="background-color:#fdcdac">
-====Eligibility criteria====
-*KCSG ST13-10: CrCl at least 60 mL/min
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
-'''21-day cycles'''
+*[[Leucovorin (Folinic acid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
-</div></div><br>
+'''14-day cycle for 9 cycles'''
+</div></div>
+===References===
+#'''ITACA-S:''' Bajetta E, Floriani I, Di Bartolomeo M, Labianca R, Falcone A, Di Costanzo F, Comella G, Amadori D, Pinto C, Carlomagno C, Nitti D, Daniele B, Mini E, Poli D, Santoro A, Mosconi S, Casaretti R, Boni C, Pinotti G, Bidoli P, Landi L, Rosati G, Ravaioli A, Cantore M, Di Fabio F, Aitini E, Marchet A; ITACA-S (Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach Trial) Study Group. Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol. 2014 Jul;25(7):1373-1378. Epub 2014 Apr 12. [https://doi.org/10.1093/annonc/mdu146 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24728035/ PubMed] [https://clinicaltrials.gov/study/NCT01640782 NCT01640782]
+==FULV/FULV & RT {{#subobject:2cd29|Regimen=1}}==
+FULV/FULV & RT: '''<u>F</u>'''luoro'''<u>U</u>'''racil & '''<u>L</u>'''euco'''<u>V</u>'''orin alternating with '''<u>F</u>'''luoro'''<u>U</u>'''racil, '''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 2500 mg/m<sup>2</sup>/day {{#subobject:b6ba4c|Variant=1}}===
+===Regimen {{#subobject:dfd3ec|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 20%" |Study
-!style="width: 33%"|Dates of enrollment
+! style="width: 20%" |Dates of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdh343 Hong et al. 2004]
+|[https://doi.org/10.1056/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]
-|NR
+|1991-1998
-| style="background-color:#91cf61" |Phase 2
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Gastric_cancer_-_null_regimens#Observation|Surgery alone]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678342/ Fuchs et al. 2017 (CALGB 80101)]
+|2002-2009
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#ECF.2FFULV_.26_RT_999|ECF/FULV & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-<div class="toccolours" style="background-color:#fdcdac">
+''Treatment is to start 20 to 40 days after surgery.''
-====Eligibility criteria====
+''Note: Study included patients with GE junction malignancy as well (20% GE junction) and included patients with a performance status of 2.''
-*Karnofsky status of at least 70%
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*INT-0116: [[Surgery#Gastrectomy|Surgery]] with R0 resection (10% underwent D2 dissection, 36% underwent D1 dissection and 54% underwent D0 dissection)
+*CALGB 80101: [[Surgery#Gastrectomy|Surgery]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Fluorouracil (5-FU)]] as follows:
-'''21-day cycle for up to 6 cycles'''
+**Cycles 1, 3, 4: 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**Cycle 2 (chemoradiation): 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
+*[[Leucovorin (Folinic acid)]] as follows:
+**Cycles 1, 3, 4: 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**Cycle 2 (chemoradiation): 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] during cycle 2: 180 cGy x 25 fractions (total of 4500 cGy)
+'''28-day course, then 9-week course, then 28-day cycle for 2 cycles'''
 </div></div>
 ===References===
-#Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep;15(9):1344-7. [https://doi.org/10.1093/annonc/mdh343 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15319239/ PubMed]
+#'''INT-0116:''' Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [https://doi.org/10.1056/NEJMoa010187 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11547741/ PubMed]
-#'''SMC 2010-04-118:''' Hwang IG, Ji JH, Kang JH, Lee HR, Lee HY, Chi KC, Park SW, Lee SJ, Kim ST, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017 May;8(3):170-175. Epub 2017 Jan 21. [https://doi.org/10.1016/j.jgo.2017.01.002 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28119041/ PubMed] [https://clinicaltrials.gov/study/NCT01470742 NCT01470742]
+##'''Update:''' Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. [https://doi.org/10.1200/JCO.2011.36.7136 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517071/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22585691/ PubMed]
-#'''KCSG ST13-10:''' Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS. A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10). Cancer Res Treat. 2022 Oct;55(4):1250-1260. Epub 2023 May 25. [https://doi.org/10.4143/crt.2023.333 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37232070/ PubMed] [https://clinicaltrials.gov/study/NCT02114359 NCT02114359]
+#'''CALGB 80101:''' Fuchs CS, Niedzwiecki D, Mamon HJ, Tepper JE, Ye X, Swanson RS, Enzinger PC, Haller DG, Dragovich T, Alberts SR, Bjarnason GA, Willett CG, Gunderson LL, Goldberg RM, Venook AP, Ilson D, O'Reilly E, Ciombor K, Berg DJ, Meyerhardt J, Mayer RJ. Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance). J Clin Oncol. 2017 Nov 10;35(32):3671-3677. Epub 2017 Oct 4. [https://doi.org/10.1200/JCO.2017.74.2130 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678342/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28976791/ PubMed] [https://clinicaltrials.gov/study/NCT00052910 NCT00052910]
-==Capecitabine & Cisplatin (CX) {{#subobject:2bd34d|Regimen=1}}==
-CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+==S-1 monotherapy {{#subobject:ec10ef|Regimen=1}}==
-<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:82b184|Variant=1}}===
+===Regimen variant #1, 21-day cycles {{#subobject:5dbc53|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,044: / Line 1,008: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdn717 Kang et al. 2009 (ML17032)]
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(14)70025-7 Tsuburaya et al. 2014 (SAMIT)]
-|2003-2005
+| rowspan="2" |2004-2009
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+|1. [[#Paclitaxel_monotherapy_999|Paclitaxel]], then [[#S-1_monotherapy|S-1]]<br>2. [[#Paclitaxel_monotherapy_999|Paclitaxel]], then [[#UFT_monotherapy|UFT]]
-| style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>Median PFS: 5.6 vs 5 mo<br>(HR 0.81, 95% CI 0.63-1.04)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://doi.org/10.1200/JCO.2011.36.2236 Ohtsu et al. 2011 (AVAGAST)]
+|3. [[#UFT_monotherapy|UFT]]
-|2007-09 to 2008-12
+| style="background-color:#1a9850" |Superior DFS<br>DFS36: 58.2% vs 53%<br>(HR 0.81, 95% CI 0.70-0.93)
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Stub#Capecitabine_.26_Cisplatin_.28CX.29_.26_Bevacizumab|CX & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://doi.org/10.1016/S1470-2045(13)70102-5 Lordick et al. 2013 (EXPAND)]
+|}
-|2008-2010
+<div class="toccolours" style="background-color:#cbd5e8">
-| style="background-color:#1a9851" |Phase 3 (C)
+====Preceding treatment====
-|[[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Cetuximab_999|CX & Cetuximab]]
+*R0 or R1 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection, within 2 to 8 weeks
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Tegafur, gimeracil, oteracil (S-1)]] 80 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+'''21-day cycle for 16 cycles (1 year)'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 42-day cycles {{#subobject:0ee98c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544634/ Shen et al. 2014 (AVATAR)]
+|[https://doi.org/10.1056/NEJMoa072252 Sakuramoto et al. 2007 (ACTS-GC)]
-|2009-03-25 to 2010-07-12
+|2001-2004
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Stub#Capecitabine_.26_Cisplatin_.28CX.29_.26_Bevacizumab|CX & Bevacizumab]]
+|[[Gastric_cancer_-_null_regimens#Observation|Observation]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>OS60: 72% vs 61%<br>(HR 0.67, 95% CI 0.54-0.83)
 |-
-|[https://doi.org/10.1016/j.ejca.2014.08.005 Kim et al. 2014 (SMC 2008-12-019)]
+|[https://doi.org/10.1016/S2468-1253(18)30383-2 Yoshikawa et al. 2019 (OPAS-1)]
-|2009-2012
+|2012-2017
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Simvastatin_999|CX & Simvastatin]]
+|[[#S-1_monotherapy|S-1]] x 6 mo
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097104/ Lu et al. 2018 (PAC-C)]
+|rowspan=2|[https://doi.org/10.1016/j.annonc.2020.11.017 Park et al. 2020 (ARTIST 2)]
-|2009-2014
+|rowspan=2|2013-2018
-| style="background-color:#1a9851" |Phase 3 (C)
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
-|[[#Capecitabine_.26_Paclitaxel_999|Capecitabine & Paclitaxel]]
+|1. [[#SOX|SOX]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+| style="background-color:#fc8d59" |Seems to have inferior DFS
 |-
-|[https://doi.org/10.1016/S1470-2045(18)30791-5 Fuchs et al. 2019 (RAINFALL)]
+|2. [[#SOX_.26_RT_333|SOXRT]]
-|2015-01-28 to 2016-09-16
+| style="background-color:#fee08b" |Might have inferior DFS
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Stub#Capecitabine_.26_Cisplatin_.28CX.29_.26_Ramucirumab|CX & Ramucirumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>1</sup>
 |-
 |}
-''<sup>1</sup>while the primary analysis of RAINFALL showed that this arm seemed to have inferior PFS, independent central review did not confirm this finding.''<br>
+''<sup>1</sup>Reported efficacy for ACTS-GC is based on the 2011 update.''
-The following studies included patients with GE junction malignancy as well:
+<div class="toccolours" style="background-color:#fdcdac">
-*''AVAGAST patients: 86% gastric and 14% GE junction. 5.4% of patients had an ECOG PS of 2.''
+====Eligibility criteria====
-*''EXPAND patients: 83% gastric, 5% GE junction and 16% unknown''
+*ACTS-GC & ARTIST 2: Stage II or III gastric cancer
-*''SMC 2008-12-019 patients: 79% gastric, 16% GE junction and 5% unknown''
+*OPAS-1: Stage II gastric cancer
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*R0 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection, within 6 weeks
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28
-**EXPAND: 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
+**Between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28
-====Supportive therapy====
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28
-*Some protocols: [[:Category:Hydration|"Hyperhydration"]] for cisplatin
+'''42-day cycle for 8 cycles (1 year)'''
-'''21-day cycles, varied duration (see below)'''
-</div>
-<div class="toccolours" style="background-color:#cbd5e7">
-====Subsequent treatment====
-*AVAGAST & AVATAR: after 6 cycles, [[#Capecitabine_monotherapy_2|capecitabine]] maintenance
-*SMC 2008-12-019: after 8 cycles, [[#Capecitabine_monotherapy_2|capecitabine]] maintenance
 </div></div>
 ===References===
-#'''ML17032:''' Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [https://doi.org/10.1093/annonc/mdn717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19153121/ PubMed] content property of [http://hemonc.org HemOnc.org] [https://clinicaltrials.gov/study/NCT02563054 NCT02563054]
+#'''ACTS-GC:''' Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007 Nov 1;357(18):1810-20. Erratum in: N Engl J Med. 2008 May 1;358(18):1977. [https://doi.org/10.1056/NEJMoa072252 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17978289/ PubMed] [https://clinicaltrials.gov/study/NCT00152217 NCT00152217]
-#'''AVAGAST:''' Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://doi.org/10.1200/JCO.2011.36.2236 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21844504/ PubMed] [https://clinicaltrials.gov/study/NCT00548548 NCT00548548]
+##'''Update:''' Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. [https://doi.org/10.1200/JCO.2011.36.5908 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22010012/ PubMed]
-#'''EXPAND:''' Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. [https://doi.org/10.1016/S1470-2045(13)70102-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23594786/ PubMed] [https://clinicaltrials.gov/study/NCT00678535 NCT00678535]
+#'''SAMIT:''' Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. [https://doi.org/10.1016/S1470-2045(14)70025-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24954805/ PubMed] UMIN C000000082
-#'''AVATAR:''' Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, Xu R, Chen L, Liu Y, Yu S, Bu L, Piao Y. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015 Jan;18(1):168-76. Epub 2014 Feb 21. [https://doi.org/10.1007/s10120-014-0351-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544634/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24557418/ PubMed] [https://clinicaltrials.gov/study/NCT00887822 NCT00887822]
+#'''OPAS-1:''' Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Fukushima N, Hato S, Choda Y, Yabusaki H, Yoshida K, Ito S, Takeno A, Yasuda T, Kawachi Y, Katayama H, Fukuda H, Boku N, Sano T, Sasako M. Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104[OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial. Lancet Gastroenterol Hepatol. 2019 Mar;4(3):208-216. Epub 2019 Jan 22. Erratum in: Lancet Gastroenterol Hepatol. 2019 Apr;4(4):e3. [https://doi.org/10.1016/S2468-1253(18)30383-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30679107/ PubMed] UMIN000007306
-#'''SMC 2008-12-019:''' Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. [https://doi.org/10.1016/j.ejca.2014.08.005 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25218337/ PubMed] [https://clinicaltrials.gov/study/NCT01099085 NCT01099085]
+##'''Update:''' Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Nomura T, Hato S, Choda Y, Yabusaki H, Yoshida K, Misawa K, Masuzawa T, Tsuda M, Kawachi Y, Katayama H, Fukuda H, Kurokawa Y, Boku N, Sano T, Sasako M. 5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer. Gastric Cancer. 2024 Jan;27(1):155-163. Epub 2023 Nov 21. [https://doi.org/10.1007/s10120-023-01447-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37989806/ PubMed]
-#'''PAC-C:''' Lu Z, Zhang X, Liu W, Liu T, Hu B, Li W, Fan Q, Xu J, Xu N, Bai Y, Pan Y, Xu Q, Bai W, Xia L, Gao Y, Wang W, Shu Y, Shen L. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018 Sep;21(5):782-791. Epub 2018 Feb 27. [https://doi.org/10.1007/s10120-018-0809-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097104/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29488121/ PubMed] [https://clinicaltrials.gov/study/NCT01015339 NCT01015339]
+#'''JACCRO GC-07:''' Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019 May 20;37(15):1296-1304. Epub 2019 Mar 29. [https://doi.org/10.1200/jco.18.01138 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6524985/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30925125/ PubMed] UMIN000010337
-#'''RAINFALL:''' Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):420-435. Epub 2019 Feb 1. Erratum in: Lancet Oncol. 2019 May;20(5):e242. [https://doi.org/10.1016/S1470-2045(18)30791-5 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30718072/ PubMed] [https://clinicaltrials.gov/study/NCT02314117 NCT02314117]
+##'''Update:''' Kakeji Y, Yoshida K, Kodera Y, Kochi M, Sano T, Ichikawa W, Lee SW, Shibahara K, Shikano T, Kataoka M, Ishiguro A, Ojima H, Sakai Y, Musha N, Takase T, Kimura T, Takeuchi M, Fujii M. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer. 2022 Jan;25(1):188-196. Epub 2021 Aug 5. [https://doi.org/10.1007/s10120-021-01224-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34351555/ PubMed]
+#'''ARTIST 2:''' Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH, Shin DB, Yu JI, Kim KM, An JY, Choi MG, Lee JH, Kim S, Hong JY, Park JO, Park YS, Lim HY, Bae JM, Kang WK; ARTIST 2 investigators. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021 Mar;32(3):368-374. Epub 2020 Dec 3. [https://doi.org/10.1016/j.annonc.2020.11.017 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33278599/ PubMed] [https://clinicaltrials.gov/study/NCT01761461 NCT01761461]
+#'''HKIT-GC:''' [https://clinicaltrials.gov/study/NCT00216034 NCT00216034]
-==Capecitabine & Cisplatin (CX) & Pembrolizumab {{#subobject:ahg7ab|Regimen=1}}==
+==SOX {{#subobject:ecig8a|Regimen=1}}==
-CX & Pembrolizumab: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), Pembrolizumab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1yt34c|Variant=1}}===
+===Regimen {{#subobject:5guz13|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,126: / Line 1,098: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ Shitara et al. 2020 (KEYNOTE-062)]
+|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc11003079/ Wang et al. 2024 (RESONANCE)]
-|rowspan=2|2015-2017
+|2012-09-01 to 2019-07-01
+| style="background-color:#1a9851" |Phase 3 (C)
+|Perioperative [[#SOX|SOX]]
+| style="background-color:#fc8d59" |Seems to have inferior DFS36
+|-
+|rowspan=2|[https://doi.org/10.1016/j.annonc.2020.11.017 Park et al. 2020 (ARTIST 2)]
+|rowspan=2|2013-2018
 |rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
-|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]<br>1b. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
+|1. [[#S-1_monotherapy|S-1]]
-| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 12.5 vs 11.1 mo<br>(HR 0.85, 95% CI 0.70-1.03)
+| style="background-color:#91cf60" |Seems to have superior DFS (primary endpoint)<br>DFS36: 74.3% vs 64.8%<br>(HR 0.69, 95% CI 0.41-0.99)
+|-
+|2. [[#SOX_.26_RT_888|SOXRT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|2. [[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d3d3d3" |Not reported
 |}
-''<sup>1</sup>Reported efficacy is for patients with CPS of 1 or greater.''<br>
+<div class="toccolours" style="background-color:#cbd5e8">
-''Note: KEYNOTE-062 included patients with GEJ malignancy.''
+====Preceding treatment====
-<div class="toccolours" style="background-color:#fdcdac">
+*R0 or R1 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection
-====Biomarker eligibility criteria====
-PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
-====Immunotherapy====
+**Between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
-'''21-day cycles'''
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+'''21-day cycle for up to 8 cycles (6 months)'''
 </div></div>
 ===References===
-<!-- #'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://doi.org/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract] -->
+#'''ARTIST 2:''' Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH, Shin DB, Yu JI, Kim KM, An JY, Choi MG, Lee JH, Kim S, Hong JY, Park JO, Park YS, Lim HY, Bae JM, Kang WK; ARTIST 2 investigators. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021 Mar;32(3):368-374. Epub 2020 Dec 3. [https://doi.org/10.1016/j.annonc.2020.11.017 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33278599/ PubMed] [https://clinicaltrials.gov/study/NCT01761461 NCT01761461]
-#'''KEYNOTE-062:''' Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. [https://doi.org/10.1001/jamaoncol.2020.3370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32880601/ PubMed] [https://clinicaltrials.gov/study/NCT02494583 NCT02494583]
+#'''TOTTG030103:''' Zhao Q, Lian C, Huo Z, Li M, Liu Y, Fan L, Tan B, Zhao X, Zhang Z, Wang D, Liu Y, Guo H, Yang P, Tian Y, Li Y. The efficacy and safety of neoadjuvant chemotherapy on patients with advanced gastric cancer: A multicenter randomized clinical trial. Cancer Med. 2020 Aug;9(16):5731-5745. Epub 2020 Jun 24. [https://doi.org/10.1002/cam4.3224 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7433829/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32583567/ PubMed] [https://clinicaltrials.gov/study/NCT01516944 NCT01516944]
-==CapeOx {{#subobject:4e3bb4|Regimen=1}}==
+#'''RESONANCE:''' Wang X, Lu C, Wei B, Li S, Li Z, Xue Y, Ye Y, Zhang Z, Sun Y, Liang H, Li K, Zhu L, Zheng Z, Zhou Y, He Y, Li F, Wang X, Liang P, Huang H, Li G, Shen X, Ji J, Tang Y, Xu Z, Chen L; RESONANCE study group. Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial. J Hematol Oncol. 2024 Apr 8;17(1):17. [https://doi.org/10.1186/s13045-024-01536-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc11003079/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/38589926/ PubMed] [https://clinicaltrials.gov/study/NCT01583361 NCT01583361]
-CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin
+==UFT monotherapy {{#subobject:ecufef|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 750/78 {{#subobject:4faj81|Variant=1}}===
+===Regimen {{#subobject:5dufuf|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 20%" |Study
-!style="width: 20%"|Dates of enrollment
+! style="width: 20%" |Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
+! style="width: 20%" |Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8120440/ Hall et al. 2021 (GO2)]
+|[https://doi.org/10.1002/bjs.5996 Nakajima et al. 2007 (NSAS-GC)]
-|rowspan=2|2014-2017
+|1997-2001
-|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-de-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|1. [[#CapeOx_2|CapeOx]]; 1000/104
+|[[Gastric_cancer_-_null_regimens#Observation|Observation]]
-| style="background-color:#d3d3d3" |Not reported
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>OS60: 86% vs 73%<br>(HR 0.48, 95% CI 0.26-0.89)
-|-
-|2. [[#CapeOx_2|CapeOx]]; 1250/130
-| style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>(HR 1.10, 95% CI 0.90-1.33)
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Gastrectomy|Gastrectomy]], with complete (R0) D2 dissection
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 375 mg/m<sup>2</sup> PO twice per day
+*[[Tegafur and uracil (UFT)]] 360 mg/m<sup>2</sup> PO once per day
-*[[Oxaliplatin (Eloxatin)]] 78 mg/m<sup>2</sup> IV once on day 1
+'''16-month course'''
-'''21-day cycles'''
+</div></div>
-</div></div><br>
+===References===
