Gastric cancer

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Note: there is significant overlap between regimens for gastric cancer and esophageal cancer, if you can't find the regimen you're looking for here, please try the esophageal cancer page. If you still can't find it, it is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page.
*Note: this page contains regimens which were not tested in biomarker-specific populations. The following links will take you to biomarker-specific subpages: 
*Regimens for HER2 positive gastric cancer are here.
Last updated on 2024-12-02:78 regimens on this page
121 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.
==ESMO==
*2024: Shitara et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer EuroPMC
**2019: Muro et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS EuroPMC
*2022: Lordick et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
**2016: Smyth et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Okines et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Jackson et al. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Cunningham & Oliveira. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Cunningham. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Cunningham et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of gastric cancer EuroPMC
*2019: Stjepanovic et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==ESMO/ESSO/ESTRO==
*2013: Waddell et al. Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==French Intergroup==
*2018: Zaanan et al. Gastric cancer: French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO) EuroPMC
==NCCN==
*NCCN Guidelines - Gastric Cancer
**2022: Ajani et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. EuroPMC
**2016: Ajani et al. Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology. EuroPMC
**2013: Ajani et al. Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines. EuroPMC
**2010: Ajani et al. Gastric cancer. EuroPMC
**2006: Ajani et al. Gastric Cancer Clinical Practice Guidelines. EuroPMC
**2003: Ajani et al. Gastric cancer. Clinical practice guidelines in oncology. EuroPMC
=Perioperative therapy=
This section contains protocols with a pre-planned neoadjuvant (preoperative) and adjuvant (postoperative) component.
==Capecitabine & Cisplatin (CX)==
CX: Cisplatin, Xeloda (Capecitabine)
XP: Xeloda (Capecitabine), Platinol (Cisplatin)
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Shitara et al. 2023 (KEYNOTE-585)	2017-10-09 to 2021-01-25	Phase 3 (C)	1a. Perioperative CX & Pembrolizumab1b. Perioperative CF & Pembrolizumab	Lower pCR rate (co-primary endpoint)Might have shorter EFS (co-primary endpoint)Median EFS: 25.3 vs 44.4 mo(HR 1.23, 95% CI 1.01-1.49)Did not meet co-primary endpoint of OS
Shitara et al. 2023 (KEYNOTE-585)	2017-10-09 to 2021-01-25	Phase 3 (C)	2. Perioperative FLOT & Pembrolizumab 	Not reported
===Neoadjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 3 cycles
===Definitive===
====Local therapy====
*Surgical resection
===Adjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 3 cycles
===References===
#KEYNOTE-585: Shitara K, Rha SY, Wyrwicz LS, Oshima T, Karaseva N, Osipov M, Yasui H, Yabusaki H, Afanasyev S, Park YK, Al-Batran SE, Yoshikawa T, Yanez P, Dib Bartolomeo M, Lonardi S, Tabernero J, Van Cutsem E, Janjigian YY, Oh DY, Xu J, Fang X, Shih CS, Bhagia P, Bang YJ; KEYNOTE-585 investigators. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol. 2024 Feb;25(2):212-224. Epub 2023 Dec 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03221426
==CapeOx==
CapeOX: Capecitabine & OXaliplatin
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tian et al. 2021 (Alien Craft 0004)	2014-09 to 2018-06 	Phase 3 (C)	1. Adjuvant CapeOx 	Not reported
Tian et al. 2021 (Alien Craft 0004)	2014-09 to 2018-06 	Phase 3 (C)	2. Perioperative DOX-CapeOx	Lower pCR rate
===Neoadjuvant===
====Chemotherapy====
*Capecitabine (Xeloda) 500 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycle for 4 cycles
===Definitive===
====Local therapy====
*Surgical resection
===Adjuvant===
====Chemotherapy====
*Capecitabine (Xeloda) 500 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycle for 4 cycles
===References===
#Alien Craft 0004: Tian Y, Zhao Q, Li Y, Fan L, Zhang Z, Zhao X, Tan B, Wang D, Yang P. Efficacy of Neoadjuvant Chemotherapy DOX and XELOX Regimens for Patients with Resectable Gastric or Gastroesophageal Junction Adenocarcinoma. Gastroenterol Res Pract. 2021 Jul 22;2021:5590626. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02555358
##Update: Tian Y, Yang P, Guo H, Liu Y, Zhang Z, Ding P, Zheng T, Deng H, Ma W, Li Y, Fan L, Zhang Z, Wang D, Zhao X, Tan B, Liu Y, Zhao Q. Neoadjuvant docetaxel, oxaliplatin plus capecitabine versus oxaliplatin plus capecitabine for patients with locally advanced gastric adenocarcinoma: long-term results of a phase III randomized controlled trial. Int J Surg. 2023 Dec 1;109(12):4000-4008. link to original article link to PMC article EuroPMC
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin & Fluorouracil
FP: Fluorouracil & Platinol (Cisplatin)
===Protocol variant #1, 80/4000===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Shitara et al. 2023 (KEYNOTE-585)	2017-10-09 to 2021-01-25	Phase 3 (C)	1a. Perioperative CX & Pembrolizumab1b. Perioperative CF & Pembrolizumab	Lower pCR rate (co-primary endpoint)Might have shorter EFS (co-primary endpoint)Median EFS: 25.3 vs 44.4 mo(HR 1.23, 95% CI 1.01-1.49)Did not meet co-primary endpoint of OS
Shitara et al. 2023 (KEYNOTE-585)	2017-10-09 to 2021-01-25	Phase 3 (C)	2. Perioperative FLOT & Pembrolizumab 	Not reported
====Chemotherapy, neoadjuvant CF portion (cycles 1 to 3)====
*Cisplatin (Platinol) 80 mg/m2 IV 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)
21-day cycle for 3 cycles
====Local therapy, definitive portion====
*Surgical resection
====Chemotherapy, adjuvant CF portion (cycles 4 to 6)====
*Cisplatin (Platinol) 80 mg/m2 IV 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)
21-day cycle for 3 cycles
===Protocol variant #2, 100/4000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ychou et al. 2011 (ACCORD 07)	1995-2003 	Phase 3 (E-esc)	Surgery alone	Longer OS (primary endpoint)OS60: 38% vs 24%(HR 0.69, 95% CI 0.50-0.95)
Note: ACCORD 07 included patients with lower esophageal malignancy as well (25% gastric, 11% lower esophagus, and 64% GE junction).
====Chemotherapy, neoadjuvant CF portion====
*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
====Local therapy, definitive portion====
*Surgical resection
====Chemotherapy, adjuvant CF portion====
*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 abstract have been reviewed by our editors EuroPMC NCT00002883
#KEYNOTE-585: Shitara K, Rha SY, Wyrwicz LS, Oshima T, Karaseva N, Osipov M, Yasui H, Yabusaki H, Afanasyev S, Park YK, Al-Batran SE, Yoshikawa T, Yanez P, Dib Bartolomeo M, Lonardi S, Tabernero J, Van Cutsem E, Janjigian YY, Oh DY, Xu J, Fang X, Shih CS, Bhagia P, Bang YJ; KEYNOTE-585 investigators. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol. 2024 Feb;25(2):212-224. Epub 2023 Dec 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03221426
==DOX-CapeOx==
DOX-CapeOX: neoadjuvant Docetaxel, Oxaliplatin, Xeloda (Capecitabine), followed by adjuvant Capecitabine & OXaliplatin
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tian et al. 2021 (Alien Craft 0004)	2014-09 to 2018-06 	Phase 3 (E-esc)	1. Adjuvant CapeOx 	Not reported
Tian et al. 2021 (Alien Craft 0004)	2014-09 to 2018-06 	Phase 3 (E-esc)	2. Perioperative CapeOx	Higher pCR rate (primary endpoint)pCR rate: 16.1% vs 4.3%
===Neoadjuvant===
====Chemotherapy====
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 500 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 4 cycles
===Definitive===
====Local therapy====
*Surgical resection
===Adjuvant===
====Chemotherapy====
*Capecitabine (Xeloda) 500 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycle for 4 cycles
===References===
#Alien Craft 0004: Tian Y, Zhao Q, Li Y, Fan L, Zhang Z, Zhao X, Tan B, Wang D, Yang P. Efficacy of Neoadjuvant Chemotherapy DOX and XELOX Regimens for Patients with Resectable Gastric or Gastroesophageal Junction Adenocarcinoma. Gastroenterol Res Pract. 2021 Jul 22;2021:5590626. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02555358
##Update: Tian Y, Yang P, Guo H, Liu Y, Zhang Z, Ding P, Zheng T, Deng H, Ma W, Li Y, Fan L, Zhang Z, Wang D, Zhao X, Tan B, Liu Y, Zhao Q. Neoadjuvant docetaxel, oxaliplatin plus capecitabine versus oxaliplatin plus capecitabine for patients with locally advanced gastric adenocarcinoma: long-term results of a phase III randomized controlled trial. Int J Surg. 2023 Dec 1;109(12):4000-4008. link to original article link to PMC article EuroPMC
==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)
Cats et al. 2018 (CRITICS) 	2007-2015 	Phase 3 (C) 	1a. ECF/CX & RT1b. ECX/CX & RT1c. EOF/CX & RT1d. EOX/CX & RT 	Did not meet primary endpoint of OSMedian OS: 43 vs 37 mo(HR 1.01, 95% CI 0.84-1.22)
Leong et al. 2024 (TOPGEAR) 	2009-09 to 2021-05 	Phase 3 (C) 	1a. ECF/5-FU & RT1b. ECF/Capecitabine & RT1c. ECX/5-FU & RT1d. ECX/Capecitabine & RT1e. FLOT/5-FU & RT1f. FLOT/Capecitabine & RT	Did not meet primary endpoint of OSMedian OS: 49 vs 46 mo(HR 0.95, 95% CI 0.76-1.20)
Reynolds et al. 2023 (Neo-AEGIS)	2013-01-24 to 2020-12-23	Phase 3 (C) 	CP & RT, then surgery 	Did not meet primary endpoint of OSMedian OS: 48 vs 49.2 mo(HR 1.03, 95% CI 0.77-1.38)
Note: MAGIC included patients with lower esophageal malignancy as well (74% gastric, 14.8% lower esophagus, and 11.2% GE junction). CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction. In CRITICS, only patients with trouble swallowing pills were assigned to this treatment arm.
===Neoadjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV 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, suggested as thrombosis prophylaxis:
**Warfarin (Coumadin) 1 mg PO once per day
21-day cycle for 3 cycles, followed by:
===Definitive===
====Local therapy====
*MAGIC: Surgical resection is performed 3 to 6 weeks after the completion of cycle 3
*CRITICS: Surgery with a D1+ lymph node resection
*TOPGEAR: Surgery with a D2 lymph node resection recommended, if possible
Followed in 6 to 12 weeks by:
===Adjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV 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, suggested as thrombosis prophylaxis:
**Warfarin (Coumadin) 1 mg PO once per day
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 abstract have been reviewed by our editors EuroPMC NCT00002615
#CRITICS: Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00407186
#Neo-AEGIS: Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. Epub 2023 Sep 18. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01726452
#TOPGEAR: Leong T, Smithers BM, Michael M, Haustermans K, Wong R, Gebski V, O'Connell RL, Zalcberg J, Boussioutas A, Findlay M, Willis D, Moore A, Murray WK, Lordick F, O'Callaghan C, Swallow C, Darling G, Miller D, Strickland A, Liberman M, Mineur L, Simes J; Australasian Gastro-Intestinal Trials Group, National Health and Medical Research Council Clinical Trials Centre, Trans-Tasman Radiation Oncology Group, European Organisation for Research and Treatment of Cancer, and Canadian Cancer Trials Group. Preoperative Chemoradiotherapy for Resectable Gastric Cancer. N Engl J Med. 2024 Nov 14;391(19):1810-1821. Epub 2024 Sep 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01924819
==ECX==
ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Cats et al. 2018 (CRITICS) 	2007-2015 	Phase 3 (C)	1a. ECF/CX & RT1b. ECX/CX & RT1c. EOF/CX & RT1d. EOX/CX & RT 	Did not meet primary endpoint of OSMedian OS: 43 vs 37 mo(HR 1.01, 95% CI 0.84-1.22)
Leong et al. 2024 (TOPGEAR) 	2009-09 to 2021-05 	Phase 3 (C)	1a. ECF/5-FU & RT1b. ECF/Capecitabine & RT1c. ECX/5-FU & RT1d. ECX/Capecitabine & RT1e. FLOT/5-FU & RT1f. FLOT/Capecitabine & RT	Did not meet primary endpoint of OSMedian OS: 49 vs 46 mo(HR 0.95, 95% CI 0.76-1.20)
Reynolds et al. 2023 (Neo-AEGIS)	2013-01-24 to 2020-12-23	Phase 3 (C)	CP & RT, then surgery 	Did not meet primary endpoint of OSMedian OS: 48 vs 49.2 mo(HR 1.03, 95% CI 0.77-1.38)
Note: CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction
===Neoadjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Capecitabine (Xeloda) by the following study-specific criteria:
**Neo-AEGIS & TOPGEAR: 625 mg/m2 PO twice per day on days 1 to 21
**CRITICS: 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 3 cycles, followed by:
===Definitive===
====Local therapy====
*Surgery with a D1+ or D2 lymph node resection
===Adjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Capecitabine (Xeloda) by the following study-specific criteria:
**Neo-AEGIS & TOPGEAR: 625 mg/m2 PO twice per day on days 1 to 21
**CRITICS: 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 3 cycles
===References===
#CRITICS: Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00407186
#Neo-AEGIS: Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. Epub 2023 Sep 18. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01726452
#TOPGEAR: Leong T, Smithers BM, Michael M, Haustermans K, Wong R, Gebski V, O'Connell RL, Zalcberg J, Boussioutas A, Findlay M, Willis D, Moore A, Murray WK, Lordick F, O'Callaghan C, Swallow C, Darling G, Miller D, Strickland A, Liberman M, Mineur L, Simes J; Australasian Gastro-Intestinal Trials Group, National Health and Medical Research Council Clinical Trials Centre, Trans-Tasman Radiation Oncology Group, European Organisation for Research and Treatment of Cancer, and Canadian Cancer Trials Group. Preoperative Chemoradiotherapy for Resectable Gastric Cancer. N Engl J Med. 2024 Nov 14;391(19):1810-1821. Epub 2024 Sep 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01924819
==EOF==
EOF: Epirubicin, Oxaliplatin, Fluourouracil
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Cats et al. 2018 (CRITICS) 	2007-2015 	Phase 3 (C)	1a. ECF/CX & RT1b. ECX/CX & RT1c. EOF/CX & RT1d. EOX/CX & RT	Did not meet primary endpoint of OSMedian OS: 43 vs 37 mo(HR 1.01, 95% CI 0.84-1.22)
Reynolds et al. 2023 (Neo-AEGIS)	2013-01-24 to 2020-12-23	Phase 3 (C)	CP & RT, then surgery 	Did not meet primary endpoint of OSMedian OS: 48 vs 49.2 mo(HR 1.03, 95% CI 0.77-1.38)
Note: CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction. Only patients with trouble swallowing pills were assigned to this treatment arm.
===Neoadjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 130 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: 4000 mg/m2)
21-day cycle for 3 cycles, followed by:
===Definitive===
====Local therapy====
*Surgery with a D1+ lymph node resection
===Adjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 130 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: 4000 mg/m2)
21-day cycle for 3 cycles
===References===
#CRITICS: Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00407186
#Neo-AEGIS: Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. Epub 2023 Sep 18. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01726452
==EOX==
EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Cats et al. 2018 (CRITICS) 	2007-2015 	Phase 3 (C)	1a. ECF/CX & RT1b. ECX/CX & RT1c. EOF/CX & RT1d. EOX/CX & RT	Did not meet primary endpoint of OSMedian OS: 43 vs 37 mo(HR 1.01, 95% CI 0.84-1.22)
Reynolds et al. 2023 (Neo-AEGIS)	2013-01-24 to 2020-12-23	Phase 3 (C)	CP & RT, then surgery 	Did not meet primary endpoint of OSMedian OS: 48 vs 49.2 mo(HR 1.03, 95% CI 0.77-1.38)
Note: CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction
===Neoadjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 625 mg/m2 PO twice per day on days 1 to 21
21-day cycle for 3 cycles, followed by:
===Definitive===
====Local therapy====
*Surgery with a D1+ lymph node resection
===Adjuvant===
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 625 mg/m2 PO twice per day on days 1 to 21
21-day cycle for 3 cycles
===References===
#CRITICS: Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00407186
#Neo-AEGIS: Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. Epub 2023 Sep 18. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01726452
==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)
Shitara et al. 2023 (KEYNOTE-585)	2017-10-09 to 2021-01-25	Phase 3 (C) 	1a. Perioperative CX & Pembrolizumab1b. Perioperative CF & Pembrolizumab2. Perioperative FLOT & Pembrolizumab 	Not reported2
Leong et al. 2024 (TOPGEAR) 	2009-09 to 2021-05 	Phase 3 (C) 	1a. ECF/5-FU & RT1b. ECF/Capecitabine & RT1c. ECX/5-FU & RT1d. ECX/Capecitabine & RT1e. FLOT/5-FU & RT1f. FLOT/Capecitabine & RT	Did not meet primary endpoint of OSMedian OS: 49 vs 46 mo(HR 0.95, 95% CI 0.76-1.20)
1Reported efficacy is based on the 2019 update.
2In KEYNOTE-585, the FLOT cohort was designated as a safety cohort and efficacy results were not reported in Shitara et al. 2023.
Note: Although TOPGEAR began enrollment in 2009, this arm was not available until 2017.
