Gastric cancer

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 Ivy Abraham, MD
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 Neeta K. Venepalli, MD, MBA
University of Illinois at Chicago
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Note: there is significant overlap between regimens for gastric cancer and esophageal cancer, if you can't find the regimen you're looking for here, please try the esophageal cancer page. If you still can't find it, it is possible that we've moved it to the historical regimens page.

71 regimens on this page
108 variants on this page


Guidelines

CAP/ASCP/ASCO

ESMO

ESMO/ESSO/ESTRO

NCCN

Neoadjuvant chemotherapy

Cisplatin & Fluorouracil

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FP: Fluorouracil & Platinol (Cisplatin)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ychou et al. 2011 (ACCORD 07) 1995-2003 Phase III (E-esc) 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 NCT00002883

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2006 (MAGIC) 1994-2002 Phase III (E-esc) Surgery alone Superior OS
Cats et al. 2018 (CRITICS) 2007-2015 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 NCT00407186

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 NCT00407186

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 NCT00407186

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 NCT00407186

FLOT

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Al-Batran et al. 2016 (FLOT4-AIO) 2010-2015 Phase II/III (E-switch-ic) 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 NCT01216644
    1. Update: Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, 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 May 11;393(10184):1948-1957. Epub 2019 Apr 11. link to original article PubMed

Adjuvant therapy

CapeOx

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CapeOX: Capecitabine & OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bang et al. 2012 (CLASSIC) 2006-2009 Phase III (E-esc) 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 NCT00411229
    1. Update: Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W, Lee JI, Shin DB, Ji J, Chen JS, Lim Y, Ha S, Bang YJ; CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1389-96. Epub 2014 Oct 15. link to original article PubMed

Carboplatin & Docetaxel

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bamias et al. 2010 2002-2005 Phase III (C) Carboplatin, Docetaxel, RT Did not meet primary endpoint of OS

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

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

Cisplatin & Fluorouracil

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ychou et al. 2011 (ACCORD 07) 1995-2003 Phase III (E-esc) 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 NCT00002883

CX

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2011 (ARTISTgastric) 2004-2008 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 NCT00323830
    1. Update: Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, Sohn I, Jung SH, Choi MG, Lee JH, Bae JM, Kim S, Kim ST, Park JO, Park YS, Lim HY, Kang WK. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: Final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015 Oct 1;33(28):3130-6. Epub 2015 Jan 5. link to original article PubMed

Docetaxel & S-1

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Protocol

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kodera et al. 2018 (JACCRO GC-07) NR in abstract Phase III (E-esc) S-1 Seems to have superior RFS

Chemotherapy, part 1

1 Cycle of:

21-day cycle for 1 cycle, followed by:

Chemotherapy, part 2

42-day cycle for 6 cycles, followed by:

Chemotherapy, part 3

  • S-1 80 to 120 mg/body PO on days 1 to 28

42-day cycle for 4 cycles

References

  1. Abstract: Kodera Y, Yoshida K, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Nakamura M, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matssuyama J, Yamada M, Ito Y, Takeuchi M, Fujii M; JACCRO. A randomized phase III study comparing S-1 plus docetaxel with S-1 alone as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer (JACCRO GC-07 trial). 2019 American Society of Clinical Oncology annual meeting. DOI: 10.1200/JCO.2018.36.15_suppl.4007 36, no. 15_suppl (May 20, 2018) 4007-4007. link to abstract UMIN000010337

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2006 (MAGIC) 1994-2002 Phase III (E-esc) Surgery alone Superior OS
Cats et al. 2018 (CRITICS) 2007-2015 Phase III (C) CX & RT Did not meet primary endpoint of OS

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 NCT00407186

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cats et al. 2018 (CRITICS) 2007-2015 Phase III (C) CX & RT Did not meet primary endpoint of OS

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 NCT00407186

EOF

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EOF: Epirubicin, Oxaliplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cats et al. 2018 (CRITICS) 2007-2015 Phase III (C) CX & RT Did not meet primary endpoint of OS

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 NCT00407186

EOX

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EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cats et al. 2018 (CRITICS) 2007-2015 Phase III (C) CX & RT Did not meet primary endpoint of OS

