Esophageal adenocarcinoma

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Ryan Nguyen, DO
University of Illinois at Chicago
Chicago, IL

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Neeta K. Venepalli, MD, MBA
University of North Carolina
Chapel Hill, NC

Note: these are regimens tested in histology-specific populations, please see the main esophageal cancer page for other regimens.

41 regimens on this page
48 variants on this page


Neoadjuvant induction therapy

Cisplatin & Fluorouracil (CF)

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

Regimen variant #1, 40/4200

Study Years of enrollment Evidence
Ajani et al. 2006 (RTOG 9904) 1999-2004 Phase II

Patients: 100% adenocarcinoma histology. The majority of patients had gastric adenocarcinoma. Although gastroesophageal junction was involved, percentages were not included.

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

Regimen variant #2, 80/4000, 4 day 5-FU infusion

Study Years of enrollment Evidence Comparator Comparative Efficacy
Alderson et al. 2017 (UK MRC OE05) 2005-2011 Phase III (C) ECX Did not meet primary endpoint of OS

UK MRC OE05 patients: 100% adenocarcinoma of the esophagus (including Siewert types 1 and 2 gastroesophageal junction tumors)

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment

Regimen variant #4, 100/4000

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 chemotherapy. It is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Patients: 100% adenocarcinoma histology (65% esophagogastric junction, 10% lower esophageal, 25% gastric adenocarcinoma)

Chemotherapy

28-day cycle for 2 or 3 cycles

Subsequent treatment

References

  1. RTOG 9904: Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, Greskovich JF, Anne PR, Bradley JD, Willett C, Rich TA. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006 Aug 20;24(24):3953-8. link to original article contains verified protocol PubMed
  2. 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. Epub 2011 Mar 28. link to original article contains verified protocol PubMed NCT00002883
  3. UK MRC OE05: Alderson D, Cunningham D, Nankivell M, Blazeby JM, Griffin SM, Crellin A, Grabsch HI, Langer R, Pritchard S, Okines A, Krysztopik R, Coxon F, Thompson J, Falk S, Robb C, Stenning S, Langley RE. Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1249-1260. Epub 2017 Aug 4. link to original article link to PMC article contains verified protocol PubMed NCT00041262

Cisplatin & Irinotecan (IC)

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IC: Irinotecan & Cisplatin

Regimen

Study Years of enrollment Evidence
Rivera et al. 2009 NR in abstract Phase II

Rivera et al. patients: 100% adenocarcinoma histology (43% gastroesophageal junction, 57% gastric adenocarcinoma)

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 & 8, prior to chemotherapy
  • One of the following:
  • At least 500 mL D5NS or NS as supportive hydration
  • Atropine (Atropen) 0.5 to 1 mg IV prn cholinergic symptoms

21-day cycle for 2 cycles

Subsequent treatment

References

  1. Rivera F, Galán M, Tabernero J, Cervantes A, Vega-Villegas ME, Gallego J, Laquente B, Rodríguez E, Carrato A, Escudero P, Massutí B, Alonso-Orduña V, Cardenal A, Sáenz A, Giralt J, Yuste AL, Antón A, Aranda E; Spanish Cooperative Group for Digestive Tumor Therapy. Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric junction adenocarcinoma. Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1430-6. Epub 2009 Jun 18. link to original article contains verified protocol PubMed

CLF

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CLF: Cisplatin, Leucovorin (Folinic acid), Fluorouracil
PLF: Platinol (Cisplatin), Leucovorin (Folinic acid), Fluorouracil

Regimen variant #1, 12 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy
Stahl et al. 2009 (POET) 2000-2005 Phase III (C) See link See link

Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.

Chemotherapy

42-day cycle for 2 cycles

Subsequent treatment

Regimen variant #2, 15 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy
Stahl et al. 2009 (POET) 2000-2005 Phase III (C) PLF x 12 wk, then EP & RT Might have inferior OS

Note: this regimen is given for 2.5 cycles, which is a highly unusual instruction; total duration of treatment is 15 weeks.

Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.