===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
===Definitive===
====Local therapy====
*Surgery with a D1+ or D2 lymph node resection
===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
#KEYNOTE-585: Shitara K, Rha SY, Wyrwicz LS, Oshima T, Karaseva N, Osipov M, Yasui H, Yabusaki H, Afanasyev S, Park YK, Al-Batran SE, Yoshikawa T, Yanez P, Dib Bartolomeo M, Lonardi S, Tabernero J, Van Cutsem E, Janjigian YY, Oh DY, Xu J, Fang X, Shih CS, Bhagia P, Bang YJ; KEYNOTE-585 investigators. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol. 2024 Feb;25(2):212-224. Epub 2023 Dec 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03221426
#TOPGEAR: Leong T, Smithers BM, Michael M, Haustermans K, Wong R, Gebski V, O'Connell RL, Zalcberg J, Boussioutas A, Findlay M, Willis D, Moore A, Murray WK, Lordick F, O'Callaghan C, Swallow C, Darling G, Miller D, Strickland A, Liberman M, Mineur L, Simes J; Australasian Gastro-Intestinal Trials Group, National Health and Medical Research Council Clinical Trials Centre, Trans-Tasman Radiation Oncology Group, European Organisation for Research and Treatment of Cancer, and Canadian Cancer Trials Group. Preoperative Chemoradiotherapy for Resectable Gastric Cancer. N Engl J Med. 2024 Nov 14;391(19):1810-1821. Epub 2024 Sep 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01924819
#MATTERHORN: NCT04592913
#RAMSES: NCT02661971
==mFOLFOX6==
mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yu et al. 2022 (FOCUSgastric)	2011-2016 	Phase 3 (C)	Perioperative SOX	Non-inferior OS36 (primary endpoint)OS36: 67.8% vs 75.2%
===Neoadjuvant===
====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
21-day cycle for 2 to 4 cycles, followed by:
===Definitive===
====Local therapy====
*Gastrectomy with at least D2 dissection
===Adjuvant===
====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
21-day cycle for 2 to 4 cycles
===References===
#FOCUSgastric: Yu J, Gao Y, Chen L, Wu D, Shen Q, Zhao Z, Liu W, Yang H, Zhang Q, Wang X, Hu P, Zheng Z, Wang X, Liu H, Xu Z, Yan Z, Wu Y, Jin M, Zhang Q, Liu X, Zhu K, Shou C. Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2022 Feb 1;5(2):e220426. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01364376
==SOX==
SOX: S-1 & OXaliplatin
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yu et al. 2022 (FOCUSgastric) 	2011-2016 	Phase 3 (E-switch-ic)	Perioperative mFOLFOX6	Non-inferior OS36 (primary endpoint)OS36: 75.2% vs 67.8%
Wang et al. 2024 (RESONANCE) 	2012-09-01 to 2019-07-01	Phase 3 (E-switch-ic)	Adjuvant SOX 	Seems to have higher DFS36 (primary endpoint)DFS36: 61.7% vs 53.8%(HR 0.76, 95% CI 0.61-0.96)
Li et al. 2025 (DRAGON IV/CAP 05)	2019-12-18 to 2022-12-31	Phase 3 (C) 	1. Perioperative SOXR 	Not reported
Li et al. 2025 (DRAGON IV/CAP 05)	2019-12-18 to 2022-12-31	Phase 3 (C) 	2. Perioperative SOXRC	Lower pCR rate (co-primary endpoint)pCR rate: 5% vs 18.3%
===Neoadjuvant===
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycle for 3 cycles, followed by:
===Definitive===
====Local therapy====
*Gastrectomy with at least D2 dissection
===Adjuvant===
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycle for 3 cycles
===References===
#RESOLVEgastric: Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, Wang X, Wu A, Li G, Su X, Xiao G, Cui M, Wu D, Chen L, Wu X, Zhou Y, Zhang L, Dang C, He Y, Zhang Z, Sun Y, Li Y, Chen H, Bai Y, Qi C, Yu P, Zhu G, Suo J, Jia B, Li L, Huang C, Li F, Ye Y, Xu H, Wang X, Yuan Y, E JY, Ying X, Yao C, Shen L, Ji J; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021 Aug;22(8):1081-1092. Epub 2021 Jul 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. link to original article EuroPMC NCT01534546
#FOCUSgastric: Yu J, Gao Y, Chen L, Wu D, Shen Q, Zhao Z, Liu W, Yang H, Zhang Q, Wang X, Hu P, Zheng Z, Wang X, Liu H, Xu Z, Yan Z, Wu Y, Jin M, Zhang Q, Liu X, Zhu K, Shou C. Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2022 Feb 1;5(2):e220426. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01364376
#RESONANCE: Wang X, Lu C, Wei B, Li S, Li Z, Xue Y, Ye Y, Zhang Z, Sun Y, Liang H, Li K, Zhu L, Zheng Z, Zhou Y, He Y, Li F, Wang X, Liang P, Huang H, Li G, Shen X, Ji J, Tang Y, Xu Z, Chen L; RESONANCE study group. Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial. J Hematol Oncol. 2024 Apr 8;17(1):17. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01583361
#DRAGON IV/CAP 05: Li C, Tian Y, Zheng Y, Yuan F, Shi Z, Yang L, Chen H, Jiang L, Wang X, Zhao P, Zhang B, Wang Z, Zhao Q, Dong J, Lian C, Xu S, Zhang A, Zheng Z, Wang K, Dang C, Wu D, Chen J, Xue Y, Liang B, Cheng X, Wang Q, Chen L, Xia T, Liu H, Xu D, Zhuang J, Wu T, Zhao X, Wu W, Wang H, Peng J, Hou Z, Zheng R, Chen Y, Yin K, Zhu Z. Pathologic Response of Phase III Study: Perioperative Camrelizumab Plus Rivoceranib and Chemotherapy Versus Chemotherapy for Locally Advanced Gastric Cancer (DRAGON IV/CAP 05). J Clin Oncol. 2025 Feb;43(4):464-474. link to original article dosing details in manuscript have been reviewed by our editors link to EuroPMC NCT04208347
==SOXRC==
SOXRC: S-1, OXaliplatin, Rivoceranib (Apatanib), Camrelizumab
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Li et al. 2025 (DRAGON IV/CAP 05)	2019-12-18 to 2022-12-31	Phase 3 (E-esc)	1. Perioperative SOXR	Not reported
Li et al. 2025 (DRAGON IV/CAP 05)	2019-12-18 to 2022-12-31	Phase 3 (E-esc)	2. Perioperative SOX 	Higher pCR rate (co-primary endpoint)pCR rate: 18.3% vs 5%
===Neoadjuvant===
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
====Targeted therapy====
*Apatinib (Aitan) as follows:
**Cycles 1 & 2: 500 mg PO once per day on days 1 to 21
**Cycle 3: 500 mg PO once per day on days 1 to 14
21-day cycle for 3 cycles, followed by:
===Definitive===
====Local therapy====
*Gastrectomy with at least D2 dissection
===Adjuvant===
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
====Targeted therapy====
*Apatinib (Aitan) 500 mg PO once per day on days 1 to 21
21-day cycle for 3 cycles
===References===
#DRAGON IV/CAP 05: Li C, Tian Y, Zheng Y, Yuan F, Shi Z, Yang L, Chen H, Jiang L, Wang X, Zhao P, Zhang B, Wang Z, Zhao Q, Dong J, Lian C, Xu S, Zhang A, Zheng Z, Wang K, Dang C, Wu D, Chen J, Xue Y, Liang B, Cheng X, Wang Q, Chen L, Xia T, Liu H, Xu D, Zhuang J, Wu T, Zhao X, Wu W, Wang H, Peng J, Hou Z, Zheng R, Chen Y, Yin K, Zhu Z. Pathologic Response of Phase III Study: Perioperative Camrelizumab Plus Rivoceranib and Chemotherapy Versus Chemotherapy for Locally Advanced Gastric Cancer (DRAGON IV/CAP 05). J Clin Oncol. 2025 Feb;43(4):464-474. link to original article dosing details in manuscript have been reviewed by our editors link to EuroPMC NCT04208347
=Neoadjuvant chemotherapy=
==DOS==
DOS: Docetaxel, Oxaliplatin, S-1
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kang et al. 2021 (PRODIGY)	2012-2017 	Phase 3 (E-esc)	No neoadjuvant therapy	Longer PFS1 (primary endpoint)PFS96: 55.8% vs 43.2%(aHR 0.70, 95% CI 0.53-0.94)Seems to have longer OS1 (secondary endpoint)OS96: 63.8% vs 54.6%(aHR 0.72, 95% CI 0.54-0.96)
1Reported efficacy is based on the 2024 update.
====Chemotherapy====
*Docetaxel (Taxotere) 50 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 100 mg/m2 IV once on day 1
*S-1 40 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgery, then adjuvant S-1
===References===
#PRODIGY: Kang YK, Yook JH, Park YK, Lee JS, Kim YW, Kim JY, Ryu MH, Rha SY, Chung IJ, Kim IH, Oh SC, Park YS, Son T, Jung MR, Heo MH, Kim HK, Park C, Yoo CH, Choi JH, Zang DY, Jang YJ, Sul JY, Kim JG, Kim BS, Beom SH, Cho SH, Ryu SW, Kook MC, Ryoo BY, Kim HK, Yoo MW, Lee NS, Lee SH, Kim G, Lee Y, Lee JH, Noh SH. PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer. J Clin Oncol. 2021 Sep 10;39(26):2903-2913. Epub 2021 Jun 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01515748
##Update: Kang YK, Kim HD, Yook JH, Park YK, Lee JS, Kim YW, Kim JY, Ryu MH, Rha SY, Chung IJ, Kim IH, Oh SC, Park YS, Cheong JH, Jeong O, Heo MH, Kim HK, Park C, Yoo CH, Kang SY, Zang DY, Jang YJ, Sul JY, Kim JG, Kim BS, Beom SH, Hwang JE, Ryu SW, Kook MC, Ryoo BY, Kim H, Yoo MW, Lee NS, Lee SH, Noh SH. Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer: Updated Overall Survival Outcomes From Phase III PRODIGY. J Clin Oncol. 2024 Sep 1;42(25):2961-2965. Epub 2024 Jul 12. link to original article EuroPMC
=Adjuvant therapy=
==CapeOx==
CapeOX: Capecitabine & OXaliplatin
===Regimen variant #1, 1000/130===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tian et al. 2021 (Alien Craft 0004)	2014-09 to 2018-06 	Phase 3 (C)	1. Perioperative CapeOx2. Perioperative DOX-CapeOx	Not reported
====Preceding treatment====
*Gastrectomy
====Chemotherapy====
*Capecitabine (Xeloda) 500 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycle for 8 cycles
===Regimen variant #2, 2000/130===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bang et al. 2012 (CLASSIC) 	2006-2009 	Phase 3 (E-esc)	Surgery alone 	Higher DFS36 (primary endpoint)DFS36: 74% vs 59%(HR 0.56, 95% CI 0.44-0.72)Longer OS1 (secondary endpoint)OS60: 78% vs 69%(HR 0.66, 95% CI 0.51-0.85)
Zhang et al. 2021 (RESOLVEgastric)	2012-2017 	Phase 3 (C) 	1. Perioperative SOX 	Seems to have lower DFS36
Zhang et al. 2021 (RESOLVEgastric)	2012-2017 	Phase 3 (C) 	2. Adjuvant SOX 	Non-inferior DFS36
Kang et al. 2024 (ATTRACTION-5) 	2017-02-01 to 2019-08-15	Phase 3 (C) 	1a. S-1 & Nivolumab1b. CapeOx & Nivolumab	Did not meet primary endpoint of RFSRFS36: 65.3% vs 68.4%(HR 1.11, 95.72% CI 0.85-1.45)
1Reported efficacy for CLASSIC is based on the 2014 update.
Note: RESOLVE should not be confused for the trial by the same name in pancreatic cancer.
====Eligibility criteria====
*ATTRACTION-5: Stage IIIA to IIIC gastric or GEJ cancer
====Preceding treatment====
*Gastrectomy with D2 dissection
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycle for 8 cycles
===References===
#CLASSIC: Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH; CLASSIC trial investigators. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012 Jan 28;379(9813):315-21. Epub 2012 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00411229
##Update: Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W, Lee JI, Shin DB, Ji J, Chen JS, Lim Y, Ha S, Bang YJ; CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1389-96. Epub 2014 Oct 15. link to original article EuroPMC
#RESOLVEgastric: Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, Wang X, Wu A, Li G, Su X, Xiao G, Cui M, Wu D, Chen L, Wu X, Zhou Y, Zhang L, Dang C, He Y, Zhang Z, Sun Y, Li Y, Chen H, Bai Y, Qi C, Yu P, Zhu G, Suo J, Jia B, Li L, Huang C, Li F, Ye Y, Xu H, Wang X, Yuan Y, E JY, Ying X, Yao C, Shen L, Ji J; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021 Aug;22(8):1081-1092. Epub 2021 Jul 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01534546
#Alien Craft 0004: Tian Y, Zhao Q, Li Y, Fan L, Zhang Z, Zhao X, Tan B, Wang D, Yang P. Efficacy of Neoadjuvant Chemotherapy DOX and XELOX Regimens for Patients with Resectable Gastric or Gastroesophageal Junction Adenocarcinoma. Gastroenterol Res Pract. 2021 Jul 22;2021:5590626. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02555358
##Update: Tian Y, Yang P, Guo H, Liu Y, Zhang Z, Ding P, Zheng T, Deng H, Ma W, Li Y, Fan L, Zhang Z, Wang D, Zhao X, Tan B, Liu Y, Zhao Q. Neoadjuvant docetaxel, oxaliplatin plus capecitabine versus oxaliplatin plus capecitabine for patients with locally advanced gastric adenocarcinoma: long-term results of a phase III randomized controlled trial. Int J Surg. 2023 Dec 1;109(12):4000-4008. link to original article link to PMC article EuroPMC
#ATTRACTION-5: Kang YK, Terashima M, Kim YW, Boku N, Chung HC, Chen JS, Ji J, Yeh TS, Chen LT, Ryu MH, Kim JG, Omori T, Rha SY, Kim TY, Ryu KW, Sakuramoto S, Nishida Y, Fukushima N, Yamada T, Bai LY, Hirashima Y, Hagihara S, Nakada T, Sasako M. Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2024 Aug;9(8):705-717. Epub 2024 Jun 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03006705
==Carboplatin & Docetaxel (DCb)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Bamias et al. 2010	2002-2005 	Phase 3 (C)	DCb & RT 	Did not meet primary endpoint of OS
Note: the original protocol was for cisplatin & docetaxel but was changed due to excess CINV. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 1
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 6 cycles
===References===
#Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, Samantas E, Christodoulou Ch, Pentheroudakis G, Pectasides D, Dimopoulos MA, Fountzilas G. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol. 2010 May;65(6):1009-21. Epub 2010 Feb 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Capecitabine & Cisplatin (CX)==
CX: Cisplatin, Xeloda (Capecitabine)
XP: Xeloda (Capecitabine), Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lee et al. 2011 (ARTISTgastric)	2004-2008 	Phase 3 (C)	XP/Capecitabine & RT	Might have shorter DFS (primary endpoint)DFS36: 74.2% vs 78.2%(HR not reported, p=0.0862)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This trial should not be confused for the one by the same name in colorectal cancer.
====Preceding treatment====
*R0 gastrectomy and at least D2 dissection
====Chemotherapy====
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 6 cycles
===References===
#ARTIST: Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, Lim HY, Choi MG, Sohn TS, Noh JH, Bae JM, Ahn YC, Sohn I, Jung SH, Park CK, Kim KM, Kang WK. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012 Jan 20;30(3):268-73. Epub 2011 Dec 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00323830
##Update: Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, Sohn I, Jung SH, Choi MG, Lee JH, Bae JM, Kim S, Kim ST, Park JO, Park YS, Lim HY, Kang WK. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: Final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015 Oct 1;33(28):3130-6. Epub 2015 Jan 5. link to original article EuroPMC
==Cisplatin & S-1==
SP: S-1 & Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lee et al. 2018 (POST)	2010-2013 	Phase 3 (C)	DS 	Did not meet primary endpoint of DFS36
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*S-1 35 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 8 cycles
===References===
#POST: Lee CK, Jung M, Kim HS, Jung I, Shin DB, Kang SY, Zang DY, Kim KH, Lee MH, Kim BS, Lee KH, Cheong JH, Hyung WJ, Noh SH, Chung HC, Rha SY. S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial. Cancer Res Treat. 2019 Jan;51(1):1-11. Epub 2018 Feb 5. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01283217
==Docetaxel & S-1==
DS: Docetaxel & S-1
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lee et al. 2018 (POST)	2010-2013 	Phase 3 (E-switch-ic)	SP 	Did not meet primary endpoint of DFS36
====Preceding treatment====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) 35 mg/m2 IV once per day on days 1 & 8
*S-1 35 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 8 cycles
===Regimen variant #2, 40/80===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Yoshida et al. 2019 (JACCRO GC-07)	2013-2017 	Phase 3 (E-esc)	S-1 	Higher RFS36 (primary endpoint)RFS36: 66% vs 50%(HR 0.632, 99.99% CI 0.40-0.998)Longer OS1 (secondary endpoint)OS36: 77.7% vs 71.2%(HR 0.74, 95% CI 0.60-0.925)
1Reported efficacy is based on the 2021 update.
Note: this dosing was for BSA less than 1.25 mg/m2.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) as follows:
**Cycles 2 to 7: 40 mg/m2 IV once on day 1
*S-1 as follows:
**Cycles 1 to 7: 40 mg/m2 PO twice per day on days 1 to 14
**Cycles 8 to 12: 40 mg/m2 PO twice per day on days 1 to 28
21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)
===Regimen variant #3, 40/100===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Yoshida et al. 2019 (JACCRO GC-07)	2013-2017 	Phase 3 (E-esc)	S-1 	Higher RFS36 (primary endpoint)RFS36: 66% vs 50%(HR 0.632, 99.99% CI 0.40-0.998)Longer OS1 (secondary endpoint)OS36: 77.7% vs 71.2%(HR 0.74, 95% CI 0.60-0.925)
1Reported efficacy is based on the 2021 update.
