Esophageal adenocarcinoma

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Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.
Note: these are regimens tested in histology-specific populations, please see the main esophageal cancer page for other regimens. Many of these regimens are also studied in gastric cancer.
Last updated on 2024-09-06:43 regimens on this page
48 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers.
=Perioperative therapy=
This section contains protocols with a pre-planned neoadjuvant (preoperative) and adjuvant (postoperative) component.
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin & Fluorouracil
FP: Fluorouracil & Platinol (Cisplatin)
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ychou et al. 2011 (ACCORD 07)	1995-2003 	Phase 3 (E-esc)	Surgery alone	Longer OS (primary endpoint)OS60: 38% vs 24%(HR 0.69, 95% CI 0.50-0.95)
Note: Study included patients with gastric malignancy as well (25% gastric, 11% lower esophagus, and 64% GE junction).
===Neoadjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
28-day cycle for 2 to 3 cycles, followed by:
===Definitive===
====Local therapy====
*Surgical resection
===Adjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 28
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
28-day cycle for 3 to 4 cycles, for a total of 6 cycles
===References===
#ACCORD 07: Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P; FNCLCC; FFCD. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002883
==ECF==
ECF: Epirubicin, Cisplatin, Fluorouracil
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cunningham et al. 2006 (MAGIC) 	1994-2002 	Phase 3 (E-esc)	Surgery alone 	Longer OS (primary endpoint)OS60: 36% vs 23%(HR 0.75, 95% CI 0.60-0.93)
Al-Batran et al. 2016 (FLOT4-AIO)	2010-2015 	Phase 2/3 (C) 	Perioperative FLOT	Shorter OS1Median OS: 35 vs 50 mo(HR 1.30, 95% CI 1.06-1.59)
1Reported efficacy for FLOT4-AIO is based on the 2019 update.
Note: MAGIC patients had 100% adenocarcinoma histology. 75% gastric adenocarcinoma, 15% lower esophagus, 11% gastroesophageal junction.
===Neoadjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV bolus once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 200 mg/m2/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m2)
21-day cycle for 3 cycles, followed by:
===Definitive===
====Local therapy====
*Surgery occurs 3 to 6 weeks after completing cycle 3
Adjuvant chemotherapy is started 6 to 12 weeks after surgery:
===Adjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV bolus once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 200 mg/m2/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m2)
====Supportive therapy====
*MAGIC: Warfarin (Coumadin) 1 mg PO once per day recommended for thrombosis prophylaxis
21-day cycle for 3 cycles
===References===
#MAGIC: Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002615
#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 EuroPMC NCT01216644
##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 EuroPMC
==ECX==
ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cunningham et al. 2017 (UK MRC ST03)	2007-2014 	Phase 3 (C) 	Perioperative ECX & Bevacizumab	Did not meet primary endpoint of OSOS36: 50.3% vs 48.1%(HR 0.93, 95% CI 0.78-1.10)
Al-Batran et al. 2016 (FLOT4-AIO) 	2010-2015 	Phase 2/3 (C)	Perioperative FLOT 	Shorter OS1Median OS: 35 vs 50 mo(HR 1.30, 95% CI 1.06-1.59)
1Reported efficacy for FLOT4-AIO is based on the 2019 update.
Note: UK MRC ST03 patients had 100% adenocarcinoma histology (36% gastric, 14% lower esophageal, 50% gastroesophageal junction). FLOT4-AIO patients had 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.
===Neoadjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 625 mg/m2 PO twice per day
21-day cycle for 3 cycles, followed by:
===Definitive===
====Local therapy====
*Surgery
===Adjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 625 mg/m2 PO twice per day
21-day cycle for 3 cycles
===References===
#FLOT4-AIO: Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. link to original article EuroPMC NCT01216644
##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 EuroPMC
#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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT00450203
==FLOT==
FLOT: Fluorouracil, Leucovorin, Oxaliplatin, Taxotere (Docetaxel)
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Al-Batran et al. 2016 (FLOT4-AIO)	2010-2015 	Phase 2/3 (E-switch-ic)	1a. Perioperative ECF1b. Perioperative ECX	Longer OS1 (primary endpoint)Median OS: 50 vs 35 mo(HR 0.77, 95% CI 0.63-0.94)
Hoeppner et al. 2025 (ESOPEC) 	2016-02 to 2020-04 	Phase 3 (E-switch-ooc) 	Neoadjuvant CP & RT 	Longer OS (primary endpoint)OS36: 57.4% vs 50.7%(HR 0.70, 95% CI 0.53-0.92)
1Reported efficacy is based on the 2019 update.
Note: FLOT4-AIO patients had 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach. 