Chemotherapy

42-day cycle for 2.5 cycles

Subsequent treatment

References

  1. POET: Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12. link to original article contains verified protocol PubMed
    1. Update: Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, Sandermann A, Bitzer M, Wilke H, Budach W. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): long-term results of a controlled randomised trial. Eur J Cancer. 2017 Aug;81:183-190. link to original article PubMed

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) See link See link
Al-Batran et al. 2016 (FLOT4-AIO) 2010-2015 Phase II/III (C) See link See link

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

Cunningham et al. Patients: 100% adenocarcinoma histology. 75% gastric adenocarcinoma, 15% lower esophagus, 11% gastroesophageal junction.

Al-Batran et. al Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach.

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

Subsequent treatment

  • Surgery occurs 3 to 6 weeks after completing cycle 3, then adjuvant ECF is started 6 to 12 weeks after surgery

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

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2017 (UK MRC ST03) 2007-2014 Phase III (C) ECX & Bevacizumab Did not meet primary endpoint of OS
Al-Batran et al. 2016 (FLOT4-AIO) 2010-2015 Phase II/III (C) See link See link

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

Cunningham et al. Patients: 100% adenocarcinoma histology (36% gastric, 14% lower esophageal, 50% gastroesophageal junction).

Al-Batran et al. Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.

Chemotherapy

21-day cycle for 3 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
  2. UK MRC ST03: Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, Griffin SM, Mansoor W, Coxon FY, Falk SJ, Darby S, Sumpter KA, Blazeby JM, Langley RE. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol. 2017 Mar;18(3):357-370. Epub 2017 Feb 3. link to original article contains protocol link to PMC article PubMed NCT00450203

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) See link See link

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

Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach

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

Neoadjuvant chemoradiotherapy

Note: while these regimens are listed as neoadjuvant (pre-operative), in some cases they are also used as definitive therapy in patients that are not surgical candidates.

Cisplatin, Etoposide, RT

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EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Stahl et al. 2009 (POET) 2000-2005 Phase III (E-esc) See link See link

Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.

Preceding treatment

Chemotherapy, to start 2 weeks after the last day of PLF

Radiotherapy

3-week course

Subsequent treatment

References

  1. POET: Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12. link to original article contains verified protocol PubMed
    1. Update: Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, Sandermann A, Bitzer M, Wilke H, Budach W. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): long-term results of a controlled randomised trial. Eur J Cancer. 2017 Aug;81:183-190. link to original article PubMed

Cisplatin & Fluorouracil (CF) & RT

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CF & RT: Cisplatin, Fluourouracil, Radiation Therapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Walsh et al. 1996 1990-1995 Randomized Phase II (E-esc) Surgery alone Superior OS

Note: of historic interest only.

Chemotherapy

Radiotherapy

Subsequent treatment

References

  1. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996 Aug 15;335(7):462-7. Erratum in: N Engl J Med 1999 Jul 29;341(5):384. link to original article contains verified protocol PubMed

Cisplatin, Irinotecan, RT

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Cisplatin, Irinotecan, RT: Cisplatin, Irinotecan, Radiation Therapy

Regimen variant #1, 60/130 x 2 + 45 Gy

Study Years of enrollment Evidence
Yoon et al. 2011 (ECOG E1201) 2002-2004 Phase II

Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.

5-week course

Subsequent treatment

  • surgery at least 28 days after finishing chemoradiation, then begin adjuvant IC at least 28 days after surgical resection

Regimen variant #2

Study Years of enrollment Evidence
Rivera et al. 2009 NR in abstract Phase II

Patients: 100% adenocarcinoma histology (43% gastroesophageal junction, 57% gastric adenocarcinoma)

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.

5-week course

Subsequent treatment

  • Surgery, 5 to 8 weeks after finishing chemoradiation

References

  1. Rivera F, Galán M, Tabernero J, Cervantes A, Vega-Villegas ME, Gallego J, Laquente B, Rodríguez E, Carrato A, Escudero P, Massutí B, Alonso-Orduña V, Cardenal A, Sáenz A, Giralt J, Yuste AL, Antón A, Aranda E; Spanish Cooperative Group for Digestive Tumor Therapy. Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric junction adenocarcinoma. Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1430-6. Epub 2009 Jun 18. link to original article contains verified protocol PubMed
  2. ECOG E1201: Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM; ECOG. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. link to original article contains verified protocol link to PMC article PubMed

Cisplatin, Paclitaxel, RT

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Cisplatin, Paclitaxel, RT: Cisplatin, Paclitaxel, Radiation Therapy

Regimen variant #1, weekly cisplatin

Study Years of enrollment Evidence
Yoon et al. 2011 (ECOG E1201) 2002-2004 Phase II

Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.