Note: this dosing was for BSA between 1.25 to 1.5 mg/m2.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) as follows:
**Cycles 2 to 7: 40 mg/m2 IV once on day 1
*S-1 as follows:
**Cycles 1 to 7: 50 mg/m2 PO twice per day on days 1 to 14
**Cycles 8 to 12: 50 mg/m2 PO twice per day on days 1 to 28
21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)
===Regimen variant #4, 40/120===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Yoshida et al. 2019 (JACCRO GC-07)	2013-2017 	Phase 3 (E-esc)	S-1 	Higher RFS36 (primary endpoint)RFS36: 66% vs 50%(HR 0.632, 99.99% CI 0.40-0.998)Longer OS1 (secondary endpoint)OS36: 77.7% vs 71.2%(HR 0.74, 95% CI 0.60-0.925)
1Reported efficacy is based on the 2021 update.
Note: this dosing was for BSA greater than 1.5 mg/m2.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) as follows:
**Cycles 2 to 7: 40 mg/m2 IV once on day 1
*S-1 as follows:
**Cycles 1 to 7: 60 mg/m2 PO twice per day on days 1 to 14
**Cycles 8 to 12: 60 mg/m2 PO twice per day on days 1 to 28
21-day cycle for 7 cycles, then 42-day cycle for up to 5 cycles (1 year total)
===References===
#POST: Lee CK, Jung M, Kim HS, Jung I, Shin DB, Kang SY, Zang DY, Kim KH, Lee MH, Kim BS, Lee KH, Cheong JH, Hyung WJ, Noh SH, Chung HC, Rha SY. S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial. Cancer Res Treat. 2019 Jan;51(1):1-11. Epub 2018 Feb 5. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01283217
#JACCRO GC-07: Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019 May 20;37(15):1296-1304. Epub 2019 Mar 29. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000010337
##Update: Kakeji Y, Yoshida K, Kodera Y, Kochi M, Sano T, Ichikawa W, Lee SW, Shibahara K, Shikano T, Kataoka M, Ishiguro A, Ojima H, Sakai Y, Musha N, Takase T, Kimura T, Takeuchi M, Fujii M. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer. 2022 Jan;25(1):188-196. Epub 2021 Aug 5. link to original article EuroPMC
==FP/Capecitabine & RT==
FP/Capecitabine & RT: Fluorouracil & Platinol (Cisplatin) alternating with Capecitabine & Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence
Lee et al. 2006	Not reported 	Phase 2
Note: In contrast to the primary reference, some guidelines list this regimen without FP cycles 1, 3, 4, 5. Dosage of Capecitabine (Xeloda) was listed as 625 to 825 mg/m2 PO twice per day on days 1 to 5 or 1 to 7 while radiation is being given. 
====Preceding treatment====
*Surgery, 3 weeks prior
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1, 3, 4, 5: 60 mg/m2 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1, 3, 4, 5: 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2)
*Capecitabine (Xeloda) as follows:
**Cycle 2 (chemoradiation): 825 mg/m2 PO twice per day on days 1 to 35
====Radiotherapy====
*Concurrent radiation therapy during cycle 2: 180 cGy fractions x 25 fractions (total dose of 4500 cGy)
21-day course, then 9-week course, then 21-day cycle for 3 cycles
===References===
#Lee HS, Choi Y, Hur WJ, Kim HJ, Kwon HC, Kim SH, Kim JS, Lee JH, Jung GJ, Kim MC. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006 Jan 28;12(4):603-7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==FULV==
FULV: 5-FU & LeucoVorin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Bajetta et al. 2014 (ITACA-S)	2005-2009 	Phase 3 (C)	FOLFIRI-DC	Did not meet primary endpoint of DFS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m2)
*Leucovorin (Folinic acid) 100 mg/m2 IV over 2 hours once per day on days 1 & 2
14-day cycle for 9 cycles
===References===
#Kim TH, Park SR, Ryu KW, Kim YW, Bae JM, Lee JH, Choi IJ, Kim YJ, Kim DY. Phase 3 trial of postoperative chemotherapy alone versus chemoradiation therapy in stage III-IV gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. Int J Radiat Oncol Biol Phys. 2012 Dec 1;84(5):e585-92. Epub 2012 Sep 11. link to original article EuroPMC
#ITACA-S: Bajetta E, Floriani I, Di Bartolomeo M, Labianca R, Falcone A, Di Costanzo F, Comella G, Amadori D, Pinto C, Carlomagno C, Nitti D, Daniele B, Mini E, Poli D, Santoro A, Mosconi S, Casaretti R, Boni C, Pinotti G, Bidoli P, Landi L, Rosati G, Ravaioli A, Cantore M, Di Fabio F, Aitini E, Marchet A; ITACA-S (Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach Trial) Study Group. Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol. 2014 Jul;25(7):1373-1378. Epub 2014 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01640782
==FULV/FULV & RT==
FULV/FULV & RT: FluoroUracil & LeucoVorin alternating with FluoroUracil, LeucoVorin, Radiation Therapy
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Macdonald et al. 2001 (INT-0116)	1991-1998 	Phase 3 (E-esc) 	Surgery alone	Longer OS (primary endpoint)Median OS: 36 vs 27 mo(HR 0.74, 95% CI 0.60-0.92)
Kim et al. 2012 	2002-05-06 to 2006-06-29	Phase 3 (E-switch-ooc)	FULV 	Did not meet primary endpoint of DFSDFS60: 60.9% vs 50%(HR not reported)
Fuchs et al. 2017 (CALGB 80101) 	2002-2009 	Phase 3 (C) 	ECF/FULV & RT	Did not meet primary endpoint of OSOS60: 44% vs 44%(aHR 1.02, 95% CI 0.81-1.28)
Treatment is to start 20 to 40 days after surgery.
Note: INT-0116 included patients with GE junction malignancy as well (20% GE junction) and included patients with a performance status of 2. 
====Preceding treatment====
*INT-0116: Surgery with R0 resection (10% underwent D2 dissection, 36% underwent D1 dissection and 54% underwent D0 dissection)
*CALGB 80101: Surgery
====Chemotherapy====
*Fluorouracil (5-FU) as follows:
**Cycles 1, 3, 4: 425 mg/m2 IV bolus once per day on days 1 to 5
**Cycle 2 (chemoradiation): 400 mg/m2 IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
*Leucovorin (Folinic acid) as follows:
**Cycles 1, 3, 4: 20 mg/m2 IV bolus once per day on days 1 to 5
**Cycle 2 (chemoradiation): 20 mg/m2 IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
====Radiotherapy====
*Concurrent radiation therapy during cycle 2: 180 cGy x 25 fractions (total 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 abstract have been reviewed by our editors EuroPMC
##Update: Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. link to original article link to PMC article EuroPMC
#Kim TH, Park SR, Ryu KW, Kim YW, Bae JM, Lee JH, Choi IJ, Kim YJ, Kim DY. Phase 3 trial of postoperative chemotherapy alone versus chemoradiation therapy in stage III-IV gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. Int J Radiat Oncol Biol Phys. 2012 Dec 1;84(5):e585-92. Epub 2012 Sep 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#CALGB 80101: Fuchs CS, Niedzwiecki D, Mamon HJ, Tepper JE, Ye X, Swanson RS, Enzinger PC, Haller DG, Dragovich T, Alberts SR, Bjarnason GA, Willett CG, Gunderson LL, Goldberg RM, Venook AP, Ilson D, O'Reilly E, Ciombor K, Berg DJ, Meyerhardt J, Mayer RJ. Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance). J Clin Oncol. 2017 Nov 10;35(32):3671-3677. Epub 2017 Oct 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00052910
==S-1 monotherapy==
===Regimen variant #1, 21-day cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tsuburaya et al. 2014 (SAMIT)	2004-2009 	Phase 3 (C)	1. Paclitaxel, then S-12. Paclitaxel, then UFT	Did not meet primary endpoint of DFS
Tsuburaya et al. 2014 (SAMIT)	2004-2009 	Phase 3 (C)	3. UFT 	Longer DFSDFS36: 58.2% vs 53%(HR 0.81, 95% CI 0.70-0.93)
====Preceding treatment====
*R0 or R1 gastrectomy with at least D2 dissection, within 2 to 8 weeks
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) 80 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 16 cycles (1 year)
===Regimen variant #2, 42-day cycles===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sakuramoto et al. 2007 (ACTS-GC) 	2001-2004 	Phase 3 (E-esc)	Observation 	Longer OS1 (primary endpoint)OS60: 72% vs 61%(HR 0.67, 95% CI 0.54-0.83)
Yoshikawa et al. 2019 (OPAS-1) 	2012-2017 	Phase 3 (C) 	S-1 x 6 mo 	Inconclusive whether non-inferior RFS
Yoshida et al. 2019 (JACCRO GC-07)	2013-2017 	Phase 3 (C) 	Docetaxel & S-1 	Lower RFS36 (primary endpoint)RFS36: 50% vs 66%(HR 1.58, 99.99% CI 1.00-2.50)Shorter OS2 (secondary endpoint)OS36: 71.2% vs 77.7%(HR 1.35, 95% CI 1.08-1.67)
Park et al. 2020 (ARTIST 2) 	2013-2018 	Phase 3 (C) 	1. SOX 	Seems to have shorter DFS
Park et al. 2020 (ARTIST 2) 	2013-2018 	Phase 3 (C) 	2. SOXRT 	Might have shorter DFS
Kang et al. 2024 (ATTRACTION-5) 	2017-02-01 to 2019-08-15	Phase 3 (C) 	1a. S-1 & Nivolumab1b. CapeOx & Nivolumab	Did not meet primary endpoint of RFSRFS36: 65.3% vs 68.4%(HR 1.11, 95.72% CI 0.85-1.45)
1Reported efficacy for ACTS-GC is based on the 2011 update.
2Reported efficacy for JACCRO GC-07 is based on the 2021 update.
====Eligibility criteria====
*ACTS-GC, ARTIST 2, JACCRO GC-07: Stage II or III gastric cancer
*OPAS-1: Stage II gastric cancer
*ATTRACTION-5: Stage IIIA to IIIC gastric or GEJ cancer
====Preceding treatment====
*R0 gastrectomy with at least D2 dissection, within 6 weeks
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 28
**Between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 28
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 28
42-day cycle for 8 cycles (1 year)
===References===
#ACTS-GC: Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007 Nov 1;357(18):1810-20. Erratum in: N Engl J Med. 2008 May 1;358(18):1977. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00152217
##Update: Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. link to original article EuroPMC
#SAMIT: Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN C000000082
#OPAS-1: Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Fukushima N, Hato S, Choda Y, Yabusaki H, Yoshida K, Ito S, Takeno A, Yasuda T, Kawachi Y, Katayama H, Fukuda H, Boku N, Sano T, Sasako M. Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104[OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial. Lancet Gastroenterol Hepatol. 2019 Mar;4(3):208-216. Epub 2019 Jan 22. Erratum in: Lancet Gastroenterol Hepatol. 2019 Apr;4(4):e3. link to original article EuroPMC UMIN000007306
##Update: Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Nomura T, Hato S, Choda Y, Yabusaki H, Yoshida K, Misawa K, Masuzawa T, Tsuda M, Kawachi Y, Katayama H, Fukuda H, Kurokawa Y, Boku N, Sano T, Sasako M. 5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer. Gastric Cancer. 2024 Jan;27(1):155-163. Epub 2023 Nov 21. link to original article EuroPMC
#JACCRO GC-07: Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019 May 20;37(15):1296-1304. Epub 2019 Mar 29. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000010337
##Update: Kakeji Y, Yoshida K, Kodera Y, Kochi M, Sano T, Ichikawa W, Lee SW, Shibahara K, Shikano T, Kataoka M, Ishiguro A, Ojima H, Sakai Y, Musha N, Takase T, Kimura T, Takeuchi M, Fujii M. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer. 2022 Jan;25(1):188-196. Epub 2021 Aug 5. link to original article EuroPMC
#ARTIST 2: Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH, Shin DB, Yu JI, Kim KM, An JY, Choi MG, Lee JH, Kim S, Hong JY, Park JO, Park YS, Lim HY, Bae JM, Kang WK; ARTIST 2 investigators. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021 Mar;32(3):368-374. Epub 2020 Dec 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01761461
#ATTRACTION-5: Kang YK, Terashima M, Kim YW, Boku N, Chung HC, Chen JS, Ji J, Yeh TS, Chen LT, Ryu MH, Kim JG, Omori T, Rha SY, Kim TY, Ryu KW, Sakuramoto S, Nishida Y, Fukushima N, Yamada T, Bai LY, Hirashima Y, Hagihara S, Nakada T, Sasako M. Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2024 Aug;9(8):705-717. Epub 2024 Jun 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03006705
#HKIT-GC: NCT00216034
==SOX==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wang et al. 2024 (RESONANCE)	2012-09-01 to 2019-07-01	Phase 3 (C) 	Perioperative SOX	Seems to have lower DFS36 (primary endpoint)DFS36: 53.8% vs 61.7%(HR 1.32, 95% CI 1.04-1.64)
Park et al. 2020 (ARTIST 2) 	2013-2018 	Phase 3 (E-esc)	1. S-1 	Seems to have longer DFS (primary endpoint)DFS36: 74.3% vs 64.8%(HR 0.69, 95% CI 0.41-0.99)
Park et al. 2020 (ARTIST 2) 	2013-2018 	Phase 3 (E-esc)	2. SOXRT 	Did not meet primary endpoint of DFS
====Preceding treatment====
*R0 or R1 gastrectomy with at least D2 dissection
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycle for up to 8 cycles (6 months)
===References===
#ARTIST 2: Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH, Shin DB, Yu JI, Kim KM, An JY, Choi MG, Lee JH, Kim S, Hong JY, Park JO, Park YS, Lim HY, Bae JM, Kang WK; ARTIST 2 investigators. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021 Mar;32(3):368-374. Epub 2020 Dec 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01761461
#TOTTG030103: Zhao Q, Lian C, Huo Z, Li M, Liu Y, Fan L, Tan B, Zhao X, Zhang Z, Wang D, Liu Y, Guo H, Yang P, Tian Y, Li Y. The efficacy and safety of neoadjuvant chemotherapy on patients with advanced gastric cancer: A multicenter randomized clinical trial. Cancer Med. 2020 Aug;9(16):5731-5745. Epub 2020 Jun 24. link to original article link to PMC article EuroPMC NCT01516944
#RESONANCE: Wang X, Lu C, Wei B, Li S, Li Z, Xue Y, Ye Y, Zhang Z, Sun Y, Liang H, Li K, Zhu L, Zheng Z, Zhou Y, He Y, Li F, Wang X, Liang P, Huang H, Li G, Shen X, Ji J, Tang Y, Xu Z, Chen L; RESONANCE study group. Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial. J Hematol Oncol. 2024 Apr 8;17(1):17. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01583361
==UFT monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Nakajima et al. 2007 (NSAS-GC)	1997-2001 	Phase 3 (E-esc)	Observation	Longer OS (primary endpoint)OS60: 86% vs 73%(HR 0.48, 95% CI 0.26-0.89)
====Preceding treatment====
*Gastrectomy, with complete (R0) D2 dissection
====Chemotherapy====
*Tegafur and uracil (UFT) 360 mg/m2 PO once per day on days 1 to 5
7-day cycle for 70 cycles (16-month course)
===References===
#NSAS-GC: Nakajima T, Kinoshita T, Nashimoto A, Sairenji M, Yamaguchi T, Sakamoto J, Fujiya T, Inada T, Sasako M, Ohashi Y; National Surgical Adjuvant Study of Gastric Cancer Group. Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg. 2007 Dec;94(12):1468-76. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00152243
#SAMIT: Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. link to original article EuroPMC UMIN C000000082
=Metastatic or locally advanced disease, first-line=
==Capecitabine monotherapy==
X: Xeloda (Capecitabine)
===Regimen variant #1, 2000 mg/m2/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hwang et al. 2017 (SMC 2010-04-118)	2010-2014 	Phase 3 (C)	XELOX 	Did not meet primary endpoint of OSMedian OS: 6.3 vs 11.1 mo(HR 1.72, 95% CI 0.89-3.33)
Lee et al. 2023 (KCSG ST13-10) 	2014-02 to 2019-01 	Phase 3 (C)	1a. mFOLFOX61b. CapeOx1c. Cisplatin & S-11d. CX	Did not meet primary endpoint of OSMedian OS: 7.5 vs 11.5 mo(HR 1.16, 95% CI 0.77-1.79)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Eligibility criteria====
*KCSG ST13-10: CrCl at least 60 mL/min
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===Regimen variant #2, 2500 mg/m2/day===
Study 	Dates of enrollment	Evidence
Hong et al. 2004	Not reported 	Phase 2
====Eligibility criteria====
*Karnofsky status of at least 70%
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycle for up to 6 cycles
===References===
#Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep;15(9):1344-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#SMC 2010-04-118: Hwang IG, Ji JH, Kang JH, Lee HR, Lee HY, Chi KC, Park SW, Lee SJ, Kim ST, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017 May;8(3):170-175. Epub 2017 Jan 21. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01470742
#KCSG ST13-10: Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS. A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10). Cancer Res Treat. 2022 Oct;55(4):1250-1260. Epub 2023 May 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02114359
==Capecitabine & Cisplatin (CX)==
CX: Cisplatin, Xeloda (Capecitabine)
XP: Xeloda (Capecitabine), Platinol (Cisplatin)
===Regimen variant #1, 6 cycles===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Ohtsu et al. 2011 (AVAGAST)	2007-09 to 2008-12 	Phase 3 (C)	CX & Bevacizumab 	Might have shorter OS (primary endpoint)Median OS: 10.1 vs 12.1 mo(HR 1.15, 95% CI 0.97-1.37)
Shen et al. 2014 (AVATAR) 	2009-03-25 to 2010-07-12	Phase 3 (C)	CX & Bevacizumab 	Did not meet primary endpoint of OSOS12: 48% vs 45%(HR 0.90, 95% CI 0.64-1.27)
Lu et al. 2018 (PAC-C) 	2009-2014 	Phase 3 (C)	Capecitabine & Paclitaxel	Did not meet primary endpoint of PFSMedian PFS: 5.3 vs 5.0 mo(HR 0.91, 95% CI 0.71-1.16)
Note: The following studies included patients with GE junction malignancy as well: 
*AVAGAST patients: 86% gastric and 14% GE junction. 5.4% of patients had an ECOG PS of 2.