===Neoadjuvant===
====Chemotherapy====
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Leucovorin (Folinic acid) 200 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
*Docetaxel (Taxotere) 50 mg/m2 IV once on day 1
14-day cycle for 4 cycles, followed by:
===Definitive===
====Local therapy====
*Surgery
===Adjuvant===
====Chemotherapy====
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Leucovorin (Folinic acid) 200 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
*Docetaxel (Taxotere) 50 mg/m2 IV once on day 1
14-day cycle for 4 cycles
===References===
#FLOT4-AIO: Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. link to original article EuroPMC NCT01216644
##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 EuroPMC
#ESOPEC: Hoeppner J, Brunner T, Schmoor C, Bronsert P, Kulemann B, Claus R, Utzolino S, Izbicki JR, Gockel I, Gerdes B, Ghadimi M, Reichert B, Lock JF, Bruns C, Reitsamer E, Schmeding M, Benedix F, Keck T, Folprecht G, Thuss-Patience P, Neumann UP, Pascher A, Imhof D, Daum S, Strieder T, Krautz C, Zimmermann S, Werner J, Mahlberg R, Illerhaus G, Grimminger P, Lordick F. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. N Engl J Med. 2025 Jan 23;392(4):323-335. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02509286
=Neoadjuvant induction therapy=
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol (Cisplatin)
===Regimen variant #1, 40/4200===
Study 	Dates of enrollment	Evidence
Ajani et al. 2006 (RTOG 9904)	1999-2004 	Phase 2
Note: Patients had 100% adenocarcinoma histology. The majority of patients had gastric adenocarcinoma. Although gastroesophageal junction was involved, percentages were not included.
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 & 5
*Fluorouracil (5-FU) 200 mg/m2/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m2)
28-day cycle for 2 cycles
====Subsequent treatment====
*Neoadjuvant fluorouracil, paclitaxel, RT, then surgery
===Regimen variant #2, 80/4000, 4 day 5-FU infusion===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Alderson et al. 2017 (UK MRC OE05)	2005-2011 	Phase 3 (C)	ECX 	Might have shorter OSMedian OS: 23.4 vs 26.1 mo(HR 1.11, 95% CI 0.95-1.30)
Note: UK MRC OE05 patients had 100% adenocarcinoma of the esophagus (including Siewert types 1 and 2 gastroesophageal junction tumors)
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
21-day cycle for 2 cycles
====Subsequent treatment====
*Surgery
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00041262
==Cisplatin & Irinotecan (IC)==
IC: Irinotecan & Cisplatin
===Regimen===
Study 	Dates of enrollment	Evidence
Rivera et al. 2009	2003-12 to 2004-10 	Phase 2
Note: Rivera et al. patients had 100% adenocarcinoma histology (43% gastroesophageal junction, 57% gastric adenocarcinoma)
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV over 30 minutes once per day on days 1 & 8, given first
*Irinotecan (Camptosar) 65 mg/m2 IV over 30 minutes once per day on days 1 & 8, given second
====Supportive therapy====
*Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 & 8, prior to chemotherapy
*One of the following:
**Granisetron 2 mg PO once per day on days 1 & 8, prior to chemotherapy
**Ondansetron (Zofran) 32 mg IV once per day on days 1 & 8, prior to chemotherapy
*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====
*Neoadjuvant cisplatin, irinotecan, RT, then surgery
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==CLF==
CLF: Cisplatin, Leucovorin, Fluorouracil
PLF: Platinol (Cisplatin), Leucovorin, Fluorouracil
===Regimen variant #1, 12 weeks===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Stahl et al. 2009 (POET)	2000-2005 	Phase 3 (E-de-esc)	See link 	See link
Note: Patients had 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV over 60 minutes once per day on days 1, 15, 29
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
*Fluorouracil (5-FU) 2000 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m2)
42-day cycle for 2 cycles
====Subsequent treatment====
*Neoadjuvant EP & RT, then surgery
===Regimen variant #2, 15 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Stahl et al. 2009 (POET)	2000-2005 	Phase 3 (C)	PLF x 12 wk, then EP & RT	Did not meet primary endpoint of OSOS36: 27.7% vs 47.4%(HR 1.49, 95% CI 0.93-2.44)
Note: this regimen is given for 2.5 cycles, which is a highly unusual instruction; total duration of treatment is 15 weeks. Patients had 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV over 60 minutes once per day on days 1, 15, 29
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
*Fluorouracil (5-FU) 2000 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m2)
42-day cycle for 2.5 cycles
====Subsequent treatment====
*Surgery, in 3 to 4 weeks
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
==ECX==
ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Alderson et al. 2017 (UK MRC OE05)	2005-2011 	Phase 3 (E-esc)	CF 	Might have longer OS (primary endpoint)Median OS: 26.1 vs 23.4 mo(HR 0.90, 95% CI 0.77-1.05)
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1250 mg/m2/day PO on days 1 to 21
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00041262
=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.
==Carboplatin & Paclitaxel (CP) & RT==
CP & RT: Carboplatin, Paclitaxel, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hoeppner et al. 2025 (ESOPEC)	2016-02 to 2020-04 	Phase 3 (C)	Perioperative FLOT	Shorter OS (primary endpoint)OS36: 50.7% vs 57.4%(HR 1.43, 95% CI 1.09-1.89)
1Reported efficacy for CROSS is based on the 2021 update.