5-week course

Subsequent treatment

References

  1. ECOG E1201: Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM; ECOG. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. link to original article contains verified protocol link to PMC article PubMed

Fluorouracil, Paclitaxel, RT

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Fluorouracil, Paclitaxel, RT: Fluorouracil, Paclitaxel, Radiation Therapy

Regimen

Study Years of enrollment Evidence
Ajani et al. 2006 (RTOG 9904) 1999-2004 Phase II

Patients: 100% adenocarcinoma histology. The majority of patients had gastric adenocarcinoma. Although gastroesophageal junction was involved, percentages were not included.

Preceding treatment

Chemotherapy

7-day cycle for 5 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy

5-week course

Subsequent treatment

References

  1. RTOG 9904: Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, Greskovich JF, Anne PR, Bradley JD, Willett C, Rich TA. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006 Aug 20;24(24):3953-8. link to original article contains verified protocol PubMed

Adjuvant therapy

Cisplatin & Fluorouracil (CF)

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CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen variant #3, 100/4000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ychou et al. 2011 (ACCORD 07) 1995-2003 Phase III (E-esc) Observation Seems to have superior OS

This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Patients: 100% adenocarcinoma histology (65% gastroesophageal junction, 10% lower esophageal, 25% gastric adenocarcinoma)

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. Epub 2011 Mar 28. link to original article contains verified protocol PubMed NCT00002883

Cisplatin & Irinotecan (IC)

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Regimen

Study Years of enrollment Evidence
Yoon et al. 2011 (ECOG E1201) 2002-2004 Phase II

Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)

Preceding treatment

Chemotherapy

21-day cycle for 3 cycles

References

  1. ECOG E1201: Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM; ECOG. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. link to original article contains verified protocol link to PMC article PubMed

Cisplatin & Paclitaxel

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Regimen

Study Years of enrollment Evidence
Yoon et al. 2011 (ECOG E1201) 2002-2004 Phase II

Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)

Preceding treatment

Chemotherapy

21-day cycle for 3 cycles

References

  1. ECOG E1201: Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM; ECOG. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. link to original article contains verified protocol link to PMC article PubMed

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) See link See link
Al-Batran et al. 2016 (FLOT4-AIO) 2010-2015 Phase II/III (C) See link See link

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

Cunningham et al. Patients: 100% adenocarcinoma histology (75% gastric adenocarcinoma, 15% lower esophagus, 11% gastroesophageal junction).

Al-Batran et. al Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach.

Preceding treatment

Chemotherapy, to start 6 to 12 weeks after surgery

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 verified protocol PubMed
  2. 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

ECF/5-FU & RT

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ECF/5-FU & RT: Epirubicin, Cisplatin, Fluorouracil alternating with 5-FluoroUracil & Radiation Therapy

Protocol

Study Years of enrollment Evidence
Leong et al. 2010 NR in abstract Phase II

Note: In contrast to the primary reference, some guidelines list this regimen without ECF cycles 1, 3, 4.

Patients: 100% adenocarcinoma (6% gastroesophageal junction, 94% gastric origin).

Preceding treatment

Chemotherapy, part 1

21-day cycle, followed 1 to 3 weeks later by:

Chemotherapy, part 2

  • Fluorouracil (5-FU) 225 mg/m2/day IV continuous infusion, started on day 1 (total dose: 7875 mg/m2)

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions for a total dose of 45 Gy

5-week course, followed 1 month later by:

Chemotherapy, part 3

21-day cycle for 2 cycles

References

  1. Leong T, Joon DL, Willis D, Jayamoham J, Spry N, Harvey J, Di Iulio J, Milner A, Mann GB, Michael M; Trans-Tasman Radiation Oncology Group. Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin, and 5-fluorouracil before and after three-dimensional conformal radiotherapy with concurrent infusional 5-fluorouracil: a multicenter study of the Trans-Tasman Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2011 Mar 1;79(3):690-5. Epub 2010 May 14. link to original article contains verified protocol PubMed

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2017 (UK MRC ST03) 2007-2014 Phase III (C) ECX & Bevacizumab Did not meet primary endpoint of OS
Al-Batran et al. 2016 (FLOT4-AIO) 2010-2015 Phase II/III (C) See link See link

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

Cunningham et al. Patients: 100% adenocarcinoma histology (36% gastric, 14% lower esophageal, 50% gastroesophageal junction).

