Gastric cancer

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Ivy Abraham, MD
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Neeta K. Venepalli, MD, MBA
University of Illinois at Chicago
Chicago, IL

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.

50 regimens on this page
72 variants on this page

Contents


Guidelines

CAP/ASCP/ASCO

ESMO

ESMO/ESSO/ESTRO

NCCN

Neoadjuvant chemotherapy

Cisplatin & Fluorouracil

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FP: Fluorouracil & Platinol (Cisplatin)

Regimen

Study Evidence Comparator Efficacy
Ychou et al. 2011 (ACCORD 07) Phase III (E) Surgery alone Seems to have superior OS

This is the neoadjuvant portion of pre-planned "perioperative" therapy.

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

Chemotherapy

28-day cycle for 2 to 3 cycles

Subsequent treatment

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. 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 protocol PubMed

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Cunningham et al. 2006 (MAGIC) Phase III (E) Surgery alone Superior OS
Cats et al. 2018 (CRITICS) Non-randomized portion of RCT

This is the neoadjuvant portion of pre-planned perioperative therapy. In CRITICS, only patients with difficulties swallowing tablets were assigned to this treatment.

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

MAGIC included patients with lower esophageal malignancy as well (74% gastric, 14.8% lower esophagus, and 11.2% GE junction).

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

Subsequent treatment

  • MAGIC: Surgical resection is performed 3 to 6 weeks after the completion of cycle 3, followed in 6 to 12 weeks by adjuvant ECF
  • CRITICS: Surgery with a D1+ lymph node resection, then adjuvant ECF versus capecitabine, cisplatin, RT

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 protocol PubMed
  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 verified protocol PubMed

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study Evidence
Cats et al. 2018 (CRITICS) Non-randomized portion of RCT

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

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

  • Surgery with a D1+ lymph node resection, then adjuvant ECX versus capecitabine, cisplatin, RT

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 verified protocol PubMed

EOF

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EOF: Epirubicin, Oxaliplatin, Fluourouracil

Regimen

Study Evidence
Cats et al. 2018 (CRITICS) Non-randomized portion of RCT

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

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

  • Surgery with a D1+ lymph node resection, then adjuvant EOF versus capecitabine, cisplatin, RT

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 verified protocol PubMed

EOX

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EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)

Regimen

Study Evidence
Cats et al. 2018 (CRITICS) Non-randomized portion of RCT

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

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

  • Surgery with a D1+ lymph node resection, then adjuvant EOX versus capecitabine, cisplatin, RT

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 verified protocol PubMed

FLOT

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

Regimen

Study Evidence Comparator Efficacy
Al-Batran et al. 2016 (FLOT4-AIO) Phase II/III (E) ECF/ECX See link Seems to have superior OS See link

This is the neoadjuvant portion of pre-planned perioperative chemotherapy.

Chemotherapy

14-day cycle for 4 cycles

Subsequent treatment

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
    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, from Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Less J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Hunter 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 Apr 10. [Epub ahead of print] link to original article PubMed

No neoadjuvant therapy

Regimen

Study Evidence Comparator Efficacy
Schuhmacher et al. 2010 (EORTC 40954) Phase III (C) Cisplatin, 5-FU, Folinic acid Seems not superior

No antineoplastic treatment prior to surgery.

Subsequent treatment

References

  1. EORTC 40954: Schuhmacher C, Gretschel S, Lordick F, Reichardt P, Hohenberger W, Eisenberger CF, Haag C, Mauer ME, Hasan B, Welch J, Ott K, Hoelscher A, Schneider PM, Bechstein W, Wilke H, Lutz MP, Nordlinger B, Van Cutsem E, Siewert JR, Schlag PM. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol. 2010 Dec 10;28(35):5210-8. Epub 2010 Nov 8. link to original article link to PMC article PubMed

Adjuvant therapy

5-FU & Leucovorin, then 5-FU, Leucovorin, RT, then 5-FU & Leucovorin

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FULV & RT: 5-FluoroUracil, LeucoVorin (Folinic acid), Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Macdonald et al. 2001 (INT-0116) Phase III (E) Surgery alone Superior OS
Fuchs et al. 2017 (CALGB 80101) Phase III (C) ECF, then FULV & RT, then ECF Seems not superior

Treatment is to start 20 to 40 days after surgery.

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, part 1

28-day cycle for 1 cycle, followed by:

Chemotherapy, part 2

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
  • Folinic acid (Leucovorin) 20 mg/m2 IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy

Radiotherapy

35-day course, followed in 1 month by:

Chemotherapy, part 3

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 protocol 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 verified protocol link to PMC article PubMed

CapeOx

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CapeOX: Capecitabine & OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Bang et al. 2012 (CLASSIC) Phase III (E) Surgery alone Superior OS (*)

Note: Reported efficacy is based on the 2014 update.

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 protocol PubMed
    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

Cisplatin & Fluorouracil

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Regimen

Study Evidence Comparator Efficacy
Ychou et al. 2011 (ACCORD 07) Phase III (E) Surgery alone Seems to have superior OS

This is the adjuvant portion of pre-planned "perioperative" therapy.

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

Preceding treatment

Chemotherapy

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. 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 protocol PubMed

CX

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

Regimen

Study Evidence Comparator Efficacy
Lee et al. 2011 (ARTISTgastric) Phase III (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 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 verified protocol PubMed
    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

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Cunningham et al. 2006 (MAGIC) Phase III (E) Surgery alone Superior OS
Cats et al. 2018 (CRITICS) Phase III (C) CX & RT Seems not superior

This is the adjuvant portion of pre-planned "perioperative" therapy. In CRITICS, only patients with trouble swallowing pills were assigned to this treatment arm.