+#'''NSAS-GC:''' Nakajima T, Kinoshita T, Nashimoto A, Sairenji M, Yamaguchi T, Sakamoto J, Fujiya T, Inada T, Sasako M, Ohashi Y; National Surgical Adjuvant Study of Gastric Cancer Group. Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg. 2007 Dec;94(12):1468-76. [https://doi.org/10.1002/bjs.5996 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17948223/ PubMed] [https://clinicaltrials.gov/study/NCT00152243 NCT00152243]
+#'''SAMIT:''' Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. [https://doi.org/10.1016/S1470-2045(14)70025-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24954805/ PubMed] UMIN C000000082
+=Metastatic or locally advanced disease, first-line=
+==Capecitabine monotherapy {{#subobject:a9eb0b|Regimen=1}}==
+X: '''<u>X</u>'''eloda (Capecitabine)
 <div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 2000 mg/m<sup>2</sup>/day {{#subobject:b6ba4c|Variant=1}}===
-===Regimen variant #2, 1000/104 {{#subobject:4faj65|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 20%" |Study
-!style="width: 20%"|Dates of enrollment
+! style="width: 20%" |Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
+! style="width: 20%" |Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8120440/ Hall et al. 2021 (GO2)]
+|[https://doi.org/10.1016/j.jgo.2017.01.002 Hwang et al. 2017 (SMC 2010-04-118)]
-|rowspan=2|2014-2017
+|2010-2014
-|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-de-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#CapeOx_2|CapeOx]]; 750/78
+|[[#CapeOx_2|XELOX]]
-| style="background-color:#d3d3d3" |Not reported
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|2. [[#CapeOx_2|CapeOx]]; 1250/130
+|[https://doi.org/10.4143/crt.2023.333 Lee et al. 2023 (KCSG ST13-10)]
-| style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>(HR 1.09, 95% CI 0.89-1.32)
+|2014-02 to 2019-01
+|style="background-color:#1a9851" |Phase 3 (C)
+|1a. [[#mFOLFOX6_2|mFOLFOX6]]<br>1b. [[#CapeOx_2|CapeOx]]<br>1c. [[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br>1d. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*KCSG ST13-10: CrCl at least 60 mL/min
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 500 mg/m<sup>2</sup> PO twice per day
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 104 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 1250/130 {{#subobject:guzj65|Variant=1}}===
+===Regimen variant #2, 2500 mg/m<sup>2</sup>/day {{#subobject:b6ba4c|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 20%"|Study
+!style="width: 33%"|Study
-!style="width: 20%"|Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8120440/ Hall et al. 2021 (GO2)]
-|2014-2017
-| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#CapeOx_2|CapeOx]]; 750/78<br>2. [[#CapeOx_2|CapeOx]]; 1000/104
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #4, 1700/130 {{#subobject:4faee3|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
 !style="width: 33%"|Dates of enrollment
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1093/annonc/mdj063 Jatoi et al. 2006]
+|[https://doi.org/10.1093/annonc/mdh343 Hong et al. 2004]
-|2002-2004
+|NR
 | style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*Karnofsky status of at least 70%
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycle for up to 6 cycles'''
-'''21-day cycles'''
+</div></div>
-</div></div><br>
+===References===
+#Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep;15(9):1344-7. [https://doi.org/10.1093/annonc/mdh343 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15319239/ PubMed]
+#'''SMC 2010-04-118:''' Hwang IG, Ji JH, Kang JH, Lee HR, Lee HY, Chi KC, Park SW, Lee SJ, Kim ST, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017 May;8(3):170-175. Epub 2017 Jan 21. [https://doi.org/10.1016/j.jgo.2017.01.002 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28119041/ PubMed] [https://clinicaltrials.gov/study/NCT01470742 NCT01470742]
+#'''KCSG ST13-10:''' Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS. A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10). Cancer Res Treat. 2022 Oct;55(4):1250-1260. Epub 2023 May 25. [https://doi.org/10.4143/crt.2023.333 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37232070/ PubMed] [https://clinicaltrials.gov/study/NCT02114359 NCT02114359]
+==Capecitabine & Cisplatin (CX) {{#subobject:2bd34d|Regimen=1}}==
+CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #5, 2000/130 {{#subobject:4fagg3|Variant=1}}===
+===Regimen variant #1, 6 cycles {{#subobject:62b184|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 20%" |Study
-!style="width: 20%"|Dates of enrollment
+! style="width: 20%" |Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
+! style="width: 20%" |Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078426/ Moehler et al. 2020 (JAVELIN Gastric 100)]
+|[https://doi.org/10.1200/JCO.2011.36.2236 Ohtsu et al. 2011 (AVAGAST)]
-|2015-2017
+|2007-09 to 2008-12
 | style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#CapeOx_2|CapeOx]] x 4, then [[#Avelumab_monotherapy_999|Avelumab]]<br>1b. [[#mFOLFOX4_888|mFOLFOX4]] x 4, then [[#Avelumab_monotherapy_999|Avelumab]]<br>1c. [[#mFOLFOX6|mFOLFOX6]] x 4, then [[#Avelumab_monotherapy_999|Avelumab]]
+|[[Stub#Capecitabine_.26_Cisplatin_.28CX.29_.26_Bevacizumab|CX & Bevacizumab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.clinicaltrials.gov/study/NCT02934464 Awaiting publication (ARMANI)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544634/ Shen et al. 2014 (AVATAR)]
-|2016-2019
+|2009-03-25 to 2010-07-12
 | style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#CapeOx_2|CapeOx]] x 3 mo, then [[#Paclitaxel_.26_Ramucirumab_888|Paclitaxel & Ramucirumab]]<br>1b. [[#FOLFOX4_888|FOLFOX4]] x 3 mo, then [[#Paclitaxel_.26_Ramucirumab_888|Paclitaxel & Ramucirumab]]<br>1c. [[#mFOLFOX6|mFOLFOX6]] x 3 mo, then [[#Paclitaxel_.26_Ramucirumab_888|Paclitaxel & Ramucirumab]]
+|[[Stub#Capecitabine_.26_Cisplatin_.28CX.29_.26_Bevacizumab|CX & Bevacizumab]]
-| style="background-color:#d3d3d3" |TBD if different primary endpoint of PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://doi.org/10.1016/s1470-2045(21)00692-6 Kang et al. 2022 (ATTRACTION-4)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097104/ Lu et al. 2018 (PAC-C)]
-|2017-03-23 to 2018-05-10
+|2009-2014
 | style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#CapeOx_.26_Nivolumab|CapeOx & Nivolumab]]<br>1b. [[#SOX_.26_Nivolumab_888|SOX & Nivolumab]]
+|[[#Capecitabine_.26_Paclitaxel_999|Capecitabine & Paclitaxel]]
-| style="background-color:#d73027" |Inferior PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
-|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ Janjigian et al. 2021 (CheckMate 649)]
+|}
-|rowspan=2|2017-03 to 2019-04
+''Note: The following studies included patients with GE junction malignancy as well:
-|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
+*''AVAGAST patients: 86% gastric and 14% GE junction. 5.4% of patients had an ECOG PS of 2.''
-|1a. [[#CapeOx_.26_Nivolumab|CapeOx & Nivolumab]]<br>1b. [[#mFOLFOX6_.26_Nivolumab|mFOLFOX6 & Nivolumab]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|2. [[#Ipilimumab_.26_Nivolumab_999|Ipilimumab & Nivolumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://www.clinicaltrials.gov/study/NCT03777657 Awaiting publication (BGB-A317-305)]
-|2018-ongoing
-| style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#CapeOx_.26_Tislelizumab_666|CapeOx & Tislelizumab]]<br>1b. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Tislelizumab_666|CF & Tislelizumab]]
-| style="background-color:#d3d3d3" |TBD if different primary endpoint of OS
-|-
-|[https://doi.org/10.1016/s1470-2045(23)00515-6 Rha et al. 2023 (KEYNOTE-859)]
-|2018-11-08 to 2021-06-11
-| style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#CapeOx_.26_Pembrolizumab|CapeOx & Pembrolizumab]]<br>1b. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab|CF & Pembrolizumab]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|}
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+====Supportive therapy====
-'''21-day cycles'''
+*Some protocols: [[:Category:Hydration|"Hyperhydration"]] for cisplatin
+'''21-day cycle for 6 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*AVAGAST & AVATAR: [[#Capecitabine_monotherapy_2|Capecitabine]] maintenance
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 8 cycles {{#subobject:628184|Variant=1}}===
-===Regimen variant #6, 2000/130, limited oxaliplatin {{#subobject:4hazb3|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 20%" |Study
-!style="width: 20%"|Dates of enrollment
+! style="width: 20%" |Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
+! style="width: 20%" |Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9017757/ Zhu et al. 2022 (EXELOX)]
+|[https://doi.org/10.1016/j.ejca.2014.08.005 Kim et al. 2014 (SMC 2008-12-019)]
-|2015-2020
+|2009-2012
-| style="background-color:#1a9851" |Phase 3 (E-de-esc)
-|[[#EOX_2|EOX]]
-| style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>Median PFS: 5 vs 5.5 mo<br>(HR 0.989, 95% CI 0.81-1.20)
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10427418/ Shah et al. 2023 (GLOW<sub>gastric</sub>)]
-|2018-11-28 to 2022-02-18
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Capectiabine_.26_Oxaliplatin_.28CapeOx.29_.26_Zolbetuximab_777|CapeOx & Zolbetuximab]]
+|[[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Simvastatin_999|CX & Simvastatin]]
-| style="background-color:#fc8d59" |Seems to have inferior OS (secondary endpoint)<br><br>Inferior PFS (primary endpoint)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
-''Note: GLOW should not be confused by the trial of the same name in CLL. In GLOW, continuation of capecitabine past cycle 8 was at the investigator's discretion.''
+''Note: The following studies included patients with GE junction malignancy as well:
-<div class="toccolours" style="background-color:#fdcdac">
+*''SMC 2008-12-019 patients: 79% gastric, 16% GE junction and 5% unknown''
-====Biomarker eligibility criteria====
-*GLOW<sub>gastric</sub>: CLDN18.2 positive
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] as follows:
+'''21-day cycle for 8 cycles'''
-**Cycles 1 up to 8: 130 mg/m<sup>2</sup> IV once on day 1
+</div>
-'''21-day cycles'''
+<div class="toccolours" style="background-color:#cbd5e7">
-</div></div>
+====Subsequent treatment====
-===References===
+*[[#Capecitabine_monotherapy_2|Capecitabine]] maintenance
-#Jatoi A, Murphy BR, Foster NR, Nikcevich DA, Alberts SR, Knost JA, Fitch TR, Rowland KM Jr; North Central Cancer Treatment Group. Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group. Ann Oncol. 2006 Jan;17(1):29-34. Epub 2005 Nov 22. [https://doi.org/10.1093/annonc/mdj063 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16303863/ PubMed]
+</div></div><br>
-#'''JAVELIN Gastric 100:''' Moehler M, Dvorkin M, Boku N, Özgüroğlu M, Ryu MH, Muntean AS, Lonardi S, Nechaeva M, Bragagnoli AC, Coşkun HS, Cubillo Gracian A, Takano T, Wong R, Safran H, Vaccaro GM, Wainberg ZA, Silver MR, Xiong H, Hong J, Taieb J, Bang YJ. Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100. J Clin Oncol. 2021 Mar 20;39(9):966-977. Epub 2020 Nov 16. [https://doi.org/10.1200/jco.20.00892 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078426/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33197226/ PubMed] [https://clinicaltrials.gov/study/NCT02625610 NCT02625610]
+<div class="toccolours" style="background-color:#eeeeee">
-#'''CheckMate 649:''' Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. [https://doi.org/10.1016/s0140-6736(21)00797-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34102137/ PubMed] [https://clinicaltrials.gov/study/NCT02872116 NCT02872116]
+===Regimen variant #3, indefinite {{#subobject:82b184|Variant=1}}===
-##'''Update:''' Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. [https://doi.org/10.1038/s41586-022-04508-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967713/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35322232/ PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#'''GO2:''' Hall PS, Swinson D, Cairns DA, Waters JS, Petty R, Allmark C, Ruddock S, Falk S, Wadsley J, Roy R, Tillett T, Nicoll J, Cummins S, Mano J, Grumett S, Stokes Z, Kamposioras KV, Chatterjee A, Garcia A, Waddell T, Guptal K, Maisey N, Khan M, Dent J, Lord S, Crossley A, Katona E, Marshall H, Grabsch HI, Velikova G, Ow PL, Handforth C, Howard H, Seymour MT; GO2 Trial Investigators. Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Jun 1;7(6):869-877. Erratum in: JAMA Oncol. 2021 Aug 1;7(8):1249. [https://doi.org/10.1001/jamaoncol.2021.0848 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8120440/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33983395/ PubMed] ISRCTN44687907
+! style="width: 20%" |Study
-#'''ATTRACTION-4:''' Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):234-247. Epub 2022 Jan 11. [https://doi.org/10.1016/s1470-2045(21)00692-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35030335/ PubMed] [https://clinicaltrials.gov/study/NCT02746796 NCT02746796]
+! style="width: 20%" |Dates of enrollment
-#'''EXELOX:''' Zhu XD, Huang MZ, Wang YS, Feng WJ, Chen ZY, He YF, Zhang XW, Liu X, Wang CC, Zhang W, Ying JE, Wu J, Yang L, Qin YR, Luo JF, Zhao XY, Li WH, Zhang Z, Qiu LX, Geng QR, Zou JL, Zhang JY, Zheng H, Song XF, Wu SS, Zhang CY, Gong Z, Liu QQ, Wang XF, Xu Q, Wang Q, Ji JM, Zhao J, Guo WJ. XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX). Cancer Commun (Lond). 2022 Apr;42(4):314-326. Epub 2022 Feb 25. [https://doi.org/10.1002/cac2.12278 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9017757/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35212487/ PubMed] [https://clinicaltrials.gov/study/NCT02395640 NCT02395640]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-#'''GLOW<sub>gastric</sub>:''' Shah MA, Shitara K, Ajani JA, Bang YJ, Enzinger P, Ilson D, Lordick F, Van Cutsem E, Gallego Plazas J, Huang J, Shen L, Oh SC, Sunpaweravong P, Soo Hoo HF, Turk HM, Oh M, Park JW, Moran D, Bhattacharya P, Arozullah A, Xu RH. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023 Aug;29(8):2133-2141. Epub 2023 Jul 31. [https://doi.org/10.1038/s41591-023-02465-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10427418/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37524953/ PubMed] [https://clinicaltrials.gov/study/NCT03653507 NCT03653507]
+! style="width: 20%" |Comparator
-#'''KEYNOTE-859:''' Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. [https://doi.org/10.1016/s1470-2045(23)00515-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37875143/ PubMed] [https://clinicaltrials.gov/study/NCT03675737 NCT03675737]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-#'''ARMANI:''' [https://clinicaltrials.gov/study/NCT02934464 NCT02934464]
-#'''BGB-A317-305:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03777657 NCT03777657]
-#'''ORIENT-16:''' [https://clinicaltrials.gov/study/NCT03745170 NCT03745170]
-==CapeOx & Nivolumab {{#subobject:1ybz18|Regimen=1}}==
-CapeOx & Nivolumab: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Nivolumab
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1bja1f|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/s1470-2045(21)00692-6 Kang et al. 2022 (ATTRACTION-4)]
+|[https://doi.org/10.1093/annonc/mdn717 Kang et al. 2009 (ML17032)]
-|2017-03-23 to 2018-05-10
+|2003-2005
-| style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|1a. [[#CapeOx_2|CapeOx]]<br>1b. [[#SOX_888|SOX]]
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
-| style="background-color:#1a9850" |Superior PFS (co-primary endpoint)<br>Median PFS: 10.45 vs 8.3 mo<br>(HR 0.68, 98.51% CI 0.51-0.90)<br><br>Did not meet co-primary endpoint of OS<br>Median OS: 17.45 vs 17.15 mo<br>(HR 0.90, 95% CI 0.75-1.08)
+| style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>Median PFS: 5.6 vs 5 mo<br>(HR 0.81, 95% CI 0.63-1.04)
 |-
-|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ Janjigian et al. 2021 (CheckMate 649)]
+|[https://doi.org/10.1016/S1470-2045(13)70102-5 Lordick et al. 2013 (EXPAND)]
-<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|2008-2010
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-290-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Cetuximab_999|CX & Cetuximab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
-|} -->
+|[https://doi.org/10.1016/S1470-2045(18)30791-5 Fuchs et al. 2019 (RAINFALL)]
-|rowspan=2|2017-03 to 2019-04
+|2015-01-28 to 2016-09-16
-|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#CapeOx_2|CapeOx]]<br>1b. [[#mFOLFOX6|mFOLFOX6]]
+|[[Stub#Capecitabine_.26_Cisplatin_.28CX.29_.26_Ramucirumab|CX & Ramucirumab]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 14.4 vs 11.1 mo<br>(HR 0.70, 95% CI 0.61-0.81)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>1</sup>
-|-
-|2. [[#Ipilimumab_.26_Nivolumab_999|Ipilimumab & Nivolumab]]
-| style="background-color:#d3d3d3" |Not reported
 |-
 |}
-''<sup>1</sup>Reported efficacy and MCBS score are for the group with PD-L1 CPS of 5 or more; reported efficacy is based on the 2022 update.''
+''<sup>1</sup>while the primary analysis of RAINFALL showed that this arm seemed to have inferior PFS, independent central review did not confirm this finding.''<br>
+The following studies included patients with GE junction malignancy as well:
+*''EXPAND patients: 83% gastric, 5% GE junction and 16% unknown''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+**Alternate dosing in EXPAND: 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
-====Immunotherapy====
+====Supportive therapy====
-*[[Nivolumab (Opdivo)]] 360 mg IV once on day 1
+*Some protocols: [[:Category:Hydration|"Hyperhydration"]] for cisplatin
 '''21-day cycles'''
 </div></div>
 ===References===
-#'''CheckMate 649:''' Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. [https://doi.org/10.1016/s0140-6736(21)00797-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34102137/ PubMed] [https://clinicaltrials.gov/study/NCT02872116 NCT02872116]
+#'''ML17032:''' Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [https://doi.org/10.1093/annonc/mdn717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19153121/ PubMed] content property of [http://hemonc.org HemOnc.org] [https://clinicaltrials.gov/study/NCT02563054 NCT02563054]
-##'''Update:''' Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. [https://doi.org/10.1038/s41586-022-04508-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967713/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35322232/ PubMed]
+#'''AVAGAST:''' Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://doi.org/10.1200/JCO.2011.36.2236 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21844504/ PubMed] [https://clinicaltrials.gov/study/NCT00548548 NCT00548548]
-#'''ATTRACTION-4:''' Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):234-247. Epub 2022 Jan 11. [https://doi.org/10.1016/s1470-2045(21)00692-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35030335/ PubMed] [https://clinicaltrials.gov/study/NCT02746796 NCT02746796]
+#'''EXPAND:''' Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. [https://doi.org/10.1016/S1470-2045(13)70102-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23594786/ PubMed] [https://clinicaltrials.gov/study/NCT00678535 NCT00678535]
-==CapeOx & Pembrolizumab {{#subobject:1yhy28|Regimen=1}}==
+#'''AVATAR:''' Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, Xu R, Chen L, Liu Y, Yu S, Bu L, Piao Y. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015 Jan;18(1):168-76. Epub 2014 Feb 21. [https://doi.org/10.1007/s10120-014-0351-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544634/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24557418/ PubMed] [https://clinicaltrials.gov/study/NCT00887822 NCT00887822]
-CapeOx & Pembrolizumab: ''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Pembrolizumab
+#'''SMC 2008-12-019:''' Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. [https://doi.org/10.1016/j.ejca.2014.08.005 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25218337/ PubMed] [https://clinicaltrials.gov/study/NCT01099085 NCT01099085]
-<div class="toccolours" style="background-color:#eeeeee">
+#'''PAC-C:''' Lu Z, Zhang X, Liu W, Liu T, Hu B, Li W, Fan Q, Xu J, Xu N, Bai Y, Pan Y, Xu Q, Bai W, Xia L, Gao Y, Wang W, Shu Y, Shen L. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018 Sep;21(5):782-791. Epub 2018 Feb 27. [https://doi.org/10.1007/s10120-018-0809-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097104/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29488121/ PubMed] [https://clinicaltrials.gov/study/NCT01015339 NCT01015339]
-===Regimen {{#subobject:acb31f|Variant=1}}===
+#'''RAINFALL:''' Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):420-435. Epub 2019 Feb 1. Erratum in: Lancet Oncol. 2019 May;20(5):e242. [https://doi.org/10.1016/S1470-2045(18)30791-5 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30718072/ PubMed] [https://clinicaltrials.gov/study/NCT02314117 NCT02314117]
+==Capecitabine & Cisplatin (CX) & Pembrolizumab {{#subobject:ahg7ab|Regimen=1}}==
+CX & Pembrolizumab: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), Pembrolizumab
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1yt34c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,404: / Line 1,355: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/s1470-2045(23)00515-6 Rha et al. 2023 (KEYNOTE-859)]
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ Shitara et al. 2020 (KEYNOTE-062)]
-|2018-11-08 to 2021-06-11
+|rowspan=2|2015-2017
-| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
-|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_2|CF]]<br>1b. [[#CapeOx_2|CapeOx]]
+|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]<br>1b. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
-| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 12.9 vs 11.5 mo<br>(HR 0.78, 95% CI 0.70-0.87)
+| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 12.5 vs 11.1 mo<br>(HR 0.85, 95% CI 0.70-1.03)
+|-
+|2. [[#Pembrolizumab_monotherapy|Pembrolizumab]]
+| style="background-color:#d3d3d3" |Not reported
 |}
-''KEYNOTE-859 included patients with GEJ malignancy''
+''<sup>1</sup>Reported efficacy is for patients with CPS of 1 or greater.''<br>
+''Note: KEYNOTE-062 included patients with GEJ malignancy.''
 <div class="toccolours" style="background-color:#fdcdac">
 ====Biomarker eligibility criteria====
-*PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
+PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1
 ====Immunotherapy====
 *[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-'''21-day cycle for up to 35 cycles'''
+'''21-day cycles'''
 </div></div>
 ===References===
-#'''KEYNOTE-859:''' Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. [https://doi.org/10.1016/s1470-2045(23)00515-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37875143/ PubMed] [https://clinicaltrials.gov/study/NCT03675737 NCT03675737]
+<!-- #'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://doi.org/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract] -->
+#'''KEYNOTE-062:''' Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. [https://doi.org/10.1001/jamaoncol.2020.3370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32880601/ PubMed] [https://clinicaltrials.gov/study/NCT02494583 NCT02494583]
-==Carboplatin & Paclitaxel (CP) {{#subobject:4df570|Regimen=1}}==
+==CapeOx {{#subobject:4e3bb4|Regimen=1}}==
+CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:9725d8|Variant=1}}===
+===Regimen variant #1, 750/78 {{#subobject:4faj81|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Dates of enrollment
+!style="width: 20%"|Dates of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://pubmed.ncbi.nlm.nih.gov/9427274 Philip et al. 1997]
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8120440/ Hall et al. 2021 (GO2)]
-|NR in abstract
+|rowspan=2|2014-2017
-| style="background-color:#91cf61" |Phase 2
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-de-esc)
+|1. [[#CapeOx_2|CapeOx]]; 1000/104
+| style="background-color:#d3d3d3" |Not reported
 |-
-|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract Gadgeel et al. 2003]
+|2. [[#CapeOx_2|CapeOx]]; 1250/130
-|1996-2000
+| style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>(HR 1.10, 95% CI 0.90-1.33)
-| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6. Philip et al. included patients with locally advanced metastatic or recurrent esophageal or gastric cancer. Gadgeel et al. study showed an ORR of 35%.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1, '''given second'''
+*[[Capecitabine (Xeloda)]] 375 mg/m<sup>2</sup> PO twice per day
-*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+*[[Oxaliplatin (Eloxatin)]] 78 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
-</div></div>
+</div></div><br>
-===References===
-#Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9427274/ PubMed]
-#Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, Philip PA. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003 Feb;26(1):37-41. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12576922/ PubMed]
-==Cisplatin & Docetaxel (DC) {{#subobject:724868|Regimen=1}}==
-DC: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin
-<br>TC: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 75/75 {{#subobject:cd0910|Variant=1}}===
+===Regimen variant #2, 1000/104 {{#subobject:4faj65|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+!style="width: 20%"|Study
-! style="width: 20%" |Dates of enrollment
+!style="width: 20%"|Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+!style="width: 20%"|Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1200/jco.2006.08.0135 Roth et al. 2007]
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8120440/ Hall et al. 2021 (GO2)]
-| rowspan="2" |1999-2003
+|rowspan=2|2014-2017
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-de-esc)
-|1. [[#ECF_3|ECF]]
+|1. [[#CapeOx_2|CapeOx]]; 750/78
 | style="background-color:#d3d3d3" |Not reported
 |-
-|2. [[#DCF|TCF]]
+|2. [[#CapeOx_2|CapeOx]]; 1250/130
-| style="background-color:#fee08b" |Might have inferior ORR
+| style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>(HR 1.09, 95% CI 0.89-1.32)
 |-
 |}
-''Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m<sup>2</sup> to 75 mg/m<sup>2</sup> based on high incidence of febrile neutropenia.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 4 hours once on day 1
+*[[Capecitabine (Xeloda)]] 500 mg/m<sup>2</sup> PO twice per day
-*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+*[[Oxaliplatin (Eloxatin)]] 104 mg/m<sup>2</sup> IV once on day 1
-====Supportive therapy====
+'''21-day cycles'''
-*3 liters per day [[:Category:Hydration|"hyperhydration"]]
-*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours prior to docetaxel, then 8 mg PO twice per day for 4 days after docetaxel
-*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis
-*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
-'''21-day cycle for up to 8 cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 75/85 {{#subobject:f1913d|Variant=1}}===
+===Regimen variant #3, 1250/130 {{#subobject:guzj65|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+!style="width: 20%"|Study
-! style="width: 20%" |Dates of enrollment
+!style="width: 20%"|Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+!style="width: 20%"|Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2005.17.376 Ajani et al. 2005 (V-325)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8120440/ Hall et al. 2021 (GO2)]
-|1998-1999
+|2014-2017
-| style="background-color:#1a9851" |Randomized Phase 2 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#DCF|DCF]]
+|1. [[#CapeOx_2|CapeOx]]; 750/78<br>2. [[#CapeOx_2|CapeOx]]; 1000/104
-| style="background-color:#fc8d59" |Seems to have inferior ORR
+| style="background-color:#eeee01" |Non-inferior PFS
 |-
 |}
-''Note: patients had 100% adenocarcinoma histology (32% esophagogastric junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1
+*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day
-*[[Docetaxel (Taxotere)]] 85 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-====Supportive therapy====
-*[[Dexamethasone (Decadron)]] 8 mg PO the night before chemotherapy, the morning of day 1, 1 hour before chemotherapy, the night of day 1, the morning of day 2, and the evening of day 2 (total dose per cycle: 48 mg)
-*[[Dexamethasone (Decadron)]] 20 mg IV prior to cisplatin and 8 hours after cisplatin
-*[[Ondansetron (Zofran)]] 8 mg IV prior to cisplatin, 4 hours after cisplatin, and 8 hours after cisplatin
-*"[[:Category:Hydration|Hydration]] was administered in a standard manner"
 '''21-day cycles'''
-</div></div>
+</div></div><br>
-===References===
-#'''V-325:''' Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [https://doi.org/10.1200/jco.2005.17.376 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16110025/ PubMed]
-#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [https://doi.org/10.1200/jco.2006.08.0135 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17664469/ PubMed]
-==Cisplatin & Fluorouracil (CF) {{#subobject:4d9936|Regimen=1}}==
-CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 60/5000 {{#subobject:9yt155|Variant=1}}===
+===Regimen variant #4, 1700/130 {{#subobject:4faee3|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 20%" |Study
+!style="width: 33%"|Study
-! style="width: 20%" |Dates of enrollment
+!style="width: 33%"|Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2699097/ Lee et al. 2009a]
+|[https://doi.org/10.1093/annonc/mdj063 Jatoi et al. 2006]
-|2000-2004
+|2002-2004
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#91cf61" |Phase 2
-|[[#Fluorouracil_.26_Heptaplatin_.28FH.29|Fluorouracil & Heptaplatin (FH)]]
-| style="background-color:#eeee01" |Equivalent OS
 |-
 |}
-''Note: this is reported to be an equivalence study but the statistical analysis does not provide details on the definition of equivalence.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
+*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup> IV over 12 hours once per day on days 1 to 5, '''given second'''
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''28-day cycles'''
+'''21-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 80/4000 x 8 {{#subobject:9abe95|Variant=1}}===
+===Regimen variant #5, 2000/130 {{#subobject:4fagg3|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+!style="width: 20%"|Study
-! style="width: 20%" |Dates of enrollment
+!style="width: 20%"|Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+!style="width: 20%"|Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdx275 Ajani et al. 2017 (DIGEST)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078426/ Moehler et al. 2020 (JAVELIN Gastric 100)]
-|2011-2014
+|2015-2017
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_S-1|CS]]
+|1a. [[#CapeOx-Avelumab_999|CapeOx-Avelumab]]<br>1b. [[#FOLFOX6-Avelumab_999|FOLFOX6-Avelumab]]<br>1c. [[#mFOLFOX6-Avelumab_999|mFOLFOX6-Avelumab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|}
+|[https://www.clinicaltrials.gov/study/NCT02934464 Awaiting publication (ARMANI)]
-<div class="toccolours" style="background-color:#b3e2cd">
+|2016-2019
-====Chemotherapy====
+| style="background-color:#1a9851" |Phase 3 (C)
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''
+|1a. [[#CapeOx_2|CapeOx]] x 3 mo, then [[#Paclitaxel_.26_Ramucirumab_888|Paclitaxel & Ramucirumab]]<br>1b. [[#FOLFOX4_888|FOLFOX4]] x 3 mo, then [[#Paclitaxel_.26_Ramucirumab_888|Paclitaxel & Ramucirumab]]<br>1c. [[#mFOLFOX6_2|mFOLFOX6]] x 3 mo, then [[#Paclitaxel_.26_Ramucirumab_888|Paclitaxel & Ramucirumab]]
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of PFS
-====Supportive therapy====
-*Some protocols: [[:Category:Hydration|"Hyperhydration"]] for cisplatin
-'''21-day cycle for 8 cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 80/4000, indefinite {{#subobject:69c795|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdn717 Kang et al. 2009 (ML17032)]
+|[https://doi.org/10.1016/s1470-2045(21)00692-6 Kang et al. 2022 (ATTRACTION-4)]
-|2003-2005
+|2017-03-23 to 2018-05-10
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
+|1a. [[#CapeOx_.26_Nivolumab|CapeOx & Nivolumab]]<br>1b. [[#SOX_.26_Nivolumab_888|SOX & Nivolumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
+| style="background-color:#d73027" |Inferior PFS
 |-
-|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ Shitara et al. 2020 (KEYNOTE-062)]
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ Janjigian et al. 2021 (CheckMate 649)]
-|rowspan=2|2015-2017
+|rowspan=2|2017-03 to 2019-04
 |rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab|CF & Pembrolizumab]]<br>1b. [[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Pembrolizumab|CX & Pembrolizumab]]
+|1a. [[#CapeOx_.26_Nivolumab|CapeOx & Nivolumab]]<br>1b. [[#mFOLFOX6_.26_Nivolumab|mFOLFOX6 & Nivolumab]]
-| style="background-color:#fee08b" |Might have inferior OS
+| style="background-color:#d73027" |Inferior OS
 |-
-|2. [[#Pembrolizumab_monotherapy|Pembrolizumab]]
+|2. [[#Ipilimumab_.26_Nivolumab_999|Ipilimumab & Nivolumab]]
-| style="background-color:#eeee01" |Non-inferior OS
+| style="background-color:#d3d3d3" |Not reported
 |-
 |[https://www.clinicaltrials.gov/study/NCT03777657 Awaiting publication (BGB-A317-305)]
@@ Line 1,607: / Line 1,525: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-====Supportive therapy====
-*Some protocols: [[:Category:Hydration|"Hyperhydration"]] for cisplatin
 '''21-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #4, 100/4000 {{#subobject:16f88f|Variant=1}}===
+===Regimen variant #6, 2000/130, limited oxaliplatin {{#subobject:4hazb3|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+!style="width: 20%"|Study
-! style="width: 20%" |Dates of enrollment
+!style="width: 20%"|Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+!style="width: 20%"|Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9017757/ Zhu et al. 2022 (EXELOX)]
+|2015-2020
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
+|[[#EOX_2|EOX]]
+| style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>Median PFS: 5 vs 5.5 mo<br>(HR 0.989, 95% CI 0.81-1.20)
 |-
-|[http://ar.iiarjournals.org/content/26/5B/3877.long Duffour et al. 2006 (FFCD 9404)]
+|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10427418/ Shah et al. 2023 (GLOW<sub>gastric</sub>)]
-|1995-1998
+|2018-11-28 to 2022-02-18
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#CLF|FLP]]
+|[[#Capectiabine_.26_Oxaliplatin_.28CapeOx.29_.26_Zolbetuximab_777|CapeOx & Zolbetuximab]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior ORR
+| style="background-color:#fc8d59" |Seems to have inferior OS (secondary endpoint)<br><br>Inferior PFS (primary endpoint)
 |-
 |}
+''Note: GLOW should not be confused by the trial of the same name in CLL. In GLOW, continuation of capecitabine past cycle 8 was at the investigator's discretion.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*GLOW<sub>gastric</sub>: CLDN18.2 positive
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on either day 1 or 2
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)]] as follows:
-'''28-day cycles'''
+**Cycles 1 up to 8: 130 mg/m<sup>2</sup> IV once on day 1
-</div></div><br>
+'''21-day cycles'''
+</div></div>
+===References===
+#Jatoi A, Murphy BR, Foster NR, Nikcevich DA, Alberts SR, Knost JA, Fitch TR, Rowland KM Jr; North Central Cancer Treatment Group. Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group. Ann Oncol. 2006 Jan;17(1):29-34. Epub 2005 Nov 22. [https://doi.org/10.1093/annonc/mdj063 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16303863/ PubMed]
+#'''JAVELIN Gastric 100:''' Moehler M, Dvorkin M, Boku N, Özgüroğlu M, Ryu MH, Muntean AS, Lonardi S, Nechaeva M, Bragagnoli AC, Coşkun HS, Cubillo Gracian A, Takano T, Wong R, Safran H, Vaccaro GM, Wainberg ZA, Silver MR, Xiong H, Hong J, Taieb J, Bang YJ. Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100. J Clin Oncol. 2021 Mar 20;39(9):966-977. Epub 2020 Nov 16. [https://doi.org/10.1200/jco.20.00892 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078426/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33197226/ PubMed] [https://clinicaltrials.gov/study/NCT02625610 NCT02625610]
+#'''CheckMate 649:''' Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. [https://doi.org/10.1016/s0140-6736(21)00797-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34102137/ PubMed] [https://clinicaltrials.gov/study/NCT02872116 NCT02872116]
+##'''Update:''' Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. [https://doi.org/10.1038/s41586-022-04508-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967713/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35322232/ PubMed]
+##'''HRQoL analysis:''' Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. [https://doi.org/10.1200/jco.23.00170 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10713185/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37713657/ PubMed]
+#'''GO2:''' Hall PS, Swinson D, Cairns DA, Waters JS, Petty R, Allmark C, Ruddock S, Falk S, Wadsley J, Roy R, Tillett T, Nicoll J, Cummins S, Mano J, Grumett S, Stokes Z, Kamposioras KV, Chatterjee A, Garcia A, Waddell T, Guptal K, Maisey N, Khan M, Dent J, Lord S, Crossley A, Katona E, Marshall H, Grabsch HI, Velikova G, Ow PL, Handforth C, Howard H, Seymour MT; GO2 Trial Investigators. Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Jun 1;7(6):869-877. Erratum in: JAMA Oncol. 2021 Aug 1;7(8):1249. [https://doi.org/10.1001/jamaoncol.2021.0848 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8120440/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33983395/ PubMed] ISRCTN44687907
+#'''ATTRACTION-4:''' Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):234-247. Epub 2022 Jan 11. [https://doi.org/10.1016/s1470-2045(21)00692-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35030335/ PubMed] [https://clinicaltrials.gov/study/NCT02746796 NCT02746796]
+#'''EXELOX:''' Zhu XD, Huang MZ, Wang YS, Feng WJ, Chen ZY, He YF, Zhang XW, Liu X, Wang CC, Zhang W, Ying JE, Wu J, Yang L, Qin YR, Luo JF, Zhao XY, Li WH, Zhang Z, Qiu LX, Geng QR, Zou JL, Zhang JY, Zheng H, Song XF, Wu SS, Zhang CY, Gong Z, Liu QQ, Wang XF, Xu Q, Wang Q, Ji JM, Zhao J, Guo WJ. XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX). Cancer Commun (Lond). 2022 Apr;42(4):314-326. Epub 2022 Feb 25. [https://doi.org/10.1002/cac2.12278 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9017757/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35212487/ PubMed] [https://clinicaltrials.gov/study/NCT02395640 NCT02395640]
+#'''GLOW<sub>gastric</sub>:''' Shah MA, Shitara K, Ajani JA, Bang YJ, Enzinger P, Ilson D, Lordick F, Van Cutsem E, Gallego Plazas J, Huang J, Shen L, Oh SC, Sunpaweravong P, Soo Hoo HF, Turk HM, Oh M, Park JW, Moran D, Bhattacharya P, Arozullah A, Xu RH. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023 Aug;29(8):2133-2141. Epub 2023 Jul 31. [https://doi.org/10.1038/s41591-023-02465-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10427418/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37524953/ PubMed] [https://clinicaltrials.gov/study/NCT03653507 NCT03653507]
+#'''KEYNOTE-859:''' Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. [https://doi.org/10.1016/s1470-2045(23)00515-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37875143/ PubMed] [https://clinicaltrials.gov/study/NCT03675737 NCT03675737]
+#'''ARMANI:''' [https://clinicaltrials.gov/study/NCT02934464 NCT02934464]
+#'''BGB-A317-305:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03777657 NCT03777657]
+#'''ORIENT-16:''' [https://clinicaltrials.gov/study/NCT03745170 NCT03745170]
+==CapeOx & Nivolumab {{#subobject:1ybz18|Regimen=1}}==
+CapeOx & Nivolumab: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Nivolumab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #5, 100/4000, split-dose cisplatin {{#subobject:16f18e|Variant=1}}===
+===Regimen {{#subobject:1bja1f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+!style="width: 20%"|Study
-! style="width: 20%" |Dates of enrollment
+!style="width: 20%"|Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+!style="width: 20%"|Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1200/jco.2003.04.130 Ohtsu et al. 2003 (JCOG 9205)]
+|[https://doi.org/10.1016/s1470-2045(21)00692-6 Kang et al. 2022 (ATTRACTION-4)]
-| rowspan="2" |1992-1997
+|2017-03-23 to 2018-05-10
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|1. [[#Fluorouracil_monotherapy|Fluorouracil]]
+|1a. [[#CapeOx_2|CapeOx]]<br>1b. [[#SOX_888|SOX]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#1a9850" |Superior PFS (co-primary endpoint)<br>Median PFS: 10.45 vs 8.3 mo<br>(HR 0.68, 98.51% CI 0.51-0.90)<br><br>Did not meet co-primary endpoint of OS<br>Median OS: 17.45 vs 17.15 mo<br>(HR 0.90, 95% CI 0.75-1.08)
+|-
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ Janjigian et al. 2021 (CheckMate 649)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-290-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
+|rowspan=2|2017-03 to 2019-04
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|1a. [[#CapeOx_2|CapeOx]]<br>1b. [[#mFOLFOX6_2|mFOLFOX6]]
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 14.4 vs 11.1 mo<br>(HR 0.70, 95% CI 0.61-0.81)
 |-
-|2. [[#UFTM|UFTM]]
+|2. [[#Ipilimumab_.26_Nivolumab_999|Ipilimumab & Nivolumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#d3d3d3" |Not reported
 |-
 |}
-''Note: this study included patients with ECOG PS of 2 (9.6%)''
+''<sup>1</sup>Reported efficacy and MCBS score are for the group with PD-L1 CPS of 5 or more; reported efficacy is based on the 2022 update.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''28-day cycle for up to 6 cycles'''
+====Immunotherapy====
-</div></div><br>
+*[[Nivolumab (Opdivo)]] 360 mg IV once on day 1
+'''21-day cycles'''
+</div></div>
+===References===
+#'''CheckMate 649:''' Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. [https://doi.org/10.1016/s0140-6736(21)00797-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34102137/ PubMed] [https://clinicaltrials.gov/study/NCT02872116 NCT02872116]
+##'''Update:''' Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. [https://doi.org/10.1038/s41586-022-04508-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967713/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35322232/ PubMed]
+##'''HRQoL analysis:''' Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. [https://doi.org/10.1200/jco.23.00170 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10713185/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37713657/ PubMed]
+#'''ATTRACTION-4:''' Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):234-247. Epub 2022 Jan 11. [https://doi.org/10.1016/s1470-2045(21)00692-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35030335/ PubMed] [https://clinicaltrials.gov/study/NCT02746796 NCT02746796]
+==CapeOx & Pembrolizumab {{#subobject:1yhy28|Regimen=1}}==
+CapeOx & Pembrolizumab: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Pembrolizumab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #6, 100/5000 {{#subobject:10f0c6|Variant=1}}===
+===Regimen {{#subobject:acb31f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,670: / Line 1,635: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2006.06.8429 Van Cutsem et al. 2006 (TAX 325)]
+|[https://doi.org/10.1016/s1470-2045(23)00515-6 Rha et al. 2023 (KEYNOTE-859)]
-|1999-2003