Al-Batran et al. Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.

Preceding treatment

Chemotherapy

21-day cycle for 3 cycles

References

  1. FLOT4-AIO: Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. link to original article PubMed NCT01216644
    1. Update: Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, 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
  2. UK MRC ST03: Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, Griffin SM, Mansoor W, Coxon FY, Falk SJ, Darby S, Sumpter KA, Blazeby JM, Langley RE. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol. 2017 Mar;18(3):357-370. Epub 2017 Feb 3. link to original article contains protocol link to PMC article PubMed NCT00450203

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) See link See link

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

Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.

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 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

FULV/FULV & RT

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

Protocol variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Macdonald et al. 2001 (INT-0116) 1991-1998 Phase III (E-esc) Observation Superior OS

Preceding treatment

Chemotherapy, part 1

28-day 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 (total dose per cycle: 2800 mg/m2)
  • 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 by:

Chemotherapy, part 3, to start one month after the completion of radiotherapy

28-day cycle for 2 cycles

Regimen variant #2

Note: No primary reference could be found for this regimen.

Preceding treatment

Chemotherapy

28-day cycle for 3 total cycles (1 cycle given before radiation, and 2 cycles to be given after radiation)

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 verified protocol PubMed

Metastatic or locally advanced disease, first-line

Capecitabine & Cisplatin (CX)

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moehler et al. 2009 2003-2006 Randomized Phase II (E-switch-ic) XI Did not meet primary endpoint of ORR
Lordick et al. 2013 (EXPAND) 2008-2010 Phase III (C) CX & Cetuximab Did not meet primary endpoint of PFS

EXPAND patients: 100% adenocarcinoma (stomach or gastroesophageal junction) locally advanced unresectable (M0) or metastatic (M1).

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
    • Lordick et al. 2013: 1000 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)

21-day cycles

References

  1. Moehler M, Kanzler S, Geissler M, Raedle J, Ebert MP, Daum S, Flieger D, Seufferlein T, Galle PR, Hoehler T; Arbeitsgemeinschaft Internistische Onkologie. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2010 Jan;21(1):71-7. Epub 2009 Jul 15. link to original article PubMed
  2. 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

Capecitabine & Cisplatin (CX) & Cetuximab

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CX-C: Cisplatin, Xeloda (Capecitabine), Cetuximab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lordick et al. 2013 (EXPAND) 2008-2010 Phase III (E-esc) CX Did not meet primary endpoint of PFS

Patients: 100% adenocarcinoma (stomach or gastroesophageal junction) locally advanced unresectable (M0) or metastatic (M1).

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV once on day 1
    • Subsequently: 250 mg/m2 IV once per day on days 1, 8, 15

21-day cycles

References

  1. 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

CapeOx

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CapeOX: Capecitabine & OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moehler et al. 2020 (JAVELIN Gastric 100) 2015-2017 Phase III (C) 1. CapeOx x 4, then Avelumab
2. mFOLFOX4 x 4, then Avelumab
3. mFOLFOX6 x 4, then Avelumab
Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

References

  1. JAVELIN Gastric 100: Moehler M, Dvorkin M, Boku N, Özgüroğlu M, Ryu MH, Muntean AS, Lonardi S, Nechaeva M, Bragagnoli AC, Coşkun HS, Cubillo Gracian A, Takano T, Wong R, Safran H, Vaccaro GM, Wainberg ZA, Silver MR, Xiong H, Hong J, Taieb J, Bang YJ. Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100. J Clin Oncol. 2021 Mar 20;39(9):966-977. Epub 2020 Nov 16. link to original article contains verified protocol PubMed NCT02625610
  2. CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article contains verified protocol PubMed NCT02872116