MAGIC included patients with lower esophageal malignancy (74% gastric, 14.8% lower esophagus, and 11.2% GE junction).

Preceding treatment

Chemotherapy

Supportive medications

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 protocol PubMed
  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 verified protocol PubMed

ECX

back to top

ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study Evidence Comparator Efficacy
Cats et al. 2018 (CRITICS) Phase III (C) CX & RT Seems not superior

Preceding treatment

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 verified protocol PubMed

EOF

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EOF: Epirubicin, Oxaliplatin, Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Cats et al. 2018 (CRITICS) Phase III (C) CX & RT Seems not superior

Only patients with trouble swallowing pills were assigned to this treatment arm.

Preceding treatment

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 verified protocol PubMed

EOX

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EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)

Regimen

Study Evidence Comparator Efficacy
Cats et al. 2018 (CRITICS) Phase III (C) CX & RT Seems not superior

Preceding treatment

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 verified protocol PubMed

FLOT

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

Regimen

Study Evidence Comparator Efficacy
Al-Batran et al. 2016 (FLOT4-AIO) Phase II/III (E) ECF/ECX See link Seems to have superior OS See link

This is the adjuvant portion of pre-planned perioperative chemotherapy.

Preceding treatment

Chemotherapy

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
    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, from Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Less J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Hunter 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 Apr 10. [Epub ahead of print] link to original article PubMed

FP, then Capecitabine & RT, then FP

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FP, then Capecitabine & RT, then FP: Fluorouracil & Platinol (Cisplatin), followed by Capecitabine & Radiation Therapy, followed by Fluorouracil & Platinol (Cisplatin)

Regimen

Study Evidence
Lee et al. 2006 Phase II

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, part 1

21-day cycle, followed immediately by:

Chemotherapy, part 2

Radiotherapy

5-week course, followed 4 weeks later by:

Chemotherapy, part 3

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 verified protocol link to PMC article PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Allum et al. 1989 Phase III (C) 5-FU & Mitomycin Seems not superior
Coombes et al. 1990 Phase III (C) FAM Seems not superior
Hallissey et al. 1994 Phase III (C) 1. FAM
2. Radiation therapy
Seems not superior
Lise et al. 1995 (EORTC 40813) Phase III (C) FAM2 Might have inferior DFS
Macdonald et al. 1995 Phase III (C) FAM Seems not superior
Nakajima et al. 1999 (JCOG8801) Phase III (C) 5-FU & Mitomycin, then UFT Seems not superior
Cirera et al. 1999 Phase III (C) Mitomycin & Tegafur Seems to have inferior OS
Macdonald et al. 2001 (INT-0116) Phase III (C) FULV & RT Inferior OS
Nashimoto et al. 2003 (JCOG 9206-1) Phase III (C) 5-FU, Ara-C, Mitomycin, then 5-FU Seems not superior
Bouché et al. 2005 (FFCD 8801) Phase III (C) Cisplatin & 5-FU Seems not superior
Nitti et al. 2005 Phase III (C) 1. FAMTX
2. FEMTX
Seems not superior
Cunningham et al. 2006 (MAGIC) Phase III (C) ECF Inferior OS
De Vita et al. 2007 (GOIM 9602) Phase III (C) ELFE Seems not superior
Sakuramoto et al. 2007 (ACTS-GC) Phase III (C) S-1 Inferior OS
Di Costanzo et al. 2008 Phase III (C) PELF Seems not superior
Kulig et al. 2010 Phase III (C) EAP Seems not superior
Miyashiro et al. 2011 (JCOG 9206-2) Phase III (C) IV/IP Cisplatin, then UFT Seems not superior

No further treatment after surgery.

Preceding treatment

  • Surgery, with varying requirements for level of dissection (see papers for details)