====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
====Supportive therapy====
*Some protocols: "Hyperhydration" for cisplatin
21-day cycle for 6 cycles
====Subsequent treatment====
*AVAGAST & AVATAR: Capecitabine maintenance
===Regimen variant #2, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kim et al. 2014 (SMC 2008-12-019)	2009-2012 	Phase 3 (C)	CX & Simvastatin	Did not meet primary endpoint of PFSMedian PFS: 4.63 vs 5.2 mo(HR 1.08, 95% CI 0.79-1.46)
Note: The following studies included patients with GE junction malignancy as well: 
*SMC 2008-12-019 patients: 79% gastric, 16% GE junction and 5% unknown
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 8 cycles
====Subsequent treatment====
*Capecitabine maintenance
===Regimen variant #3, indefinite===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kang et al. 2009 (ML17032) 	2003-2005 	Phase 3 (E-switch-ic)	CF 	Non-inferior PFS (primary endpoint)Median PFS: 5.6 vs 5 mo(HR 0.81, 95% CI 0.63-1.04)
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)
Fuchs et al. 2019 (RAINFALL)	2015-01-28 to 2016-09-16	Phase 3 (C) 	CX & Ramucirumab	Shorter PFS1 (primary endpoint)Median PFS: 5.4 vs 5.7 mo(HR 1.33, 95% CI 1.07-1.65)
1while the primary analysis of RAINFALL showed that this arm had shorter PFS, independent central review did not confirm this finding.
The following studies included patients with GE junction malignancy as well: 
*EXPAND patients: 83% gastric, 5% GE junction and 16% unknown
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV over 2 hours once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
**Alternate dosing in EXPAND: 1000 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
====Supportive therapy====
*Some protocols: "Hyperhydration" for cisplatin
21-day cycles
===References===
#ML17032: Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC content property of HemOnc.org NCT02563054
#AVAGAST: Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00548548
#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
#AVATAR: Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, Xu R, Chen L, Liu Y, Yu S, Bu L, Piao Y. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015 Jan;18(1):168-76. Epub 2014 Feb 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00887822
#SMC 2008-12-019: Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01099085
#PAC-C: Lu Z, Zhang X, Liu W, Liu T, Hu B, Li W, Fan Q, Xu J, Xu N, Bai Y, Pan Y, Xu Q, Bai W, Xia L, Gao Y, Wang W, Shu Y, Shen L. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018 Sep;21(5):782-791. Epub 2018 Feb 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01015339
#RAINFALL: Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):420-435. Epub 2019 Feb 1. Erratum in: Lancet Oncol. 2019 May;20(5):e242. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02314117
==Capecitabine & Cisplatin (CX) & Pembrolizumab==
CX & Pembrolizumab: Cisplatin, Xeloda (Capecitabine), Pembrolizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shitara et al. 2020 (KEYNOTE-062)	2015-2017 	Phase 3 (E-esc)	1a. CF1b. CX 	Might have longer OS1 (co-primary endpoint)Median OS: 12.5 vs 11.1 mo(HR 0.85, 95% CI 0.70-1.03)
Shitara et al. 2020 (KEYNOTE-062)	2015-2017 	Phase 3 (E-esc)	2. Pembrolizumab	Not reported
1Reported efficacy is for patients with CPS of 1 or greater.
Note: KEYNOTE-062 included patients with GEJ malignancy.
====Biomarker eligibility criteria====
PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycles
===References===
#KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02494583
##HRQoL analysis: Van Cutsem E, Valderrama A, Bang YJ, Fuchs CS, Shitara K, Janjigian YY, Qin S, Larson TG, Shankaran V, Stein S, Norquist JM, Kher U, Shah S, Alsina M. Quality of life with first-line pembrolizumab for PD-L1-positive advanced gastric/gastroesophageal junction adenocarcinoma: results from the randomised phase III KEYNOTE-062 study. ESMO Open. 2021 Aug;6(4):100189. link to original article link to EuroPMC
==CapeOx==
CapeOX: Capecitabine & OXaliplatin
===Regimen variant #1, 750/78===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hall et al. 2021 (GO2)	2014-2017 	Phase 3 (E-de-esc)	1. CapeOx; 1000/104	Not reported
Hall et al. 2021 (GO2)	2014-2017 	Phase 3 (E-de-esc)	2. CapeOx; 1250/130	Non-inferior PFS (primary endpoint)(HR 1.10, 95% CI 0.90-1.33)
====Chemotherapy====
*Capecitabine (Xeloda) 375 mg/m2 PO twice per day
*Oxaliplatin (Eloxatin) 78 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 1000/104===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hall et al. 2021 (GO2)	2014-2017 	Phase 3 (E-de-esc)	1. CapeOx; 750/78 	Not reported
Hall et al. 2021 (GO2)	2014-2017 	Phase 3 (E-de-esc)	2. CapeOx; 1250/130	Non-inferior PFS (primary endpoint)(HR 1.09, 95% CI 0.89-1.32)
====Chemotherapy====
*Capecitabine (Xeloda) 500 mg/m2 PO twice per day
*Oxaliplatin (Eloxatin) 104 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #3, 1250/130===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hall et al. 2021 (GO2)	2014-2017 	Phase 3 (C)	1. CapeOx; 750/782. CapeOx; 1000/104	Non-inferior PFS
====Chemotherapy====
*Capecitabine (Xeloda) 625 mg/m2 PO twice per day
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #4, 1700/130===
Study 	Dates of enrollment	Evidence
Jatoi et al. 2006	2002-2004 	Phase 2
====Chemotherapy====
*Capecitabine (Xeloda) 850 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #5, 2000/130===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Moehler et al. 2020 (JAVELIN Gastric 100)	2015-2017 	Phase 3 (C)	1a. CapeOx-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)
Kang et al. 2022 (ATTRACTION-4) 	2017-03-23 to 2018-05-10	Phase 3 (C)	1a. CapeOx & Nivolumab1b. SOX & Nivolumab 	Shorter PFS1 (co-primary endpoint)Median PFS: 8.48 vs 10.94 mo(HR 1.49, 95% CI 1.22-1.82)Might have shorter OS1 (co-primary endpoint)Median OS: 17.15 vs 17.45 mo(HR 1.12, 95% CI 0.95-1.33)
Janjigian et al. 2021 (CheckMate 649) 	2017-03 to 2019-04 	Phase 3 (C)	1a. CapeOx & Nivolumab1b. mFOLFOX6 & Nivolumab 	Shorter OSMedian OS: 11.1 vs 14.4 mo(HR 1.43, 95% CI 1.23-1.64)
Janjigian et al. 2021 (CheckMate 649) 	2017-03 to 2019-04 	Phase 3 (C)	2. Ipilimumab & Nivolumab 	Not reported
Qiu et al. 2024 (RATIONALE-305) 	2018-12-13 to 2021-02-09	Phase 3 (C)	1a. CapeOx & Tislelizumab1b. CF & Tislelizumab 	Shorter OSMedian OS: 12.9 vs 15 mo(HR 1.25, 95% CI 1.09-1.43)
Rha et al. 2023 (KEYNOTE-859) 	2018-11-08 to 2021-06-11	Phase 3 (C)	1a. CapeOx & Pembrolizumab1b. CF & Pembrolizumab 	Shorter OSMedian OS: 11.5 vs 12.9 mo(HR 1.28, 95% CI 1.15-1.43)
Xu et al. 2023 (ORIENT-16) 	2019-01-03 to 2020-08-05	Phase 3 (C)	CapeOx & Sintilimab 	Shorter OS (primary endpoint)Median OS: 12.3 vs 15.2 mo(HR 1.30, 95% CI 1.06-1.59)
Ramaswamy et al. 2024 	2020-07-15 to 2022-11-10	Phase 3 (C)	1a. DOF1b. DOX 	Might have shorter OS (primary endpoint)RMST: 8.57 vs 8.97 mo(RMST ratio 1.05, 95% CI 0.96-1.14)
1Reported efficacy for ATTRACTION-4 is based on the 2024 update.
====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 cycle for varying durations: 6 cycles (ORIENT-16, RATIONALE-305); 8 cycles (Ramaswamy et al. 2024); indefinitely (ATTRACTION-4, CheckMate 649, JAVELIN Gastric 100, KEYNOTE-859)
====Subsequent treatment====
*RATIONALE-305: Optional Capecitabine maintenance
*ORIENT-16: Capecitabine maintenance
===Regimen variant #6, 2000/130, limited oxaliplatin===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Zhu et al. 2022 (EXELOX) 	2015-2020 	Phase 3 (E-de-esc)	EOX 	Non-inferior PFS (primary endpoint)Median PFS: 5 vs 5.5 mo(HR 0.989, 95% CI 0.81-1.20)
Shah et al. 2023 (GLOWgastric)	2018-11-28 to 2022-02-18	Phase 3 (C) 	CapeOx & Zolbetuximab	Shorter PFS (primary endpoint)Median PFS: 6.8 vs 8.21 mo(HR 1.45, 95% CI 1.15-1.85)Seems to have shorter OS (secondary endpoint)Median OS: 12.16 vs 14.39 mo(HR 1.30, 95% CI 1.03-1.61)
Note: GLOW should not be confused by the trial of the same name in CLL. In GLOW, continuation of capecitabine past cycle 8 was at the investigator's discretion.
====Biomarker eligibility criteria====
*GLOWgastric: CLDN18.2 positive
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) as follows:
**Cycles 1 up to 8: 130 mg/m2 IV once on day 1
21-day cycles
===References===
#Jatoi A, Murphy BR, Foster NR, Nikcevich DA, Alberts SR, Knost JA, Fitch TR, Rowland KM Jr; North Central Cancer Treatment Group. Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group. Ann Oncol. 2006 Jan;17(1):29-34. Epub 2005 Nov 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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
#GO2: Hall PS, Swinson D, Cairns DA, Waters JS, Petty R, Allmark C, Ruddock S, Falk S, Wadsley J, Roy R, Tillett T, Nicoll J, Cummins S, Mano J, Grumett S, Stokes Z, Kamposioras KV, Chatterjee A, Garcia A, Waddell T, Guptal K, Maisey N, Khan M, Dent J, Lord S, Crossley A, Katona E, Marshall H, Grabsch HI, Velikova G, Ow PL, Handforth C, Howard H, Seymour MT; GO2 Trial Investigators. Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Jun 1;7(6):869-877. Erratum in: JAMA Oncol. 2021 Aug 1;7(8):1249. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN44687907
#ATTRACTION-4: Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):234-247. Epub 2022 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02746796
##Update: Boku N, Omori T, Shitara K, Sakuramoto S, Yamaguchi K, Kato K, Kadowaki S, Tsuji K, Ryu MH, Oh DY, Oh SC, Rha SY, Lee KW, Chung IJ, Sym SJ, Chen LT, Chen JS, Bai LY, Nakada T, Hagihara S, Makino R, Nishiyama E, Kang YK. Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial. Gastric Cancer. 2024 Nov;27(6):1287-1301. Epub 2024 Aug 20. link to original article link to PMC article EuroPMC
#EXELOX: Zhu XD, Huang MZ, Wang YS, Feng WJ, Chen ZY, He YF, Zhang XW, Liu X, Wang CC, Zhang W, Ying JE, Wu J, Yang L, Qin YR, Luo JF, Zhao XY, Li WH, Zhang Z, Qiu LX, Geng QR, Zou JL, Zhang JY, Zheng H, Song XF, Wu SS, Zhang CY, Gong Z, Liu QQ, Wang XF, Xu Q, Wang Q, Ji JM, Zhao J, Guo WJ. XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX). Cancer Commun (Lond). 2022 Apr;42(4):314-326. Epub 2022 Feb 25. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02395640
#GLOWgastric: Shah MA, Shitara K, Ajani JA, Bang YJ, Enzinger P, Ilson D, Lordick F, Van Cutsem E, Gallego Plazas J, Huang J, Shen L, Oh SC, Sunpaweravong P, Soo Hoo HF, Turk HM, Oh M, Park JW, Moran D, Bhattacharya P, Arozullah A, Xu RH. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023 Aug;29(8):2133-2141. Epub 2023 Jul 31. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03653507
##Pooled HRQoL analysis: Lordick F, Van Cutsem E, Shitara K, Xu RH, Ajani JA, Shah MA, Oh M, Ganguli A, Chang L, Rhoten S, Bhattacharya P, Matsangou M, Park JW, Pophale R, Ranganath R, Kang YK. Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials. ESMO Open. 2024 Aug;9(8):103663. Epub 2024 Aug 14. link to original article link to PMC article EuroPMC
#KEYNOTE-859: Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03675737
#ORIENT-16: Xu J, Jiang H, Pan Y, Gu K, Cang S, Han L, Shu Y, Li J, Zhao J, Pan H, Luo S, Qin Y, Guo Q, Bai Y, Ling Y, Yang J, Yan Z, Yang L, Tang Y, He Y, Zhang L, Liang X, Niu Z, Zhang J, Mao Y, Guo Y, Peng B, Li Z, Liu Y, Wang Y, Zhou H; ORIENT-16 Investigators. Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial. JAMA. 2023 Dec 5;330(21):2064-2074. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03745170
#RATIONALE-305: Qiu MZ, Oh DY, Kato K, Arkenau T, Tabernero J, Correa MC, Zimina AV, Bai Y, Shi J, Lee KW, Wang J, Poddubskaya E, Pan H, Rha SY, Zhang R, Hirano H, Spigel D, Yamaguchi K, Chao Y, Wyrwicz L, Disel U, Cid RP, Fornaro L, Evesque L, Wang H, Xu Y, Li J, Sheng T, Yang S, Li L, Moehler M, Xu RH; RATIONALE-305 Investigators. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024 May 28;385:e078876. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03777657
#Ramaswamy A, Bhargava P, Dubashi B, Gupta A, Kapoor A, Srinivas S, Shetty O, Jadhav P, Desai V, Noronha V, Joshi A, Menon N, Patil VM, Mishra BK, Sansar B, Singh A, Patel S, Singh SN, Dhal I, Vinayak KR, Pal V, Mandavkar S, Kannan S, Chaugule D, Patil R, Parulekar M, Nashikkar C, Ankathi SK, Kaushal RK, Shah A, Ganesan P, Kayal S, Ananthakrishnan R, Syed N, Samaddar D, Kapu V, Shah A, Kaaviya D, Suganiya R, Srinivasan ND, Prabhash K, Ostwal V. Docetaxel-oxaliplatin-capecitabine/5-fluorouracil (DOX/F) followed by docetaxel versus oxaliplatin-capecitabine/5-fluorouracil (CAPOX/FOLFOX) in HER2-negative advanced gastric cancers. JNCI Cancer Spectr. 2024 Jul 1;8(4):pkae054. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2020/03/023944
==CapeOx & Nivolumab==
CapeOx & Nivolumab: Capecitabine, OXaliplatin, Nivolumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kang et al. 2022 (ATTRACTION-4) 	2017-03-23 to 2018-05-10	Phase 3 (E-esc) 	1a. CapeOx1b. SOX 	Longer PFS1 (co-primary endpoint)Median PFS: 10.94 vs 8.48 mo(HR 0.67, 95% CI 0.55-0.82)Might have longer OS1 (co-primary endpoint)Median OS: 17.45 vs 17.15 mo(HR 0.89, 95% CI 0.75-1.05)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (E-RT-esc)	1a. CapeOx1b. mFOLFOX6 	Longer OS2 (co-primary endpoint)Median OS: 14.4 vs 11.1 mo(HR 0.70, 95% CI 0.61-0.81)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (E-RT-esc)	2. Ipilimumab & Nivolumab	Not reported
1Reported efficacy for ATTRACTION-4 is based on the 2024 update.
2Reported efficacy and MCBS score are for the group with PD-L1 CPS of 5 or more; reported efficacy is based on the 2022 update.
====Chemotherapy====
*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 (Opdivo) 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
#ATTRACTION-4: Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):234-247. Epub 2022 Jan 11. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02746796
##Update: Boku N, Omori T, Shitara K, Sakuramoto S, Yamaguchi K, Kato K, Kadowaki S, Tsuji K, Ryu MH, Oh DY, Oh SC, Rha SY, Lee KW, Chung IJ, Sym SJ, Chen LT, Chen JS, Bai LY, Nakada T, Hagihara S, Makino R, Nishiyama E, Kang YK. Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial. Gastric Cancer. 2024 Nov;27(6):1287-1301. Epub 2024 Aug 20. link to original article link to PMC article EuroPMC
==CapeOx & Pembrolizumab==
CapeOx & Pembrolizumab: Capecitabine, OXaliplatin, Pembrolizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Rha et al. 2023 (KEYNOTE-859)	2018-11-08 to 2021-06-11	Phase 3 (E-RT-esc)	1a. CF1b. CapeOx	Longer OS (primary endpoint)Median OS: 12.9 vs 11.5 mo(HR 0.78, 95% CI 0.70-0.87)
KEYNOTE-859 included patients with GEJ malignancy
====Biomarker eligibility criteria====
*PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
====Chemotherapy====
*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====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
#KEYNOTE-859: Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03675737
==CapeOx & Sintilimab==
CapeOX & Sintilimab: Capecitabine, OXaliplatin, Sintilimab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Xu et al. 2023 (ORIENT-16)	2019-01-03 to 2020-08-05	Phase 3 (E-esc)	CapeOx 	Longer OS (primary endpoint)Median OS: 15.2 vs 12.3 mo(HR 0.77, 95% CI 0.63-0.94)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) as follows:
**Cycles 1 to 6: 130 mg/m2 IV once on day 1
====Immunotherapy====
*Sintilimab (Tyvyt) by the following weight-based criteria:
**Less than 60 kg: 3 mg/kg IV once on day 1
**60 kg or more: 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
#ORIENT-16: Xu J, Jiang H, Pan Y, Gu K, Cang S, Han L, Shu Y, Li J, Zhao J, Pan H, Luo S, Qin Y, Guo Q, Bai Y, Ling Y, Yang J, Yan Z, Yang L, Tang Y, He Y, Zhang L, Liang X, Niu Z, Zhang J, Mao Y, Guo Y, Peng B, Li Z, Liu Y, Wang Y, Zhou H; ORIENT-16 Investigators. Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial. JAMA. 2023 Dec 5;330(21):2064-2074. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03745170
==CapeOx & Tislelizumab==
CapeOX & Tislelizumab: Capecitabine, OXaliplatin, Tislelizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Qiu et al. 2024 (RATIONALE-305)	2018-12-13 to 2021-02-09	Phase 3 (E-esc)	1a. CapeOx1b. CF	Longer OS (primary endpoint)Median OS: 15 vs 12.9 mo(HR 0.80, 95% CI 0.70-0.92)
====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====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-305: Qiu MZ, Oh DY, Kato K, Arkenau T, Tabernero J, Correa MC, Zimina AV, Bai Y, Shi J, Lee KW, Wang J, Poddubskaya E, Pan H, Rha SY, Zhang R, Hirano H, Spigel D, Yamaguchi K, Chao Y, Wyrwicz L, Disel U, Cid RP, Fornaro L, Evesque L, Wang H, Xu Y, Li J, Sheng T, Yang S, Li L, Moehler M, Xu RH; RATIONALE-305 Investigators. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024 May 28;385:e078876. link to original article dosing details on CT.gov have been reviewed by our editors EuroPMC NCT03777657
==CapeOx & Zolbetuximab==
CapeOX & Zolbetuximab: Capecitabine, OXaliplatin, Zolbetuximab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Shah et al. 2023 (GLOWgastric)	2018-11-28 to 2022-02-18	Phase 3 (E-RT-esc)	CapeOx 	Longer PFS (primary endpoint)Median PFS: 8.21 vs 6.8 mo(HR 0.69, 95% CI 0.54-0.87)Seems to have longer OS (secondary endpoint)Median OS: 14.39 vs 12.16 mo(HR 0.77, 95% CI 0.62-0.97)
Note: GLOW should not be confused by the trial of the same name in CLL. In GLOW, continuation of capecitabine past cycle 8 was at the investigator's discretion.