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 NCT00407186

FLOT

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Al-Batran et al. 2016 (FLOT4-AIO) 2010-2015 Phase II/III (E-switch-ic) 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/Capecitabine & RT

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

Protocol

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

FULV/FULV & RT

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FULV/FULV & RT: FluoroUracil & LeucoVorin (Folinic acid) alternating with FluoroUracil, LeucoVorin (Folinic acid) & Radiation Therapy

Protocol

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

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 NCT00052910

S-1 monotherapy

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Regimen variant #1, 21-day cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Tsuburaya et al. 2014 (SAMIT) 2004-2009 Phase III (C) 1. Paclitaxel, then S-1
2. Paclitaxel, then UFT 		Did not meet primary endpoint of DFS
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

Regimen variant #2, 42-day cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sakuramoto et al. 2007 (ACTS-GC) 2001-2004 Phase III (E-esc) Observation Superior OS
Yoshikawa et al. 2019 (OPAS-1) 2012-2017 Phase III (C) S-1 x 6 mo Inconclusive whether non-inferior RFS

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 UMIN C000000082
  3. OPAS-1: Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Fukushima N, Hato S, Choda Y, Yabusaki H, Yoshida K, Ito S, Takeno A, Yasuda T, Kawachi Y, Katayama H, Fukuda H, Boku N, Sano T, Sasako M. Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104[OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial. Lancet Gastroenterol Hepatol. 2019 Mar;4(3):208-216. Epub 2019 Jan 22. Erratum in: Lancet Gastroenterol Hepatol. 2019 Apr;4(4):e3. link to original article PubMed UMIN000007306

Metastatic or locally advanced disease, first-line

Capecitabine monotherapy

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X: Xeloda (Capecitabine)

Regimen variant #1, 2000 mg/m2/day

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hwang et al. 2017 (SMC 2010-04-118) 2010-2014 Phase III (C) XELOX Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

Regimen 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. SMC 2010-04-118: Hwang IG, Ji JH, Kang JH, Lee HR, Lee HY, Chi KC, Park SW, Lee SJ, Kim ST, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017 May;8(3):170-175. Epub 2017 Jan 21. link to original article contains protocol PubMed NCT01470742

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


Capecitabine, Oxaliplatin, Lapatinib

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Study Years of enrollment Evidence Comparator Comparative Efficacy
Hecht et al. 2016 2008-2012 Phase III (C) Capecitabine, Oxaliplatin and Placebo Did not meet primary endpoint of OS


Chemotherapy

21-day cycles

References

  1. Hecht, J. Randolph, et al. "Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2–positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC—a randomized phase III trial." Journal of Clinical Oncology 34.5 (2016): 443-451.

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

Regimen variant #1, 75/75

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

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

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles

Regimen variant #2, 75/85

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ajani et al. 2005 (V-325) 1998-1999 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)

Regimen variant #1, 80/4000 x 6

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bang et al. 2010 (ToGA) 2005-2008 Phase III (C) CF & Trastuzumab Inferior OS

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

Biomarker eligibility criteria

  • Overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.

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

Regimen variant #2, 80/4000 x 8

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

Chemotherapy

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

Supportive medications

21-day cycle for 8 cycles

Regimen variant #3, 80/4000, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kang et al. 2009 2003-2005 Phase III (C) CX Non-inferior PFS
Shitara et al. 2020 (KEYNOTE-062) 2015-2017 Phase III (C) CF & Pembrolizumab Seems to have inferior OS

Chemotherapy

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

Supportive medications

21-day cycles

Regimen variant #4, 100/4000

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

Chemotherapy

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

28-day cycles

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

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

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

Regimen variant #6, 100/5000

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

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; JCOG. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. link to original article contains 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. TAX 325: Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. link to original article contains 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 NCT00400179
  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 NCT00548548
  9. DIGEST: Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. link to original article contains verified protocol PubMed NCT01285557
  10. KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Sep 3. Epub ahead of print. link to original article PubMed NCT02494583


Cisplatin, Fluorouracil, Pembrolizumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shitara et al. 2020 (KEYNOTE-062) 2015-2017 Phase III (E-esc) CF Seems to have superior OS