References

  1. Allum WH, Hallissey MT, Kelly KA; British Stomach Cancer Group. Adjuvant chemotherapy in operable gastric cancer: 5 year follow-up of first British Stomach Cancer Group trial. Lancet. 1989 Mar 18;1(8638):571-4. link to original article PubMed
  2. Coombes RC, Schein PS, Chilvers CE, Wils J, Beretta G, Bliss JM, Rutten A, Amadori D, Cortes-Funes H, Villar-Grimalt A, McArdle C, Rauschecker HF, Boven E, Vassilopoulos P, Welvaart K, Pinto Ferreira E, Wiig J, Gisselbrecht C, Rougier P, Woods EMA; International Collaborative Cancer Group. A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. J Clin Oncol. 1990 Aug;8(8):1362-9. link to original article PubMed
  3. Hallissey MT, Dunn JA, Ward LC, Allum WH; British Stomach Cancer Group. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet. 1994 May 28;343(8909):1309-12. link to original article PubMed
  4. EORTC 40813: Lise M, Nitti D, Marchet A, Sahmoud T, Buyse M, Duez N, Fiorentino M, Dos Santos JG, Labianca R, Rougier P, Gignoux M. Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer. J Clin Oncol. 1995 Nov;13(11):2757-63. link to original article PubMed
  5. Macdonald JS, Fleming TR, Peterson RF, Berenberg JL, McClure S, Chapman RA, Eyre HJ, Solanki D, Cruz AB Jr, Gagliano R, Estes NC, Tangen CM, Rivkin S. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study. Ann Surg Oncol. 1995 Nov;2(6):488-94. link to original article PubMed
  6. JCOG8801: Nakajima T, Nashimoto A, Kitamura M, Kito T, Iwanaga T, Okabayashi K, Goto M; Gastric Cancer Surgical Study Group. Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Lancet. 1999 Jul 24;354(9175):273-7. link to original article PubMed
  7. Cirera L, Balil A, Batiste-Alentorn E, Tusquets I, Cardona T, Arcusa A, Jolis L, Saigí E, Guasch I, Badia A, Boleda M. Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol. 1999 Dec;17(12):3810-5. link to original article PubMed
  8. 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 protocol 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
  9. JCOG 9206-1: Nashimoto A, Nakajima T, Furukawa H, Kitamura M, Kinoshita T, Yamamura Y, Sasako M, Kunii Y, Motohashi H, Yamamoto S; Gastric Cancer Surgical Study Group, Japan Clinical Oncology Group. Randomized trial of adjuvant chemotherapy with mitomycin, Fluorouracil, and Cytosine arabinoside followed by oral Fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1. J Clin Oncol. 2003 Jun 15;21(12):2282-7. link to original article PubMed
  10. FFCD 8801: Bouché O, Ychou M, Burtin P, Bedenne L, Ducreux M, Lebreton G, Baulieux J, Nordlinger B, Martin C, Seitz JF, Tigaud JM, Echinard E, Stremsdoerfer N, Milan C, Rougier P; Fédération Francophone de Cancérologie Digestive Group. Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Ann Oncol. 2005 Sep;16(9):1488-97. Epub 2005 Jun 6. link to original article PubMed
  11. Nitti D, Wils J, Dos Santos JG, Fountzilas G, Conte PF, Sava C, Tres A, Coombes RC, Crivellari D, Marchet A, Sanchez E, Bliss JM, Homewood J, Couvreur ML, Hall E, Baron B, Woods E, Emson M, Van Cutsem E, Lise M; EORTC GI Group; ICCG. Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer: a combined analysis of the EORTC GI Group and the ICCG. Ann Oncol. 2006 Feb;17(2):262-9. Epub 2005 Nov 17. link to original article PubMed
  12. 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 protocol PubMed
  13. GOIM 9602: De Vita F, Giuliani F, Orditura M, Maiello E, Galizia G, Di Martino N, Montemurro F, Cartenì G, Manzione L, Romito S, Gebbia V, Ciardiello F, Catalano G, Colucci G; Gruppo Oncologico Italia Meridionale. Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study). Ann Oncol. 2007 Aug;18(8):1354-8. Epub 2007 May 24. link to original article PubMed
  14. 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 verified protocol PubMed
    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
  15. Di Costanzo F, Gasperoni S, Manzione L, Bisagni G, Labianca R, Bravi S, Cortesi E, Carlini P, Bracci R, Tomao S, Messerini L, Arcangeli A, Torri V, Bilancia D, Floriani I, Tonato M; Italian Oncology Group for Cancer Research. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst. 2008 Mar 19;100(6):388-98. Epub 2008 Mar 11. link to original article PubMed
  16. Kulig J, Kolodziejczyk P, Sierzega M, Bobrzynski L, Jedrys J, Popiela T, Dadan J, Drews M, Jeziorski A, Krawczyk M, Starzynska T, Wallner G. Adjuvant chemotherapy with etoposide, adriamycin and cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial. Oncology. 2010;78(1):54-61. Epub 2010 Mar 6. link to original article PubMed
  17. JCOG 9206-2: Miyashiro I, Furukawa H, Sasako M, Yamamoto S, Nashimoto A, Nakajima T, Kinoshita T, Kobayashi O, Arai K; Gastric Cancer Surgical Study Group in the Japan Clinical Oncology Group. Randomized clinical trial of adjuvant chemotherapy with intraperitoneal and intravenous cisplatin followed by oral fluorouracil (UFT) in serosa-positive gastric cancer versus curative resection alone: final results of the Japan Clinical Oncology Group trial JCOG9206-2. Gastric Cancer. 2011 Aug;14(3):212-8. Epub 2011 Feb 19. link to original article PubMed

S-1 monotherapy

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Variant #1, 21-day cycles

Study Evidence Comparator Efficacy
Tsuburaya (SAMIT) Phase III (C) 1. Paclitaxel, then S-1
2. Paclitaxel, then UFT
Seems not superior
3. UFT Superior DFS

Preceding treatment

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

Chemotherapy

21-day cycle for 16 cycles

Variant #2, 42-day cycles

Study Evidence Comparator Efficacy
Sakuramoto et al. 2007 (ACTS-GC) Phase III (E) Observation Superior OS
Yoshikawa et al. 2019 (OPAS-1) Phase III (C) S-1 x 6 mo Inconclusive whether non-inferior

Preceding treatment

  • R0 gastrectomy with at least D2 dissection, within 6 weeks

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA 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

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 verified protocol PubMed
    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 verified protocol PubMed
  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

Metastatic or locally advanced disease, first-line

Capecitabine monotherapy

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X: Xeloda (Capecitabine)

Variant #1, 2000 mg/m2/day

Study Evidence Comparator Efficacy
Hwang et al. 2017 Phase III (C) XELOX Seems not superior

Chemotherapy

21-day cycles

Variant #2, 2500 mg/m2/day

Study Evidence
Hong et al. 2004 Phase II

Study only included patients with 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 verified protocol PubMed
  2. 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 protocol PubMed