+|2018-11-08 to 2021-06-11
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[#DCF|DCF]]
+|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_2|CF]]<br>1b. [[#CapeOx_2|CapeOx]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 12.9 vs 11.5 mo<br>(HR 0.78, 95% CI 0.70-0.87)
-|-
-|[https://doi.org/10.1093/annonc/mdn166 Dank et al. 2008]
-|2000-2002
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#FOLFIRI|IF]]
-| style="background-color:#fee08b" |Might have inferior TTP
-|-
-|[https://doi.org/10.1200/JCO.2009.25.4706 Ajani et al. 2010 (FLAGS)]
-|2005-2007
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_S-1|CS]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
 |}
-''Note: TAX 325 patients had 100% adenocarcinoma histology (22% Esophagogastric junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70. Dank et al patients had 100% adenocarcinoma histology (20% Esophagogastric junction, 80% gastric origin). 96% with metastatic disease. 1% with Karnofsky PS of 70.''
+''KEYNOTE-859 included patients with GEJ malignancy''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 5000 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-====Supportive therapy====
+====Immunotherapy====
-*As described in Dank et al. 2008:
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-*[[:Category:Hydration|"Hyperhydration"]] for 2 to 3 days with each infusion
+'''21-day cycle for up to 35 cycles'''
-*[[Ondansetron (Zofran)]] IV for antiemetic prophylaxis
-*[[Dexamethasone (Decadron)]] IV for antiemetic prophylaxis, then PO for 2 to 3 days
-*[[Metoclopramide (Reglan)]] for antiemetic prophylaxis
-*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/μL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection
-*[[Atropine (Atropen)]] prn cholinergic symptoms
-*[[Loperamide (Imodium)]] prn delayed diarrhea
-'''28-day cycles'''
 </div></div>
 ===References===
-#'''JCOG 9205:''' Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; [[Study_Groups#JCOG|JCOG]]. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [https://doi.org/10.1200/jco.2003.04.130 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12506170/ PubMed]
-#'''FFCD 9404:''' Duffour J, Bouché O, Rougier P, Milan C, Bedenne L, Seitz JF, Buecher B, Legoux JL, Ducreux M, Vetter D, Raoul JL, François E, Ychou M. Safety of cisplatin combined with continuous 5-FU versus bolus 5-FU and leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised trial). Anticancer Res. 2006 Sep-Oct;26(5B):3877-83. [http://ar.iiarjournals.org/content/26/5B/3877.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17094417/ PubMed]
-#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [https://doi.org/10.1200/jco.2006.06.8429 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17075117/ PubMed]
-#Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. [https://doi.org/10.1093/annonc/mdn166 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18558665/ PubMed]
-#'''ML17032:''' Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [https://doi.org/10.1093/annonc/mdn717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19153121/ PubMed] [https://clinicaltrials.gov/study/NCT02563054 NCT02563054]
-#Lee KH, Hyun MS, Kim HK, Jin HM, Yang J, Song HS, Do YR, Ryoo HM, Chung JS, Zang DY, Lim HY, Jin JY, Yim CY, Park HS, Kim JS, Sohn CH, Lee SN. Randomized, multicenter, phase III trial of heptaplatin 1-hour infusion and 5-fluorouracil combination chemotherapy comparing with cisplatin and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer. Cancer Res Treat. 2009 Mar;41(1):12-8. Epub 2009 Mar 31. [https://doi.org/10.4143/crt.2009.41.1.12 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2699097/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19688066/ PubMed]
-#'''FLAGS:''' Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. [https://doi.org/10.1200/JCO.2009.25.4706 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20159816/ PubMed] [https://clinicaltrials.gov/study/NCT00400179 NCT00400179]
-#'''AVAGAST:''' Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://doi.org/10.1200/JCO.2011.36.2236 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21844504/ PubMed] [https://clinicaltrials.gov/study/NCT00548548 NCT00548548]
-#'''DIGEST:''' Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. [https://doi.org/10.1093/annonc/mdx275 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28911091/ PubMed] [https://clinicaltrials.gov/study/NCT01285557 NCT01285557]
-<!-- #'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://doi.org/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract] -->
-#'''KEYNOTE-062:''' Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. [https://doi.org/10.1001/jamaoncol.2020.3370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32880601/ PubMed] [https://clinicaltrials.gov/study/NCT02494583 NCT02494583]
 #'''KEYNOTE-859:''' Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. [https://doi.org/10.1016/s1470-2045(23)00515-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37875143/ PubMed] [https://clinicaltrials.gov/study/NCT03675737 NCT03675737]
-#'''BGB-A317-305:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03777657 NCT03777657]
-==Cisplatin & Fluorouracil (CF) & Pembrolizumab {{#subobject:25ncw1|Regimen=1}}==
+==Carboplatin & Paclitaxel (CP) {{#subobject:4df570|Regimen=1}}==
-CF & Pembrolizumab: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, Pembrolizumab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:4fewd7|Variant=1}}===
+===Regimen {{#subobject:9725d8|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 20%" |Study
+!style="width: 33%"|Study
-! style="width: 20%" |Dates of enrollment
+!style="width: 33%"|Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ Shitara et al. 2020 (KEYNOTE-062)]
+|[https://pubmed.ncbi.nlm.nih.gov/9427274 Philip et al. 1997]
-|rowspan=2|2015-2017
+|NR in abstract
-|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#91cf61" |Phase 2
-|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]<br>1b. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
-| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)<br>Median OS: 12.5 vs 11.1 mo<br>(HR 0.85, 95% CI 0.70-1.03)
 |-
-|2. [[#Pembrolizumab_monotherapy|Pembrolizumab]]
+|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract Gadgeel et al. 2003]
-| style="background-color:#d3d3d3" |Not reported
+|1996-2000
+| style="background-color:#91cf61" |Phase 2
 |-
-|[https://doi.org/10.1016/s1470-2045(23)00515-6 Rha et al. 2023 (KEYNOTE-859)]
-|2018-11-08 to 2021-06-11
-| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_2|CF]]<br>1b. [[#CapeOx_2|CapeOx]]
-| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 12.9 vs 11.5 mo<br>(HR 0.78, 95% CI 0.70-0.87)
 |}
-''KEYNOTE-062 & KEYNOTE-859 included patients with GEJ malignancy''
+''Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6. Philip et al. included patients with locally advanced metastatic or recurrent esophageal or gastric cancer. Gadgeel et al. study showed an ORR of 35%.''
-<div class="toccolours" style="background-color:#fdcdac">
-====Biomarker eligibility criteria====
-PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1
+*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1, '''given second'''
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-====Immunotherapy====
+'''21-day cycles'''
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-'''21-day cycle for up to 35 cycles'''
 </div></div>
 ===References===
-<!-- #'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://doi.org/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract] -->
+#Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9427274/ PubMed]
-#'''KEYNOTE-062:''' Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. [https://doi.org/10.1001/jamaoncol.2020.3370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32880601/ PubMed] [https://clinicaltrials.gov/study/NCT02494583 NCT02494583]
+#Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, Philip PA. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003 Feb;26(1):37-41. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12576922/ PubMed]
-#'''KEYNOTE-859:''' Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. [https://doi.org/10.1016/s1470-2045(23)00515-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37875143/ PubMed] [https://clinicaltrials.gov/study/NCT03675737 NCT03675737]
+==Cisplatin & Docetaxel (DC) {{#subobject:724868|Regimen=1}}==
-==Cisplatin & S-1 {{#subobject:252c51|Regimen=1}}==
+DC: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin
-CS: '''<u>C</u>'''isplatin & '''<u>S</u>'''-1
+<br>TC: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin
-<br>SP: '''<u>S</u>'''-1 & '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, q3wk ("SP3") {{#subobject:4ff7cf|Variant=1}}===
+===Regimen variant #1, 75/75 {{#subobject:cd0910|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,775: / Line 1,696: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdv316 Ryu et al. 2015 (SOS)]
+| rowspan="2" |[https://doi.org/10.1200/jco.2006.08.0135 Roth et al. 2007]
-|2009-2012
+| rowspan="2" |1999-2003
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
-|[[#Cisplatin_.26_S-1|Cisplatin & S-1]]; SP5
+|1. [[#ECF_3|ECF]]
-| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 5.5 vs 4.9 mo<br>(HR 0.82, 95% CI 0.68-0.99)
+| style="background-color:#d3d3d3" |Not reported
 |-
-|[https://doi.org/10.1007/s10120-020-01101-4 Lee et al. 2020 (SOPP)]
+|2. [[#DCF|TCF]]
-|2012-2014
+| style="background-color:#fee08b" |Might have inferior ORR
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#SOX_888|SOX]]
-| style="background-color:#eeee01" |Non-inferior PFS
 |-
 |}
+''Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m<sup>2</sup> to 75 mg/m<sup>2</sup> based on high incidence of febrile neutropenia.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 4 hours once on day 1
-*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-'''21-day cycles'''
+====Supportive therapy====
+*3 liters per day [[:Category:Hydration|"hyperhydration"]]
+*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours prior to docetaxel, then 8 mg PO twice per day for 4 days after docetaxel
+*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis
+*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
+'''21-day cycle for up to 8 cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, q4wk {{#subobject:03b3c4|Variant=1}}===
+===Regimen variant #2, 75/85 {{#subobject:f1913d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,803: / Line 1,727: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/JCO.2009.25.4706 Ajani et al. 2010 (FLAGS)]
+|[https://doi.org/10.1200/jco.2005.17.376 Ajani et al. 2005 (V-325)]
-|2005-2007
+|1998-1999
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+|[[#DCF|DCF]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#fc8d59" |Seems to have inferior ORR
-|-
-|[https://doi.org/10.1093/annonc/mdx275 Ajani et al. 2017 (DIGEST)]
-|2011-2014
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: this is an experimental arm of a study where the primary endpoint was not met. Included because CS has been shown to be superior in comparison to other regimens (see above).''
+''Note: patients had 100% adenocarcinoma histology (32% esophagogastric junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1
-*[[Tegafur, gimeracil, oteracil (S-1)]] 25 mg/m<sup>2</sup> PO twice per day on days 1 to 21
+*[[Docetaxel (Taxotere)]] 85 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-'''28-day cycles'''
+====Supportive therapy====
-</div></div><br>
+*[[Dexamethasone (Decadron)]] 8 mg PO the night before chemotherapy, the morning of day 1, 1 hour before chemotherapy, the night of day 1, the morning of day 2, and the evening of day 2 (total dose per cycle: 48 mg)
+*[[Dexamethasone (Decadron)]] 20 mg IV prior to cisplatin and 8 hours after cisplatin
+*[[Ondansetron (Zofran)]] 8 mg IV prior to cisplatin, 4 hours after cisplatin, and 8 hours after cisplatin
+*"[[:Category:Hydration|Hydration]] was administered in a standard manner"
+'''21-day cycles'''
+</div></div>
+===References===
+#'''V-325:''' Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [https://doi.org/10.1200/jco.2005.17.376 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16110025/ PubMed]
+#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [https://doi.org/10.1200/jco.2006.08.0135 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17664469/ PubMed]
+==Cisplatin & Fluorouracil (CF) {{#subobject:4d9936|Regimen=1}}==
+CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, q5wk ("SP5") {{#subobject:cdcc15|Variant=1}}===
+===Regimen variant #1, 60/5000 {{#subobject:9yt155|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,832: / Line 1,761: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S1470-2045(08)70035-4 Koizumi et al. 2008 (SPIRITS)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2699097/ Lee et al. 2009a]
-|2002-2004
+|2000-2004
-| style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#S-1_monotherapy_2|S-1]]
+|[[#Fluorouracil_.26_Heptaplatin_.28FH.29|Fluorouracil & Heptaplatin (FH)]]
-| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 13 vs 11 mo<br>(HR 0.77, 95% CI 0.61-0.98)
+| style="background-color:#eeee01" |Equivalent OS
 |-
-|[https://doi.org/10.1016/S1470-2045(15)00553-7 Fujitani et al. 2016 (REGATTA)]
+|}
-|2008-2013
+''Note: this is reported to be an equivalence study but the statistical analysis does not provide details on the definition of equivalence.''
-| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+<div class="toccolours" style="background-color:#b3e2cd">
-| style="background-color:#d3d3d3" |
+====Chemotherapy====
-| style="background-color:#d3d3d3" |
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup> IV over 12 hours once per day on days 1 to 5, '''given second'''
+'''28-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 80/4000 x 8 {{#subobject:9abe95|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdv316 Ryu et al. 2015 (SOS)]
+|[https://doi.org/10.1093/annonc/mdx275 Ajani et al. 2017 (DIGEST)]
-|2009-2012
+|2011-2014
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_S-1|Cisplatin & S-1]]; SP3
+|[[#Cisplatin_.26_S-1|CS]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://doi.org/10.1093/annonc/mdu472 Yamada et al. 2014 (G-SOX)]
+|}
-|2010-01 to 2011-10
+<div class="toccolours" style="background-color:#b3e2cd">
-| style="background-color:#1a9851" |Phase 3 (C)
+====Chemotherapy====
-|[[#SOX_888|SOX]]
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''
-| style="background-color:#eeee01" |Non-inferior PFS
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)
+====Supportive therapy====
+*Some protocols: [[:Category:Hydration|"Hyperhydration"]] for cisplatin
+'''21-day cycle for 8 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 80/4000, indefinite {{#subobject:69c795|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/JCO.2018.77.8613 Ishigami et al. 2018 (PHOENIX-GC)]
+|[https://doi.org/10.1093/annonc/mdn717 Kang et al. 2009 (ML17032)]
-|2011-2013
+|2003-2005
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Paclitaxel_.26_S-1|IV/IP Paclitaxel & S-1]]
+|[[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
+| style="background-color:#eeee01" |Non-inferior PFS
+|-
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ Shitara et al. 2020 (KEYNOTE-062)]
+|rowspan=2|2015-2017
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
+|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab|CF & Pembrolizumab]]<br>1b. [[#Capecitabine_.26_Cisplatin_.28CX.29_.26_Pembrolizumab|CX & Pembrolizumab]]
 | style="background-color:#fee08b" |Might have inferior OS
 |-
-|[https://doi.org/10.1016/s2468-1253(19)30083-4 Yamada et al. 2019 (JCOG1013)]
+|2. [[#Pembrolizumab_monotherapy|Pembrolizumab]]
-|2012-2016
+| style="background-color:#eeee01" |Non-inferior OS
+|-
+|[https://www.clinicaltrials.gov/study/NCT03777657 Awaiting publication (BGB-A317-305)]
+|2018-ongoing
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_Docetaxel_.28DC.29_.26_S-1_999|Cisplatin, Docetaxel, S-1]]
+|1a. [[#CapeOx_.26_Tislelizumab_666|CapeOx & Tislelizumab]]<br>1b. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Tislelizumab_666|CF & Tislelizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of OS
 |-
-|[https://doi.org/10.1016/s1470-2045(20)30315-6 Kang et al. 2020 (SOLAR)]
+|[https://doi.org/10.1016/s1470-2045(23)00515-6 Rha et al. 2023 (KEYNOTE-859)]
-|2015-01-28 to 2016-12-05
+|2018-11-08 to 2021-06-11
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Oxaliplatin_.26_TAS-118_777|Oxaliplatin & TAS-118]]
+|1a. [[#CapeOx_.26_Pembrolizumab|CapeOx & Pembrolizumab]]<br>1b. [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab|CF & Pembrolizumab]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-''Note: in REGATTA, there was no difference in outcome amongst patients who did or did not undergo surgery. SPIRITS trial included patients with ECOG PS of 2 (3% of patients).''
-<div class="toccolours" style="background-color:#fdcdac">
-====Eligibility criteria====
-*REGATTA: presence of a single non-curable factor (ex: hepatic, peritoneal, and para-aortic mets), see link for further details
-*PHEONIX-GC: patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details
-</div>
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*REGATTA: Non-laparoscopic [[Surgery#Gastrectomy|gastrectomy]] with D1 [[Surgery#Lymphadenectomy|lymphadenectomy]] versus [[Surgery#No_surgery|no surgery]]; chemotherapy began within 8 weeks of surgery
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 8
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''
-*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)
-**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 21
+====Supportive therapy====
-**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 21
+*Some protocols: [[:Category:Hydration|"Hyperhydration"]] for cisplatin
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 21
+'''21-day cycles'''
-'''35-day cycles'''
+</div></div><br>
-</div></div>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 100/4000 {{#subobject:16f88f|Variant=1}}===
-===References===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#'''SPIRITS:''' Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. [https://doi.org/10.1016/S1470-2045(08)70035-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18282805/ PubMed] [https://clinicaltrials.gov/study/NCT00150670 NCT00150670]
+! style="width: 20%" |Study
-#'''FLAGS:''' Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. [https://doi.org/10.1200/JCO.2009.25.4706 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20159816/ PubMed] [https://clinicaltrials.gov/study/NCT00400179 NCT00400179]
+! style="width: 20%" |Dates of enrollment
-#'''G-SOX:''' Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015 Jan;26(1):141-8. Epub 2014 Oct 14. [https://doi.org/10.1093/annonc/mdu472 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25316259/ PubMed] JapicCTI-101021
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-#'''SOS:''' Ryu MH, Baba E, Lee KH, Park YI, Boku N, Hyodo I, Nam BH, Esaki T, Yoo C, Ryoo BY, Song EK, Cho SH, Kang WK, Yang SH, Zang DY, Shin DB, Park SR, Shinozaki K, Takano T, Kang YK; SOS study investigators. Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS). Ann Oncol. 2015 Oct;26(10):2097-101. Epub 2015 Jul 27. [https://doi.org/10.1093/annonc/mdv316 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26216386/ PubMed] [https://clinicaltrials.gov/study/NCT00915382 NCT00915382]
+! style="width: 20%" |Comparator
-#'''REGATTA:''' Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, Iwasaki Y, Hyung WJ, Takagane A, Park DJ, Yoshikawa T, Hahn S, Nakamura K, Park CH, Kurokawa Y, Bang YJ, Park BJ, Sasako M, Tsujinaka T; REGATTA study investigators. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016 Mar;17(3):309-18. Epub 2016 Jan 26. [https://doi.org/10.1016/S1470-2045(15)00553-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26822397/ PubMed] UMIN000001012
-#'''DIGEST:''' Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. [https://doi.org/10.1093/annonc/mdx275 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28911091/ PubMed] [https://clinicaltrials.gov/study/NCT01285557 NCT01285557]
-#'''PHOENIX-GC:''' Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. [https://doi.org/10.1200/JCO.2018.77.8613 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29746229/ PubMed] UMIN000005930
-#'''JCOG1013:''' Yamada Y, Boku N, Mizusawa J, Iwasa S, Kadowaki S, Nakayama N, Azuma M, Sakamoto T, Shitara K, Tamura T, Chin K, Hata H, Nakamori M, Hara H, Yasui H, Katayama H, Fukuda H, Yoshikawa T, Sasako M, Terashima M. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 Jul;4(7):501-510. Epub 2019 May 14. [https://doi.org/10.1016/s2468-1253(19)30083-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31101534/ PubMed] UMIN000007652
-#'''SOPP:''' Lee KW, Chung IJ, Ryu MH, Park YI, Nam BH, Oh HS, Lee KH, Han HS, Seo BG, Jo JC, Lee HR, Kim JW, Park SR, Cho SH, Kang YK; SOPP study investigators. Multicenter phase III trial of S-1 and cisplatin versus S-1 and oxaliplatin combination chemotherapy for first-line treatment of advanced gastric cancer (SOPP trial). Gastric Cancer. 2021 Jan;24(1):156-167. Epub 2020 Jun 28. [https://doi.org/10.1007/s10120-020-01101-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/32596783/ PubMed] [https://clinicaltrials.gov/study/NCT01671449 NCT01671449]