KEYNOTE-062 included patients with GEJ malignancy

Biomarker eligibility criteria

PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test

Chemotherapy

  • Cisplatin (Platinol) 80 mg/m2 IV once on day 1
  • Fluorouracil (5-FU) 800 mg/m2 IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
    • Alternative: capecitabine 1000 mg/m2 PO BID on days 1-14

Immunotherapy

21-day cycles

References

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

Cisplatin & S-1

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

Regimen variant #1, q3wk ("SP3")

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ryu et al. 2015 (SOS) 2009-2012 Phase III (E-switch-ic) Cisplatin & S-1; SP5 Seems to have superior PFS

Chemotherapy

21-day cycles

Regimen variant #2, q4wk

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

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

Chemotherapy

28-day cycles

Regimen variant #3, q5wk ("SP5")

Study Years of enrollment Evidence Comparator Comparative Efficacy
Koizumi et al. 2008 (SPIRITS) 2002-2004 Phase III (E-esc) S-1 Seems to have superior OS
Fujitani et al. 2016 (REGATTA) 2008-2013 Non-randomized portion of RCT
Ryu et al. 2015 (SOS) 2009-2012 Phase III (C) Cisplatin & S-1; SP3 Seems to have inferior PFS
Yamada et al. 2014 (G-SOX) 2010-2011 Phase III (C) SOX Non-inferior PFS
Ishigami et al. 2018 (PHOENIX-GC) 2011-2013 Phase III (C) IV/IP Paclitaxel & S-1 Might have inferior OS
Yamada et al. 2019 (JCOG1013) 2012-2016 Phase III (C) Cisplatin, Docetaxel, S-1 Did not meet primary endpoint of OS
Kang et al. 2020 (SOLAR) 2015-2016 Phase III (C) Oxaliplatin & TAS-118 Seems to have inferior PFS

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

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

CLF

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

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Al-Batran et al. 2008 2003-2006 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

Regimen variant #2

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

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

Chemotherapy

Supportive 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. 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 Years of enrollment Evidence Comparator Comparative Efficacy
Kang et al. 2009 2003-2005 Phase III (E-switch-ic) CF Non-inferior PFS
Ohtsu et al. 2011 (AVAGAST) 2007-2008 Phase III (C) CX & Bevacizumab Did not meet primary endpoint of OS
Lordick et al. 2013 (EXPAND) 2008-2010 Phase III (C) CX & Cetuximab Did not meet primary endpoint of PFS
Shen et al. 2014 (AVATAR) 2009-2010 Phase III (C) CX & Bevacizumab Did not meet primary endpoint of OS
Kim et al. 2014 (SMC 2008-12-019) 2009-2012 Phase III (C) CX & Simvastatin Did not meet primary endpoint of PFS
Lu et al. 2018 (PAC-C) 2009-2014 Phase III (C) Capecitabine & Paclitaxel Did not meet primary endpoint of PFS
Fuchs et al. 2019 (RAINFALL) 2015-2016 Phase III (C) CX & Ramucirumab Did not meet primary endpoint of PFS (*)

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
  • SMC 2008-12-019 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 NCT00548548
  3. EXPAND: Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. link to original article contains verified protocol PubMed EudraCT 2007-004219-75
  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 NCT00887822
  5. SMC 2008-12-019: Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. link to original article contains verified protocol PubMed NCT01099085
  6. PAC-C: Lu Z, Zhang X, Liu W, Liu T, Hu B, Li W, Fan Q, Xu J, Xu N, Bai Y, Pan Y, Xu Q, Bai W, Xia L, Gao Y, Wang W, Shu Y, Shen L. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018 Sep;21(5):782-791. Epub 2018 Feb 27. link to original article link to PMC article contains verified protocol PubMed NCT01015339
  7. RAINFALL: Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):420-435. Epub 2019 Feb 1. Erratum in: Lancet Oncol. 2019 May;20(5):e242. link to original article contains protocol PubMed NCT02314117

CX & Trastuzumab

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

Regimen variant #1, 80/1600

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shah et al. 2017 (HELOISE) 2011-2015 Phase IIIb (C) CX & Trastuzumab; high-dose Did not meet primary endpoint of OS