CapeOx

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CapeOX: Capecitabine & OXaliplatin

Regimen

Study Evidence
Jatoi et al. 2006 Phase II

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 protocol PubMed

Carboplatin & Paclitaxel

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Regimen

Study Evidence
Philip et al. 1997 Phase II
Gadgeel et al. 2003 Phase II

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 protocol 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 protocol PubMed

Cisplatin & Docetaxel

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

Variant #1

Study Evidence Comparator Efficacy
Roth et al. 2007 Randomized Phase II (E) 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 medications

21-day cycle for up to 8 cycles

Variant #2

Study Evidence Comparator Efficacy
Ajani et al. 2005 (V-325) Randomized Phase II (C) DCF Seems to have inferior ORR

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

Chemotherapy

Supportive medications

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 verified protocol 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 verified protocol PubMed

Cisplatin & Fluorouracil

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

Variant #1, 80/4000 x 6

Study Evidence Comparator Efficacy
Bang et al. 2010 (ToGA) Phase III (C) CF & Trastuzumab Inferior OS

Patients in ToGA had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.

ToGA Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.

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 medications

21-day cycle for up to 6 cycles

Variant #2, 80/4000 x 8

Study Evidence Comparator Efficacy
Ajani et al. 2017 (DIGEST) Phase III (C) CS Seems not superior

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 medications

21-day cycle for 8 cycles

Variant #3, 80/4000, indefinite

Study Evidence Comparator Efficacy
Kang et al. 2009 Phase III (C) CX Non-inferior PFS

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 medications

21-day cycles

Variant #4, 100/4000

Study Evidence Comparator Efficacy
Duffour et al. 2006 (FFCD 9404) Phase III (C) FLP Seems not superior

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

Variant #5, 100/4000, split-dose cisplatin

Study Evidence Comparator Efficacy
Ohtsu et al. 2003 (JCOG 9205) Phase III (E) 1. Fluorouracil Superior PFS
2. UFTM Seems not superior

Study included patients with PFS 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

Variant #6, 100/5000

Study Evidence Comparator Efficacy
Van Cutsem et al. 2006 (V325) Phase III (C) DCF Seems to have inferior OS
Dank et al. 2008 Phase III (C) IF Seems not superior
Ajani et al. 2010 (FLAGS) Phase III (C) CS Seems not superior

Van Cutsem et al Patients: 100% adenocarcinoma histology (22% Esophagogastric junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70.

Dank et al Patients: 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 medications

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; Japan Clinical Oncology Group Study (JCOG9205). 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 verified protocol 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 verified protocol PubMed
  3. V325: 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 verified protocol 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 verified protocol PubMed
  5. 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 verified protocol PubMed
  6. 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 protocol PubMed
  7. ToGA: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. link to original article contains verified protocol PubMed
  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 verified protocol PubMed
  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 verified protocol PubMed

Cisplatin & S-1

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

Variant #1, q3wk ("SP3")

Study Evidence Comparator Efficacy
Ryu et al. 2015 (SOS) Phase III (E) SP5 Seems to have superior PFS

Chemotherapy

21-day cycles

Variant #2, q4wk

Study Evidence Comparator Efficacy
Ajani et al. 2017 (DIGEST) Phase III (E) CF Seems not superior

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

Variant #3, q5wk ("SP5")

Study Evidence Comparator Efficacy
Koizumi et al. 2008 (SPIRITS) Phase III (E) S-1 Seems to have superior OS
Yamada et al. 2014 (G-SOX) Phase III (C) SOX Non-inferior PFS
Ryu et al. 2015 (SOS) Phase III (C) SP3 Seems to have inferior PFS
Fujitani et al. 2016 (REGATTA) Non-randomized portion of RCT
Ishigami et al. 2018 (PHOENIX-GC) Phase III (C) IV/IP Paclitaxel & S-1 Might have inferior OS
Yamada et al. 2019 (JCOG1013) Phase III (C) Cisplatin, Docetaxel, S-1 Seems not superior

Note: in REGATTA, there was no difference in outcome amongst patients who did or did not undergo surgery.

Inclusion criteria for REGATTA included the presence of a single non-curable factor (ex: hepatic, peritoneal, and para-aortic mets), see link for further details

SPIRITS trial included patients with ECOG of 2 (3% of patients)

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

Preceding treatment

Chemotherapy

  • Cisplatin (Platinol) 60 mg/m2 IV once on day 8
  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA 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 verified protocol PubMed
  2. 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 protocol PubMed
  3. 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 protocol PubMed
  4. 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 verified protocol PubMed
  5. 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 verified protocol PubMed
  6. 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 verified protocol PubMed
  7. 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 May 14. [Epub ahead of print] link to original article contains protocol PubMed

CLF

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

Variant #1

Study Evidence Comparator Efficacy
Al-Batran et al. 2008 Phase III (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: 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric).