Note: van Meerten et al. patients had 76% adenocarcinoma, 22% squamous cell, 2% large cell histology. 91% lower esophagus, 9% thoracic esophagus. CROSS patients had 75% adenocarcinoma, 23% squamous cell, 2% other histology. 24% gastroesophageal junction.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, 22, 29
*Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1, 8, 15, 22, 29
====Radiotherapy====
*Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 31 (23 fractions, for a total dose of 4140 cGy)
5-week course
====Subsequent treatment====
*Surgery
===References===
#ESOPEC: Hoeppner J, Brunner T, Schmoor C, Bronsert P, Kulemann B, Claus R, Utzolino S, Izbicki JR, Gockel I, Gerdes B, Ghadimi M, Reichert B, Lock JF, Bruns C, Reitsamer E, Schmeding M, Benedix F, Keck T, Folprecht G, Thuss-Patience P, Neumann UP, Pascher A, Imhof D, Daum S, Strieder T, Krautz C, Zimmermann S, Werner J, Mahlberg R, Illerhaus G, Grimminger P, Lordick F. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. N Engl J Med. 2025 Jan 23;392(4):323-335. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02509286
==Cisplatin & Etoposide (EP) & RT==
EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Stahl et al. 2009 (POET)	2000-2005 	Phase 3 (E-esc)	See link 	See link
Note: Patients had 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III. Chemoradiation is to start 2 weeks after the last day of PLF.
====Preceding treatment====
*PLF induction x 12 wk
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV over 60 minutes once per day on days 1 & 8
*Etoposide (Vepesid) 80 mg/m2 IV over 60 minutes once per day on days 3 to 5
====Radiotherapy====
*Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19 (15 fractions; target dose of 3000 cGy)
3-week course
====Subsequent treatment====
*Surgery, in 3 to 4 weeks
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
==Cisplatin & Fluorouracil (CF) & RT==
CF & RT: Cisplatin, Fluourouracil, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Walsh et al. 1996	1990-1995 	Randomized Phase 2 (E-esc)	Surgery alone	Longer OS (primary endpoint)Median OS: 16 vs 11 mo(HR not reported, p=0.01)
Note: of historic interest only.
====Chemotherapy====
*Cisplatin (Platinol) 15 mg/kg IV over 16 hours once per day on days 1 to 5
*Fluorouracil (5-FU) 75 mg/m2 IV over 8 hours once on day 7
====Radiotherapy====
*Concurrent radiation therapy as follows:
**Cycle 1: 267 cGy per fraction on days 1 to 5, 8 to 12, 15 to 19
5-week cycle for 2 cycles
====Subsequent treatment====
*Surgery
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin, Irinotecan, RT==
Cisplatin, Irinotecan, RT: Cisplatin, Irinotecan, Radiation Therapy
===Regimen variant #1, 60/130 x 2 + 4500 cGy===
Study 	Dates of enrollment	Evidence
Yoon et al. 2011 (ECOG E1201)	2002-2004 	Phase 2
Note: Patients had 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1, 8, 22, 29
*Irinotecan (Camptosar) 65 mg/m2 IV once per day on days 1, 8, 22, 29
====Radiotherapy====
*Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 4500 cGy)
5-week course
====Subsequent treatment====
*surgery no earlier than 28 days after finishing chemoradiation, then adjuvant IC, beginning no earlier than 28 days after surgical resection
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Rivera et al. 2009	2003-12 to 2004-10 	Phase 2
Note: Patients had 100% adenocarcinoma histology (43% gastroesophageal junction, 57% gastric adenocarcinoma)
====Preceding treatment====
*IC induction x 2
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1, 8, 15, 22
*Irinotecan (Camptosar) 65 mg/m2 IV once per day on days 1, 8, 15, 22
====Radiotherapy====
*Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 4500 cGy)
5-week course
====Subsequent treatment====
*Surgery, 5 to 8 weeks after finishing chemoradiation
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Cisplatin & Paclitaxel (TP) & RT==
Cisplatin, Paclitaxel, RT: Cisplatin, Paclitaxel, Radiation Therapy
===Regimen variant #1, weekly cisplatin===
Study 	Dates of enrollment	Evidence
Yoon et al. 2011 (ECOG E1201)	2002-2004 	Phase 2
Note: Patients had 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1, 8, 15, 22, 29
*Paclitaxel (Taxol) 50 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29
====Radiotherapy====
*Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 4500 cGy)
5-week course
====Subsequent treatment====
*Surgery no earlier than 28 days after finishing chemoradiation, then adjuvant cisplatin & paclitaxel no earlier than 28 days after surgical resection
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Fluorouracil, Paclitaxel, RT==
Fluorouracil, Paclitaxel, RT: Fluorouracil, Paclitaxel, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence
Ajani et al. 2006 (RTOG 9904)	1999-2004 	Phase 2
Note: Patients had 100% adenocarcinoma histology. The majority of patients had gastric adenocarcinoma. Although gastroesophageal junction was involved, percentages were not included.
====Preceding treatment====
*CF induction x 2
====Chemotherapy====
*Fluorouracil (5-FU) 300 mg/m2/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 22, 29 (total dose: 7500 mg/m2)
*Paclitaxel (Taxol) 45 mg/m2 IV once per day on days 1, 8, 15, 22, 29
====Radiotherapy====
*Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 4500 cGy)
5-week course
====Subsequent treatment====
*Surgery
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
=Adjuvant therapy=
==Cisplatin & Irinotecan (IC)==
===Regimen===
Study 	Dates of enrollment	Evidence
Yoon et al. 2011 (ECOG E1201)	2002-2004 	Phase 2
Note: Patients had 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)
====Preceding treatment====
*Neoadjuvant cisplatin, irinotecan, RT, then surgery
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1 & 8
*Irinotecan (Camptosar) 65 mg/m2 IV once per day on days 1 & 8
21-day cycle for 3 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Cisplatin & Paclitaxel (TP)==
===Regimen===
Study 	Dates of enrollment	Evidence
Yoon et al. 2011 (ECOG E1201)	2002-2004 	Phase 2
Note: Patients had 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)
====Preceding treatment====
*Neoadjuvant cisplatin, paclitaxel, RT, then surgery
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 3 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==ECF/5-FU & RT==
ECF/5-FU & RT: Epirubicin, Cisplatin, Fluorouracil alternating with 5-FluoroUracil & Radiation Therapy sandwich
===Regimen===
Study 	Dates of enrollment	Evidence
Leong et al. 2010	2003-07 to 2006-10 	Phase 2
Note: In contrast to the primary reference, some guidelines list this regimen without ECF cycles 1, 3, 4. Patients had 100% adenocarcinoma (6% gastroesophageal junction, 94% gastric origin).