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

Biomarker eligibility criteria

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

Chemotherapy

Targeted therapy

  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 8 mg/kg IV once on day 1 (compared to HD-Trastuzumab at 10 mg/kg IV)
    • Subsequent cycles: 6 mg/kg IV once on day 1

21-day cycle for up to 6 cycles

Subsequent treatment

  • Trastuzumab maintenance

Regimen variant #2, 80/2000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bang et al. 2010 (ToGA) 2005-2008 Phase III (E-RT-esc) CX Superior OS
Tabernero et al. 2018 (JACOB) 2013-2016 Phase III (C) CX, Pertuzumab, Trastuzumab Might have inferior OS

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

Biomarker eligibility criteria

  • ToGA: overexpression of HER2 protein by immunohistochemistry OR gene amplification by fluorescence in-situ hybridization.

Chemotherapy

Targeted therapy

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 NCT01450696
  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 NCT01774786

DCF

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

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ajani et al. 2005 (V-325) 1998-1999 Randomized Phase II (E-esc) DC Seems to have superior ORR
Van Cutsem et al. 2006 (TAX 325) 1999-2003 Phase III (E-RT-esc) 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

Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Roth et al. 2007 1999-2003 Randomized Phase II (E-esc) 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. TAX 325: Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. link to original article contains 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

Regimen variant #1, 40/40/2800

Study Evidence
Shah et al. 2010 (MSK 06-096) 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

Regimen variant #2, 60/60/3000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2015 (DOCET L 02195) 2008-2010 Phase III (E-esc) 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. MSK 06-096: Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. link to original article contains verified protocol link to PMC article PubMed NCT00390416
  2. 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 NCT00811447

mDCF & Bevacizumab

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

Regimen

Study Evidence
Shah et al. 2010 (MSK 06-096) Phase II

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

Chemotherapy

Targeted therapy

Supportive medications

  • "Standard premedication and delayed emesis regimens"

14-day cycles

References

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

Docetaxel & S-1

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Koizumi et al. 2013 (STARTgastric) 2005-2008 Phase III (E-esc) 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; KCSG. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. link to original article link to PMC article contains verified protocol PubMed NCT00287768

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

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

Regimen variant #1, continuous capecitabine

Study Years of enrollment Evidence Comparator Comparative Efficacy
Catenacci et al. 2017 (RILOMET-1) 2012-2014 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

Regimen variant #2, intermittent capecitabine

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

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 NCT01697072

Fluorouracil monotherapy

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Regimen variant #1, CI

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

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

Chemotherapy

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

28-day cycles

Regimen variant #2, intermittent, BSA-based

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

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

Chemotherapy

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

Regimen variant #3, intermittent, weight-based

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

Chemotherapy

21- to 28-day cycles

Regimen variant #4, PVI

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

Chemotherapy

Up to 24-week course

References

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

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

FOLFIRI

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

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

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

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

Chemotherapy

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

Supportive medications

7-week cycles

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

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

Patients: 100% adenocarcinoma (70% gastric origin, 30% cardia).

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

Chemotherapy

14-day cycle for at least 4 cycles

Regimen variant #3, 400/2800/180

Study Years of enrollment Evidence Comparator Comparative Efficacy
Guimbaud et al. 2014 (FFCD 03-07) 2005-2008 Phase III (E-switch-ic) ECX Superior TTF

Chemotherapy

14-day cycles

References

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

FULV

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FULV: 5-FU & LeucoVorin (Folinic acid)

Regimen

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

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

Patients: 100% adenocarcinoma (70% gastric origin, 30% cardia)

Chemotherapy

14-day cycle for at least 4 cycles

References

  1. FFCD 9803: Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. link to original article contains verified 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 Years of enrollment Evidence Comparator Comparative Efficacy
Al-Batran et al. 2008 2003-2006 Phase III (E-switch-ic) 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 Years of enrollment Evidence Comparator Comparative Efficacy
Ishigami et al. 2018 (PHOENIX-GC) 2011-2013 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

Pembrolizumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shitara et al. 2020 (KEYNOTE-062) 2015-2017 Phase III (E-switch-ooc) Chemotherapy Mixed endpoints

KEYNOTE-062 included patients with GEJ malignancy

Biomarker eligibility criteria

Improved OS was seen in patients with PD-L1 CPS score of 10 or more (HR: 0.62) but was not tested per analysis plan

Immunotherapy

21-day cycles

References

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

S-1 monotherapy

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Regimen variant #1, BSA-based

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

Chemotherapy

42-day cycles

Regimen variant #2, weight-based

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

Note: there is another trial named START in NSCLC.