Chemotherapy

Supportive medications

  • Up to 3 liters normal saline as hydration with Cisplatin (Platinol)
  • Antiemetic medications per "local protocols"

8-week cycles

Variant #2

Study Evidence Comparator Efficacy
Bouché et al. 2004 (FFCD 9803) Randomized Phase II (E) 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 medications

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 Group. 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 verified protocol 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 verified protocol PubMed

CX

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

Regimen

Study Evidence Comparator Efficacy
Kang et al. 2009 Phase III (E) CF Non-inferior PFS
Ohtsu et al. 2011 (AVAGAST) Phase III (C) CX & Bevacizumab Seems not superior
Lordick et al. 2013 (EXPAND) Phase III (C) CX & Cetuximab Seems not superior
Shen et al. 2014 (AVATAR) Phase III (C) CX & Bevacizumab Seems not superior
Kim et al. 2014 Phase III (C) CX & Simvastatin Seems not superior
Lu et al. 2018 (PAC-C) Phase III (C) Capecitabine & Paclitaxel Seems not superior
Fuchs et al. 2019 (RAINFALL) Phase III (C) CX & Ramucirumab Seems not superior (*)

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 of 2.
  • EXPAND patients: 83% gastric, 5% GE junction and 16% unknown
  • Kim et al patients: 79% gastric, 16% GE junction and 5% unknown

Note: while the primary analysis of RAINFALL showed that this arm seemed to have inferior PFS, independent central review did not confirm this finding.

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 medications

21-day cycles, varied duration (see below)

Subsequent treatment

References

  1. 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 verified protocol PubMed content property of HemOnc.org
  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 verified protocol PubMed
  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 (AIO) and EXPAND Investigators. 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 verified protocol PubMed
  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 verified protocol PubMed
  5. 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 verified protocol PubMed
  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 verified protocol PubMed
  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 protocol PubMed

CX & Trastuzumab

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

Variant #1, 80/1600

Study Evidence Comparator Efficacy
Shah et al. 2017 (HELOISE) Phase IIIb (C) CX & HD-Trastuzumab Seems not superior

Patients had overexpression of HER2 protein by immunohistochemistry AND gene amplification by in-situ hybridisation.

Patients: 79% gastric, 21% GE junction, and all patients had an ECOG of 2

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

  • Trastuzumab maintenance

Variant #2, 80/2000

Study Evidence Comparator Efficacy
Bang et al. 2010 (ToGA) Phase III (E) CX Superior OS
Tabernero et al. 2018 (JACOB) Phase III (C) CX, Pertuzumab, Trastuzumab Might have inferior OS

ToGA patients had overexpression of HER2 protein by immunohistochemistry OR gene amplification by fluorescence in-situ hybridisation.

ToGA patients: 81% gastric, 19% GE junction. 10% of patients with ECOG of 2.

Chemotherapy

21-day cycles

References

  1. ToGA: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. link to original article contains verified protocol PubMed
  2. HELOISE: Shah MA, Xu RH, Bang YJ, Hoff PM, Liu T, Herráez-Baranda LA, Xia F, Garg A, Shing M, Tabernero J. HELOISE: Phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2017 Aug 1;35(22):2558-2567. Epub 2017 Jun 2.link to original article contains verified protocol PubMed
  3. JACOB: Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, Song C, Wu H, Eng-Wong J, Kim K, Kang YK. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018 Oct;19(10):1372-1384. Epub 2018 Sep 11. link to original article contains protocol PubMed

DCF

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

Variant #1

Study Evidence Comparator Efficacy
Ajani et al. 2005 (V-325) Randomized Phase II (E) DC Seems to have superior ORR
Van Cutsem et al. 2006 (V325) Phase III (E) CF Seems to have superior OS

Note: In contrast to the original references, some guidelines list each cycle as lasting 28 days.

Anjani et al. Patients: 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70.

Van Cutsem et al Patients: 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS score of 70.

Chemotherapy

Supportive medications

21-day cycles

Variant #2

Study Evidence Comparator Efficacy
Roth et al. 2007 Randomized Phase II (E) 1. ECF Not reported
2. TC Might have superior 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 medications

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 verified protocol PubMed
  2. V325: 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 verified protocol 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 verified protocol PubMed

mDCF

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mDCF: modified Docetaxel, Cisplatin, Fluorouracil

Variant #1, 40/40/2800

Study Evidence
Shah et al. 2010 Phase II

Note: In contrast to the primary reference, some guidelines list this regimen without bevacizumab. Please see below for the original mDCF regimen that included bevacizumab.

Patients: 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.

Chemotherapy

Supportive medications

  • "Standard premedication and delayed emesis regimens"

14-day cycles

Variant #2, 60/60/3000

Study Evidence Comparator Comparative Efficacy
Ozal et al. 2010 Phase II
Wang et al. 2015 (DOCET_L_02195) Phase III (E) CF Seems to have superior OS

Chemotherapy

  • Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
  • Cisplatin (Platinol) 60 mg/m2 IV once on day 1
  • Fluorouracil (5-FU) by one of the following:
    • 600 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3000 mg/m2)
    • 750 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m2)

21-day cycles

References

  1. Abstract: G. Ozal, M. Dogan, H. Akbulut, B. Yalcin, G. Utkan, Y. Urun, F. Icli. The safety and efficacy of modified-dose docetaxel, cisplatin, and 5-fluorouracil (mDCF) combination in the front-line treatment of advanced gastric cancer. 2010 Gastrointestinal Cancers Symposium abstract 113. link to abstract
  2. 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 verified protocol link to PMC article PubMed
  3. 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 verified protocol PubMed

mDCF & Bevacizumab

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mDCF: modified Docetaxel, Cisplatin, Fluorouracil

Regimen

Study Evidence
Shah et al. 2010 Phase II

Patients: 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.