====Preceding treatment====
*Surgery, within 10 weeks
====Chemotherapy====
*Epirubicin (Ellence) as follows:
**Cycle 1: 50 mg/m2 IV bolus once on day 1
**Cycles 3 & 4: 50 mg/m2 IV bolus once on day 1
*Cisplatin (Platinol) as follows:
**Cycle 1: 60 mg/m2 IV once on day 1
**Cycles 3 & 4: 60 mg/m2 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycle 1: 200 mg/m2/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m2)
**Cycle 2 (chemoradiation): 225 mg/m2/day IV continuous infusion over 35 days, started on day 1 (total dose: 7875 mg/m2)
**Cycles 3 & 4: 200 mg/m2/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy as follows:
**Cycle 2 (chemoradiation): 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)
4- to 6-week course, then 9-week course, then 21-day cycle for 2 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==FULV & RT==
FULV & RT: FluoroUracil, LeucoVorin, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Macdonald et al. 2001 (INT-0116)	1991-1998 	Phase 3 (E-esc)	Observation	Longer OS (primary endpoint)Median OS: 36 vs 27 mo(HR 0.74, 95% CI 0.60-0.92)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) as follows:
**Cycles 1, 3, 4: 425 mg/m2 IV bolus once per day on days 1 to 5 (total dose per cycle: 2125 mg/m2)
**Cycle 2 (chemoradiation): 400 mg/m2 IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy (total dose: 2800 mg/m2)
*Leucovorin (Folinic acid) as follows:
**Cycles 1, 3, 4: 20 mg/m2 IV bolus once per day on days 1 to 5
**Cycle 2 (chemoradiation): 20 mg/m2 IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
====Radiotherapy====
*Concurrent radiation therapy as follows:
**Cycle 2 (chemoradiation): 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)
28-day course, then 9-week course, then 28-day cycle for 2 cycles
===References===
#INT-0116: Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Metastatic or locally advanced disease, first-line=
==Capecitabine & Cisplatin (CX)==
CX: Cisplatin & Xeloda (Capecitabine)
XP: Xeloda (Capecitabine) & Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moehler et al. 2009 	2003-2006 	Randomized Phase 2 (E-switch-ic)	XI 	Did not meet primary endpoint of ORR
Lordick et al. 2013 (EXPAND)	2008-2010 	Phase 3 (C) 	CX & Cetuximab	Did not meet primary endpoint of PFSMedian PFS: 5.6 vs 4.4 mo(HR 0.92, 95% CI 0.78-1.09)
Note: EXPAND patients had 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
**Alternative dosing in 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===
#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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00678535
==Capecitabine & Cisplatin (CX) & Cetuximab==
CX-C: Cisplatin, Xeloda (Capecitabine), Cetuximab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lordick et al. 2013 (EXPAND)	2008-2010 	Phase 3 (E-esc)	CX 	Did not meet primary endpoint of PFSMedian PFS: 4.4 vs 5.6 mo(HR 1.09, 95% CI 0.92-1.28)
Note: Patients had 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 from the evening of day 1 to the morning of day 15 (28 doses per cycle)
====Targeted therapy====
*Cetuximab (Erbitux) as follows:
**Cycle 1: 400 mg/m2 IV once on day 1
**Cycle 2 onwards: 250 mg/m2 IV once per day on days 1, 8, 15
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00678535
==CapeOx==
CapeOX: Capecitabine & OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moehler et al. 2020 (JAVELIN Gastric 100)	2015-2017 	Phase 3 (C)	1a. CapeOx-Avelumab1b. FOLFOX6-Avelumab1c. mFOLFOX6-Avelumab	Did not meet primary endpoint of OSMedian OS: 10.9 vs 10.4 mo(HR 1.10, 95% CI 0.90-1.35)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02625610
#CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02872116
##Update: Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Lin D, Nguyen H, Shah R, Qiao Y, Hartman J, Sugarman R. Quality-adjusted time without symptoms or toxicity analysis of nivolumab plus chemotherapy versus chemotherapy alone for the management of previously untreated patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. Gastric Cancer. 2023 May;26(3):415-424. Epub 2023 Mar 21. link to original article link to PMC article EuroPMC
##HRQoL analysis: Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. link to original article link to PMC article EuroPMC
##Update: Janjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C, Wyrwicz L, Yamaguchi K, Cleary JM, Elimova E, Karamouzis M, Bruges R, Skoczylas T, Bragagnoli A, Liu T, Tehfe M, Zander T, Kowalyszyn R, Pazo-Cid R, Schenker M, Feeny K, Wang R, Lei M, Chen C, Nathani R, Shitara K. First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial. J Clin Oncol. 2024 Jun 10;42(17):2012-2020. Epub 2024 Feb 21. link to original article link to PMC article EuroPMC
==CapeOx & Nivolumab==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (E-RT-esc)	1a. CapeOx1b. mFOLFOX6 	Longer OS1 (co-primary endpoint)Median OS: 14.4 vs 11.1 mo(HR 0.70, 95% CI 0.61-0.81)Longer PFS (co-primary endpoint)Median PFS: 7.7 vs 6.05 mo(HR 0.68, 98% CI 0.56-0.81)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (E-RT-esc)	2. Ipilimumab & Nivolumab	Not reported
1Reported efficacy and MCBS score are for the group with PD-L1 CPS of 5 or more; reported efficacy is based on the 2022 update.