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) 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 NCT00150670
  2. JCOG 9912: Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. link to original article contains protocol PubMed NCT00142350
  3. TOP-002: Narahara H, Iishi H, Imamura H, Tsuburaya A, Chin K, Imamoto H, Esaki T, Furukawa H, Hamada C, Sakata Y. Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002). Gastric Cancer. 2011 Mar;14(1):72-80. Epub 2011 Feb 23. link to original article link to PMC article contains 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; KCSG. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. link to original article link to PMC article contains verified protocol PubMed NCT00287768
  5. JFMC36-0701: Yoshino S, Nishikawa K, Morita S, Takahashi T, Sakata K, Nagao J, Nemoto H, Murakami N, Matsuda T, Hasegawa H, Shimizu R, Yoshikawa T, Osanai H, Imano M, Naitoh H, Tanaka A, Tajiri T, Gochi A, Suzuki M, Sakamoto J, Saji S, Oka M. Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). Eur J Cancer. 2016 Sep;65:164-71. Epub 2016 Aug 5. link to original article PubMed UMIN000000574

UFTM

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UFTM: UFT (Tegafur and uracil) & Mitomycin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ohtsu et al. 2003 (JCOG 9205) 1992-1995 Phase III (E-esc) 1. Fluorouracil Did not meet primary endpoint of OS
2. FP Did not meet primary endpoint of OS

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; JCOG. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. link to original article contains 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 (SMC 2008-12-019) Non-randomized portion of RCT

AVAGAST patients: 86% gastric and 14% GEJ. 5.4% of patients had an ECOG of 2.

SMC 2008-12-019 patients: 79% gastric, 5% GEJ, and 16% unknown. 2% of patients had an ECOG of 2.

Preceding treatment

  • AVAGAST: CX x 6
  • SMC 2008-12-019: CX x 8

Chemotherapy

21-day cycles

References

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

Metastatic or locally advanced disease, subsequent lines of therapy

Apatinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kang et al. 2019 (ANGEL) 2017-2018 Phase III (E-esc) Placebo Superior PFS

ANGEL included patients with GEJ malignancy

Targeted therapy

28-day cycles

References

  1. Abstract: Kang Y, Kang WK, Di Bartolomeo M, Chau I, Yoon HH, Cascinu S, Ryu M, Kim JG, Lee K, Oh SC, Takashima A, Kryzhanivska A, Chao Y, Vladimirov V, Evesque L, Schenker M, McGinn A, Sankar N, Wyrwicz L, Boku N. Randomized Phase 3 ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastatic gastric cancer. 2019 European Society of Medical Oncology annual meeting. Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394 link to abstract NCT03042611

Docetaxel monotherapy

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Regimen variant #1, 60 mg/m2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kang et al. 2012 (SMC 2008-08-055) 2008-2010 Phase III (E-esc) Best supportive care Superior OS

Chemotherapy

21-day cycles

Regimen variant #2, 75 mg/m2 x 6

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ford et al. 2014 (COUGAR-02) 2008-2012 Phase III (E-esc) Best supportive care Superior OS

Chemotherapy

21-day cycle for up to 6 cycles

Regimen variant #3, 75 mg/m2, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Thuss-Patience et al. 2017 (GATSBY) 2012-2013 Phase II/III (C) T-DM1 Did not meet primary endpoint of OS

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

Biomarker eligibility criteria

  • GATSBY: HER2-positive disease

Chemotherapy

21-day cycles

References

  1. SMC 2008-08-055: Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. link to original article contains protocol PubMed
  2. PEP0206: Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. link to original article PubMed NCT00813072
  3. COUGAR-02: Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. link to original article contains protocol PubMed
  4. 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 NCT01641939

Fam-trastuzumab deruxtecan monotherapy

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Regimen variant #1, 60 mg/m2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shitara et al. 2020 (DESTINY-Gastric01) 2017-2019 Randomized Phase II (E-switch-ooc) Investigator's choice of:
1. Irinotecan
2. Paclitaxel 		Superior OS

Note: the dose is different from the FDA-approved dose for breast cancer.