Chemotherapy

Supportive medications

  • "Standard premedication and delayed emesis regimens"

14-day cycles

References

  1. 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 verified protocol link to PMC article PubMed

Docetaxel & S-1

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Regimen

Study Evidence Comparator Efficacy
Koizumi et al. 2013 (STARTgastric) Phase III (E) S-1 Seems to have superior OS

Chemotherapy

  • Docetaxel (Taxotere) 40 mg/m2 IV once on day 1
  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA 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

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 and KCSG Study Group. 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 verified protocol PubMed

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Findlay et al. 1994 Phase II
Webb et al. 1997 Phase III (E) FAMTX Superior OS
Ross et al. 2002 Phase III (C) MCF Seems to have noninferior OS
Roth et al. 2007 Randomized Phase II (C) 1. TC
2. TCF
Not reported
Cunningham et al. 2008 (REAL-2) Phase III (C) 1. ECX Non-inferior OS
2. EOF Non-inferior OS
3. EOX Seems to have inferior OS

Findlay et al. Patients: all metastatic gastric cancer

Ross et al. Patients: adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer.

Roth et al. Patients: all metastatic gastric cancer

REAL-2 Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.

Chemotherapy

Supportive medications

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

21-day cycle for up to 8 cycles

References

  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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol PubMed

ECX

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

Variant #1, continuous capecitabine

Study Evidence Comparator Efficacy
Catenacci et al. 2017 (RILOMET-1) Randomized Phase II (C) ECX & Rilotumumab Superior OS

Patients had unresectable or metastatic MET-positive gastric or gastro-esophageal junction cancer.

Patients: ~80% gastric, 20% GE junction and 10% distal esophageal

Chemotherapy

21-day cycle for up to 10 cycles

Variant #2, intermittent capecitabine

Study Evidence Comparator Efficacy
Konings et al. 2010 Randomized Phase II (C) ECC & Pravastatin Seems not superior

Patients: 6.6% of patients had an ECOG of 2

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. 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 verified protocol PubMed
  2. 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 verified protocol PubMed

Fluorouracil monotherapy

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Variant #1, CI

Study Evidence Comparator Efficacy
Ohtsu et al. 2003 (JCOG 9205) Phase III (C) 1. FP Inferior PFS
2. UFTM Seems not superior
Boku et al. 2009 (JCOG 9912) Phase III (C) 1. Cisplatin & Irinotecan Might have inferior OS
2. S-1 Non-inferior OS
Shirao et al. 2013 (JCOG 0106) Phase III (C) MF Seems not superior

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

Variant #2, intermittent

Study Evidence Comparator Efficacy
Cullinan et al. 1985 Phase III (E) 1. FA
2. FAM
Seems not superior

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

Variant #3, PVI

Study Evidence Comparator Efficacy
Tebbutt et al. 2002 Phase III (C) 5-FU & Mitomycin Seems not superior

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. 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 verified protocol PubMed
  3. 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; Japan Clinical Oncology Group Study (JCOG9205). 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 verified protocol PubMed
  4. 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 protocol PubMed
  5. 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 verified protocol PubMed

Fluorouracil, Folinic acid, Mitomycin

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Regimen

Study Evidence
Hofheinz et al. 2002 Phase II, <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 protocol PubMed

Irinotecan monotherapy

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Regimen

Study Evidence
Enzinger et al. 2005 Phase II

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."

Study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GEJ and 33% distal esophagus)

Regimen 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

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

Regimen

Study Evidence Comparator Efficacy
Al-Batran et al. 2008 Phase III (E) FLP Might have superior PFS

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

Chemotherapy

Supportive medications

  • Antiemetic medications per "local protocols"

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 verified protocol PubMed

Paclitaxel & S-1

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Regimen

Study Evidence Comparator Efficacy
Ishigami et al. 2018 (PHOENIX-GC) Phase III (C) Cisplatin & S-1 Might have superior OS

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) as follows:
    • 40 to 60 mg twice per day, depending on body surface area, as follows:
      • if less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
      • if 1.25 to less than 1.5 m2: 50 mg PO twice per day on days 1 to 14
      • if 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 medications

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 verified protocol PubMed

S-1 monotherapy

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Variant #1, BSA-based

Study Evidence Comparator Efficacy
Boku et al. 2009 (JCOG 9912) Phase III (E) 1. Cisplatin & Irinotecan Not reported
2. 5-FU Non-inferior OS

Chemotherapy

42-day cycles

Variant #2, weight-based

Study Evidence Comparator Efficacy
Koizumi et al. 2008 (SPIRITS) Phase III (C) Cisplatin & S-1 Seems to have inferior OS
Narahara et al. 2011 (TOP-002) Phase III (C) IRIS Seems not superior
Koizumi et al. 2013 (STARTgastric) Phase III (C) Docetaxel & S-1 Seems to have inferior OS
Yoshino et al. 2016 (JFMC36-0701) Phase III (C) Lentinan & S-1 Seems not superior

Note: there is another trial named START in NSCLC.

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA 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

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 verified protocol PubMed
  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 protocol PubMed
  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 verified protocol PubMed
  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 and KCSG Study Group. 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 verified protocol PubMed
  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

UFTM

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UFTM: UFT (Tegafur and uracil) & Mitomycin

Regimen

Study Evidence Comparator Efficacy
Ohtsu et al. 2003 (JCOG 9205) Phase III (E) 1. Fluorouracil Seems not superior
2. FP Seems not superior

Study included patients with PFS of 2 (9.6%)

Chemotherapy

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; Japan Clinical Oncology Group Study (JCOG9205). 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 verified protocol PubMed

Maintenance after first-line therapy

Capecitabine monotherapy

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Regimen

Study Evidence
Ohtsu et al. 2011 (AVAGAST) Non-randomized portion of RCT
Kim et al. 2014 Non-randomized portion of RCT

Ohtsu et al patients: 86% gastric and 14% GEJ. 5.4% of patients had an ECOG of 2.