====Biomarker eligibility criteria====
*CLDN18.2 positive
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) as follows:
**Cycles 1 up to 8: 130 mg/m2 IV once on day 1
====Targeted therapy====
*Zolbetuximab (Vyloy) as follows:
**Cycle 1: 800 mg/m2 IV once on day 1
**Cycle 2 onwards: 600 mg/m2 IV once on day 1
21-day cycles
===References===
#GLOWgastric: Shah MA, Shitara K, Ajani JA, Bang YJ, Enzinger P, Ilson D, Lordick F, Van Cutsem E, Gallego Plazas J, Huang J, Shen L, Oh SC, Sunpaweravong P, Soo Hoo HF, Turk HM, Oh M, Park JW, Moran D, Bhattacharya P, Arozullah A, Xu RH. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023 Aug;29(8):2133-2141. Epub 2023 Jul 31. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03653507
##Pooled HRQoL analysis: Lordick F, Van Cutsem E, Shitara K, Xu RH, Ajani JA, Shah MA, Oh M, Ganguli A, Chang L, Rhoten S, Bhattacharya P, Matsangou M, Park JW, Pophale R, Ranganath R, Kang YK. Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials. ESMO Open. 2024 Aug;9(8):103663. Epub 2024 Aug 14. link to original article link to PMC article EuroPMC
==Carboplatin & Paclitaxel (CP)==
===Regimen===
Study 	Dates of enrollment 	Evidence	Efficacy
Philip et al. 1997 	Not reported in abstract	Phase 2 	
Gadgeel et al. 2003	1996-2000 	Phase 2 	ORR: 33%, 95% CI 17-54
Note: Philip et al. 1997 included patients with locally advanced metastatic or recurrent esophageal or gastric cancer. The full manuscript was not available for review. 
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1, given second
*Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycles
====Dose and schedule modifications====
*Gadgeel et al. 2003: Carboplatin dose was escalated to AUC 6 in cycle 2 onwards, if the nadir ANC was at least 1000/uL, nadir platelet count was at least 100 x 109/L, and maximum non-hematologic toxicity was grade I or less, not including alopecia or CINV.
*Gadgeel et al. 2003: Paclitaxel dose was escalated to 225 mg/m2 in cycle 2 onwards, if the nadir ANC was at least 1000/uL, nadir platelet count was at least 100 x 109/L, and maximum non-hematologic toxicity was grade I or less, not including alopecia or CINV.
===References===
#Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. dosing details in abstract have been reviewed by our editors EuroPMC
#Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, Philip PA. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003 Feb;26(1):37-41. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Docetaxel (DC)==
DC: Docetaxel, Cisplatin
TC: Taxotere (Docetaxel), Cisplatin
===Regimen variant #1, 75/75===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Roth et al. 2007	1999-2003 	Randomized Phase 2 (E-de-esc)	1. ECF 	Not reported
Roth et al. 2007	1999-2003 	Randomized Phase 2 (E-de-esc)	2. TCF 	Might have lower ORR
Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m2 to 75 mg/m2 based on high incidence of febrile neutropenia.
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 4 hours once on day 1
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
====Supportive therapy====
*3 liters per day "hyperhydration"
*Dexamethasone (Decadron) 8 mg PO given 12 hours & 6 hours prior to docetaxel, then 8 mg PO twice per day for 4 days after docetaxel
*5-HT3 antagonist for emesis prophylaxis
*Growth factor support allowed, such as with Filgrastim (Neupogen)
21-day cycle for up to 8 cycles
===Regimen variant #2, 75/85===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ajani et al. 2005 (V-325)	1998-1999 	Randomized Phase 2 (C)	DCF 	Seems to have lower ORR
Note: patients had 100% adenocarcinoma histology (32% esophagogastric junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70. 
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 1 to 3 hours once on day 1
*Docetaxel (Taxotere) 85 mg/m2 IV over 60 minutes once on day 1
====Supportive therapy====
*Dexamethasone (Decadron) 8 mg PO the night before chemotherapy, the morning of day 1, 1 hour before chemotherapy, the night of day 1, the morning of day 2, and the evening of day 2 (total dose per cycle: 48 mg)
*Dexamethasone (Decadron) 20 mg IV prior to cisplatin and 8 hours after cisplatin
*Ondansetron (Zofran) 8 mg IV prior to cisplatin, 4 hours after cisplatin, and 8 hours after cisplatin
*"Hydration was administered in a standard manner"
21-day cycles
===References===
#V-325: Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol (Cisplatin)
===Regimen variant #1, 60/5000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lee et al. 2009a	2000-2004 	Phase 3 (C)	Fluorouracil & Heptaplatin (FH)	Equivalent OS
Note: this is reported to be an equivalence study but the statistical analysis does not provide details on the definition of equivalence. 
====Chemotherapy====
*Cisplatin (Platinol) 60 mg/m2 IV over 60 minutes once on day 1, given first
*Fluorouracil (5-FU) 1000 mg/m2 IV over 12 hours once per day on days 1 to 5, given second
28-day cycles
===Regimen variant #2, 80/4000 x 8===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ajani et al. 2017 (DIGEST)	2011-2014 	Phase 3 (C)	CS 	Did not meet primary endpoint of OSMedian OS: 6.6 vs 7.5 mo(HR 1.01, 95% CI 0.78-1.32)
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV over 1 to 3 hours once on day 1, given first
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 4000 mg/m2)
====Supportive therapy====
*Some protocols: "Hyperhydration" for cisplatin
21-day cycle for 8 cycles
===Regimen variant #3, 80/4000, indefinite===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kang et al. 2009 (ML17032) 	2003-2005 	Phase 3 (C)	CX 	Non-inferior PFSMedian PFS: 5 vs 5.6 mo(HR 1.23, 95% CI 0.96-1.59)
Shitara et al. 2020 (KEYNOTE-062)	2015-2017 	Phase 3 (C)	1a. CF & Pembrolizumab1b. CX & Pembrolizumab 	Might have shorter OS1
Shitara et al. 2020 (KEYNOTE-062)	2015-2017 	Phase 3 (C)	2. Pembrolizumab 	Non-inferior OS
Qiu et al. 2024 (RATIONALE-305) 	2018-12-13 to 2021-02-09	Phase 3 (C)	1a. CapeOx & Tislelizumab1b. CF & Tislelizumab 	Shorter OSMedian OS: 12.9 vs 15 mo(HR 1.25, 95% CI 1.09-1.43)
Rha et al. 2023 (KEYNOTE-859) 	2018-11-08 to 2021-06-11	Phase 3 (C)	1a. CapeOx & Pembrolizumab1b. CF & Pembrolizumab	Shorter OSMedian OS: 11.5 vs 12.9 mo(HR 1.28, 95% CI 1.15-1.43)
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV over 1 to 3 hours once on day 1, given first
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 4000 mg/m2)
====Supportive therapy====
*Some protocols: "Hyperhydration" for cisplatin
21-day cycles
===Regimen variant #4, 100/4000===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Duffour et al. 2006 (FFCD 9404)	1995-1998 	Phase 3 (C)	FLP 	Inconclusive whether non-inferior ORR
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on either day 1 or 2
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
28-day cycles
===Regimen variant #5, 100/4000, split-dose cisplatin===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ohtsu et al. 2003 (JCOG 9205)	1992-1997 	Phase 3 (E-esc)	1. Fluorouracil	Did not meet primary endpoint of OS
Ohtsu et al. 2003 (JCOG 9205)	1992-1997 	Phase 3 (E-esc)	2. UFTM 	Did not meet primary endpoint of OS
Note: this study included patients with ECOG PS of 2 (9.6%) 
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 to 5
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
28-day cycle for up to 6 cycles
===Regimen variant #6, 100/5000===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Van Cutsem et al. 2006 (TAX 325)	1999-2003 	Phase 3 (C)	DCF 	Seems to have 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 TTP (primary endpoint)Median TTP: 4.2 vs 5 mo(HR 1.23, 95% CI 0.97-1.56)
Ajani et al. 2010 (FLAGS) 	2005-2007 	Phase 3 (C)	CS 	Might have shorter OSMedian OS: 7.9 vs 8.6 mo(HR 1.09, 95% CI 0.95-1.25)
Note: TAX 325 patients had 100% adenocarcinoma histology (22% Esophagogastric junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70. Dank et al patients had 100% adenocarcinoma histology (20% Esophagogastric junction, 80% gastric origin). 96% with metastatic disease. 1% with Karnofsky PS of 70. 
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 1 to 3 hours once on day 1, given first
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 5000 mg/m2)
====Supportive therapy====
*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===
#JCOG 9205: Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; JCOG. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#FFCD 9404: Duffour J, Bouché O, Rougier P, Milan C, Bedenne L, Seitz JF, Buecher B, Legoux JL, Ducreux M, Vetter D, Raoul JL, François E, Ychou M. Safety of cisplatin combined with continuous 5-FU versus bolus 5-FU and leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised trial). Anticancer Res. 2006 Sep-Oct;26(5B):3877-83. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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
#ML17032: Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02563054
#Lee KH, Hyun MS, Kim HK, Jin HM, Yang J, Song HS, Do YR, Ryoo HM, Chung JS, Zang DY, Lim HY, Jin JY, Yim CY, Park HS, Kim JS, Sohn CH, Lee SN. Randomized, multicenter, phase III trial of heptaplatin 1-hour infusion and 5-fluorouracil combination chemotherapy comparing with cisplatin and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer. Cancer Res Treat. 2009 Mar;41(1):12-8. Epub 2009 Mar 31. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
#FLAGS: Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00400179
##Update: Ajani JA, Buyse M, Lichinitser M, Gorbunova V, Bodoky G, Douillard JY, Cascinu S, Heinemann V, Zaucha R, Carrato A, Ferry D, Moiseyenko V. Combination of cisplatin/S-1 in the treatment of patients with advanced gastric or gastroesophageal adenocarcinoma: Results of noninferiority and safety analyses compared with cisplatin/5-fluorouracil in the First-Line Advanced Gastric Cancer Study. Eur J Cancer. 2013 Nov;49(17):3616-24. Epub 2013 Jul 27. link to original article EuroPMC
##PRO analysis: Bodoky G, Scheulen ME, Rivera F, Jassem J, Carrato A, Moiseyenko V, Vynnychenko I, Prausová J, Van Laethem JL, Cascinu S, Ajani JA. Clinical Benefit and Health-Related Quality of Life Assessment in Patients Treated with Cisplatin/S-1 Versus Cisplatin/5-FU: Secondary End Point Results From the First-Line Advanced Gastric Cancer Study (FLAGS). J Gastrointest Cancer. 2015 Jun;46(2):109-17. link to original article EuroPMC
#AVAGAST: Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00548548
#DIGEST: Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01285557
#KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02494583
##HRQoL analysis: Van Cutsem E, Valderrama A, Bang YJ, Fuchs CS, Shitara K, Janjigian YY, Qin S, Larson TG, Shankaran V, Stein S, Norquist JM, Kher U, Shah S, Alsina M. Quality of life with first-line pembrolizumab for PD-L1-positive advanced gastric/gastroesophageal junction adenocarcinoma: results from the randomised phase III KEYNOTE-062 study. ESMO Open. 2021 Aug;6(4):100189. link to original article link to EuroPMC
#KEYNOTE-859: Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03675737
#RATIONALE-305: Qiu MZ, Oh DY, Kato K, Arkenau T, Tabernero J, Correa MC, Zimina AV, Bai Y, Shi J, Lee KW, Wang J, Poddubskaya E, Pan H, Rha SY, Zhang R, Hirano H, Spigel D, Yamaguchi K, Chao Y, Wyrwicz L, Disel U, Cid RP, Fornaro L, Evesque L, Wang H, Xu Y, Li J, Sheng T, Yang S, Li L, Moehler M, Xu RH; RATIONALE-305 Investigators. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024 May 28;385:e078876. link to original article dosing details on CT.gov have been reviewed by our editors EuroPMC NCT03777657
==Cisplatin & Fluorouracil (CF) & Pembrolizumab==
CF & Pembrolizumab: Cisplatin, Fluorouracil, Pembrolizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Shitara et al. 2020 (KEYNOTE-062)	2015-2017 	Phase 3 (E-esc) 	1a. CF1b. CX 	Might have longer OS (co-primary endpoint)Median OS: 12.5 vs 11.1 mo(HR 0.85, 95% CI 0.70-1.03)
Shitara et al. 2020 (KEYNOTE-062)	2015-2017 	Phase 3 (E-esc) 	2. Pembrolizumab	Not reported
Rha et al. 2023 (KEYNOTE-859) 	2018-11-08 to 2021-06-11	Phase 3 (E-RT-esc)	1a. CF1b. CapeOx	Longer OS (primary endpoint)Median OS: 12.9 vs 11.5 mo(HR 0.78, 95% CI 0.70-0.87)
KEYNOTE-062 & KEYNOTE-859 included patients with GEJ malignancy
====Biomarker eligibility criteria====
PD-L1 Combined Positive Score (CPS) of 1 or more as determined by an FDA-approved test
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV 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)
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
===References===
#KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02494583
##HRQoL analysis: Van Cutsem E, Valderrama A, Bang YJ, Fuchs CS, Shitara K, Janjigian YY, Qin S, Larson TG, Shankaran V, Stein S, Norquist JM, Kher U, Shah S, Alsina M. Quality of life with first-line pembrolizumab for PD-L1-positive advanced gastric/gastroesophageal junction adenocarcinoma: results from the randomised phase III KEYNOTE-062 study. ESMO Open. 2021 Aug;6(4):100189. link to original article link to EuroPMC
#KEYNOTE-859: Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Fernández MG, Li J, Lowery MA, Çil T, Cruz FM, Qin S, Luo S, Pan H, Wainberg ZA, Yin L, Bordia S, Bhagia P, Wyrwicz LS; KEYNOTE-859 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Nov;24(11):1181-1195. Epub 2023 Oct 21. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03675737
==Cisplatin & Fluorouracil (CF) & Tislelizumab==
CF & Tislelizumab: Cisplatin, Fluorouracil, Tislelizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Qiu et al. 2024 (RATIONALE-305)	2018-12-13 to 2021-02-09	Phase 3 (E-esc)	1a. CapeOx1b. CF	Longer OS (primary endpoint)Median OS: 15 vs 12.9 mo(HR 0.80, 95% CI 0.70-0.92)
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV 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)
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-305: Qiu MZ, Oh DY, Kato K, Arkenau T, Tabernero J, Correa MC, Zimina AV, Bai Y, Shi J, Lee KW, Wang J, Poddubskaya E, Pan H, Rha SY, Zhang R, Hirano H, Spigel D, Yamaguchi K, Chao Y, Wyrwicz L, Disel U, Cid RP, Fornaro L, Evesque L, Wang H, Xu Y, Li J, Sheng T, Yang S, Li L, Moehler M, Xu RH; RATIONALE-305 Investigators. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024 May 28;385:e078876. link to original article dosing details on CT.gov have been reviewed by our editors EuroPMC NCT03777657
==Cisplatin & S-1==
CS: Cisplatin & S-1
SP: S-1 & Platinol (Cisplatin)
===Regimen variant #1, q3wk ("SP3")===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ryu et al. 2015 (SOS) 	2009-2012 	Phase 3 (E-switch-ic)	Cisplatin & S-1; SP5	Seems to have longer PFS (primary endpoint)Median PFS: 5.5 vs 4.9 mo(HR 0.82, 95% CI 0.68-0.99)
Lee et al. 2020 (SOPP)	2012-2014 	Phase 3 (C) 	SOX 	Non-inferior PFSMedian PFS: 5.7 vs 5.6 mo(HR 1.18, 95% CI 0.93-1.49)
====Chemotherapy====
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===Regimen variant #2, q4wk===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ajani et al. 2010 (FLAGS) 	2005-2007 	Phase 3 (E-switch-ic)	CF 	Might have longer OS (primary endpoint)Median OS: 8.6 vs 7.9 mo(HR 0.92, 95% CI 0.80-1.05)
Ajani et al. 2017 (DIGEST)	2011-2014 	Phase 3 (E-switch-ic)	CF 	Did not meet primary endpoint of OSMedian OS: 7.5 vs 6.6 mo(HR 0.99, 95% CI 0.76-1.28)
Note: This was an experimental arm of a study where the primary endpoint was not met. Included because CS has been shown to be superior in comparison to other regimens (see above).