Patients had received a median of two prior therapies for advanced or metastatic disease (17% had received at least four prior therapies, 72% had previously received ramucirumab and 86% had received taxanes).

The median time since the last administration of trastuzumab was 5.9 months in the trastuzumab deruxtecan group and 6.5 months among those in the investigator's choice group.

Biomarker eligibility criteria

  • HER2 over-expression

Chemotherapy

21-day cycles

References

  1. DESTINY-Gastric01: Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430. Epub 2020 May 29. link to original article contains verified protocol PubMed NCT03329690

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 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

Regimen variant #2, 150 mg/m2 q2wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hironaka et al. 2013 (WJOG 4007) 2007-2010 Phase III (E-switch-ic) Paclitaxel Did not meet primary endpoint of OS
Nishikawa et al. 2015 (TRICS) 2007-2011 Phase III (C) Cisplatin & Irinotecan Did not meet primary endpoint of OS
Kang et al. 2012 (SMC 2008-08-055) 2008-2010 Phase III (E-esc) Best supportive care Superior OS
Higuchi et al. 2014 (BIRIP) 2008-2011 Phase III (C) Cisplatin & Irinotecan Seems to have inferior PFS
Tanabe et al. 2015 (JACCRO GC-05) 2008-2011 Phase III (C) Irinotecan & S-1 Did not meet primary endpoint of OS
Bang et al. 2018 (JAVELIN Gastric 300) 2015-2017 Phase III (C) Avelumab Did not meet primary endpoint of OS
Shitara et al. 2020 (DESTINY-Gastric01) 2017-2019 Randomized Phase II (C) Trastuzumab deruxtecan Inferior OS

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

=Biomarker eligibility criteria

  • DESTINY-Gastric01: HER2 over-expression

Chemotherapy

14-day cycles

Regimen variant #3, 300 mg/m2 q3wk

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

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

Chemotherapy

21-day cycles

Regimen variant #4, 350 mg/m2 q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Thuss-Patience et al. 2011 2002-2006 Phase III (E-esc) Best supportive care Seems to have superior OS

Thuss-Patience et al. 2011 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. SMC 2008-08-055: Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. link to original article PubMed
  4. PEP0206: Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. link to original article PubMed NCT00813072
  5. WJOG 4007: Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. link to original artile contains 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. 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 UMIN000001028
  7. TRICS: Nishikawa K, Fujitani K, Inagaki H, Akamaru Y, Tokunaga S, Takagi M, Tamura S, Sugimoto N, Shigematsu T, Yoshikawa T, Ishiguro T, Nakamura M, Morita S, Miyashita Y, Tsuburaya A, Sakamoto J, Tsujinaka T. Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial. Eur J Cancer. 2015 May;51(7):808-16. Epub 2015 Mar 18. link to original article contains 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. Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05). Ann Oncol. 2015 Sep;26(9):1916-22. Epub 2015 Jun 24. link to original article PubMed NCT00639327
  9. JAVELIN Gastric 300: Bang YJ, 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 NCT02625623
  10. DESTINY-Gastric01: Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430. Epub 2020 May 29. link to original article contains verified protocol PubMed NCT03329690

Irinotecan liposomal monotherapy

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Regimen

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

Chemotherapy

21-day cycles

References

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

Nivolumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Janjigian et al. 2018 (CheckMate-032) 2013-2015 Phase II
Kang et al. 2017 (ATTRACTION-2) 2014-2016 Phase III (E-esc) Placebo Superior OS

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 NCT01928394

Paclitaxel monotherapy

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

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

Chemotherapy

28-day cycles

Regimen variant #2, 80 mg/m2 weekly

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kodera et al. 2007 (CCOG0302) 2003-2006 Phase II
Thuss-Patience et al. 2017 (GATSBY) 2012-2013 Phase II/III (C) T-DM1 Did not meet primary endpoint of OS