Kim et al patients: 79% gastric, 5% GEJ, and 16% unknown. 2% of patients had an ECOG of 2.

Preceding treatment

  • AVAGAST: CX x 6
  • Kim et al. 2014: CX x 8

Chemotherapy

21-day cycles

References

  1. 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 verified protocol PubMed
  2. 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 verified protocol PubMed

Metastatic or locally advanced disease, subsequent lines of therapy

Best supportive care

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Regimen

Study Evidence Comparator Efficacy
Thuss-Patience et al. 2011 Phase III (C) Irinotecan Seems to have inferior OS
Kang et al. 2012 Phase III (C) 1. Docetaxel
2. Irinotecan
Inferior OS
Ford et al. 2014 (COUGAR-02) Phase III (C) Docetaxel Inferior OS
Ohtsu et al. 2013 (GRANITE-1) Phase III (C) Everolimus Seems not superior

No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.

Thuss-Patience et al. patients: ~58% gastric, 43% GEJ. 21% of patients had an ECOG of 2.

GRANITE-1 study patients: 29% had GEJ involvement. 7.9% of patients had an ECOG of 2.

References

  1. 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 verified protocol PubMed
  2. 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
  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 protocol PubMed
  4. GRANITE-1: Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, Muro K, Kim YH, Ferry D, Tebbutt NC, Al-Batran SE, Smith H, Costantini C, Rizvi S, Lebwohl D, Van Cutsem E. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013 Nov 1;31(31):3935-43. Epub 2013 Sep 16. link to original article PubMed

Docetaxel monotherapy

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Variant #1, 60 mg/m2

Study Evidence Comparator Efficacy
Kang et al. 2012 Phase III (E) Best supportive care Superior OS

Chemotherapy

21-day cycles

Variant #2, 75 mg/m2 x 6

Study Evidence Comparator Efficacy
Ford et al. 2014 (COUGAR-02) Phase III (E) Best supportive care Superior OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #3, 75 mg/m2, indefinite

Study Evidence Comparator Efficacy
Thuss-Patience et al. 2017 (GATSBY) Phase III (C) T-DM1 Seems not superior

Patients in GATSBY had HER2-positive disease. Study patients could only have been treated by one other regimen and could not have been exposed to anthracyclines

Patients: 68% gastric, 32% GEJ

Chemotherapy

21-day cycles

References

  1. 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 protocol PubMed
  2. 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 protocol PubMed
  3. GATSBY: Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. Epub 2017 Mar 23. link to original article contains protocol PubMed

Fluorouracil, Folinic acid, Mitomycin

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Regimen

Study Evidence
Hofheinz et al. 2002 Phase II, <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 protocol PubMed

Irinotecan monotherapy

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

Study Evidence
Enzinger et al. 2005 Phase II

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."

Study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GE junction and 33% distal esophagus)

Regimen showed a 14% response rate and 53% disease control rate.

Chemotherapy

42-day cycles

Variant #2, 150 mg/m2 q2wk

Study Evidence Comparator Efficacy
Kang et al. 2012 Phase III (E) Best supportive care Superior OS
Hironaka et al. 2013 (WJOG 4007) Phase III (E) Paclitaxel Seems not superior
Higuchi et al. 2014 (BIRIP) Phase III (C) Cisplatin & Irinotecan Seems to have inferior PFS
Nishikawa et al. 2015 (TRICS) Phase III (C) Cisplatin & Irinotecan Seems not superior
Tanabe et al. 2015 (JACCRO GC-05) Phase III (C) Irinotecan & S-1 Seems not superior
Bang et al. 2018 (JAVELIN Gastric 300) Phase III (C) Avelumab Seems not superior

Hironaka et al patients: 3.7% patients with an ECOG PS of 2

Chemotherapy

14-day cycles

Variant #3, 300 mg/m2 q3wk

Study Evidence Comparator
Roy et al. 2013 (PEP0206) Randomized Phase II (C) 1. Docetaxel
2. Irinotecan liposome

Study included patients with GE junction malignancy (77% gastric, 23% GE junction) and included patients with ECOG of 2

Chemotherapy

21-day cycles

Variant #4, 350 mg/m2 q3wk

Study Evidence Comparator Efficacy
Thuss-Patience et al. 2011 Phase III (E) Best supportive care Seems to have superior OS

Thuss-Patience et al. included patients with GE junction malignancy (~58% gastric, 43% GE junction) and included patients with ECOG 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 medications

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 verified protocol PubMed
  3. 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
  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
  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 protocol PubMed
  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, Tokyo, Japan. 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 protocol PubMed
  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 protocol PubMed
  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 GC-05 study group. 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
  9. JAVELIN Gastric 300: Bang YJ, Ruiz EY, 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 protocol PubMed

Irinotecan liposomal monotherapy

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Regimen

Study Evidence Comparator
Roy et al. 2013 (PEP0206) Randomized Phase II (E) 1. Docetaxel
2. Irinotecan

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 verified protocol PubMed

Nivolumab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Kang et al. 2017 (ATTRACTION-2) Phase III (E) Placebo Superior OS
Janjigian et al. 2018 (CheckMate-032) Phase II