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 1 to 3 hours once on day 1
*Tegafur, gimeracil, oteracil (S-1) 25 mg/m2 PO twice per day on days 1 to 21
28-day cycles
===Regimen variant #3, q5wk ("SP5")===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Koizumi et al. 2008 (SPIRITS) 	2002-2004 	Phase 3 (E-esc) 	S-1 	Seems to have longer OS (primary endpoint)Median OS: 13 vs 11 mo(HR 0.77, 95% CI 0.61-0.98)
Fujitani et al. 2016 (REGATTA) 	2008-2013 	Non-randomized part of phase 3 RCT	 	
Ryu et al. 2015 (SOS) 	2009-2012 	Phase 3 (C) 	Cisplatin & S-1; SP3 	Seems to have shorter PFSMedian PFS: 4.9 vs 5.5 mo(HR 1.22, 95% CI 1.01-1.47)
Yamada et al. 2014 (G-SOX) 	2010-01 to 2011-10 	Phase 3 (C) 	SOX 	Non-inferior PFSMedian PFS: 5.4 vs 5.5 mo(HR 0.996, 95% CI 0.83-1.19)
Ishigami et al. 2018 (PHOENIX-GC)	2011-2013 	Phase 3 (C) 	IV/IP Paclitaxel & S-1	Might have shorter OS (primary endpoint)Median OS: 15.2 vs 17.7 mo(HR 1.39, 95% CI 0.96-2.04)
Yamada et al. 2019 (JCOG1013) 	2012-2016 	Phase 3 (C) 	DC & S-1 	Did not meet primary endpoint of OSMedian OS: 15.3 vs 14.2 mo(HR 1.01, 95% CI 0.86-1.18)
Kang et al. 2020 (SOLAR) 	2015-01-28 to 2016-12-05	Phase 3 (C) 	Oxaliplatin & TAS-118 	Seems to have shorter OS (primary endpoint)Median OS: 15.1 vs 16 mo(HR 1.20, 95% CI 1.01-1.45)
Note: in REGATTA, there was no difference in outcome amongst patients who did or did not undergo surgery. SPIRITS trial included patients with ECOG PS of 2 (3% of patients).
====Eligibility criteria====
*REGATTA: presence of a single non-curable factor (ex: hepatic, peritoneal, and para-aortic mets), see link for further details
*PHEONIX-GC: patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details
====Preceding treatment====
*REGATTA: Non-laparoscopic gastrectomy with D1 lymphadenectomy versus no surgery; chemotherapy began within 8 weeks of surgery
====Chemotherapy====
*Cisplatin (Platinol) 60 mg/m2 IV once on day 8
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 21
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 21
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 21
35-day cycles
===References===
#SPIRITS: Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00150670
#FLAGS: Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00400179
##Update: Ajani JA, Buyse M, Lichinitser M, Gorbunova V, Bodoky G, Douillard JY, Cascinu S, Heinemann V, Zaucha R, Carrato A, Ferry D, Moiseyenko V. Combination of cisplatin/S-1 in the treatment of patients with advanced gastric or gastroesophageal adenocarcinoma: Results of noninferiority and safety analyses compared with cisplatin/5-fluorouracil in the First-Line Advanced Gastric Cancer Study. Eur J Cancer. 2013 Nov;49(17):3616-24. Epub 2013 Jul 27. link to original article EuroPMC
##PRO analysis: Bodoky G, Scheulen ME, Rivera F, Jassem J, Carrato A, Moiseyenko V, Vynnychenko I, Prausová J, Van Laethem JL, Cascinu S, Ajani JA. Clinical Benefit and Health-Related Quality of Life Assessment in Patients Treated with Cisplatin/S-1 Versus Cisplatin/5-FU: Secondary End Point Results From the First-Line Advanced Gastric Cancer Study (FLAGS). J Gastrointest Cancer. 2015 Jun;46(2):109-17. link to original article EuroPMC
#G-SOX: Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015 Jan;26(1):141-8. Epub 2014 Oct 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-101021
#SOS: Ryu MH, Baba E, Lee KH, Park YI, Boku N, Hyodo I, Nam BH, Esaki T, Yoo C, Ryoo BY, Song EK, Cho SH, Kang WK, Yang SH, Zang DY, Shin DB, Park SR, Shinozaki K, Takano T, Kang YK; SOS study investigators. Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS). Ann Oncol. 2015 Oct;26(10):2097-101. Epub 2015 Jul 27. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00915382
#REGATTA: Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, Iwasaki Y, Hyung WJ, Takagane A, Park DJ, Yoshikawa T, Hahn S, Nakamura K, Park CH, Kurokawa Y, Bang YJ, Park BJ, Sasako M, Tsujinaka T; REGATTA study investigators. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016 Mar;17(3):309-18. Epub 2016 Jan 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000001012
#DIGEST: Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01285557
#PHOENIX-GC: Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000005930
#JCOG1013: Yamada Y, Boku N, Mizusawa J, Iwasa S, Kadowaki S, Nakayama N, Azuma M, Sakamoto T, Shitara K, Tamura T, Chin K, Hata H, Nakamori M, Hara H, Yasui H, Katayama H, Fukuda H, Yoshikawa T, Sasako M, Terashima M. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 Jul;4(7):501-510. Epub 2019 May 14. link to original article dosing details in abstract have been reviewed by our editors EuroPMC UMIN000007652
#SOPP: Lee KW, Chung IJ, Ryu MH, Park YI, Nam BH, Oh HS, Lee KH, Han HS, Seo BG, Jo JC, Lee HR, Kim JW, Park SR, Cho SH, Kang YK; SOPP study investigators. Multicenter phase III trial of S-1 and cisplatin versus S-1 and oxaliplatin combination chemotherapy for first-line treatment of advanced gastric cancer (SOPP trial). Gastric Cancer. 2021 Jan;24(1):156-167. Epub 2020 Jun 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01671449
#SOLAR: Kang YK, Chin K, Chung HC, Kadowaki S, Oh SC, Nakayama N, Lee KW, Hara H, Chung IJ, Tsuda M, Park SH, Hosaka H, Hironaka S, Miyata Y, Ryu MH, Baba H, Hyodo I, Bang YJ, Boku N. S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Aug;21(8):1045-1056. Epub 2020 Jul 16. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02322593
==CLF==
CLF: Cisplatin, Leucovorin, Fluorouracil
FLP: Fluorouracil, Leucovorin, Platinol (Cisplatin)
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Al-Batran et al. 2008	2003-2006 	Phase 3 (C)	FLO 	Might have shorter PFS (primary endpoint)Median PFS: 3.9 vs 5.8 mo(HR not reported)
Note: In contrast to the original reference, some guidelines list 5-FU as being given every 2 weeks rather than the schedule below. Patients had 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric).
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV over 2 hours once per day on days 1, 15, 29, 43
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1, 15, 29, 43
*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)
====Supportive therapy====
*Up to 3 liters normal saline as hydration with cisplatin
*Antiemetic medications per "local protocols"
8-week cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bouché et al. 2004 (FFCD 9803)	1999-2001 	Randomized Phase 2 (E-esc)	1. LV5FU22. LV5FU2 & Irinotecan	Not powered to draw conclusions
Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used.
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV over 60 minutes once on either day 1 or 2
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2 IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m2)
====Supportive therapy====
*1 liter hydration over 3 hours, given before and after cisplatin
*5-HT3 antagonist IV, given prior to cisplatin
*Methylprednisolone (Solumedrol) 120 mg IV over 10 minutes, given prior to cisplatin
*Oral antiemetics and corticosteroids from days 2 to 5
14-day cycle for at least 4 cycles
===References===
#FFCD 9803: Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==DCF==
DCF: Docetaxel, Cisplatin, Fluorouracil
TCF: Taxotere (Docetaxel), Cisplatin, Fluorouracil
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ajani et al. 2005 (V-325) 	1998-1999 	Randomized Phase 2 (E-esc)	DC 	Seems to have higher ORR
Van Cutsem et al. 2006 (TAX 325)	1999-2003 	Phase 3 (E-RT-esc) 	CF 	Seems to have longer OS (secondary endpoint)Median OS: 9.2 vs 8.6 mo(HR 0.78, 95% CI 0.63-1.00)Longer TTP (primary endpoint)Median TTP: 5.6 vs 3.7 mo(HR 0.68, 95% CI 0.55-0.84)
Note: In contrast to the original references, some guidelines list each cycle as lasting 28 days. V-325 patients had 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70. TAX 325 patients had 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS score of 70.
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
*Cisplatin (Platinol) 75 mg/m2 IV over 1 to 3 hours once on day 1
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m2)
====Supportive therapy====
*(varied depending on reference):
*Dexamethasone (Decadron) 8 mg PO once the night before chemotherapy, then 8 mg PO once on day 1; 1 hour prior to chemotherapy, then 8 mg PO twice per day until day 2 (total dose per cycle: 48 mg)
*Dexamethasone (Decadron) 20 mg IV prior to cisplatin and 8 hours after cisplatin
*Ondansetron (Zofran) 8 mg IV prior to cisplatin, 4 hours after cisplatin, and 8 hours after cisplatin
*"Hydration (was) administered in a standard manner"
21-day cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Roth et al. 2007	1999-2003 	Randomized Phase 2 (E-esc)	1. ECF 	Not reported
Roth et al. 2007	1999-2003 	Randomized Phase 2 (E-esc)	2. TC 	Might have higher ORR (primary endpoint)
Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m2 to 75 mg/m2 based on high incidence of febrile neutropenia.
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
*Cisplatin (Platinol) 75 mg/m2 IV over 4 hours once on day 1
*Fluorouracil (5-FU) 300 mg/m2/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m2)
====Supportive therapy====
*3 liters per day "hyperhydration"
*Dexamethasone (Decadron) 8 mg PO given 12 hours & 6 hours prior to docetaxel, then 8 mg PO twice per day for 4 days after docetaxel
*5-HT3 antagonist for emesis prophylaxis
*Growth factor support allowed, such as with Filgrastim (Neupogen)
21-day cycle for up to 8 cycles
===References===
#V-325: Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==mDCF==
mDCF: modified Docetaxel, Cisplatin, Fluorouracil
===Regimen variant #1, 60/60/3000, 4-day 5-FU infusion===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Wang et al. 2015 (DOCET L 02195)	2008-2010 	Phase 3 (E-esc)	CF 	Seems to have longer OS (secondary endpoint)Median OS: 10.2 vs 8.5 mo(HR 0.71, 95% CI 0.52-0.97)
====Chemotherapy====
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m2)
21-day cycles
===Regimen variant #2, 60/60/3000, 5-day 5-FU infusion===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Wang et al. 2015 (DOCET L 02195)	2008-2010 	Phase 3 (E-esc)	CF 	Seems to have longer OS (secondary endpoint)Median OS: 10.2 vs 8.5 mo(HR 0.71, 95% CI 0.52-0.97)
====Chemotherapy====
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3000 mg/m2)
21-day cycles
===References===
#DOCET L 02195: Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S, Dai G, Xu J, Liu Y, Fan N, Shu Y, Ba Y, Ma D, Qin S, Zheng L, Chen W, Shen L. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer. 2016 Jan;19(1):234-44. Epub 2015 Jan 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00811447
==mDCF & Bevacizumab==
mDCF & Bevacizumab: modified Docetaxel, Cisplatin, Fluorouracil & Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence
Shah et al. 2010 (MSK 06-096)	2006-2008 	Phase 2
Note: patients had 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy. Unlike most DCF regimens that we are aware of, this one includes leucovorin.
====Chemotherapy====
*Docetaxel (Taxotere) 40 mg/m2 IV over 60 minutes once on day 1
*Cisplatin (Platinol) 40 mg/m2 IV over 1 to 3 hours once on day 3
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m2)
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once on day 1
====Supportive therapy====
*"Standard premedication and delayed emesis regimens"
14-day cycles
===References===
#MSK 06-096: Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00390416
==Docetaxel & S-1==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Koizumi et al. 2013 (STARTgastric)	2005-2008 	Phase 3 (E-esc)	S-1 	Seems to have longer OS (primary endpoint)Median OS: 12.5 vs 10.8 mo(HR 0.84, 95% CI 0.71-0.99)
====Chemotherapy====
*Docetaxel (Taxotere) 40 mg/m2 IV once on day 1
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 14
21-day cycles
===References===
#START: Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO; KCSG. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00287768
==ECF==
ECF: Epirubicin, Cisplatin, Fluorouracil
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Findlay et al. 1994 	1988-1992 	Phase 2 	 	
Webb et al. 1997 	1992-1995 	Randomized (E-switch-ic)	FAMTX 	Longer OS (primary endpoint)Median OS: 8.9 vs 5.7 mo(aHR 0.61, 95% CI 0.45-0.81)
Ross et al. 2002 	1995-1998 	Phase 3 (C) 	MCF 	Seems to have non-inferior OS
Roth et al. 2007 	1999-2003 	Randomized Phase 2 (C) 	1. TC2. TCF	Not reported
Cunningham et al. 2008 (REAL-2)	2000-2005 	Phase 3 (C) 	1. ECX 	Non-inferior OS
Cunningham et al. 2008 (REAL-2)	2000-2005 	Phase 3 (C) 	2. EOF 	Non-inferior OS
Cunningham et al. 2008 (REAL-2)	2000-2005 	Phase 3 (C) 	3. EOX 	Seems to have shorter OS
Note: Findlay et al. patients all had metastatic gastric cancer. Ross et al. patients had adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer. Roth et al. patients all had metastatic gastric cancer. REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2. 
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV bolus once on day 1
*Cisplatin (Platinol) 60 mg/m2 IV over 4 hours 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====
*(varied depending on reference):
*3 liters per day "hyperhydration"
*5-HT3 antagonist for emesis prophylaxis
*Growth factor support allowed, such as with Filgrastim (Neupogen)
*Ross et al. 2002 & Cunningham et al. 2008 used Warfarin (Coumadin) 1 mg PO once per day for catheter thrombosis prophylaxis
21-day cycle for up to 8 cycles
===References===
#Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson V, Nash A, Sacks N, Ford H, Carter R, Hill A. A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol. 1994 Sep;5(7):609-16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997 Jan;15(1):261-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Hickish T. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer. 1999 Apr;80(1-2):269-72. link to original article link to PMC article EuroPMC
#Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN51678883
==ECX==
ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)
ECC: Epirubicin, Cisplatin, Capecitabine
===Regimen variant #1, continuous capecitabine===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cunningham et al. 2008 (REAL-2) 	2000-2005 	Phase 3 (E-RT-switch-ic)	1. ECF 	Non-inferior OS (primary endpoint)
Cunningham et al. 2008 (REAL-2) 	2000-2005 	Phase 3 (E-RT-switch-ic)	2. EOF 3. EOX 	Non-inferior OS (primary endpoint)
Catenacci et al. 2017 (RILOMET-1)	2012-2014 	Randomized Phase 2 (C) 	ECX & Rilotumumab	Longer OS (primary endpoint)Median OS: 10.7 vs 8.8 mo(HR 0.75, 95% CI 0.61-0.91)
Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2. RILOMET-1 patients had unresectable or metastatic MET-positive gastric or gastro-esophageal junction cancer. ~80% gastric, 20% GE junction and 10% distal esophageal.
====Chemotherapy====
*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 up to 8 cycles (REAL-2) or 10 cycles (RILOMET-1)
===Regimen variant #2, intermittent capecitabine===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Konings et al. 2010	2005-2009 	Randomized Phase 2 (C)	ECC & Pravastatin	Did not meet primary endpoint of PFS6PFS6: 46.7% vs 42.8%
Note: 6.6% of patients had an ECOG PS of 2
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV bolus once on day 1, given first
*Cisplatin (Platinol) 60 mg/m2 IV over 3 hours once on day 1, given second
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for up to 6 cycles
===References===
#REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN51678883
#Konings IR, van der Gaast A, van der Wijk LJ, de Jongh FE, Eskens FA, Sleijfer S. The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial. Eur J Cancer. 2010 Dec;46(18):3200-4. Epub 2010 Aug 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#RILOMET-1: Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe M, De Vita F, Turkington C, Tang R, Ang A, Zhang Y, Hoang T, Sidhu R, Cunningham D. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1467-1482. Epub 2017 Sep 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01697072
==EOF==
EOF: Epirubicin, Oxaliplatin, Fluorouracil
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cunningham et al. 2008 (REAL-2)	2000-2005 	Phase 3 (E-switch-ic)	1. ECF2. ECX	Non-inferior OS (primary endpoint)
Cunningham et al. 2008 (REAL-2)	2000-2005 	Phase 3 (E-switch-ic)	3. EOX 	Non-inferior OS (primary endpoint)
Note: patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV bolus once on day 1
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 200 mg/m2/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m2)
====Supportive therapy====
*Warfarin (Coumadin) 1 mg PO once per day for catheter thrombosis prophylaxis
21-day cycle for up to 8 cycles
===References===
#REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN51678883
==EOX==
EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)
EOC: Epirubicin, Oxaliplatin, Capecitabine
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cunningham et al. 2008 (REAL-2)	2000-2005 	Phase 3 (E-RT-switch-ic)	1. ECF 	Seems to have longer OS (secondary endpoint)Median OS: 11.2 vs 9.9 mo(HR 0.80, 95% CI 0.66-0.97)
Cunningham et al. 2008 (REAL-2)	2000-2005 	Phase 3 (E-RT-switch-ic)	2. ECX 	Non-inferior OS (primary endpoint)
Cunningham et al. 2008 (REAL-2)	2000-2005 	Phase 3 (E-RT-switch-ic)	3. EOF 	Non-inferior OS (primary endpoint)
Waddell et al. 2013 (REAL3) 	2008-2011 	Phase 3 (C) 	mEOC+P 	Longer OS (primary endpoint)Median OS: 11.3 vs 8.3 mo(HR 0.73, 95% CI 0.57-0.93)
Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2. REAL3 patients had 99% adenocarcinoma, 1% undifferentiated histology. 39% esophagus, 31% gastroesophageal junction, 30% gastric. 6% ECOF PS of 2. 89% metastatic disease. 