Note: CheckMate 649 included patients on both 21-day (Nivo/CapeOx) and 14-day (Nivo/FOLFOX) regimens in the immunotherapy + chemo arm. 60% PD-L1 CPS >5, 82% PD-L1 CPS >1. 
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
====Immunotherapy====
*Nivolumab 360 mg IV once on day 1
21-day cycles
===References===
#CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02872116
##Update: Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Lin D, Nguyen H, Shah R, Qiao Y, Hartman J, Sugarman R. Quality-adjusted time without symptoms or toxicity analysis of nivolumab plus chemotherapy versus chemotherapy alone for the management of previously untreated patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. Gastric Cancer. 2023 May;26(3):415-424. Epub 2023 Mar 21. link to original article link to PMC article EuroPMC
##HRQoL analysis: Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. link to original article link to PMC article EuroPMC
##Update: Janjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C, Wyrwicz L, Yamaguchi K, Cleary JM, Elimova E, Karamouzis M, Bruges R, Skoczylas T, Bragagnoli A, Liu T, Tehfe M, Zander T, Kowalyszyn R, Pazo-Cid R, Schenker M, Feeny K, Wang R, Lei M, Chen C, Nathani R, Shitara K. First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial. J Clin Oncol. 2024 Jun 10;42(17):2012-2020. Epub 2024 Feb 21. link to original article link to PMC article EuroPMC
==CAPIRI==
CapeIRI: Capecitabine and IRInotecan
CAPIRI: CAPecitabine and IRInotecan
XELIRI: XELox (Capecitabine) and IRInotecan
XI: Xeloda (Capecitabine) and Irinotecan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Moehler et al. 2009	2003-2006 	Randomized Phase 2 (E-switch-ic)	XP 	Did not meet primary endpoint of ORR
Note: Patients had 45% esophageal, 38% gastroesophageal junction, 17% gastric origin. 93% adenocarcinoma, 7% squamous cell histology. 86% metastatic disease. 14% ECOG PS of 2. 
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 250 mg/m2 IV over 30 to 90 minutes once on day 1
====Supportive therapy====
*Atropine (Atropen) 0.25 mg SC once on day 1, given prior to irinotecan
*Loperamide (Imodium) 4 mg PO prn first unformed stool, then 2 mg PO Q2H x at least 12 hours, or for 12 hours after last liquid stool
*Ciprofloxacin (Cipro) 250 mg PO twice per day prn diarrhea lasting longer than 24 hours despite loperamide
 
21-day cycles
===References===
#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 EuroPMC
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Van Cutsem et al. 2006 (TAX 325)	1999-2003 	Phase 3 (C)	DCF 	Seems to have shorter OS (secondary endpoint)Median OS: 8.6 vs 9.2 mo(HR 1.28, 95% CI 1.00-1.59)Shorter TTP (primary endpoint)Median TTP: 3.7 vs 5.6 mo(HR 1.47, 95% CI 1.19-1.82)
Dank et al. 2008 	2000-2002 	Phase 3 (C)	IF 	Might have shorter TTPMedian TTP: 4.2 vs 5.0 mo(HR 1.23, 95% CI 0.97-1.57)
Note: TAX 325 patients had 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70. Dank et al. patients had 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 therapy====
*As described in Dank et al. 2008:
*"Hyperhydration" for 2 to 3 days with each infusion
*Ondansetron (Zofran) IV for antiemetic prophylaxis
*Dexamethasone (Decadron) IV for antiemetic prophylaxis, then PO for 2 to 3 days
*Metoclopramide (Reglan) for antiemetic prophylaxis
*Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/μL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection
*Atropine (Atropen) prn cholinergic symptoms
*Loperamide (Imodium) prn delayed diarrhea
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==ECX==
ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)
===Regimen variant #1, 50/60/1250===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Iveson et al. 2014 (Amgen 20060317)	2009 	Randomized Phase 2 (C)	ECX & Rilotumumab	Seems to have shorter PFS (primary endpoint)Median PFS: 4.2 vs 5.7 mo(HR 1.67, 80% CI 1.27-2.22)
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV bolus once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV over 4 hours once on day 1
*Capecitabine (Xeloda) 625 mg/m2 PO twice per day on days 1 to 21
21-day cycles
===Regimen variant #2, 50/60/2000===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Guimbaud et al. 2014 (FFCD 03-07)	2005-2008 	Phase 3 (C)	FOLFIRI 	Shorter TTFMedian TTF: 4.24 vs 5.08 mo(HR 1.30, 95% CI 1.08-1.59)
====Chemotherapy====
*Epirubicin (Ellence) as follows:
**Cycles 1 to 18: 50 mg/m2 IV over 15 minutes once on day 1 (maximum cumulative dose of 900 mg/m2)
*Cisplatin (Platinol) 60 mg/m2 IV over 60 minutes once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 2 to 15
21-day cycles
===References===
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00719550
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00374036
==Erlotinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Dragovich et al. 2006 (SWOG 0127)	2002-2003 	Phase 2
Note: Patients had 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 on days 1 to 28, taken at least 1 hour before a meal or 2 hours after a meal
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00032123
==FLOT==
FLOT: Fluorouracil, Leucovorin, Oxaliplatin, Taxotere (Docetaxel)
===Regimen===
Study 	Dates of enrollment	Evidence
Al-Batran et al. 2008a	2006 	Phase 2
Note: Patients had 100% adenocarcinoma histology (44% gastroesophageal junction, 56% gastric origin). 93% metastatic disease. 15% with ECOG 2-3.