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 verified protocol PubMed
    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. 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 PubMed

Paclitaxel monotherapy

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Variant #1, 80 mg/m2 weekly

Study Evidence Comparator Efficacy
Kodera et al. 2007 (CCOG0302) Phase II
Thuss-Patience et al. 2017 (GATSBY) Phase III (C) T-DM1 Seems not superior

Patients had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation

Study included patients with GE junction malignancy (68% gastric, 32% GE junction)

Chemotherapy

21-day cycles

Variant #2, 80 mg/m2, 3 out of 4 weeks

Study Evidence Comparator Efficacy
Hironaka et al. 2006 Non-randomized
Hironaka et al. 2013 (WJOG 4007) Phase III (E) Irinotecan Seems not superior
Satoh et al. 2014 (TyTAN) Phase III (C) Lapatinib & Paclitaxel Seems not superior
Wilke et al. 2014 (RAINBOW) Phase III (C) Paclitaxel & Ramucirumab Seems to have inferior OS
Shitara et al. 2017 (ABSOLUTE) Phase III (C) 1. nab-Paclitaxel weekly Non-inferior OS
2. nab-Paclitaxel q3wk Might have superior OS
Bang et al. 2017 (GOLD) Phase III (C) Olaparib & Paclitaxel Might have inferior OS
Shitara et al. 2018 (KEYNOTE-061) Phase III (C) Pembrolizumab Might have inferior OS
Bang et al. 2018 (JAVELIN Gastric 300) Phase III (C) Avelumab Seems not superior

Eligibility criteria for patients in RAINBOW included: "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." Patients in TyTAN had HER2-positive disease.

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

Satoh et al. patients: 98.5% gastric. 1.5 other

Hironaka et al patients: 3.7% patients with a PFS of 2

Chemotherapy

28-day cycles

Variant #3, 175 mg/m2 q3wk

Study Evidence Comparator Efficacy
Kang et al. 2018 (DREAM) Phase III (C) DHP107 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 verified protocol 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 protocol 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 protocol PubMed
  4. TyTAN: Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, Tsuji A, Omuro Y, Li J, Wang JW, Miwa H, Qin SK, Chung IJ, Yeh KH, Feng JF, Mukaiyama A, Kobayashi M, Ohtsu A, Bang YJ. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol. 2014 Jul 1;32(19):2039-49. Epub 2014 May 27. link to original article contains verified protocol PubMed
  5. 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. link to original article contains verified protocol PubMed
  6. 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 protocol PubMed
  7. GATSBY: Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. Epub 2017 Mar 23. link to original article contains protocol PubMed
  8. 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
  9. 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 protocol PubMed
  10. 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 verified protocol PubMed
  11. JAVELIN Gastric 300: Bang YJ, Ruiz EY, 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 protocol PubMed

nab-Paclitaxel monotherapy

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Regimen

Study Evidence Comparator Efficacy
Shitara et al. 2017 (ABSOLUTE) Phase III (E) 1. Weekly Paclitaxel Non-inferior OS
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 protocol PubMed

Paclitaxel & Ramucirumab

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Regimen

FDA-recommended dose
Study Evidence ORR Comparator Comparator ORR Efficacy
Wilke et al. 2014 (RAINBOW) Phase III (E) 28% (95% CI 23-33%) Paclitaxel 16% (95% CI 13-20%) Seems to have superior OS

Eligibility criteria for patients in RAINBOW included: "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."

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

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. link to original article contains verified protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Fuchs et al. 2018 (KEYNOTE-059) Phase II ORR: 12% (95% CI 8-16)
Shitara et al. 2018 (KEYNOTE-061) Phase III (E) Paclitaxel Might have superior OS

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

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 verified protocol PubMed
  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 verified protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
Fuchs et al. 2013 (REGARD) Phase III (C) Ramucirumab Seems to have inferior OS
Pavlakis et al. 2016 (INTEGRATE) Randomized Phase II (C) Regorafenib Inferior PFS
Kang et al. 2017 (ATTRACTION-2) Randomized Phase II (C) Nivolumab Inferior OS
Shitara et al. 2018 (TAGS) Phase III (C) Trifluridine/tipiracil Inferior OS

All studies included patients with GE junction malignancy:

  • REGARD: 75% gastric, 25% GE junction
  • INTEGRATE: 62% stomach or other, 38% GE junction
  • ATTRACTION-2: 82.6% gastric, 8.5% GE junction

Patients in REGARD previously had "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."

No active antineoplastic treatment.

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 verified protocol PubMed
  2. 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 verified protocol link to PMC article PubMed
  3. 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 verified protocol PubMed
  4. 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 protocol PubMed

Ramucirumab monotherapy

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Regimen

FDA-recommended dose
Study Evidence ORR Comparator Comparator ORR Efficacy
Fuchs et al. 2013 (REGARD) Phase III (E) 3% Placebo 3% Seems to have superior OS

Patients in REGARD previously had "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."

Study includes patients with GE junction malignancy (75% gastric, 25% GE junction).

Chemotherapy

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 verified protocol PubMed

Regorafenib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Pavlakis et al. 2016 (INTEGRATE) Randomized Phase II (E) Placebo Superior PFS

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

Chemotherapy

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 verified protocol link to PMC article PubMed

Trifluridine and tipiracil monotherapy

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Regimen

Study Evidence Comparator Efficacy
Shitara et al. 2018 (TAGS) Phase III (E) Placebo Superior OS

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 protocol PubMed