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
*Capecitabine (Xeloda) 625 mg/m2 PO twice per day on days 1 to 21
21-day cycle for up to 8 cycles
===Regimen variant #2, with maintenance capecitabine===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zhu et al. 2022 (EXELOX)	2015-2020 	Phase 3 (C)	CapeOx 	Non-inferior PFSMedian PFS: 5.5 vs 5 mo(HR 1.01, 95% CI 0.83-1.23)
====Chemotherapy====
*Epirubicin (Ellence) as follows:
**Cycles 1 up to 8: 50 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) as follows:
**Cycles 1 up to 8: 130 mg/m2 IV over 2 hours once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
#REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC content property of HemOnc.org ISRCTN51678883
#REAL3: Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, Wotherspoon A, Saffery C, Middleton G, Wadsley J, Ferry D, Mansoor W, Crosby T, Coxon F, Smith D, Waters J, Iveson T, Falk S, Slater S, Peckitt C, Barbachano Y. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):481-9. Epub 2013 Apr 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00824785
#EXELOX: Zhu XD, Huang MZ, Wang YS, Feng WJ, Chen ZY, He YF, Zhang XW, Liu X, Wang CC, Zhang W, Ying JE, Wu J, Yang L, Qin YR, Luo JF, Zhao XY, Li WH, Zhang Z, Qiu LX, Geng QR, Zou JL, Zhang JY, Zheng H, Song XF, Wu SS, Zhang CY, Gong Z, Liu QQ, Wang XF, Xu Q, Wang Q, Ji JM, Zhao J, Guo WJ. XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX). Cancer Commun (Lond). 2022 Apr;42(4):314-326. Epub 2022 Feb 25. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02395640
==Fluorouracil monotherapy==
===Regimen variant #1, CI===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ohtsu et al. 2003 (JCOG 9205) 	1992-1997 	Phase 3 (C)	1. FP 	Did not meet primary endpoint of OS
Ohtsu et al. 2003 (JCOG 9205) 	1992-1997 	Phase 3 (C)	2. UFTM 	Did not meet primary endpoint of OS
Boku et al. 2009 (JCOG 9912) 	2000-2006 	Phase 3 (C)	1. Cisplatin & Irinotecan	Might have shorter OS
Boku et al. 2009 (JCOG 9912) 	2000-2006 	Phase 3 (C)	2. S-1 	Non-inferior OS
Shirao et al. 2013 (JCOG 0106)	2002-2007 	Phase 3 (C)	MF 	Did not meet primary endpoint of OS50%Median OS: 9.4 vs 10.6 mo(HR 1.06, 95% CI 0.82-1.39)
Note: JCOG 9205 included patients with PFS of 2 (9.6%)
====Chemotherapy====
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
28-day cycles
===Regimen variant #2, intermittent, BSA-based===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cullinan et al. 1985	Not reported 	Phase 3 (E-de-esc)	1. FA2. FAM	Did not meet primary endpoint of OS
Note: This was an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 to 5
28-day cycle for 2 cycles, then 35-day cycles
===Regimen variant #3, intermittent, weight-based===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kolarić et al. 1986	Not reported 	Phase 3 (C)	Epirubicin & Fluorouracil	Seems to have shorter DOR
====Chemotherapy====
*Fluorouracil (5-FU) 12 mg/kg IV once per day on days 1 to 5
21- to 28-day cycles
===Regimen variant #4, PVI===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tebbutt et al. 2002	1994-2001 	Phase 3 (C)	5-FU & Mitomycin	Did not meet primary endpoint of ORR
====Chemotherapy====
*Fluorouracil (5-FU) 300 mg/m2/day IV continuous infusion
Up to 24-week course
===References===
#Cullinan SA, Moertel CG, Fleming TR, Rubin JR, Krook JE, Everson LK, Windschitl HE, Twito DI, Marschke RF, Foley JF, Pfeifle DM, Barlow JF. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA. 1985 Apr 12;253(14):2061-7. link to original article EuroPMC
#Kolarić K, Potrebica V, Stanovnik M. Controlled phase III clinical study of 4-epi-doxorubicin + 5-fluorouracil versus 5-fluorouracil alone in metastatic gastric and rectosigmoid cancer. Oncology. 1986;43(2):73-7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Tebbutt NC, Norman A, Cunningham D, Iveson T, Seymour M, Hickish T, Harper P, Maisey N, Mochlinski K, Prior Y, Hill M. A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil (5-FU) with PVI 5-FU plus mitomycin C in patients with inoperable oesophago-gastric cancer. Ann Oncol. 2002 Oct;13(10):1568-75. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#JCOG 9205: Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; JCOG. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#JCOG 9912: Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00142350
#JCOG 0106: Shirao K, Boku N, Yamada Y, Yamaguchi K, Doi T, Goto M, Nasu J, Denda T, Hamamoto Y, Takashima A, Fukuda H, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Randomized Phase III study of 5-fluorouracil continuous infusion vs sequential methotrexate and 5-fluorouracil therapy in far advanced gastric cancer with peritoneal metastasis (JCOG0106). Jpn J Clin Oncol. 2013 Oct;43(10):972-80. Epub 2013 Sep 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00149201
==Fluorouracil & Heptaplatin (FH)==
FH: Fluorouracil & Heptaplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lee et al. 2009a	2000-2004 	Phase 3 (E-switch-ic)	CF 	Equivalent OS (primary endpoint)Median OS: 7.3 vs 7.9 mo
Note: this is reported to be an equivalence study but the statistical analysis does not provide details on the definition of equivalence. 
====Chemotherapy====
*Fluorouracil (5-FU) 1000 mg/m2 IV over 12 hours once per day on days 1 to 5, given second
*Heptaplatin (SunPla) 400 mg/m2 IV over 60 minutes once on day 1, given first
28-day cycles
===References===
#Lee KH, Hyun MS, Kim HK, Jin HM, Yang J, Song HS, Do YR, Ryoo HM, Chung JS, Zang DY, Lim HY, Jin JY, Yim CY, Park HS, Kim JS, Sohn CH, Lee SN. Randomized, multicenter, phase III trial of heptaplatin 1-hour infusion and 5-fluorouracil combination chemotherapy comparing with cisplatin and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer. Cancer Res Treat. 2009 Mar;41(1):12-8. Epub 2009 Mar 31. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
==Fluorouracil, Folinic acid, Mitomycin==
===Regimen===
Study 	Dates of enrollment	Evidence
Hofheinz et al. 2002	1998-2000 	Phase 2, fewer than 20 pts in this subgroup
====Chemotherapy====
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 15,600 mg/m2)
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
*Mitomycin (Mutamycin) 10 mg/m2 IV once per day on days 1 & 22
56-day cycle for 2 cycles
===References===
#Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: a phase II study. Onkologie. 2002 Jun;25(3):255-60. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==FOLFIRI==
FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan
IF: Irinotecan & 5-Fluorouracil
===Regimen variant #1, 6 out of 7 weeks ("AIO regimen")===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Dank et al. 2008	2000-2002 	Phase 3 (E-switch-ic)	CF 	Might have longer TTP (primary endpoint)Median TTP: 5 vs 4.2 mo(HR 0.81, 95% CI 0.64-1.03)
Note: patients had 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric origin). 96% with metastatic disease. 
====Chemotherapy====
*Fluorouracil (5-FU) 2000 mg/m2 IV continuous infusion over 22 hours, started on days 1, 8, 15, 22, 29, 36, given third (total dose per cycle: 12,000 mg/m2)
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given second
*Irinotecan (Camptosar) 80 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, given first
====Supportive therapy====
*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
7-week cycles
===Regimen variant #2, LV5FU2 & Irinotecan (200/1600/180)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bouché et al. 2004 (FFCD 9803)	1999-2001 	Randomized Phase 2 (E-esc)	1. LV5FU22. LV5FU2 & Cisplatin	Not powered to draw conclusions
Note: patients had 100% adenocarcinoma (70% gastric origin, 30% cardia). The primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more typical schedule was used.
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2 IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1
14-day cycle for at least 4 cycles
===Regimen variant #3, 400/2800/180===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Guimbaud et al. 2014 (FFCD 03-07)	2005-2008 	Phase 3 (E-switch-ic)	ECX 	Longer TTF (primary endpoint)Median TTF: 5.08 vs 4.24 mo(HR 0.77, 95% CI 0.63-0.93)
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1
14-day cycles 
===References===
#FFCD 9803: Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. link to original article 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
#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
==mFOLFOX6==
mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen variant #1, no 5-FU bolus===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Ramaswamy et al. 2024	2020-07-15 to 2022-11-10	Phase 3 (C)	1a. DOF1b. DOX	Might have shorter OS (primary endpoint)RMST: 8.57 vs 8.97 mo(RMST ratio 1.05, 95% CI 0.96-1.14)
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) 2400 mg/m2 IV continuous infusion over 46 hours, started on day 1
*Leucovorin (Folinic acid) 200 mg/m2 IV over 60 minutes once on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycle for 12 cycles
===Regimen variant #2, with 5-FU bolus===
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)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (C)	1a. CapeOx & Nivolumab1b. mFOLFOX6 & Nivolumab	Shorter OSMedian OS: 11.1 vs 14.4 mo(HR 1.43, 95% CI 1.23-1.64)
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (C)	2. Ipilimumab & Nivolumab 	Not reported
Shitara et al. 2023 (SPOTLIGHT) 	2018-06-21 to 2022-04-01	Phase 3 (C)	mFOLFOX6 & Zolbetuximab 	Shorter PFS (primary endpoint)Median PFS: 8.67 vs 10.61 mo(HR 1.33, 95% CI 1.06-1.67)Shorter OS (secondary endpoint)Median OS: 15.54 vs 18.23 mo(HR 1.33, 95% CI 1.06-1.67)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Biomarker eligibility criteria====
*SPOTLIGHT: CLDN18.2 positive
====Chemotherapy====
*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
14-day cycle for varying durations: 12 cycles (GAMMA-1); indefinitely (CheckMate 649, SPOTLIGHT)
====Subsequent treatment====
*GAMMA-1: 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
#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
#SPOTLIGHT: Shitara K, Lordick F, Bang YJ, Enzinger P, Ilson D, Shah MA, Van Cutsem E, Xu RH, Aprile G, Xu J, Chao J, Pazo-Cid R, Kang YK, Yang J, Moran D, Bhattacharya P, Arozullah A, Park JW, Oh M, Ajani JA. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023 May 20;401(10389):1655-1668. Epub 2023 Apr 15. Erratum in: Lancet. 2023 Jul 22;402(10398):290. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03504397
##Pooled HRQoL analysis: Lordick F, Van Cutsem E, Shitara K, Xu RH, Ajani JA, Shah MA, Oh M, Ganguli A, Chang L, Rhoten S, Bhattacharya P, Matsangou M, Park JW, Pophale R, Ranganath R, Kang YK. Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials. ESMO Open. 2024 Aug;9(8):103663. Epub 2024 Aug 14. link to original article link to PMC article EuroPMC
#Ramaswamy A, Bhargava P, Dubashi B, Gupta A, Kapoor A, Srinivas S, Shetty O, Jadhav P, Desai V, Noronha V, Joshi A, Menon N, Patil VM, Mishra BK, Sansar B, Singh A, Patel S, Singh SN, Dhal I, Vinayak KR, Pal V, Mandavkar S, Kannan S, Chaugule D, Patil R, Parulekar M, Nashikkar C, Ankathi SK, Kaushal RK, Shah A, Ganesan P, Kayal S, Ananthakrishnan R, Syed N, Samaddar D, Kapu V, Shah A, Kaaviya D, Suganiya R, Srinivasan ND, Prabhash K, Ostwal V. Docetaxel-oxaliplatin-capecitabine/5-fluorouracil (DOX/F) followed by docetaxel versus oxaliplatin-capecitabine/5-fluorouracil (CAPOX/FOLFOX) in HER2-negative advanced gastric cancers. JNCI Cancer Spectr. 2024 Jul 1;8(4):pkae054. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2020/03/023944
==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 FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Nivolumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Janjigian et al. 2021 (CheckMate 649)	2017-03 to 2019-04 	Phase 3 (E-RT-esc)	1a. CapeOx1b. mFOLFOX6 	Longer OS1 (co-primary endpoint)Median OS: 14.4 vs 11.1 mo(HR 0.70, 95% CI 0.61-0.81)
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.
====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 (Opdivo) 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
==mFOLFOX6 & Zolbetuximab==
mFOLFOX6 & Zolbetuximab: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Zolbetuximab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Shitara et al. 2023 (SPOTLIGHT)	2018-06-21 to 2022-04-01	Phase 3 (E-RT-esc)	mFOLFOX6 	Longer PFS (primary endpoint)Median PFS: 10.61 vs 8.67 mo(HR 0.75, 95% CI 0.60-0.94)Longer OS (secondary endpoint)Median OS: 18.23 vs 15.54 mo(HR 0.75, 95% CI 0.60-0.94)
Note: Continuation of 5-FU and Leucovorin in maintenance (cycle 5 onwards) was at the investigator's discretion.
====Biomarker eligibility criteria====
*CLDN18.2 positive
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1, 15, 29, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours (total dose per cycle: 8400 mg/m2)
*Leucovorin (Folinic acid) 400 mg/m2 IV once per day on days 1, 15, 29
*Oxaliplatin (Eloxatin) as follows:
**Cycles 1 to 4: 85 mg/m2 IV once per day on days 1, 15, 29
====Targeted therapy====
*Zolbetuximab (Vyloy) as follows:
**Cycle 1: 800 mg/m2 IV once on day 1, then 600 mg/m2 IV once on day 22
**Cycle 2 onwards: 600 mg/m2 IV once per day on days 1 & 22
42-day cycles
===References===
#SPOTLIGHT: Shitara K, Lordick F, Bang YJ, Enzinger P, Ilson D, Shah MA, Van Cutsem E, Xu RH, Aprile G, Xu J, Chao J, Pazo-Cid R, Kang YK, Yang J, Moran D, Bhattacharya P, Arozullah A, Park JW, Oh M, Ajani JA. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023 May 20;401(10389):1655-1668. Epub 2023 Apr 15. Erratum in: Lancet. 2023 Jul 22;402(10398):290. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03504397
##Pooled HRQoL analysis: Lordick F, Van Cutsem E, Shitara K, Xu RH, Ajani JA, Shah MA, Oh M, Ganguli A, Chang L, Rhoten S, Bhattacharya P, Matsangou M, Park JW, Pophale R, Ranganath R, Kang YK. Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials. ESMO Open. 2024 Aug;9(8):103663. Epub 2024 Aug 14. link to original article link to PMC article EuroPMC
==FULV==
FULV: 5-FU & LeucoVorin
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bouché et al. 2004 (FFCD 9803)	1999-2001 	Randomized Phase 2 (E-de-esc)	1. LV5FU2 & Cisplatin2. LV5FU2 & Irinotecan	Not powered to draw conclusions
Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more typical schedule was used. Patients had 100% adenocarcinoma histology (70% gastric origin, 30% cardia).
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2 IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m2)
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once on day 1
14-day cycle for at least 4 cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lee et al. 2023 (KCSG ST13-10)	2014-02 to 2019-01 	Phase 3 (C)	1a. mFOLFOX61b. CapeOx1c. Cisplatin & S-11d. CX	Did not meet primary endpoint of OSMedian OS: 7.5 vs 11.5 mo(HR 1.16, 95% CI 0.77-1.79)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Fluorouracil (5-FU) 2400 mg/m2 IV continuous infusion over 46 hours, started on day 1
*Leucovorin (Folinic acid) 100 mg/m2 IV once on day 1
14-day cycles
===References===
#FFCD 9803: Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#KCSG ST13-10: Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS. A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10). Cancer Res Treat. 2022 Oct;55(4):1250-1260. Epub 2023 May 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02114359
==FULV (L-Leucovorin)==
FULV: 5-FU & Levo-LeucoVorin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Nakajima et al. 2020 (JCOG1108)	2013-2017 	Phase 2/3 (C)	FLTAX 	Did not meet primary endpoint of OSMedian OS: 6.1 vs 7.3 mo(HR 1.26, 80% CI 0.95-1.68)
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, given second, 60 minutes after levoleucovorin
*Levoleucovorin (Fusilev) 250 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given first
8-week cycles
===References===
#JCOG1108: Nakajima TE, Yamaguchi K, Boku N, Hyodo I, Mizusawa J, Hara H, Nishina T, Sakamoto T, Shitara K, Shinozaki K, Katayama H, Nakamura S, Muro K, Terashima M. Randomized phase II/III study of 5-fluorouracil/l-leucovorin versus 5-fluorouracil/l-leucovorin plus paclitaxel administered to patients with severe peritoneal metastases of gastric cancer (JCOG1108/WJOG7312G). Gastric Cancer. 2020 Jul;23(4):677-688. Epub 2020 Feb 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000010949
==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 references, some guidelines list a dosing schedule of 125 mg/m2 IV once per day on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when irinotecan is used as a single-agent, a tri-weekly schedule may be preferable." This study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GEJ and 33% distal esophagus). The results showed a 14% response rate and 53% disease control rate.
====Chemotherapy====
*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
==OLF==
OLF: Oxaliplatin, Leucovorin, Fluorouracil
FLO: Fluorouracil, Leucovorin, Oxaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Al-Batran et al. 2008	2003-2006 	Phase 3 (E-switch-ic)	FLP 	Might have longer PFS (primary endpoint)Median PFS: 5.8 vs 3.9 mo(HR not reported)
Note: Patients had 100% adenocarcinoma histology (20% esophagogastric junction, 80% gastric).