====Chemotherapy====
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on day 1, given fourth
*Leucovorin (Folinic acid) 200 mg/m2 IV over 1 to 2 hours once on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 1 to 2 hours once on day 1
*Docetaxel (Taxotere) 50 mg/m2 IV over 1 to 2 hours once on day 1
====Supportive therapy====
*Dexamethasone (Decadron) 8 mg PO once per day on days 0 to 3
14-day cycle for up to 8 (or more) cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==FOLFIRI==
FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan
IF: Irinotecan & 5-Fluorouracil
===Regimen===
Study 	Dates of enrollment	Evidence
Wolff et al. 2009	2002-2006 	Phase 2
====Chemotherapy====
*Fluorouracil (5-FU) 2000 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36, given second (total dose per cycle: 12,000 mg/m2)
*Leucovorin (Folinic acid) 500 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36, given second
*Irinotecan (Camptosar) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, given first
====Supportive therapy====
*Ondansetron (Zofran) for antiemetic prophylaxis
*Dexamethasone (Decadron) for antiemetic prophylaxis
*Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/μL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection
*Atropine (Atropen) prn cholinergic symptoms
*Loperamide (Imodium) prn delayed diarrhea
8-week cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Irinotecan monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Enzinger et al. 2005	1997-12 to 2000-08 	Phase 2
Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m2 IV once per day on days 1 & 8, with 21-day cycles. Patients had 100% adenocarcinoma histology, both gastric and esophageal.
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
42-day cycles
===References===
#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. link to original article EuroPMC
==Irinotecan & Mitomycin==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lustberg et al. 2010	2002-2006 	Randomized Phase 2 (E-switch-ic)	Irinotecan & Mitomycin; alternate schedule	No statistical comparison
Note: Patients had 56% lower esophageal, 44% gastroesophageal junction. 100% adenocarcinoma histology. 100% previously untreated 6% with ECOG PS = 2. 77% stage four disease. 
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 2 & 9
*Mitomycin (Mutamycin) 6 mg/m2 IV once on day 1
====Supportive therapy====
*Ondansetron (Zofran) or Granisetron and Dexamethasone (Decadron) premedication
*Loperamide (Imodium) started with first episode of diarrhea
*Erythropoietin for hemoglobin less than 10 g/dL permitted
28-day cycle for up to 6 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==FOLFOX6==
FOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moehler et al. 2020 (JAVELIN Gastric 100)	2015-2017 	Phase 3 (C)	1a. CapeOx-Avelumab1b. FOLFOX6-Avelumab1c. mFOLFOX6-Avelumab	Did not meet primary endpoint of OSMedian OS: 10.9 vs 10.4 mo(HR 1.10, 95% CI 0.90-1.35)
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on day 1, given last
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
14-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02625610
==mFOLFOX6==
mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shah et al. 2017 (METGastric)	2012-2014 	Phase 3 (C)	mFOLFOX6 & Onartuzumab 	Did not meet primary endpoint of OSMedian OS: 11.3 vs 11 mo(sHR 1.22, 95% CI 0.87-1.69)
Shah et al. 2021 (GAMMA-1) 	2015-2019 	Phase 3 (C)	mFOLFOX6 & Andecaliximab	Did not meet primary endpoint of OSMedian OS: 11.8 vs 12.5 mo(sHR 1.08, 95% CI 0.85-1.35)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Biomarker eligibility criteria====
*METGastric: MET-positive
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycle for 12 cycles
====Subsequent treatment====
*FULV maintenance
===References===
#METGastric: Shah MA, Bang YJ, Lordick F, Alsina M, Chen M, Hack SP, Bruey JM, Smith D, McCaffery I, Shames DS, Phan S, Cunningham D. Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial. JAMA Oncol. 2017 May 1;3(5):620-627. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01662869
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02545504
#CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02872116
##Update: Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Lin D, Nguyen H, Shah R, Qiao Y, Hartman J, Sugarman R. Quality-adjusted time without symptoms or toxicity analysis of nivolumab plus chemotherapy versus chemotherapy alone for the management of previously untreated patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. Gastric Cancer. 2023 May;26(3):415-424. Epub 2023 Mar 21. link to original article link to PMC article EuroPMC
##HRQoL analysis: Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. link to original article link to PMC article EuroPMC