-#'''SOLAR:''' Kang YK, Chin K, Chung HC, Kadowaki S, Oh SC, Nakayama N, Lee KW, Hara H, Chung IJ, Tsuda M, Park SH, Hosaka H, Hironaka S, Miyata Y, Ryu MH, Baba H, Hyodo I, Bang YJ, Boku N. S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Aug;21(8):1045-1056. Epub 2020 Jul 16. [https://doi.org/10.1016/s1470-2045(20)30315-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/32682457/ PubMed] [https://clinicaltrials.gov/study/NCT02322593 NCT02322593]
-==CLF {{#subobject:b913d6|Regimen=1}}==
-CLF: '''<u>C</u>'''isplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil
-<br>FLP: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>P</u>'''latinol (Cisplatin)
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:beef19|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2007.13.9378 Al-Batran et al. 2008]
+|[http://ar.iiarjournals.org/content/26/5B/3877.long Duffour et al. 2006 (FFCD 9404)]
-|2003-2006
+|1995-1998
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#OLF|FLO]]
+|[[#CLF|FLP]]
-| style="background-color:#fee08b" |Might have inferior PFS
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior ORR
 |-
 |}
-''Note: In contrast to the original reference, some guidelines list 5-FU as being given every 2 weeks rather than the schedule below. Patients had 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric).''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43
+*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on either day 1 or 2
-*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
+'''28-day cycles'''
-====Supportive therapy====
-*Up to 3 liters [[normal saline]] as hydration with cisplatin
-*[[:Category:Emesis prevention|Antiemetic medications]] per "local protocols"
-'''8-week cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2 {{#subobject:34890|Variant=1}}===
+===Regimen variant #5, 100/4000, split-dose cisplatin {{#subobject:16f18e|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,945: / Line 1,875: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2004.01.140 Bouché et al. 2004 (FFCD 9803)]
+| rowspan="2" |[https://doi.org/10.1200/jco.2003.04.130 Ohtsu et al. 2003 (JCOG 9205)]
-|1999-2001
+| rowspan="2" |1992-1997
-| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
-|1. [[#FULV_2|LV5FU2]]<br>2. [[#FOLFIRI|LV5FU2 & Irinotecan]]
+|1. [[#Fluorouracil_monotherapy|Fluorouracil]]
-| style="background-color:#d3d3d3" |Not powered to draw conclusions
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|2. [[#UFTM|UFTM]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used.''
+''Note: this study included patients with ECOG PS of 2 (9.6%)''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on either day 1 or 2
+*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
-*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup>)
+'''28-day cycle for up to 6 cycles'''
-====Supportive therapy====
+</div></div><br>
-*1 liter [[:Category:Hydration|hydration]] over 3 hours before and after cisplatin
-*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] IV prior to cisplatin
-*[[Methylprednisolone (Solumedrol)]] 120 mg IV 10 minutes prior to cisplatin
-*Oral [[:Category:Emesis prevention|antiemetics]] and [[:Category:Steroids|corticosteroids]] from days 2 to 5
-'''14-day cycle for at least 4 cycles'''
-</div></div>
-===References===
-#'''FFCD 9803:''' Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [https://doi.org/10.1200/jco.2004.01.140 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15514373/ PubMed]
-#Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. [https://doi.org/10.1200/jco.2007.13.9378 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18349393/ PubMed]
-==DCF {{#subobject:efbdc5|Regimen=1}}==
-DCF: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-<br>TCF: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:5aba07|Variant=1}}===
+===Regimen variant #6, 100/5000 {{#subobject:10f0c6|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,980: / Line 1,901: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2005.17.376 Ajani et al. 2005 (V-325)]
+|[https://doi.org/10.1200/jco.2006.06.8429 Van Cutsem et al. 2006 (TAX 325)]
-|1998-1999
+|1999-2003
-| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_Docetaxel_.28DC.29|DC]]
+|[[#DCF|DCF]]
-| style="background-color:#91cf60" |Seems to have superior ORR
+| style="background-color:#fc8d59" |Seems to have inferior OS
+|-
+|[https://doi.org/10.1093/annonc/mdn166 Dank et al. 2008]
+|2000-2002
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FOLFIRI|IF]]
+| style="background-color:#fee08b" |Might have inferior TTP
 |-
-|[https://doi.org/10.1200/jco.2006.06.8429 Van Cutsem et al. 2006 (TAX 325)]
+|[https://doi.org/10.1200/JCO.2009.25.4706 Ajani et al. 2010 (FLAGS)]
-|1999-2003
+|2005-2007
-| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+|[[#Cisplatin_.26_S-1|CS]]
-| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br><br>Superior TTP (primary endpoint)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: In contrast to the original references, some guidelines list each cycle as lasting 28 days. V-325 patients had 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70. TAX 325 patients had 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS score of 70.''
+''Note: TAX 325 patients had 100% adenocarcinoma histology (22% Esophagogastric junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70. Dank et al patients had 100% adenocarcinoma histology (20% Esophagogastric junction, 80% gastric origin). 96% with metastatic disease. 1% with Karnofsky PS of 70.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 5000 mg/m<sup>2</sup>)
-*[[Fluorouracil (5-FU)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m<sup>2</sup>)
 ====Supportive therapy====
-*(varied depending on reference):
+*As described in Dank et al. 2008:
-*[[Dexamethasone (Decadron)]] 8 mg PO once the night before chemotherapy, then 8 mg PO once on day 1; 1 hour prior to chemotherapy, then 8 mg PO twice per day until day 2 (total dose per cycle: 48 mg)
+*[[:Category:Hydration|"Hyperhydration"]] for 2 to 3 days with each infusion
-*[[Dexamethasone (Decadron)]] 20 mg IV prior to cisplatin and 8 hours after cisplatin
+*[[Ondansetron (Zofran)]] IV for antiemetic prophylaxis
-*[[Ondansetron (Zofran)]] 8 mg IV prior to cisplatin, 4 hours after cisplatin, and 8 hours after cisplatin
+*[[Dexamethasone (Decadron)]] IV for antiemetic prophylaxis, then PO for 2 to 3 days
-*"[[:Category:Hydration|Hydration]] (was) administered in a standard manner"
+*[[Metoclopramide (Reglan)]] for antiemetic prophylaxis
-'''21-day cycles'''
+*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/μL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection
-</div></div><br>
+*[[Atropine (Atropen)]] prn cholinergic symptoms
+*[[Loperamide (Imodium)]] prn delayed diarrhea
+'''28-day cycles'''
+</div></div>
+===References===
+#'''JCOG 9205:''' Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; [[Study_Groups#JCOG|JCOG]]. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [https://doi.org/10.1200/jco.2003.04.130 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12506170/ PubMed]
+#'''FFCD 9404:''' Duffour J, Bouché O, Rougier P, Milan C, Bedenne L, Seitz JF, Buecher B, Legoux JL, Ducreux M, Vetter D, Raoul JL, François E, Ychou M. Safety of cisplatin combined with continuous 5-FU versus bolus 5-FU and leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised trial). Anticancer Res. 2006 Sep-Oct;26(5B):3877-83. [http://ar.iiarjournals.org/content/26/5B/3877.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17094417/ PubMed]
+#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [https://doi.org/10.1200/jco.2006.06.8429 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17075117/ PubMed]
+#Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. [https://doi.org/10.1093/annonc/mdn166 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18558665/ PubMed]
+#'''ML17032:''' Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [https://doi.org/10.1093/annonc/mdn717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19153121/ PubMed] [https://clinicaltrials.gov/study/NCT02563054 NCT02563054]
+#Lee KH, Hyun MS, Kim HK, Jin HM, Yang J, Song HS, Do YR, Ryoo HM, Chung JS, Zang DY, Lim HY, Jin JY, Yim CY, Park HS, Kim JS, Sohn CH, Lee SN. Randomized, multicenter, phase III trial of heptaplatin 1-hour infusion and 5-fluorouracil combination chemotherapy comparing with cisplatin and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer. Cancer Res Treat. 2009 Mar;41(1):12-8. Epub 2009 Mar 31. [https://doi.org/10.4143/crt.2009.41.1.12 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2699097/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19688066/ PubMed]
+#'''FLAGS:''' Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. [https://doi.org/10.1200/JCO.2009.25.4706 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20159816/ PubMed] [https://clinicaltrials.gov/study/NCT00400179 NCT00400179]
+#'''AVAGAST:''' Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://doi.org/10.1200/JCO.2011.36.2236 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21844504/ PubMed] [https://clinicaltrials.gov/study/NCT00548548 NCT00548548]
+#'''DIGEST:''' Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. [https://doi.org/10.1093/annonc/mdx275 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28911091/ PubMed] [https://clinicaltrials.gov/study/NCT01285557 NCT01285557]
+<!-- #'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://doi.org/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract] -->
+#'''KEYNOTE-062:''' Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. [https://doi.org/10.1001/jamaoncol.2020.3370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32880601/ PubMed] [https://clinicaltrials.gov/study/NCT02494583 NCT02494583]
+#'''KEYNOTE-859:''' Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. [https://doi.org/10.1016/s1470-2045(23)00515-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37875143/ PubMed] [https://clinicaltrials.gov/study/NCT03675737 NCT03675737]
+#'''BGB-A317-305:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03777657 NCT03777657]
+==Cisplatin & Fluorouracil (CF) & Pembrolizumab {{#subobject:25ncw1|Regimen=1}}==
+CF & Pembrolizumab: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, Pembrolizumab
 <div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:4fewd7|Variant=1}}===
-===Regimen variant #2 {{#subobject:baa015|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 2,017: / Line 1,962: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1200/jco.2006.08.0135 Roth et al. 2007]
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ Shitara et al. 2020 (KEYNOTE-062)]
-| rowspan="2" |1999-2003
+|rowspan=2|2015-2017
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
-|1. [[#ECF_3|ECF]]
+|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]<br>1b. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
+| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)<br>Median OS: 12.5 vs 11.1 mo<br>(HR 0.85, 95% CI 0.70-1.03)
+|-
+|2. [[#Pembrolizumab_monotherapy|Pembrolizumab]]
 | style="background-color:#d3d3d3" |Not reported
 |-
-|2. [[#Cisplatin_.26_Docetaxel_.28DC.29|TC]]
+|[https://doi.org/10.1016/s1470-2045(23)00515-6 Rha et al. 2023 (KEYNOTE-859)]
-| style="background-color:#d9ef8b" |Might have superior ORR (primary endpoint)
+|2018-11-08 to 2021-06-11
-|-
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|1a. [[#Cisplatin_.26_Fluorouracil_.28CF.29_2|CF]]<br>1b. [[#CapeOx_2|CapeOx]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 12.9 vs 11.5 mo<br>(HR 0.78, 95% CI 0.70-0.87)
 |}
-''Note: the protocol was amended to change the original dose of ''docetaxel from'' 85 mg/m<sup>2</sup> to 75 mg/m<sup>2</sup> based on high incidence of febrile neutropenia.''
+''KEYNOTE-062 & KEYNOTE-859 included patients with GEJ malignancy''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 4 hours once on day 1
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+====Immunotherapy====
-====Supportive therapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-*3 liters per day [[:Category:Hydration|"hyperhydration"]]
+'''21-day cycle for up to 35 cycles'''
-*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours prior to docetaxel, then 8 mg PO twice per day for 4 days after docetaxel
-*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis
-*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
-'''21-day cycle for up to 8 cycles'''
 </div></div>
 ===References===
-#'''V-325:''' Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [https://doi.org/10.1200/jco.2005.17.376 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16110025/ PubMed]
+<!-- #'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://doi.org/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract] -->
-#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [https://doi.org/10.1200/jco.2006.06.8429 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17075117/ PubMed]
+#'''KEYNOTE-062:''' Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. [https://doi.org/10.1001/jamaoncol.2020.3370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32880601/ PubMed] [https://clinicaltrials.gov/study/NCT02494583 NCT02494583]
-#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [https://doi.org/10.1200/jco.2006.08.0135 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17664469/ PubMed]
+#'''KEYNOTE-859:''' Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. [https://doi.org/10.1016/s1470-2045(23)00515-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37875143/ PubMed] [https://clinicaltrials.gov/study/NCT03675737 NCT03675737]
-==mDCF {{#subobject:70e20f|Regimen=1}}==
+==Cisplatin & S-1 {{#subobject:252c51|Regimen=1}}==
-mDCF: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+CS: '''<u>C</u>'''isplatin & '''<u>S</u>'''-1
+<br>SP: '''<u>S</u>'''-1 & '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 40/40/2800 {{#subobject:372f9c|Variant=1}}===
+===Regimen variant #1, q3wk ("SP3") {{#subobject:4ff7cf|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Dates of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ Shah et al. 2010 (MSK 06-096)]
-|2006-2008
-| style="background-color:#91cf61" |Phase 2
-|-
-|}
-''Note: In contrast to the primary reference, some guidelines list this regimen without bevacizumab. Please see below for the original mDCF regimen that included bevacizumab. Patients had 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 3
-*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-====Supportive therapy====
-*"Standard premedication and delayed emesis regimens"
-'''14-day cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 60/60/3000, 4-day 5-FU infusion {{#subobject:323b13|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 2,078: / Line 2,006: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688303/ Wang et al. 2015 (DOCET L 02195)]
+|[https://doi.org/10.1093/annonc/mdv316 Ryu et al. 2015 (SOS)]
-|2008-2010
+|2009-2012
-| style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+|[[#Cisplatin_.26_S-1|Cisplatin & S-1]]; SP5
-| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 10.2 vs 8.5 mo<br>(HR 0.71, 95% CI 0.52-0.97)
+| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 5.5 vs 4.9 mo<br>(HR 0.82, 95% CI 0.68-0.99)
+|-
+|[https://doi.org/10.1007/s10120-020-01101-4 Lee et al. 2020 (SOPP)]
+|2012-2014
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#SOX_888|SOX]]
+| style="background-color:#eeee01" |Non-inferior PFS
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
 *[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)
+*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 '''21-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 60/60/3000, 5-day 5-FU infusion {{#subobject:323bug|Variant=1}}===
+===Regimen variant #2, q4wk {{#subobject:03b3c4|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 2,101: / Line 2,034: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688303/ Wang et al. 2015 (DOCET L 02195)]
+|[https://doi.org/10.1200/JCO.2009.25.4706 Ajani et al. 2010 (FLAGS)]
-|2008-2010
+|2005-2007
-| style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://doi.org/10.1093/annonc/mdx275 Ajani et al. 2017 (DIGEST)]
+|2011-2014
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 |[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
-| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 10.2 vs 8.5 mo<br>(HR 0.71, 95% CI 0.52-0.97)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+''Note: This was an experimental arm of a study where the primary endpoint was not met. Included because CS has been shown to be superior in comparison to other regimens (see above).''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Tegafur, gimeracil, oteracil (S-1)]] 25 mg/m<sup>2</sup> PO twice per day on days 1 to 21
-*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)
+'''28-day cycles'''
-'''21-day cycles'''
+</div></div><br>
-</div></div>
-===References===
-#'''MSK 06-096:''' Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [https://doi.org/10.1200/jco.2010.32.0770 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21189380/ PubMed] [https://clinicaltrials.gov/study/NCT00390416 NCT00390416]
-#'''DOCET L 02195:''' Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S, Dai G, Xu J, Liu Y, Fan N, Shu Y, Ba Y, Ma D, Qin S, Zheng L, Chen W, Shen L. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer. 2016 Jan;19(1):234-44. Epub 2015 Jan 21. [https://doi.org/10.1007/s10120-015-0457-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688303/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25604851/ PubMed] [https://clinicaltrials.gov/study/NCT00811447 NCT00811447]
-==mDCF & Bevacizumab {{#subobject:30ea9e|Regimen=1}}==
-mDCF & Bevacizumab: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil & Bevacizumab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:5485f9|Variant=1}}===
+===Regimen variant #3, q5wk ("SP5") {{#subobject:cdcc15|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 20%" |Study
-!style="width: 33%"|Dates of enrollment
+! style="width: 20%" |Dates of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ Shah et al. 2010 (MSK 06-096)]
-|2006-2008
-| style="background-color:#91cf61" |Phase 2
-|-
-|}
-''Note: patients had 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 3
-*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
-====Supportive therapy====
-*"Standard premedication and delayed emesis regimens"
-'''14-day cycles'''
-</div></div>
-===References===
-#'''MSK 06-096:''' Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [https://doi.org/10.1200/jco.2010.32.0770 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21189380/ PubMed] [https://clinicaltrials.gov/study/NCT00390416 NCT00390416]
-==Docetaxel & S-1 {{#subobject:a22c2a|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:82ca03|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ Koizumi et al. 2013 (START<sub>gastric</sub>)]
+|[https://doi.org/10.1016/S1470-2045(08)70035-4 Koizumi et al. 2008 (SPIRITS)]
-|2005-2008
+|2002-2004
 | style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[#S-1_monotherapy_2|S-1]]
-| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 12.5 vs 10.8 mo<br>(HR 0.84, 95% CI 0.71-0.99)
+| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 13 vs 11 mo<br>(HR 0.77, 95% CI 0.61-0.98)
-|}
+|-
-<div class="toccolours" style="background-color:#b3e2cd">
+|[https://doi.org/10.1016/S1470-2045(15)00553-7 Fujitani et al. 2016 (REGATTA)]
-====Chemotherapy====
+|2008-2013
-*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
-'''21-day cycles'''
-</div></div>
-===References===
-#'''START:''' Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO; KCSG. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. [https://doi.org/10.1007/s00432-013-1563-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24366758/ PubMed] [https://clinicaltrials.gov/study/NCT00287768 NCT00287768]
-==ECF {{#subobject:6325cb|Regimen=1}}==
-ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:e5ede0|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/oxfordjournals.annonc.a058932 Findlay et al. 1994]
-|1988-1992
-| style="background-color:#91cf61" |Phase 2
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[https://doi.org/10.1200/JCO.1997.15.1.261 Webb et al. 1997]
+|[https://doi.org/10.1093/annonc/mdv316 Ryu et al. 2015 (SOS)]
-|1992-1995
+|2009-2012
-| style="background-color:#1a9851" |Randomized (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Gastric_cancer_-_historical#FAMTX|FAMTX]]
+|[[#Cisplatin_.26_S-1|Cisplatin & S-1]]; SP3
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#fc8d59" |Seems to have inferior PFS
 |-
-|[https://doi.org/10.1200/jco.2002.08.105 Ross et al. 2002]
+|[https://doi.org/10.1093/annonc/mdu472 Yamada et al. 2014 (G-SOX)]
-|1995-1998
+|2010-01 to 2011-10
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#MCF|MCF]]
+|[[#SOX_888|SOX]]
-| style="background-color:#eeee01" |Seems to have non-inferior OS
+| style="background-color:#eeee01" |Non-inferior PFS
 |-
-|[https://doi.org/10.1200/jco.2006.08.0135 Roth et al. 2007]
+|[https://doi.org/10.1200/JCO.2018.77.8613 Ishigami et al. 2018 (PHOENIX-GC)]
-|1999-2003
+|2011-2013
-| style="background-color:#1a9851" |Randomized Phase 2 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Cisplatin_.26_Docetaxel_.28DC.29|TC]]<br>2. [[#DCF|TCF]]
+|[[#Paclitaxel_.26_S-1|IV/IP Paclitaxel & S-1]]
-| style="background-color:#d3d3d3" |Not reported
+| style="background-color:#fee08b" |Might have inferior OS
 |-
-| rowspan="3" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+|[https://doi.org/10.1016/s2468-1253(19)30083-4 Yamada et al. 2019 (JCOG1013)]
-| rowspan="3" |2000-2005
+|2012-2016
-| rowspan="3" style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#ECX_2|ECX]]