CapeOx & Nivolumab

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Janjigian et al. 2021 (CheckMate 649) 2017-2019 Phase III (E-RT-esc) 1. CapeOx
2. mFOLFOX6
Superior OS1
Median OS: 14.4 vs 11.1 mo
(HR 0.71, 98.4% CI 0.59-0.86)
3. Ipilimumab & Nivolumab Not reported

1Reported efficacy is for the group with PD-L1 CPS of 5 or more.
60% PD-L1 CPS >5, 82% PD-L1 CPS >1 CheckMate 649 included patients on both 21-day (Nivo/CapeOx) and 14-day (Nivo/FOLFOX) regimens in the immunotherapy + chemo arm

Chemotherapy

Immunotherapy

21-day cycles

References

  1. CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article contains verified protocol PubMed NCT02872116

CAPIRI

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CapeIRI: Capecitabine and IRInotecan
CAPIRI: CAPecitabine and IRInotecan
XELIRI: XELox (Capecitabine) and IRInotecan
XI: Xeloda (Capecitabine) and Irinotecan

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moehler et al. 2009 2003-2006 Randomized Phase II (E-switch-ic) XP Did not meet primary endpoint of ORR

Patients: 45% esophageal, 38% gastroesophageal junction, 17% gastric origin. 93% adenocarcinoma, 7% squamous cell histology. 86% metastatic disease. 14% ECOG PS of 2.

Chemotherapy

Supportive medications

21-day cycles

References

  1. Moehler M, Kanzler S, Geissler M, Raedle J, Ebert MP, Daum S, Flieger D, Seufferlein T, Galle PR, Hoehler T; Arbeitsgemeinschaft Internistische Onkologie. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2010 Jan;21(1):71-7. Epub 2009 Jul 15. link to original article PubMed

Cisplatin & Fluorouracil (CF)

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CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen

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

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

Dank et al Patients: 100% adenocarcinoma histology (20% gastroesophageal 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. 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
  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

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen variant #1, 50/60/1250

Study Years of enrollment Evidence Comparator Comparative Efficacy
Iveson et al. 2014 (Amgen 20060317) 2009 Randomized Phase II (C) ECX & Rilotumumab Seems to have inferior PFS

Chemotherapy

21-day cycles

Regimen variant #2, 50/60/2000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Guimbaud et al. 2014 (FFCD 03-07) 2005-2008 Phase III (C) FOLFIRI Inferior TTF

Chemotherapy

21-day cycles

References

  1. Amgen 20060317: Iveson T, Donehower RC, Davidenko I, Tjulandin S, Deptala A, Harrison M, Nirni S, Lakshmaiah K, Thomas A, Jiang Y, Zhu M, Tang R, Anderson A, Dubey S, Oliner KS, Loh E. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 2014 Aug;15(9):1007-18. Epub 2014 Jun 22. link to original article contains protocol PubMed NCT00719550
  2. 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

Erlotinib monotherapy

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Regimen

Study Years of enrollment Evidence
Dragovich et al. 2006 (SWOG 0127) 2002-2003 Phase II

Patients: 100% adenocarcinoma (63% gastroesophageal junction, 37% gastric origin). All with ECOG PS of 0 or 1.

Targeted therapy

  • Erlotinib (Tarceva) 150 mg PO once per day, at least 1 hour before a meal, or 2 hours after a meal

28-day cycles

References

  1. SWOG 0127: Dragovich T, McCoy S, Fenoglio-Preiser CM, Wang J, Benedetti JK, Baker AF, Hackett CB, Urba SG, Zaner KS, Blanke CD, Abbruzzese JL. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006 Oct 20;24(30):4922-7. link to original article contains verified protocol PubMed NCT00032123

FLOT

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

Regimen

Study Years of enrollment Evidence
Al-Batran et al. 2008a 2006 Phase II

Patients: 100% adenocarcinoma histology (44% gastroesophageal junction, 56% gastric origin). 93% metastatic disease. 15% with ECOG 2-3.

