Gastric cancer

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Section editor
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 Travis Zack, MD, PhD
University of California San Francisco
San Francisco, CA, USA
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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.
65 regimens on this page
98 variants on this page


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.

ESMO

ESMO/ESSO/ESTRO

French Intergroup

NCCN

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) 1. Perioperative CX & Pembrolizumab
2. Perioperative CF & Pembrolizumab
3. FLOT & Pembrolizumab 		To be determined

Neoadjuvant

Chemotherapy

21-day cycle for 3 cycles


Definitive

Local therapy


Adjuvant

Chemotherapy

21-day cycle for 3 cycles

References

  1. 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) 1. Perioperative CX & Pembrolizumab
2. Perioperative CF & Pembrolizumab
3. FLOT & Pembrolizumab 		To be determined

Chemotherapy, neoadjuvant CF portion (cycles 1 to 3)

21-day cycle for 3 cycles

Local therapy, definitive portion

Chemotherapy, adjuvant CF portion (cycles 4 to 6)

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

28-day cycle for 2 to 3 cycles

Local therapy, definitive portion

Chemotherapy, adjuvant CF portion

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

References

  1. 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. link to original article contains dosing details in abstract PubMed NCT00002883
  2. 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

Supportive therapy

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

Supportive therapy

21-day cycle for 3 cycles

References

  1. 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
  2. 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
  3. 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

21-day cycle for 3 cycles, followed by:


Definitive

Local therapy

  • Surgery with a D1+ lymph node resection

Adjuvant

Chemotherapy

21-day cycle for 3 cycles

References

  1. 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
  2. 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

21-day cycle for 3 cycles, followed by:


Definitive

Local therapy

  • Surgery with a D1+ lymph node resection

Adjuvant

Chemotherapy

21-day cycle for 3 cycles

References

  1. 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
  2. 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

21-day cycle for 3 cycles, followed by:


Definitive

Local therapy

  • Surgery with a D1+ lymph node resection

Adjuvant

Chemotherapy

21-day cycle for 3 cycles

References

  1. 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
  2. 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) 1. Perioperative CX & Pembrolizumab
2. Perioperative CF & Pembrolizumab
3. FLOT & Pembrolizumab 		To be determined

Chemotherapy, neoadjuvant FLOT portion (cycles 1 to 3)

21-day cycle for 3 cycles

Local therapy, definitive portion

Chemotherapy, adjuvant FLOT portion (cycles 4 to 6)

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)

14-day cycle for 4 cycles

Local therapy, definitive portion

Chemotherapy, adjuvant FLOT portion (cycles 5 to 8)

14-day cycle for 4 cycles

References

  1. 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
  2. KEYNOTE-585: contains dosing details on CT.gov NCT03221426
  3. MATTERHORN: NCT04592913
  4. RAMSES: NCT02661971

SOX

SOX: S-1 & OXaliplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yu et al. 2022 (FOCUSgastric) 2011-2016 Phase 3 (E-switch-ic) Perioperative mFOLFOX6 Non-inferior OS36 (primary endpoint)
OS36: 75.2% vs 67.8%

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


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

  1. RESOLVEgastric: 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
  2. FOCUSgastric: 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

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

21-day cycle for 3 cycles

Subsequent treatment

References

  1. 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

21-day cycle for 3 cycles

References

  1. 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 (RESOLVEgastric) 2012-2017 Phase 3 (C) 1. Perioperative SOX Seems to have inferior DFS36
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

Chemotherapy

21-day cycle for 8 cycles

References

  1. 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
  2. RESOLVEgastric: 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) Carboplatin, Docetaxel, 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

Chemotherapy

21-day cycle for 6 cycles

References

  1. 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 (ARTISTgastric) 2004-2008 Phase 3 (C) XP, then RT, then XP 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

Chemotherapy

21-day cycle for 6 cycles

References

  1. 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

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

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #2

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.

Preceding treatment

Chemotherapy

  • Docetaxel (Taxotere) as follows:
    • Cycles 1 to 7: 40 mg/m2 IV once on day 1
  • S-1 as follows:
    • Cycles 1 to 7: 80 to 120 mg/m2 PO on days 1 to 14
    • Cycles 8 to 11: 80 to 120 mg/m2 PO on days 1 to 28

21-day course, then 42-day cycle for 10 cycles

References

  1. 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
  2. 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

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

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: 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

References

  1. 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

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

  1. 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 & RT

FULV & RT: 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

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

References

  1. 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
  2. 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
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

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
2. SOXRT Might have inferior DFS

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

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
    • BSA between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 28
    • BSA 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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. HKIT-GC: NCT00216034

SOX

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
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)
2. SOXRT Did not meet primary endpoint of DFS

Preceding treatment

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
    • BSA between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
    • BSA 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

  1. 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
  2. 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

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

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

21-day cycle for up to 6 cycles

References

  1. 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
  2. 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
  3. 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

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)
Ohtsu et al. 2011 (AVAGAST) 2007-09 to 2008-12 Phase 3 (C) CX & Bevacizumab Did not meet primary endpoint of OS
Lordick et al. 2013 (EXPAND) 2008-2010 Phase 3 (C) CX & Cetuximab Did not meet primary endpoint of PFS
Shen et al. 2014 (AVATAR) 2009-03-25 to 2010-07-12 Phase 3 (C) CX & Bevacizumab Did not meet primary endpoint of OS
Kim et al. 2014 (SMC 2008-12-019) 2009-2012 Phase 3 (C) CX & Simvastatin Did not meet primary endpoint of PFS
Lu et al. 2018 (PAC-C) 2009-2014 Phase 3 (C) Capecitabine & Paclitaxel 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:

  • AVAGAST patients: 86% gastric and 14% GE junction. 5.4% of patients had an ECOG PS of 2.
  • EXPAND patients: 83% gastric, 5% GE junction and 16% unknown
  • SMC 2008-12-019 patients: 79% gastric, 16% GE junction and 5% 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
    • 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

21-day cycles, varied duration (see below)

Subsequent treatment

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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)
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

Immunotherapy

21-day cycles

References

  1. 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
2. CapeOx; 1250/130 Non-inferior PFS (primary endpoint)
(HR 1.10, 95% CI 0.90-1.33)

Chemotherapy

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
2. CapeOx; 1250/130 Non-inferior PFS (primary endpoint)
(HR 1.09, 95% CI 0.89-1.32)

Chemotherapy

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

21-day cycles


Regimen variant #4, 1700/130

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

Chemotherapy

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 x 4, then Avelumab
1b. mFOLFOX4 x 4, then Avelumab
1c. mFOLFOX6 x 4, then 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
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

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 (GLOWgastric) 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

  • GLOWgastric: CLDN18.2 positive

Chemotherapy

21-day cycles

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. GLOWgastric: 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
  8. 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
  9. ARMANI: NCT02934464
  10. BGB-A317-305: contains dosing details on CT.gov NCT03777657
  11. 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)
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

Immunotherapy

21-day cycles

References

  1. 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. 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: Cape'citabine, 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

Immunotherapy

21-day cycle for up to 35 cycles

References

  1. 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

21-day cycles

References

  1. 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
  2. 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
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

Supportive therapy

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

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

  1. 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
  2. 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

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

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
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

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
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

28-day cycles

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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)
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

Immunotherapy

21-day cycle for up to 35 cycles

References

  1. 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
  2. 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

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 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).

Chemotherapy

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

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
    • BSA at least 1.25 m2 and less than 1.5 m2: 50 mg PO twice per day on days 1 to 21
    • BSA 1.5 m2 or more: 60 mg PO twice per day on days 1 to 21

35-day cycles

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

Supportive therapy

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

Supportive therapy

14-day cycle for at least 4 cycles

References

  1. 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
  2. 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

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
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

Supportive therapy

21-day cycle for up to 8 cycles

References

  1. 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
  2. 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
  3. 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

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

21-day cycles

References

  1. 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

Targeted therapy

Supportive therapy

  • "Standard premedication and delayed emesis regimens"

14-day cycles

References

  1. 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 (STARTgastric) 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

  1. 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

Supportive therapy

21-day cycle for up to 8 cycles

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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)
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
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

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

21-day cycle for up to 6 cycles

References

  1. 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
  2. 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
  3. 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)
3. EOX Non-inferior OS (primary endpoint)

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

Chemotherapy

Supportive therapy

21-day cycle for up to 8 cycles

References

  1. 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

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

21-day cycles

References

  1. 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
  2. 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
  3. 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
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
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 is an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.

Chemotherapy

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

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

Up to 24-week course

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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

28-day cycles

References

  1. 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

56-day cycle for 2 cycles

References

  1. 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

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

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

14-day cycles

References

  1. 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
  2. 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
  3. 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

14-day cycle for 12 cycles

Subsequent treatment


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
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

14-day cycles

References

  1. 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
  2. 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
  3. 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

14-day cycle for 12 cycles

Subsequent treatment

References

  1. 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
  2. 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)
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

Immunotherapy

14-day cycles

References

  1. 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

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

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

14-day cycles

References

  1. 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
  2. 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

  1. 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 NR in abstract 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

42-day cycles

References

  1. 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

Supportive therapy

8-week cycles

References

  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. 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
    • BSA 1.25 to less than 1.5 m2: 50 mg PO twice per day on days 1 to 14
    • BSA 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

  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. 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)
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

21-day cycles

References

  1. 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
2. 5-FU Non-inferior OS (primary endpoint)

Chemotherapy

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 (STARTgastric) 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
    • BSA between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 28
    • BSA 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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
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

7-day cycles (see note)

References

  1. 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: CX x 6
  • SMC 2008-12-019: CX x 8

Chemotherapy

21-day cycles

References

  1. 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
  2. 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

Apatinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (ANGEL) 2017-2018 Phase 3 (E-esc) Placebo Superior PFS (secondary endpoint)

Note: ANGEL included patients with GEJ malignancy

Targeted therapy

28-day cycles

References

  1. ANGEL: NCT03042611
    1. 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 link to abstract

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

21-day cycles


Regimen variant #2, 75 mg/m2 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ford et al. 2014 (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

21-day cycle for up to 6 cycles

References

  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. link to original article contains dosing details in abstract PubMed NCT00821990
  2. 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
  3. 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
  4. 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

56-day cycle for 2 cycles

References

  1. 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 NR in abstract 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

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

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

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

21-day cycle for up to 10 cycles

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

21-day cycles

References

  1. 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 NR in abstract Phase 2

Note: Patients had advanced gastric and colorectal cancers.

Prior treatment criteria

  • 5-fluorouracil-based chemotherapy

Chemotherapy

14-day cycles

References

  1. 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) 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

14-day cycles

References

  1. 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
  2. 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. 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

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

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
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

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

21-day cycles

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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)
2. nab-Paclitaxel; q3wk Not reported

Chemotherapy

28-day cycles

References

  1. 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

Chemotherapy

28-day cycles

References

  1. 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
  2. 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
  3. 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

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

References

  1. 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
  2. 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

14-day cycles

References

  1. 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

28-day cycles

References

  1. 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

28-day cycles

References

  1. 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
  2. INTEGRATEIIb: NCT04879368
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