##Update: Janjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C, Wyrwicz L, Yamaguchi K, Cleary JM, Elimova E, Karamouzis M, Bruges R, Skoczylas T, Bragagnoli A, Liu T, Tehfe M, Zander T, Kowalyszyn R, Pazo-Cid R, Schenker M, Feeny K, Wang R, Lei M, Chen C, Nathani R, Shitara K. First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial. J Clin Oncol. 2024 Jun 10;42(17):2012-2020. Epub 2024 Feb 21. link to original article link to PMC article EuroPMC
==mFOLFOX6 (L-Leucovorin)==
mFOLFOX6: modified L-FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shah et al. 2021 (GAMMA-1)	2015-2019 	Phase 3 (C)	mFOLFOX6 & Andecaliximab	Did not meet primary endpoint of OSMedian OS: 11.8 vs 12.5 mo(sHR 1.08, 95% CI 0.85-1.35)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Levoleucovorin (Fusilev) 200 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
14-day cycle for 12 cycles
====Subsequent treatment====
*FULV maintenance
===References===
#GAMMA-1: Shah MA, Bodoky G, Starodub A, Cunningham D, Yip D, Wainberg ZA, Bendell J, Thai D, He J, Bhargava P, Ajani JA. Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1). J Clin Oncol. 2021 Mar 20;39(9):990-1000. Epub 2021 Feb 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02545504
==mFOLFOX6 & Nivolumab==
mFOLFOX6 & Nivolumab: modified L-FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Nivolumab
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (E-RT-esc)	1a. CapeOx1b. mFOLFOX6 	Longer OS1 (co-primary endpoint)Median OS: 14.4 vs 11.1 mo(HR 0.70, 95% CI 0.61-0.81)Longer PFS (co-primary endpoint)Median PFS: 7.7 vs 6.05 mo(HR 0.68, 98% CI 0.56-0.81)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (E-RT-esc)	2. Ipilimumab & Nivolumab	Not reported
1Reported efficacy and MCBS score are for the group with PD-L1 CPS of 5 or more; reported efficacy is based on the 2022 update.
Note: CheckMate 649 included patients on both 21-day (Nivo/CapeOx) and 14-day (Nivo/FOLFOX) regimens in the immunotherapy + chemo arm. 60% PD-L1 CPS >5, 82% PD-L1 CPS >1.
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
====Immunotherapy====
*Nivolumab 240 mg IV once on day 1
14-day cycles
===References===
#CheckMate 649: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. Epub 2021 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02872116
##Update: Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. Epub 2022 Mar 23. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Lin D, Nguyen H, Shah R, Qiao Y, Hartman J, Sugarman R. Quality-adjusted time without symptoms or toxicity analysis of nivolumab plus chemotherapy versus chemotherapy alone for the management of previously untreated patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. Gastric Cancer. 2023 May;26(3):415-424. Epub 2023 Mar 21. link to original article link to PMC article EuroPMC
##HRQoL analysis: Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, Ajani JA, Janjigian YY, Garrido M, Shen L, Yamaguchi K, Liu T, Schenker M, Kowalyszyn R, Bragagnoli AC, Bruges R, Montesarchio V, Pazo-Cid R, Hunter S, Davenport E, Wang J, Kondo K, Li M, Wyrwicz L. Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649. J Clin Oncol. 2023 Dec 10;41(35):5388-5399. Epub 2023 Sep 15. link to original article link to PMC article EuroPMC
##Update: Janjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C, Wyrwicz L, Yamaguchi K, Cleary JM, Elimova E, Karamouzis M, Bruges R, Skoczylas T, Bragagnoli A, Liu T, Tehfe M, Zander T, Kowalyszyn R, Pazo-Cid R, Schenker M, Feeny K, Wang R, Lei M, Chen C, Nathani R, Shitara K. First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial. J Clin Oncol. 2024 Jun 10;42(17):2012-2020. Epub 2024 Feb 21. link to original article link to PMC article EuroPMC
=Metastatic or locally advanced disease, subsequent lines of therapy=
==Apatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Li et al. 2016 (HENGRUI 20101208)	2011-01 to 2012-11 	Phase 3 (E-esc)	Placebo 	Longer OS (co-primary endpoint)Median OS: 6.5 vs 4.7 mo(HR 0.71, 95% CI 0.54-0.94)
====Targeted therapy====
*Apatinib (Aitan) 850 mg PO once per day on days 1 to 28
28-day cycles
===References===
#HENGRUI 20101208: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01512745
==Cetuximab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Gold et al. 2010 (SWOG S0415)	2005-2007 	Phase 2
Note: Patients had 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 once on day 1
**Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once on day 1
====Supportive therapy====
*Diphenhydramine (Benadryl) 50 mg IV or PO once, given 30 to 60 minutes prior to cetuximab
7-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00096031
==Docetaxel monotherapy==
===Regimen variant #1, 75 mg/m2 x 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ford et al. 2013 (COUGAR-02)	2008-2012 	Phase 3 (E-esc)	Active symptom control	Longer OS (primary endpoint)Median OS: 5.2 vs 3.6 mo(HR 0.67, 95% CI 0.49-0.92)
Note: COUGAR-02 patients had 100% adenocarcinoma histology (20% esophageal, 35% gastroesophageal junction, 45% stomach). 15% ECOG PS of 2. 12% locally advanced, 88% metastatic disease. 