Chemotherapy

Supportive medications

14-day cycle for up to 8 (or more) cycles

References

  1. Al-Batran SE, Hartmann JT, Hofheinz R, Homann N, Rethwisch V, Probst S, Stoehlmacher J, Clemens MR, Mahlberg R, Fritz M, Seipelt G, Sievert M, Pauligk C, Atmaca A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2008 Nov;19(11):1882-7. Epub 2008 Jul 31. link to original article contains verified protocol PubMed

FOLFIRI

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

Regimen

Study Years of enrollment Evidence
Wolff et al. 2009 2002-2006 Phase II

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

References

  1. Wolff K, Wein A, Reulbach U, Männlein G, Brückl V, Meier C, Ostermeier N, Schwab SA, Horbach T, Hohenberger W, Hahn EG, Boxberger F. Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial. Anticancer Drugs. 2009 Mar;20(3):165-73. link to original article contains protocol PubMed

Irinotecan monotherapy

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Regimen

Study Years of enrollment Evidence
Enzinger et al. 2005 NR in abstract Phase II

Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m2 IV once per day on days 1 & 8, with 21-day cycles.

Patients: 100% adenocarcinoma histology, both gastric and esophageal

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

Irinotecan & Mitomycin

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lustberg et al. 2010 2002-2006 Randomized Phase II (E-switch-ic) Irinotecan & Mitomycin (alternate schedule) No statistical comparison

Patients: 56% lower esophageal, 44% gastroesophageal junction. 100% adenocarcinoma histology. 100% previously untreated 6% with ECOG PS = 2. 77% stage four disease.

Chemotherapy

Supportive medications

28-day cycle for up to 6 cycles

References

  1. Lustberg MB, Bekaii-Saab T, Young D, Otterson G, Burak W, Abbas A, McCracken-Bussa B, Lustberg ME, Villalona-Calero MA. Phase II randomized study of two regimens of sequentially administered mitomycin C and irinotecan in patients with unresectable esophageal and gastroesophageal adenocarcinoma. J Thorac Oncol. 2010 May;5(5):713-8. link to original article contains verified protocol link to PMC article PubMed

mFOLFOX6

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

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

Chemotherapy

14-day cycle for 12 cycles

Subsequent treatment

References

  1. GAMMA-1: Shah MA, Bodoky G, Starodub A, Cunningham D, Yip D, Wainberg ZA, Bendell J, Thai D, He J, Bhargava P, Ajani JA. Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1). J Clin Oncol. 2021 Mar 20;39(9):990-1000. Epub 2021 Feb 12. link to original article contains verified protocol PubMed NCT02545504
  2. CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article contains verified protocol PubMed NCT02872116

mFOLFOX6 (L-Leucovorin)

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mFOLFOX6: modified L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

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

Chemotherapy

14-day cycle for 12 cycles

Subsequent treatment

References

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

mFOLFOX6 & Nivolumab

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Janjigian et al. 2021 (CheckMate 649) 2017-2019 Phase III (E-RT-esc) 1. CapeOx
2. mFOLFOX6
Superior OS1
Median OS: 14.4 vs 11.1 mo
(HR 0.71, 98.4% CI 0.59-0.86)
3. Ipilimumab & Nivolumab Not reported

1Reported efficacy is for the group with PD-L1 CPS of 5 or more.
60% PD-L1 CPS >5, 82% PD-L1 CPS >1 CheckMate 649 included patients on both 21-day (Nivo/CapeOx) and 14-day (Nivo/FOLFOX) regimens in the immunotherapy + chemo arm

Chemotherapy

Immunotherapy

14-day cycles

References

  1. CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article contains verified protocol PubMed NCT02872116

Metastatic or locally advanced disease, subsequent lines of therapy

Apatinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Li et al. 2016 2011-2012 Phase III (E-esc) Placebo Seems to have superior OS

Targeted therapy

Continued indefinitely

References

  1. Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R, Wang Z, Wang Q, Ouyang X, Yang Y, Ba Y, Liang J, Lin X, Luo D, Zheng R, Wang X, Sun G, Wang L, Zheng L, Guo H, Wu J, Xu N, Yang J, Zhang H, Cheng Y, Wang N, Chen L, Fan Z, Sun P, Yu H. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016 May 1;34(13):1448-54. Epub 2016 Feb 16. link to original article contains protocol PubMed

Cetuximab monotherapy

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Regimen

Study Years of enrollment Evidence
Gold et al. 2010 (SWOG S0415) 2005-2007 Phase II

Patients: 100% metastatic esophageal adenocarcinoma who failed one prior chemotherapy regimen. 10% had ECOG PS of 2.