+|[[#Cisplatin_.26_Docetaxel_.28DC.29_.26_S-1_999|Cisplatin, Docetaxel, S-1]]
-| style="background-color:#eeee01" |Non-inferior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|2. [[#EOF_2|EOF]]
+|[https://doi.org/10.1016/s1470-2045(20)30315-6 Kang et al. 2020 (SOLAR)]
-| style="background-color:#eeee01" |Non-inferior OS
+|2015-01-28 to 2016-12-05
-|-
+| style="background-color:#1a9851" |Phase 3 (C)
-|3. [[#EOX_2|EOX]]
+|[[#Oxaliplatin_.26_TAS-118_777|Oxaliplatin & TAS-118]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
+| style="background-color:#fc8d59" |Seems to have inferior PFS
 |-
 |}
-''Note: Findlay et al. patients all had metastatic gastric cancer. Ross et al. patients had adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer. Roth et al. patients all had metastatic gastric cancer. REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
+''Note: in REGATTA, there was no difference in outcome amongst patients who did or did not undergo surgery. SPIRITS trial included patients with ECOG PS of 2 (3% of patients).''
-<div class="toccolours" style="background-color:#b3e2cd">
+<div class="toccolours" style="background-color:#fdcdac">
-====Chemotherapy====
+====Eligibility criteria====
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
+*REGATTA: presence of a single non-curable factor (ex: hepatic, peritoneal, and para-aortic mets), see link for further details
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1
+*PHEONIX-GC: patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+</div>
-====Supportive therapy====
+<div class="toccolours" style="background-color:#cbd5e8">
-*(varied depending on reference):
+====Preceding treatment====
-*3 liters per day [[:Category:Hydration|"hyperhydration"]]
+*REGATTA: Non-laparoscopic [[Surgery#Gastrectomy|gastrectomy]] with D1 [[Surgery#Lymphadenectomy|lymphadenectomy]] versus [[Surgery#No_surgery|no surgery]]; chemotherapy began within 8 weeks of surgery
-*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis
+</div>
-*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
+<div class="toccolours" style="background-color:#b3e2cd">
-*Ross et al. 2002 & Cunningham et al. 2008 used [[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
+====Chemotherapy====
-'''21-day cycle for up to 8 cycles'''
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 8
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 21
+**Between 1.25 m<sup>2</sup> and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 21
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 21
+'''35-day cycles'''
 </div></div>
 ===References===
-#Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson V, Nash A, Sacks N, Ford H, Carter R, Hill A. A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol. 1994 Sep;5(7):609-16. [https://doi.org/10.1093/oxfordjournals.annonc.a058932 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7993836/ PubMed]
+#'''SPIRITS:''' Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. [https://doi.org/10.1016/S1470-2045(08)70035-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18282805/ PubMed] [https://clinicaltrials.gov/study/NCT00150670 NCT00150670]
-#Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997 Jan;15(1):261-7. [https://doi.org/10.1200/JCO.1997.15.1.261 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8996151/ PubMed]
+#'''FLAGS:''' Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. [https://doi.org/10.1200/JCO.2009.25.4706 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20159816/ PubMed] [https://clinicaltrials.gov/study/NCT00400179 NCT00400179]
-##'''Update:''' Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Hickish T. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer. 1999 Apr;80(1-2):269-72. [https://doi.org/10.1038/sj.bjc.6690350 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363002/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/10390007/ PubMed]
+#'''G-SOX:''' Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015 Jan;26(1):141-8. Epub 2014 Oct 14. [https://doi.org/10.1093/annonc/mdu472 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25316259/ PubMed] JapicCTI-101021
-#Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. [https://doi.org/10.1200/jco.2002.08.105 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11956258/ PubMed]
+#'''SOS:''' Ryu MH, Baba E, Lee KH, Park YI, Boku N, Hyodo I, Nam BH, Esaki T, Yoo C, Ryoo BY, Song EK, Cho SH, Kang WK, Yang SH, Zang DY, Shin DB, Park SR, Shinozaki K, Takano T, Kang YK; SOS study investigators. Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS). Ann Oncol. 2015 Oct;26(10):2097-101. Epub 2015 Jul 27. [https://doi.org/10.1093/annonc/mdv316 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26216386/ PubMed] [https://clinicaltrials.gov/study/NCT00915382 NCT00915382]
-#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [https://doi.org/10.1200/jco.2006.08.0135 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17664469/ PubMed]
+#'''REGATTA:''' Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, Iwasaki Y, Hyung WJ, Takagane A, Park DJ, Yoshikawa T, Hahn S, Nakamura K, Park CH, Kurokawa Y, Bang YJ, Park BJ, Sasako M, Tsujinaka T; REGATTA study investigators. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016 Mar;17(3):309-18. Epub 2016 Jan 26. [https://doi.org/10.1016/S1470-2045(15)00553-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26822397/ PubMed] UMIN000001012
-#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
+#'''DIGEST:''' Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. [https://doi.org/10.1093/annonc/mdx275 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28911091/ PubMed] [https://clinicaltrials.gov/study/NCT01285557 NCT01285557]
-==ECX {{#subobject:36cac7|Regimen=1}}==
+#'''PHOENIX-GC:''' Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. [https://doi.org/10.1200/JCO.2018.77.8613 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29746229/ PubMed] UMIN000005930
-ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+#'''JCOG1013:''' Yamada Y, Boku N, Mizusawa J, Iwasa S, Kadowaki S, Nakayama N, Azuma M, Sakamoto T, Shitara K, Tamura T, Chin K, Hata H, Nakamori M, Hara H, Yasui H, Katayama H, Fukuda H, Yoshikawa T, Sasako M, Terashima M. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 Jul;4(7):501-510. Epub 2019 May 14. [https://doi.org/10.1016/s2468-1253(19)30083-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31101534/ PubMed] UMIN000007652
-<br>ECC: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>C</u>'''apecitabine
+#'''SOPP:''' Lee KW, Chung IJ, Ryu MH, Park YI, Nam BH, Oh HS, Lee KH, Han HS, Seo BG, Jo JC, Lee HR, Kim JW, Park SR, Cho SH, Kang YK; SOPP study investigators. Multicenter phase III trial of S-1 and cisplatin versus S-1 and oxaliplatin combination chemotherapy for first-line treatment of advanced gastric cancer (SOPP trial). Gastric Cancer. 2021 Jan;24(1):156-167. Epub 2020 Jun 28. [https://doi.org/10.1007/s10120-020-01101-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/32596783/ PubMed] [https://clinicaltrials.gov/study/NCT01671449 NCT01671449]
+#'''SOLAR:''' Kang YK, Chin K, Chung HC, Kadowaki S, Oh SC, Nakayama N, Lee KW, Hara H, Chung IJ, Tsuda M, Park SH, Hosaka H, Hironaka S, Miyata Y, Ryu MH, Baba H, Hyodo I, Bang YJ, Boku N. S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Aug;21(8):1045-1056. Epub 2020 Jul 16. [https://doi.org/10.1016/s1470-2045(20)30315-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/32682457/ PubMed] [https://clinicaltrials.gov/study/NCT02322593 NCT02322593]
+==CLF {{#subobject:b913d6|Regimen=1}}==
+CLF: '''<u>C</u>'''isplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil
+<br>FLP: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, continuous capecitabine {{#subobject:f0efc0|Variant=1}}===
+===Regimen variant #1 {{#subobject:beef19|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 2,255: / Line 2,149: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+|[https://doi.org/10.1200/jco.2007.13.9378 Al-Batran et al. 2008]
-|rowspan=2|2000-2005
+|2003-2006
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#ECF_2|ECF]]
+|[[#OLF|FLO]]
-| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|2. [[#EOF_2|EOF]]<br> 3. [[#EOX_2|EOX]]
-| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5898242/ Catenacci et al. 2017 (RILOMET-1)]
-|2012-2014
-| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|[[#ECX_.26_Rilotumumab_777|ECX & Rilotumumab]]
-| style="background-color:#1a9850" |Superior OS<br>Median OS: 10.7 vs 8.8 mo<br>(HR 0.75, 95% CI 0.61-0.91)
 |-
 |}
-''Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2. RILOMET-1 patients had unresectable or metastatic MET-positive gastric or gastro-esophageal junction cancer. ~80% gastric, 20% GE junction and 10% distal esophageal.''
+''Note: In contrast to the original reference, some guidelines list 5-FU as being given every 2 weeks rather than the schedule below. Patients had 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric).''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day
+*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
-'''21-day cycle for up to 10 cycles'''
+====Supportive therapy====
+*Up to 3 liters [[normal saline]] as hydration with cisplatin
+*[[:Category:Emesis prevention|Antiemetic medications]] per "local protocols"
+'''8-week cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, intermittent capecitabine {{#subobject:f0efc0|Variant=1}}===
+===Regimen variant #2 {{#subobject:34890|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 2,288: / Line 2,176: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/j.ejca.2010.07.036 Konings et al. 2010]
+|[https://doi.org/10.1200/jco.2004.01.140 Bouché et al. 2004 (FFCD 9803)]
-|2005-2009
+|1999-2001
-| style="background-color:#1a9851" |Randomized Phase 2 (C)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
-|[[#ECX_.26_Pravastatin_999|ECC & Pravastatin]]
+|1. [[#FULV_2|LV5FU2]]<br>2. [[#FOLFIRI|LV5FU2 & Irinotecan]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS6
+| style="background-color:#d3d3d3" |Not powered to draw conclusions
 |-
 |}
-''Note: 6.6% of patients had an ECOG PS of 2''
+''Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1, '''given first'''
+*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on either day 1 or 2
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given second'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup>)
-'''21-day cycle for up to 6 cycles'''
+====Supportive therapy====
-</div></div>
+*1 liter [[:Category:Hydration|hydration]] over 3 hours before and after cisplatin
-===References===
+*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] IV prior to cisplatin
-#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
+*[[Methylprednisolone (Solumedrol)]] 120 mg IV 10 minutes prior to cisplatin
-#Konings IR, van der Gaast A, van der Wijk LJ, de Jongh FE, Eskens FA, Sleijfer S. The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial. Eur J Cancer. 2010 Dec;46(18):3200-4. Epub 2010 Aug 18. [https://doi.org/10.1016/j.ejca.2010.07.036 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20727735/ PubMed]
+*Oral [[:Category:Emesis prevention|antiemetics]] and [[:Category:Steroids|corticosteroids]] from days 2 to 5
-#'''RILOMET-1:''' Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe M, De Vita F, Turkington C, Tang R, Ang A, Zhang Y, Hoang T, Sidhu R, Cunningham D. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1467-1482. Epub 2017 Sep 25. [https://doi.org/10.1016/S1470-2045(17)30566-1 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5898242/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28958504/ PubMed] [https://clinicaltrials.gov/study/NCT01697072 NCT01697072]
+'''14-day cycle for at least 4 cycles'''
-==EOF {{#subobject:a6390c|Regimen=1}}==
+</div></div>
-EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
+===References===
-<div class="toccolours" style="background-color:#eeeeee">
+#'''FFCD 9803:''' Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [https://doi.org/10.1200/jco.2004.01.140 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15514373/ PubMed]
-===Regimen {{#subobject:abf19f|Variant=1}}===
+#Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. [https://doi.org/10.1200/jco.2007.13.9378 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18349393/ PubMed]
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+==DCF {{#subobject:efbdc5|Regimen=1}}==
-!style="width: 20%"|Study
+DCF: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-!style="width: 20%"|Dates of enrollment
+<br>TCF: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:5aba07|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.2005.17.376 Ajani et al. 2005 (V-325)]
+|1998-1999
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|[[#Cisplatin_.26_Docetaxel_.28DC.29|DC]]
+| style="background-color:#91cf60" |Seems to have superior ORR
+|-
+|[https://doi.org/10.1200/jco.2006.06.8429 Van Cutsem et al. 2006 (TAX 325)]
+|1999-2003
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br><br>Superior TTP (primary endpoint)
+|-
+|}
+''Note: In contrast to the original references, some guidelines list each cycle as lasting 28 days. V-325 patients had 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70. TAX 325 patients had 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS score of 70.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1
+*[[Fluorouracil (5-FU)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m<sup>2</sup>)
+====Supportive therapy====
+*(varied depending on reference):
+*[[Dexamethasone (Decadron)]] 8 mg PO once the night before chemotherapy, then 8 mg PO once on day 1; 1 hour prior to chemotherapy, then 8 mg PO twice per day until day 2 (total dose per cycle: 48 mg)
+*[[Dexamethasone (Decadron)]] 20 mg IV prior to cisplatin and 8 hours after cisplatin
+*[[Ondansetron (Zofran)]] 8 mg IV prior to cisplatin, 4 hours after cisplatin, and 8 hours after cisplatin
+*"[[:Category:Hydration|Hydration]] (was) administered in a standard manner"
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:baa015|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1200/jco.2006.08.0135 Roth et al. 2007]
+| rowspan="2" |1999-2003
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|1. [[#ECF_3|ECF]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+|2. [[#Cisplatin_.26_Docetaxel_.28DC.29|TC]]
+| style="background-color:#d9ef8b" |Might have superior ORR (primary endpoint)
+|-
+|}
+''Note: the protocol was amended to change the original dose of ''docetaxel from'' 85 mg/m<sup>2</sup> to 75 mg/m<sup>2</sup> based on high incidence of febrile neutropenia.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 4 hours once on day 1
+*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+====Supportive therapy====
+*3 liters per day [[:Category:Hydration|"hyperhydration"]]
+*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours prior to docetaxel, then 8 mg PO twice per day for 4 days after docetaxel
+*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis
+*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
+'''21-day cycle for up to 8 cycles'''
+</div></div>
+===References===
+#'''V-325:''' Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [https://doi.org/10.1200/jco.2005.17.376 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16110025/ PubMed]
+#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [https://doi.org/10.1200/jco.2006.06.8429 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17075117/ PubMed]
+#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [https://doi.org/10.1200/jco.2006.08.0135 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17664469/ PubMed]
+==mDCF {{#subobject:70e20f|Regimen=1}}==
+mDCF: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 60/60/3000, 4-day 5-FU infusion {{#subobject:323b13|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688303/ Wang et al. 2015 (DOCET L 02195)]
+|2008-2010
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 10.2 vs 8.5 mo<br>(HR 0.71, 95% CI 0.52-0.97)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 60/60/3000, 5-day 5-FU infusion {{#subobject:323bug|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688303/ Wang et al. 2015 (DOCET L 02195)]
+|2008-2010
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 10.2 vs 8.5 mo<br>(HR 0.71, 95% CI 0.52-0.97)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)
+'''21-day cycles'''
+</div></div>
+===References===
+#'''DOCET L 02195:''' Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S, Dai G, Xu J, Liu Y, Fan N, Shu Y, Ba Y, Ma D, Qin S, Zheng L, Chen W, Shen L. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer. 2016 Jan;19(1):234-44. Epub 2015 Jan 21. [https://doi.org/10.1007/s10120-015-0457-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688303/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25604851/ PubMed] [https://clinicaltrials.gov/study/NCT00811447 NCT00811447]
+==mDCF & Bevacizumab {{#subobject:30ea9e|Regimen=1}}==
+mDCF & Bevacizumab: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil & Bevacizumab
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:5485f9|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ Shah et al. 2010 (MSK 06-096)]
+|2006-2008
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+''Note: patients had 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy. Unlike most DCF regimens that we are aware of, this one includes leucovorin.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 3
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
+====Supportive therapy====
+*"Standard premedication and delayed emesis regimens"
+'''14-day cycles'''
+</div></div>
+===References===
+#'''MSK 06-096:''' Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [https://doi.org/10.1200/jco.2010.32.0770 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21189380/ PubMed] [https://clinicaltrials.gov/study/NCT00390416 NCT00390416]
+==Docetaxel & S-1 {{#subobject:a22c2a|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:82ca03|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ Koizumi et al. 2013 (START<sub>gastric</sub>)]
+|2005-2008
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#S-1_monotherapy_2|S-1]]
+| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 12.5 vs 10.8 mo<br>(HR 0.84, 95% CI 0.71-0.99)
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
+**Between 1.25 m<sup>2</sup> and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
+'''21-day cycles'''
+</div></div>
+===References===
+#'''START:''' Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO; KCSG. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. [https://doi.org/10.1007/s00432-013-1563-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24366758/ PubMed] [https://clinicaltrials.gov/study/NCT00287768 NCT00287768]
+==ECF {{#subobject:6325cb|Regimen=1}}==
+ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e5ede0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1093/oxfordjournals.annonc.a058932 Findlay et al. 1994]
+|1988-1992
+| style="background-color:#91cf61" |Phase 2
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1200/JCO.1997.15.1.261 Webb et al. 1997]
+|1992-1995
+| style="background-color:#1a9851" |Randomized (E-switch-ic)
+|[[Gastric_cancer_-_historical#FAMTX|FAMTX]]
+| style="background-color:#1a9850" |Superior OS
+|-
+|[https://doi.org/10.1200/jco.2002.08.105 Ross et al. 2002]
+|1995-1998
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#MCF|MCF]]
+| style="background-color:#eeee01" |Seems to have non-inferior OS
+|-
+|[https://doi.org/10.1200/jco.2006.08.0135 Roth et al. 2007]
+|1999-2003
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|1. [[#Cisplatin_.26_Docetaxel_.28DC.29|TC]]<br>2. [[#DCF|TCF]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+| rowspan="3" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+| rowspan="3" |2000-2005
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#ECX_2|ECX]]
+| style="background-color:#eeee01" |Non-inferior OS
+|-
+|2. [[#EOF_2|EOF]]
+| style="background-color:#eeee01" |Non-inferior OS
+|-
+|3. [[#EOX_2|EOX]]
+| style="background-color:#fc8d59" |Seems to have inferior OS
+|-
+|}
+''Note: Findlay et al. patients all had metastatic gastric cancer. Ross et al. patients had adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer. Roth et al. patients all had metastatic gastric cancer. REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+====Supportive therapy====
+*(varied depending on reference):
+*3 liters per day [[:Category:Hydration|"hyperhydration"]]
+*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis
+*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
+*Ross et al. 2002 & Cunningham et al. 2008 used [[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
+'''21-day cycle for up to 8 cycles'''
+</div></div>
+===References===
+#Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson V, Nash A, Sacks N, Ford H, Carter R, Hill A. A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol. 1994 Sep;5(7):609-16. [https://doi.org/10.1093/oxfordjournals.annonc.a058932 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7993836/ PubMed]
+#Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997 Jan;15(1):261-7. [https://doi.org/10.1200/JCO.1997.15.1.261 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8996151/ PubMed]
+##'''Update:''' Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Hickish T. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer. 1999 Apr;80(1-2):269-72. [https://doi.org/10.1038/sj.bjc.6690350 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363002/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/10390007/ PubMed]