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

Biomarker eligibility criteria

  • GATSBY: overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation

Chemotherapy

21-day cycles

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hironaka et al. 2006 2002-2004 Non-randomized
Satoh et al. 2014 (TyTAN) 2007-2009 Phase III (C) Lapatinib & Paclitaxel Did not meet primary endpoint of OS
Hironaka et al. 2013 (WJOG 4007) 2007-2010 Phase III (E-switch-ic) Irinotecan Did not meet primary endpoint of OS
Wilke et al. 2014 (RAINBOW) 2010-2012 Phase III (C) Paclitaxel & Ramucirumab Seems to have inferior OS
Shitara et al. 2017 (ABSOLUTE) 2013-2015 Phase III (C) 1. nab-Paclitaxel weekly Non-inferior OS
2. nab-Paclitaxel q3wk Might have superior OS
Bang et al. 2017 (GOLD) 2013-2016 Phase III (C) Olaparib & Paclitaxel Might have inferior OS
Shitara et al. 2018 (KEYNOTE-061) 2015-2016 Phase III (C) Pembrolizumab Might have inferior OS
Bang et al. 2018 (JAVELIN Gastric 300) 2015-2017 Phase III (C) Avelumab Did not meet primary endpoint of OS
Shitara et al. 2020 (DESTINY-Gastric01) 2017-2019 Randomized Phase II (C) Trastuzumab deruxtecan Inferior 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)

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

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

Biomarker eligibility criteria

  • TyTAN & DESTINY-Gastric01: HER2-positive disease

Chemotherapy

28-day cycles

Regimen variant #4, 175 mg/m2 q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kang et al. 2018 (DREAM) 2013-2015 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 NCT00486954
  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. Epub 2014 Sep 17. 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 JapicCTI-132059
  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 NCT01641939
  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 NCT01924533
  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 NCT01839773
  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 NCT02370498
  11. KCSG ST10-01: Lee KW, Maeng CH, Kim TY, Zang DY, Kim YH, Hwang IG, Oh SC, Chung JS, Song HS, Kim JW, Jeong SJ, Cho JY. A phase III study to compare the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer who failed in first-line therapy (KCSG ST10-01). Oncologist. 2019 Jan;24(1):18-e24. Epub 2018 Aug 20. link to original article contains protocol link to PMC article PubMed NCT01224652
  12. 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 NCT02625623
  13. DESTINY-Gastric01: Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430. Epub 2020 May 29. link to original article contains verified protocol PubMed NCT03329690

nab-Paclitaxel monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shitara et al. 2017 (ABSOLUTE) 2013-2015 Phase III (E-switch-ic) 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 JapicCTI-132059

Paclitaxel & Ramucirumab

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Wilke et al. 2014 (RAINBOW) 2010-2012 Phase III (E-RT-esc) Paclitaxel Seems to have superior OS 28% (95% CI 23-33%) 16% (95% CI 13-20%)

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).

Targeted therapy

Chemotherapy

28-day cycles

References

  1. RAINBOW: Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. Epub 2014 Sep 17. link to original article contains verified protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fuchs et al. 2018 (KEYNOTE-059) 2015-2016 Phase II (RT) ORR: 12% (95% CI 8-16)
Shitara et al. 2018 (KEYNOTE-061) 2015-2016 Phase III (E-switch-ooc) 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

Biomarker eligibility criteria

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

Immunotherapy

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

References

  1. KEYNOTE-059: Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018 May 10;4(5):e180013. Epub 2018 May 10. link to original article link to PMC article contains 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 NCT02370498

Ramucirumab monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Fuchs et al. 2013 (REGARD) 2009-2012 Phase III (E-RT-esc) Placebo Seems to have superior OS 3% 3%

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).

Targeted therapy

14-day cycles

References

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

Regorafenib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Pavlakis et al. 2016 (INTEGRATE) 2012-2014 Randomized Phase II (E-esc) Placebo Superior PFS

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

Targeted therapy

28-day cycles

References

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

Trifluridine and tipiracil monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shitara et al. 2018 (TAGS) 2016-2018 Phase III (E-RT-esc) 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
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