====Prior treatment criteria====
*Progression on or within 6 months of treatment with a platinum-fluoropyrimidine combination
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for up to 6 cycles
===Regimen variant #2, 75 mg/m2, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Roy et al. 2013 (PEP0206)	2008-2010 	Randomized Phase 2 (C)	1. Irinotecan2. Irinotecan liposomal	Not powered to draw conclusions
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===References===
#PEP0206: Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00813072
#COUGAR-02: Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00978549
==Irinotecan monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Roy et al. 2013 (PEP0206)	2008-2010 	Randomized Phase 2 (C)	1. Docetaxel2. Irinotecan liposomal	Not powered to draw conclusions
====Chemotherapy====
*Irinotecan (Camptosar) 300 mg/m2 IV over 90 minutes once on day 1
21-day cycles
===References===
#PEP0206: Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00813072
==Irinotecan liposomal monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Roy et al. 2013 (PEP0206)	2008-2010 	Randomized Phase 2 (E-switch-ic)	1. Docetaxel2. Irinotecan	Not powered to draw conclusions
====Chemotherapy====
*Irinotecan liposome (Onivyde) 120 mg/m2 IV over 90 minutes once on day 1
21-day cycles
===References===
#PEP0206: Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00813072
==Irinotecan & Mitomycin==
===Regimen===
Study 	Dates of enrollment	Evidence
Giuliani et al. 2005 (GOIM 2106)	2001-05 to 2003-04 	Phase 2
Note: Patients had 100% gastric adenocarcinoma. Treatment given as second-line chemotherapy for pretreated patients with advanced or metastatic disease. 
====Chemotherapy====
*Irinotecan (Camptosar) by the following age-based criteria:
**70 years old and younger: 150 mg/m2 IV over 90 minutes once per day on days 1 & 15
**Older than 70 years old: 120 mg/m2 IV over 90 minutes once per day on days 1 & 15
*Mitomycin (Mutamycin) 8 mg/m2 IV bolus once on day 1, given second, immediately after irinotecan
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Nivolumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Janjigian et al. 2018 (CheckMate 032UGI)	2013-2015 	Phase 1/2 	 	
Kang et al. 2017 (ATTRACTION-2) 	2014-2016 	Phase 3 (E-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 5.26 vs 4.14 mo(HR 0.63, 95% CI 0.51-0.78)
Note: ATTRACTION-2 included patients with GE junction malignancy (82.6% gastric, 8.5% GE junction) and 12.3% of patients had a PD-L1 CPS score of at least 1.
====Immunotherapy====
*Nivolumab (Opdivo) 3 mg/kg IV once on day 1
14-day cycles
===References===
#ATTRACTION-2: Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02267343
##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 EuroPMC
#CheckMate 032UGI: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01928394
==Paclitaxel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wilke et al. 2014 (RAINBOW)	2010-2012 	Phase 3 (C)	Paclitaxel & Ramucirumab	Seems to have shorter OS (primary endpoint)Median OS: 7.4 vs 9.6 mo(HR 1.23, 95% CI 1.04-1.47)
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===References===
#RAINBOW: Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. Epub 2014 Sep 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01170663
##PRO analysis: Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim TY, Cunningham D, Rougier P, Muro K, Liepa AM, Chandrawansa K, Emig M, Ohtsu A, Wilke H. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016 Apr;27(4):673-9. Epub 2016 Jan 7. link to original article link to PMC article EuroPMC
==Paclitaxel & Ramucirumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Wilke et al. 2014 (RAINBOW)	2010-2012 	Phase 3 (E-esc)	Paclitaxel	Seems to have longer OS (primary endpoint)Median OS: 9.6 vs 7.4 mo(HR 0.81, 95% CI 0.68-0.96)
Note: Patients had 100% adenocarcinoma histology, 20% gastroesophageal junction, 80% gastric origin. 
====Prior treatment criteria====
*RAINBOW: documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline
====Targeted therapy====
*Ramucirumab (Cyramza) 8 mg/kg IV once per day on days 1 & 15
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===References===
#RAINBOW: Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. Epub 2014 Sep 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01170663
##PRO analysis: Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim TY, Cunningham D, Rougier P, Muro K, Liepa AM, Chandrawansa K, Emig M, Ohtsu A, Wilke H. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016 Apr;27(4):673-9. Epub 2016 Jan 7. link to original article link to PMC article EuroPMC
==Ramucirumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Fuchs et al. 2013 (REGARD)	2009-2012 	Phase 3 (E-esc)	Placebo 	Seems to have longer OS (primary endpoint)Median OS: 5.2 vs 3.8 mo(HR 0.78, 95% CI 0.60-0.998)
Note: Patients in REGARD had 100% adenocarcinoma histology (25% gastroesophageal junction, 75% gastric origin).
====Prior treatment criteria====
*REGARD: disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment
====Targeted therapy====
*Ramucirumab (Cyramza) 8 mg/kg IV once on day 1
14-day cycles
===References===
#REGARD: Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00917384
Category:Esophageal cancer regimens
Category:Histology-specific pages
Category:Esophageal cancers