+#Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. [https://doi.org/10.1200/jco.2002.08.105 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11956258/ PubMed]
+#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [https://doi.org/10.1200/jco.2006.08.0135 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17664469/ PubMed]
+#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
+==ECX {{#subobject:36cac7|Regimen=1}}==
+ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+<br>ECC: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>C</u>'''apecitabine
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, continuous capecitabine {{#subobject:f0efc0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+|rowspan=2|2000-2005
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|1. [[#ECF_2|ECF]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+|-
+|2. [[#EOF_2|EOF]]<br> 3. [[#EOX_2|EOX]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5898242/ Catenacci et al. 2017 (RILOMET-1)]
+|2012-2014
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#ECX_.26_Rilotumumab_999|ECX & Rilotumumab]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 10.7 vs 8.8 mo<br>(HR 0.75, 95% CI 0.61-0.91)
+|-
+|}
+''Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2. RILOMET-1 patients had unresectable or metastatic MET-positive gastric or gastro-esophageal junction cancer. ~80% gastric, 20% GE junction and 10% distal esophageal.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day
+'''21-day cycle for up to 8 cycles (REAL-2) or 10 cycles (RILOMET-1)'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, intermittent capecitabine {{#subobject:f0efc0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/j.ejca.2010.07.036 Konings et al. 2010]
+|2005-2009
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#ECX_.26_Pravastatin_999|ECC & Pravastatin]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS6
+|-
+|}
+''Note: 6.6% of patients had an ECOG PS of 2''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1, '''given first'''
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given second'''
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+'''21-day cycle for up to 6 cycles'''
+</div></div>
+===References===
+#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
+#Konings IR, van der Gaast A, van der Wijk LJ, de Jongh FE, Eskens FA, Sleijfer S. The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial. Eur J Cancer. 2010 Dec;46(18):3200-4. Epub 2010 Aug 18. [https://doi.org/10.1016/j.ejca.2010.07.036 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20727735/ PubMed]
+#'''RILOMET-1:''' Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe M, De Vita F, Turkington C, Tang R, Ang A, Zhang Y, Hoang T, Sidhu R, Cunningham D. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1467-1482. Epub 2017 Sep 25. [https://doi.org/10.1016/S1470-2045(17)30566-1 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5898242/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28958504/ PubMed] [https://clinicaltrials.gov/study/NCT01697072 NCT01697072]
+==EOF {{#subobject:a6390c|Regimen=1}}==
+EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:abf19f|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+|rowspan=2|2000-2005
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|1. [[#ECF_2|ECF]]<br>2. [[#ECX_2|ECX]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+|-
+|3. [[#EOX_2|EOX]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+|-
+|}
+''Note: patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+====Supportive therapy====
+*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
+'''21-day cycle for up to 8 cycles'''
+</div></div>
+===References===
+#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
+==EOX {{#subobject:438182|Regimen=1}}==
+EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)
+<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:339609|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+| rowspan="3" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|rowspan=2|2000-2005
+|rowspan=3|2000-2005
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-|1. [[#ECF_2|ECF]]<br>2. [[#ECX_2|ECX]]
+|1. [[#ECF_2|ECF]]
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 11.2 vs 9.9 mo<br>(HR 0.80, 95% CI 0.66-0.97)
+|-
+|2. [[#ECX_2|ECX]]
 | style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
 |-
-|3. [[#EOX_2|EOX]]
+|3. [[#EOF_2|EOF]]
-| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
-|-
-|}
-''Note: patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
-====Supportive therapy====
-*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
-'''21-day cycle for up to 8 cycles'''
-</div></div>
-===References===
-#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
-==EOX {{#subobject:438182|Regimen=1}}==
-EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)
-<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:339609|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="3" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|rowspan=3|2000-2005
-| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-|1. [[#ECF_2|ECF]]
-| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 11.2 vs 9.9 mo<br>(HR 0.80, 95% CI 0.66-0.97)
-|-
-|2. [[#ECX_2|ECX]]
-| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
-|-
-|3. [[#EOF_2|EOF]]
 | style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
 |-
@@ Line 2,430: / Line 2,641: @@
 | rowspan="2" |2000-2006
 | rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Cisplatin_.26_Irinotecan_888|Cisplatin & Irinotecan]]
+|1. [[#Cisplatin_.26_Irinotecan_333|Cisplatin & Irinotecan]]
 | style="background-color:#fee08b" |Might have inferior OS
 |-
@@ Line 2,461: / Line 2,672: @@
 |NR
 | style="background-color:#1a9851" |Phase 3 (E-de-esc)
-|1. [[#Doxorubicin_.26_Fluorouracil_.28FA.29_888|FA]]<br>2. [[Gastric_cancer_-_historical#FAM|FAM]]
+|1. [[#Doxorubicin_.26_Fluorouracil_.28FA.29_888|FA]]<br>2. [[Gastric_cancer_-_historical#FAM_2|FAM]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: this is an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.''
+''Note: This was an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
@@ Line 2,668: / Line 2,879: @@
 |2015-2019
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#mFOLFOX6_.26_Andecaliximab_777|mFOLFOX6 & Andecaliximab]]
+|[[#mFOLFOX6_.26_Andecaliximab_999|mFOLFOX6 & Andecaliximab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
@@ Line 2,725: / Line 2,936: @@
 #'''CheckMate 649:''' Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. [https://doi.org/10.1016/s0140-6736(21)00797-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34102137/ PubMed] [https://clinicaltrials.gov/study/NCT02872116 NCT02872116]
 ##'''Update:''' Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. [https://doi.org/10.1038/s41586-022-04508-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967713/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35322232/ PubMed]
+##'''HRQoL analysis:''' Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. [https://doi.org/10.1200/jco.23.00170 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10713185/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37713657/ PubMed]
 #'''SPOTLIGHT:''' Shitara K, Lordick F, Bang YJ, Enzinger P, Ilson D, Shah MA, Van Cutsem E, Xu RH, Aprile G, Xu J, Chao J, Pazo-Cid R, Kang YK, Yang J, Moran D, Bhattacharya P, Arozullah A, Park JW, Oh M, Ajani JA. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023 May 20;401(10389):1655-1668. Epub 2023 Apr 15. Erratum in: Lancet. 2023 Jul 22;402(10398):290. [https://doi.org/10.1016/s0140-6736(23)00620-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37068504/ PubMed] [https://clinicaltrials.gov/study/NCT03504397 NCT03504397]
@@ Line 2,741: / Line 2,953: @@
 |2015-2019
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#mFOLFOX6_.26_Andecaliximab_777|mFOLFOX6 & Andecaliximab]]
+|[[#mFOLFOX6_.26_Andecaliximab_999|mFOLFOX6 & Andecaliximab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
@@ Line 2,778: / Line 2,990: @@
 |rowspan=2|2017-03 to 2019-04
 |rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|1a. [[#CapeOx_2|CapeOx]]<br>1b. [[#mFOLFOX6|mFOLFOX6]]
+|1a. [[#CapeOx_2|CapeOx]]<br>1b. [[#mFOLFOX6_2|mFOLFOX6]]
 | style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 14.4 vs 11.1 mo<br>(HR 0.70, 95% CI 0.61-0.81)
 |-
@@ Line 2,798: / Line 3,010: @@
 #'''CheckMate 649:''' Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. [https://doi.org/10.1016/s0140-6736(21)00797-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34102137/ PubMed] [https://clinicaltrials.gov/study/NCT02872116 NCT02872116]
 ##'''Update:''' Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. [https://doi.org/10.1038/s41586-022-04508-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967713/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35322232/ PubMed]
+##'''HRQoL analysis:''' Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. [https://doi.org/10.1200/jco.23.00170 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10713185/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37713657/ PubMed]
 ==FULV {{#subobject:5aad1e|Regimen=1}}==
 FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin
@@ Line 2,835: / Line 3,048: @@
 |2014-02 to 2019-01
 |style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#mFOLFOX6|mFOLFOX6]]<br>1b. [[#CapeOx_2|CapeOx]]<br>1c. [[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br>1d. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
+|1a. [[#mFOLFOX6_2|mFOLFOX6]]<br>1b. [[#CapeOx_2|CapeOx]]<br>1c. [[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br>1d. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
@@ Line 2,883: / Line 3,096: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://link.springer.com/article/10.1007/s10620-005-3038-2 Enzinger et al. 2005]
+|[https://doi.org/10.1007/s10620-005-3038-2 Enzinger et al. 2005]
-|NR in abstract
+|1997-12 to 2000-08
 | style="background-color:#91cf61" |Phase 2
 |-
@@ Line 2,895: / Line 3,108: @@
 </div></div>
 ===References===
-#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [http://link.springer.com/article/10.1007/s10620-005-3038-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16416165/ PubMed]
+#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [https://doi.org/10.1007/s10620-005-3038-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16416165/ PubMed]
 ==OLF {{#subobject:98b4fa|Regimen=1}}==
 OLF: '''<u>O</u>'''xaliplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil
@@ Line 2,949: / Line 3,162: @@
 *[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
 **Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
-**BSA 1.25 to less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
+**Between 1.25 to 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
-**BSA more than 1.5 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 14
+**More than 1.5 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 14
 *[[Paclitaxel (Taxol)]] 20 mg/m<sup>2</sup> IP once per day over 1 hour on days 1 and 8
 ====Supportive therapy====
@@ Line 3,048: / Line 3,261: @@
 |2007-2010
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Lentinan_.26_S-1_777|Lentinan & S-1]]
+|[[#Lentinan_.26_S-1_999|Lentinan & S-1]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
@@ Line 3,057: / Line 3,270: @@
 *[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
 **Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28
+**Between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28
 '''42-day cycles'''
 </div></div><br>
@@ Line 3,073: / Line 3,286: @@
 |2014-02 to 2019-01
 |style="background-color:#1a9851" |Phase 3 (C)
-|1a. [[#mFOLFOX6|mFOLFOX6]]<br>1b. [[#CapeOx_2|CapeOx]]<br>1c. [[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br>1d. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
+|1a. [[#mFOLFOX6_2|mFOLFOX6]]<br>1b. [[#CapeOx_2|CapeOx]]<br>1c. [[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br>1d. [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
@@ Line 3,145: / Line 3,358: @@
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*AVAGAST: [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]] x 6
+*AVAGAST: First-line [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]] x 6
-*SMC 2008-12-019: [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]] x 8
+*SMC 2008-12-019: First-line [[#Capecitabine_.26_Cisplatin_.28CX.29_3|CX]] x 8
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
@@ Line 3,158: / Line 3,371: @@
 =Metastatic or locally advanced disease, subsequent lines of therapy=
-==Apatinib monotherapy {{#subobject:ao594c|Regimen=1}}==
+==Docetaxel monotherapy {{#subobject:4f3230|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:913ap2|Variant=1}}===
+===Regimen variant #1, 60 mg/m<sup>2</sup> {{#subobject:577cd6|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 3,168: / Line 3,381: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.clinicaltrials.gov/study/NCT03042611 Awaiting publication (ANGEL)]
+|[https://doi.org/10.1200/jco.2011.39.4585 Kang et al. 2012 (SMC 2008-08-055)]
-|2017-2018
+|2008-2010
 | style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Gastric cancer_-_null_regimens#Placebo|Placebo]]
+|[[Gastric_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
-| style="background-color:#1a9850" |Superior PFS (secondary endpoint)
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 5.3 vs 3.8 mo<br>(HR 0.66, 95% CI 0.485-0.89)
+|-
 |}
-''Note: ANGEL included patients with GEJ malignancy''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Apatinib (Aitan)]] 700 mg once per day
+*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
-'''28-day cycles'''
+'''21-day cycles'''
-</div></div>
+</div></div><br>
-===References===
-#'''ANGEL:''' [https://clinicaltrials.gov/study/NCT03042611 NCT03042611]
-##'''Abstract:''' Kang Y, Kang WK, Di Bartolomeo M, Chau I, Yoon HH, Cascinu S, Ryu M, Kim JG, Lee K, Oh SC, Takashima A, Kryzhanivska A, Chao Y, Vladimirov V, Evesque L, Schenker M, McGinn A, Sankar N, Wyrwicz L, Boku N. Randomized Phase 3 ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastatic gastric cancer. 2019 European Society of Medical Oncology annual meeting. Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394 [https://doi.org/10.1093/annonc/mdz394.034 link to abstract]
-==Docetaxel monotherapy {{#subobject:4f3230|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 60 mg/m<sup>2</sup> {{#subobject:577cd6|Variant=1}}===
+===Regimen variant #2, 75 mg/m<sup>2</sup> x 6 {{#subobject:3b4816|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 3,193: / Line 3,402: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2011.39.4585 Kang et al. 2012 (SMC 2008-08-055)]
+|[https://doi.org/10.1016/S1470-2045(13)70549-7 Ford et al. 2013 (COUGAR-02)]
-|2008-2010
+|2008-2012
 | style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[Gastric_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
-| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 5.3 vs 3.8 mo<br>(HR 0.66, 95% CI 0.485-0.89)
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 5.2 vs 3.6 mo<br>(HR 0.67, 95% CI 0.49-0.92)
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-'''21-day cycles'''
+'''21-day cycle for up to 6 cycles'''
-</div></div><br>
+</div></div>
-<div class="toccolours" style="background-color:#eeeeee">
+===References===
-===Regimen variant #2, 75 mg/m<sup>2</sup> x 6 {{#subobject:3b4816|Variant=1}}===
+#'''SMC 2008-08-055:''' Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [https://doi.org/10.1200/jco.2011.39.4585 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22412140/ PubMed] [https://clinicaltrials.gov/study/NCT00821990 NCT00821990]
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [https://doi.org/10.1093/annonc/mdt002 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23406728/ PubMed] [https://clinicaltrials.gov/study/NCT00813072 NCT00813072]
-! style="width: 20%" |Study
+#'''COUGAR-02:''' Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. [https://doi.org/10.1016/S1470-2045(13)70549-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24332238/ PubMed] [https://clinicaltrials.gov/study/NCT00978549 NCT00978549]
-! style="width: 20%" |Dates of enrollment
+#'''INTEGRATEIIb:''' [https://clinicaltrials.gov/study/NCT04879368 NCT04879368]
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1016/S1470-2045(13)70549-7 Ford et al. 2014 (COUGAR-02)]
-|2008-2012
-| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Gastric_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
-| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 5.2 vs 3.6 mo<br>(HR 0.67, 95% CI 0.49-0.92)
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for up to 6 cycles'''
-</div></div>
-===References===
-#'''SMC 2008-08-055:''' Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [https://doi.org/10.1200/jco.2011.39.4585 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22412140/ PubMed] [https://clinicaltrials.gov/study/NCT00821990 NCT00821990]
-#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [https://doi.org/10.1093/annonc/mdt002 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23406728/ PubMed] [https://clinicaltrials.gov/study/NCT00813072 NCT00813072]
-#'''COUGAR-02:''' Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. [https://doi.org/10.1016/S1470-2045(13)70549-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24332238/ PubMed] [https://clinicaltrials.gov/study/NCT00978549 NCT00978549]
-#'''INTEGRATEIIb:''' [https://clinicaltrials.gov/study/NCT04879368 NCT04879368]
 ==Fluorouracil, Folinic acid, Mitomycin {{#subobject:b4ca9d|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
@@ Line 3,261: / Line 3,450: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://link.springer.com/article/10.1007/s10620-005-3038-2 Enzinger et al. 2005]
+|[https://doi.org/10.1007/s10620-005-3038-2 Enzinger et al. 2005]
-|NR in abstract
+|1997-12 to 2000-08
 | style="background-color:#91cf61" |Phase 2
 |-
@@ Line 3,375: / Line 3,564: @@
 </div></div>
 ===References===
-#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [http://link.springer.com/article/10.1007/s10620-005-3038-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16416165/ PubMed]
+#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [https://doi.org/10.1007/s10620-005-3038-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16416165/ PubMed]
 #Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. [https://doi.org/10.1016/j.ejca.2011.06.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21742485/ PubMed] [https://clinicaltrials.gov/study/NCT00144378 NCT00144378]
 #'''SMC 2008-08-055:''' Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [https://doi.org/10.1200/jco.2011.39.4585 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22412140/ PubMed] [https://clinicaltrials.gov/study/NCT00821990 NCT00821990]
@@ Line 3,419: / Line 3,608: @@
 |-
 |[https://doi.org/10.1179/joc.2003.15.3.275 Bamias et al. 2003a]
-|NR in abstract
+|1999-07 to 2001-02
 | style="background-color:#91cf61" |Phase 2
 |-
@@ Line 3,450: / Line 3,639: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161834/ Janjigian et al. 2018 (CheckMate 032)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161834/ Janjigian et al. 2018 (CheckMate 032<sub>UGI</sub>)]
 |2013-2015
 | style="background-color:#91cf61" |Phase 1/2
@@ Line 3,475: / Line 3,664: @@
 ##'''Update:''' Chen LT, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Sameshima H, Kang YK, Boku N. A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data. Gastric Cancer. 2020 May;23(3):510-519. Epub 2019 Dec 20. [https://doi.org/10.1007/s10120-019-01034-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7165140/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31863227/ PubMed]
 ##'''Update:''' Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Nishiyama T, Chen LT, Kang YK. Nivolumab in previously treated advanced gastric cancer (ATTRACTION-2): 3-year update and outcome of treatment beyond progression with nivolumab. Gastric Cancer. 2021 Jul;24(4):946-958. Epub 2021 Mar 20. [https://doi.org/10.1007/s10120-021-01173-w link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8205916/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33743112/ PubMed]
-#'''CheckMate 032:''' Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, de Braud F, Chau I, Harbison CT, Dorange C, Tschaika M, Le DT. CheckMate 032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol. 2018 Oct 1;36(28):2836-2844. Epub 2018 Aug 15. [https://doi.org/10.1200/JCO.2017.76.6212 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161834/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30110194/ PubMed] [https://clinicaltrials.gov/study/NCT01928394 NCT01928394]
+#'''CheckMate 032<sub>UGI</sub>:''' Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, de Braud F, Chau I, Harbison CT, Dorange C, Tschaika M, Le DT. CheckMate 032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol. 2018 Oct 1;36(28):2836-2844. Epub 2018 Aug 15. [https://doi.org/10.1200/JCO.2017.76.6212 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161834/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30110194/ PubMed] [https://clinicaltrials.gov/study/NCT01928394 NCT01928394]
 ==Paclitaxel monotherapy {{#subobject:2dcad9|Regimen=1}}==
@@ Line 3,561: / Line 3,750: @@
 |2013-2016
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Olaparib_.26_Paclitaxel_888|Olaparib & Paclitaxel]]
+|[[#Olaparib_.26_Paclitaxel_333|Olaparib & Paclitaxel]]
 | style="background-color:#fee08b" |Might have inferior OS
 |-