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8, 15, 22
    • Cycle 2 onwards: 250 mg/m2 IV once per day on days 1, 8, 15, 22

Supportive medications

28-day cycles

References

  1. SWOG S0415: Gold PJ, Goldman B, Iqbal S, Leichman LP, Zhang W, Lenz HJ, Blanke CD. Cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma: a phase II Southwest Oncology Group Study (S0415). J Thorac Oncol. 2010 Sep;5(9):1472-6. link to original article contains verified protocol link to PMC article PubMed NCT00096031

Docetaxel monotherapy

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Regimen variant #1, 75 mg/m2 x 6

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ford et al. 2013 (COUGAR-02) 2008-2012 Phase III (E-esc) Active symptom control Superior OS

COUGAR-02 patients: 100% adenocarcinoma histology (20% esophageal, 35% gastroesophageal junction, 45% stomach) that progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. 15% ECOG PS of 2. 12% locally advanced, 88% metastatic disease.

Chemotherapy

21-day cycle for up to 6 cycles

Regimen variant #2, 75 mg/m2, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Roy et al. 2013 (PEP0206) 2008-2010 Randomized Phase II (C) 1. Irinotecan
2. Irinotecan liposomal
Not powered to draw conclusions

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
  2. COUGAR-02: Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. link to original article contains verified protocol PubMed

Irinotecan monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Roy et al. 2013 (PEP0206) 2008-2010 Randomized Phase II (C) 1. Docetaxel
2. Irinotecan liposomal
Not powered to draw conclusions

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

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
Not powered to draw conclusions

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

Irinotecan & Mitomycin

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Regimen

Study Years of enrollment Evidence
Giuliani et al. 2005 (GOIM 2106) NR in abstract Phase II

Patients: 100% gastric adenocarcinoma. Treatment given as second-line chemotherapy for pretreated patients with advanced or metastatic disease.

Chemotherapy

28-day cycles

References

  1. GOIM 2106: Giuliani F, Molica S, Maiello E, Battaglia C, Gebbia V, Di Bisceglie M, Vinciarelli G, Gebbia N, Colucci G; Gruppo Oncologico dell' Italia Meridionale. Irinotecan (CPT-11) and mitomycin-C (MMC) as second-line therapy in advanced gastric cancer: a phase II study of the Gruppo Oncologico dell' Italia Meridionale (prot 2106). Am J Clin Oncol. 2005 Dec;28(6):581-5. link to original article contains protocol PubMed

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 NCT02267343
    1. Subgroup analysis: Kato K, Satoh T, Muro K, Yoshikawa T, Tamura T, Hamamoto Y, Chin K, Minashi K, Tsuda M, Yamaguchi K, Machida N, Esaki T, Goto M, Komatsu Y, Nakajima TE, Sugimoto N, Yoshida K, Oki E, Nishina T, Tsuji A, Fujii H, Kunieda K, Saitoh S, Omuro Y, Azuma M, Iwamoto Y, Taku K, Fushida S, Chen LT, Kang YK, Boku N. A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2). Gastric Cancer. 2019 Mar;22(2):344-354. Epub 2018 Dec 1. link to original article link to original article PubMed
  2. 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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Wilke et al. 2014 (RAINBOW) 2010-2012 Phase III (C) Paclitaxel & Ramucirumab Seems to have inferior OS

Chemotherapy

28-day cycles

References

  1. RAINBOW: Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. link to original article contains protocol PubMed NCT01170663

Paclitaxel & Ramucirumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Wilke et al. 2014 (RAINBOW) 2010-2012 Phase III (E-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."

Patients: 100% adenocarcinoma histology, 20% gastroesophageal junction, 80% gastric origin.

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. link to original article contains verified protocol PubMed NCT01170663

Ramucirumab monotherapy

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Regimen

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

Patients in REGARD previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."

Patients: 100% adenocarcinoma histology (25% gastroesophageal junction, 75% gastric origin)

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