Difference between revisions of "Gastric cancer"

Revision as of 11:35, 13 May 2024

Guidelines

ESMO

ESMO/ESSO/ESTRO

French Intergroup

NCCN

Perioperative therapy

Capecitabine & Cisplatin (CX)

Neoadjuvant

Chemotherapy

Definitive

Local therapy

Adjuvant

Chemotherapy

References

Cisplatin & Fluorouracil (CF)

Protocol variant #1, 80/4000

Chemotherapy, neoadjuvant CF portion (cycles 1 to 3)

Local therapy, definitive portion

Chemotherapy, adjuvant CF portion (cycles 4 to 6)

Protocol variant #2, 100/4000

Chemotherapy, neoadjuvant CF portion

Local therapy, definitive portion

Chemotherapy, adjuvant CF portion

References

ECF

Neoadjuvant

Chemotherapy

Supportive therapy

Definitive

Local therapy

Adjuvant

Chemotherapy

Supportive therapy

References

ECX

Neoadjuvant

Chemotherapy

Definitive

Local therapy

Adjuvant

Chemotherapy

References

EOF

Neoadjuvant

Chemotherapy

Definitive

Local therapy

Adjuvant

Chemotherapy

References

EOX

Neoadjuvant

Chemotherapy

Definitive

Local therapy

Adjuvant

Chemotherapy

References

FLOT

Protocol variant #1, 3 + 3

Chemotherapy, neoadjuvant FLOT portion (cycles 1 to 3)

Local therapy, definitive portion

Chemotherapy, adjuvant FLOT portion (cycles 4 to 6)

Protocol variant #2, 4 + 4

Chemotherapy, neoadjuvant FLOT portion (cycles 1 to 4)

Local therapy, definitive portion

Chemotherapy, adjuvant FLOT portion (cycles 5 to 8)

References

mFOLFOX6

Neoadjuvant

Chemotherapy

Definitive

Local therapy

Adjuvant

Chemotherapy

References

SOX

Neoadjuvant