====Chemotherapy====
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once per day on days 1, 15, 29, 43
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1, 15, 29, 43
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on days 1, 15, 29, 43 (total dose per cycle: 10,400 mg/m2)
====Supportive therapy====
*Antiemetic medications per "local protocols"
8-week cycles
===References===
#Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Paclitaxel & S-1==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ishigami et al. 2018 (PHOENIX-GC)	2011-2013 	Phase 3 (E-switch-ooc)	Cisplatin & S-1	Might have longer OS (primary endpoint)Median OS: 17.7 vs 15.2 mo(HR 0.72, 95% CI 0.49-1.04)
Note: Inclusion criteria for PHOENIX-GC included patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details
====Chemotherapy====
*Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1 and 8
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 to 1.5 m2: 50 mg PO twice per day on days 1 to 14
**More than 1.5 m2: 60 mg PO twice per day on days 1 to 14
*Paclitaxel (Taxol) 20 mg/m2 IP once per day over 1 hour on days 1 and 8
====Supportive therapy====
*500 mL of normal saline was given prior to intraperitoneal paclitaxel
35-day cycles
===References===
#PHOENIX-GC: Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000005930
==Pembrolizumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shitara et al. 2020 (KEYNOTE-062)	2015-2017 	Phase 3 (E-switch-ooc)	1a. CF1b. CX 	Non-inferior OS1 (co-primary endpoint)
Shitara et al. 2020 (KEYNOTE-062)	2015-2017 	Phase 3 (E-switch-ooc)	2a. CF & Pembrolizumab2b. CX & Pembrolizumab	Not reported
1Reported efficacy is for patients with PD-L1 CPS score of 1 or more. Improved OS was seen in patients with PD-L1 CPS score of 10 or more (HR: 0.62) but was not tested per analysis plan.
KEYNOTE-062 included patients with GEJ malignancy.
====Biomarker eligibility criteria====
*PD-L1 CPS score of 1 or more
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
===References===
#KEYNOTE-062: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. Epub 2020 Sep 3. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02494583
##HRQoL analysis: Van Cutsem E, Valderrama A, Bang YJ, Fuchs CS, Shitara K, Janjigian YY, Qin S, Larson TG, Shankaran V, Stein S, Norquist JM, Kher U, Shah S, Alsina M. Quality of life with first-line pembrolizumab for PD-L1-positive advanced gastric/gastroesophageal junction adenocarcinoma: results from the randomised phase III KEYNOTE-062 study. ESMO Open. 2021 Aug;6(4):100189. link to original article link to EuroPMC
==S-1 monotherapy==
===Regimen variant #1, BSA-based===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Boku et al. 2009 (JCOG 9912)	2000-2006 	Phase 3 (E-switch-ic)	1. Cisplatin & Irinotecan	Not reported
Boku et al. 2009 (JCOG 9912)	2000-2006 	Phase 3 (E-switch-ic)	2. 5-FU 	Non-inferior OS (primary endpoint)
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO twice per day on days 1 to 28
42-day cycles
===Regimen variant #2, weight-based===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Koizumi et al. 2008 (SPIRITS) 	2002-2004 	Phase 3 (C)	Cisplatin & S-1	Seems to have shorter OSMedian OS: 11 vs 13 mo(HR 1.30, 95% CI 1.02-1.64)
Narahara et al. 2011 (TOP-002) 	2004-06 to 2005-11 	Phase 3 (C)	IRI-S 	Did not meet primary endpoint of OSMedian OS: 10.5 vs 12.8 mo(HR 1.17)
Koizumi et al. 2013 (STARTgastric)	2005-2008 	Phase 3 (C)	Docetaxel & S-1	Seems to have shorter OSMedian OS: 10.8 vs 12.5 mo(HR 1.19, 95% CI 1.01-1.41)
Yoshino et al. 2016 (JFMC36-0701) 	2007-2010 	Phase 3 (C)	Lentinan & S-1 	Did not meet primary endpoint of OSMedian OS: 13.8 vs 9.9 mo(HR 0.86, 95% CI 0.67-1.09)
Note: there is another trial named START in NSCLC.
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 28
**Between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 28
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 28
42-day cycles
===Regimen variant #3, 14 of 21 days===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lee et al. 2023 (KCSG ST13-10)	2014-02 to 2019-01 	Phase 3 (C)	1a. mFOLFOX61b. CapeOx1c. Cisplatin & S-11d. CX	Did not meet primary endpoint of OSMedian OS: 7.5 vs 11.5 mo(HR 1.16, 95% CI 0.77-1.79)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following renal function-based criteria:
**CrCl 60 mL/min or more: 40 mg/m2 PO twice per day on days 1 to 14
**CrCl less than 60 mL/min: 30 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
#SPIRITS: Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00150670
#JCOG 9912: Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00142350
#TOP-002: Narahara H, Iishi H, Imamura H, Tsuburaya A, Chin K, Imamoto H, Esaki T, Furukawa H, Hamada C, Sakata Y. Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002). Gastric Cancer. 2011 Mar;14(1):72-80. Epub 2011 Feb 23. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-050083
#START: Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO; KCSG. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00287768
#JFMC36-0701: Yoshino S, Nishikawa K, Morita S, Takahashi T, Sakata K, Nagao J, Nemoto H, Murakami N, Matsuda T, Hasegawa H, Shimizu R, Yoshikawa T, Osanai H, Imano M, Naitoh H, Tanaka A, Tajiri T, Gochi A, Suzuki M, Sakamoto J, Saji S, Oka M. Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). Eur J Cancer. 2016 Sep;65:164-71. Epub 2016 Aug 5. link to original article EuroPMC UMIN000000574
#KCSG ST13-10: Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS. A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10). Cancer Res Treat. 2022 Oct;55(4):1250-1260. Epub 2023 May 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02114359
#RESCUE-GC: NCT02867839
==SOX==
SOX: S-1 & OXaliplatin
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Yamada et al. 2014 (G-SOX)	2010-01 to 2011-10 	Phase 3 (E-switch-ic)	CS 	Non-inferior PFS (primary endpoint)Median PFS: 5.5 vs 5.4 mo(HR 1.004, 95% CI 0.84-1.20)
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 1
21-day cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lee et al. 2020 (SOPP)	2012-2014 	Phase 3 (E-switch-ic)	CS 	Non-inferior PFS (primary endpoint)Median PFS: 5.6 vs 5.7 mo(HR 0.85, 95% CI 0.67-1.07)
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1, given first
21-day cycles
===References===
#G-SOX: Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015 Jan;26(1):141-8. Epub 2014 Oct 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-101021
#SOPP: Lee KW, Chung IJ, Ryu MH, Park YI, Nam BH, Oh HS, Lee KH, Han HS, Seo BG, Jo JC, Lee HR, Kim JW, Park SR, Cho SH, Kang YK; SOPP study investigators. Multicenter phase III trial of S-1 and cisplatin versus S-1 and oxaliplatin combination chemotherapy for first-line treatment of advanced gastric cancer (SOPP trial). Gastric Cancer. 2021 Jan;24(1):156-167. Epub 2020 Jun 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01671449
==UFTM==
UFTM: UFT (Tegafur and uracil) & Mitomycin 
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ohtsu et al. 2003 (JCOG 9205)	1992-1997 	Phase 3 (E-esc)	1. Fluorouracil	Did not meet primary endpoint of OS
Ohtsu et al. 2003 (JCOG 9205)	1992-1997 	Phase 3 (E-esc)	2. FP 	Did not meet primary endpoint of OS
Note: this arm of the study was terminated early, in 1995. Study included patients with PFS of 2 (9.6%). Mitomycin was interrupted for 1 month after patients received a total cumulative dose of 60 mg.
====Chemotherapy====
*Tegafur and uracil (UFT) 187.5 mg/m2 PO twice per day
*Mitomycin (Mutamycin) 5 mg/m2 IV once on day 1
7-day cycles (see note)
===References===
#JCOG 9205: Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; JCOG. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Maintenance after first-line therapy=
==Capecitabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Ohtsu et al. 2011 (AVAGAST) 	2007-09 to 2008-12 	Non-randomized part of phase 3 RCT
Kim et al. 2014 (SMC 2008-12-019)	2009-2012 	Non-randomized part of phase 3 RCT
Note: AVAGAST patients had 86% gastric and 14% GEJ. 5.4% of patients had an ECOG PS of 2. SMC 2008-12-019 patients had 79% gastric, 5% GEJ, and 16% unknown. 2% of patients had an ECOG PS of 2.
====Preceding treatment====
*AVAGAST: First-line CX x 6
*SMC 2008-12-019: First-line CX x 8
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
#AVAGAST: Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00548548
#SMC 2008-12-019: Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01099085
==Paclitaxel & Ramucirumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Randon et al. 2024 (ARMANI)	2017-01-01 to 2023-10-02	Phase 3 (E-switch-ooc)	1a. CapeOx continuation1b. FOLFOX continuation	Longer PFS (primary endpoint)Median PFS: 6.6 vs 3.5 mo(RMST: 8.8 vs 6.1 mo)
Note: the proportional hazards assumption was violated.
====Biomarker eligibility criteria====
*HER2-negative
====Preceding treatment====
*CapeOx x 4 or FOLFOX x 3, with at least stable disease
====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===
#ARMANI: Randon G, Lonardi S, Fassan M, Palermo F, Tamberi S, Giommoni E, Ceccon C, Di Donato S, Fornaro L, Brunetti O, De Vita F, Bittoni A, Chini C, Spallanzani A, Nappo F, Bethaz V, Strippoli A, Latiano T, Cardellino GG, Giuliani F, Morano F, Niger M, Raimondi A, Prisciandaro M, Pircher CC, Sciortino C, Marchesi S, Garattini SK, Airò G, Miceli R, Di Bartolomeo M, Pietrantonio F. Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line oxaliplatin-based chemotherapy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer (ARMANI): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2024 Dec;25(12):1539-1550. Epub 2024 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02934464
=Metastatic or locally advanced disease, subsequent lines of therapy=
==Docetaxel monotherapy==
===Regimen variant #1, 60 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kang et al. 2012 (SMC 2008-08-055)	2008-2010 	Phase 3 (E-esc)	Best supportive care	Longer OS (primary endpoint)Median OS: 5.3 vs 3.8 mo(HR 0.66, 95% CI 0.485-0.89)
====Chemotherapy====
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 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)	Best supportive care	Longer OS (primary endpoint)Median OS: 5.2 vs 3.6 mo(HR 0.67, 95% CI 0.49-0.92)
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for up to 6 cycles
===References===
#SMC 2008-08-055: Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00821990
#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 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
#INTEGRATEIIb: NCT04879368
==Fluorouracil, Folinic acid, Mitomycin==
===Regimen===
Study 	Dates of enrollment	Evidence
Hofheinz et al. 2002	1998-2000 	Phase 2, fewer than 20 pts in this subgroup
====Chemotherapy====
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 15,600 mg/m2)
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
*Mitomycin (Mutamycin) 10 mg/m2 IV once per day on days 1 & 22
56-day cycle for 2 cycles
===References===
#Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: a phase II study. Onkologie. 2002 Jun;25(3):255-60. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==Irinotecan monotherapy==
===Regimen variant #1, 125 mg/m2, 4 weeks out of 6===
Study 	Dates of enrollment	Evidence
Enzinger et al. 2005	1997-12 to 2000-08 	Phase 2
Note: In contrast to the primary references, some guidelines list a dosing schedule of 125 mg/m2 IV once per day on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when irinotecan is used as a single-agent, a tri-weekly schedule may be preferable." This study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GE junction and 33% distal esophagus), and showed a 14% response rate and 53% disease control rate. 
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
42-day cycles
===Regimen variant #2, 150 mg/m2 q2wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hironaka et al. 2013 (WJOG 4007) 	2007-2010 	Phase 3 (E-switch-ic)	Paclitaxel 	Did not meet primary endpoint of OS
Nishikawa et al. 2015 (TRICS) 	2007-2011 	Phase 3 (C) 	Cisplatin & Irinotecan	Did not meet primary endpoint of OS
Kang et al. 2012 (SMC 2008-08-055) 	2008-2010 	Phase 3 (E-esc) 	Best supportive care 	Longer OS (primary endpoint)Median OS: 5.3 vs 3.8 mo(HR 0.66, 95% CI 0.485-0.89)
Higuchi et al. 2014 (BIRIP) 	2008-2011 	Phase 3 (C) 	Cisplatin & Irinotecan	Seems to have shorter PFS (primary endpoint)Median PFS: 2.8 vs 3.8 mo(HR 1.47, 95% CI 1.02-2.13)
Tanabe et al. 2015 (JACCRO GC-05) 	2008-2011 	Phase 3 (C) 	Irinotecan & S-1 	Did not meet primary endpoint of OSMedian OS: 9.5 vs 8.8 mo(HR 1.01, 95% CI 0.80-1.28)
Bang et al. 2018 (JAVELIN Gastric 300)	2015-2017 	Phase 3 (C) 	Avelumab 	Did not meet primary endpoint of OSMedian OS: 5 vs 4.6 mo(HR 0.91, 95% CI 0.71-1.11)
Note: WJOG 4007 had 3.7% patients with an ECOG PS of 2
====Chemotherapy====
*Irinotecan (Camptosar) 150 mg/m2 IV once on day 1
14-day cycles
===Regimen variant #3, 300 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Roy et al. 2013 (PEP0206)	2008-2010 	Randomized Phase 2 (C)	1. Docetaxel2. Irinotecan liposomal	Did not meet primary endpoint of ORR
Note: this study included patients with GE junction malignancy (77% gastric, 23% GE junction) and included patients with ECOG PS of 2
====Chemotherapy====
*Irinotecan (Camptosar) 300 mg/m2 IV over 90 minutes once on day 1
21-day cycles
===Regimen variant #4, 350 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Thuss-Patience et al. 2011	2002-2006 	Phase 3 (E-esc)	Best supportive care	Longer OSMedian OS: 4 vs 2.4 mo(HR 0.48, 95% CI 0.25-0.92)
Note: Thuss-Patience et al. 2011 included patients with GE junction malignancy (~58% gastric, 43% GE junction) and included patients with ECOG PS of 2.
====Chemotherapy====
*Irinotecan (Camptosar) as follows:
**Cycle 1: 250 mg/m2 (maximum dose of 500 mg) IV over 30 minutes once on day 1
**Cycles 2 to 10 (depending on toxicity): 350 mg/m2 IV over 30 minutes once on day 1
====Supportive therapy====
*Atropine (Atropen) 0.25 mg SC once on day 1, given prior to irinotecan
*5-HT3 antagonist
*Dexamethasone (Decadron)
21-day cycle for up to 10 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
#Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00144378
#SMC 2008-08-055: Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. link to original article EuroPMC NCT00821990
#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 EuroPMC NCT00813072
#WJOG 4007: Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. link to original artile dosing details in abstract have been reviewed by our editors EuroPMC UMIN000001252
#BIRIP: Higuchi K, Tanabe S, Shimada K, Hosaka H, Sasaki E, Nakayama N, Takeda Y, Moriwaki T, Amagai K, Sekikawa T, Sakuyama T, Kanda T, Sasaki T, Azuma M, Takahashi F, Takeuchi M, Koizumi W; Tokyo Cooperative Oncology Group. Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial). Eur J Cancer. 2014 May;50(8):1437-45. Epub 2014 Feb 20. link to original article dosing details in abstract have been reviewed by our editors EuroPMC UMIN000001028
#TRICS: Nishikawa K, Fujitani K, Inagaki H, Akamaru Y, Tokunaga S, Takagi M, Tamura S, Sugimoto N, Shigematsu T, Yoshikawa T, Ishiguro T, Nakamura M, Morita S, Miyashita Y, Tsuburaya A, Sakamoto J, Tsujinaka T. Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial. Eur J Cancer. 2015 May;51(7):808-16. Epub 2015 Mar 18. link to original article dosing details in abstract have been reviewed by our editors EuroPMC UMIN000002571
#JACCRO GC-05: Tanabe K, Fujii M, Nishikawa K, Kunisaki C, Tsuji A, Matsuhashi N, Takagane A, Ohno T, Kawase T, Kochi M, Yoshida K, Kakeji Y, Ichikawa W, Chin K, Terashima M, Takeuchi M, Nakajima T; JACCRO. Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05). Ann Oncol. 2015 Sep;26(9):1916-22. Epub 2015 Jun 24. link to original article EuroPMC NCT00639327
#JAVELIN Gastric 300: Bang YJ, Yanez Ruiz E, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, Al-Batran SE, Park SH, Lichinitser M, Boku N, Moehler MH, Hong J, Xiong H, Hallwachs R, Conti I, Taieb J. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018 Oct 1;29(10):2052-2060. link to original article link to PMC article dosing details in abstract have been reviewed by our editors EuroPMC NCT02625623
#INTEGRATEIIb: NCT04879368
==Irinotecan liposomal monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Roy et al. 2013 (PEP0206)	2008-2010 	Randomized Phase 2 (E-switch-ic)	1. Docetaxel2. Irinotecan	Did not meet primary endpoint of ORR
====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
Bamias et al. 2003a	1999-07 to 2001-02 	Phase 2
Note: Patients had advanced gastric and colorectal cancers.
====Prior treatment criteria====
*5-fluorouracil-based chemotherapy
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once on day 1
*Mitomycin (Mutamycin) 5 mg/m2 IV bolus once on day 1
14-day cycles
===References===
#Bamias A, Papamichael D, Syrigos K, Pavlidis N. Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother. 2003 Jun;15(3):275-81. link to original article 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 OS1 (primary endpoint)Median OS: 5.3 vs 4.1 mo(HR 0.62, 95% CI 0.50-0.75)
1Reported efficacy for ATTRACTION-2 is based on the 2021 update.
Note: ATTRACTION-2 included patients with GE junction malignancy (82.6% gastric, 8.5% GE junction) and 12.3% of patients had a PD-L1 CPS score of at least 1
====Immunotherapy====
*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
##Update: Chen LT, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Sameshima H, Kang YK, Boku N. A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data. Gastric Cancer. 2020 May;23(3):510-519. Epub 2019 Dec 20. link to original article link to PMC article EuroPMC
##Update: Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Nishiyama T, Chen LT, Kang YK. Nivolumab in previously treated advanced gastric cancer (ATTRACTION-2): 3-year update and outcome of treatment beyond progression with nivolumab. Gastric Cancer. 2021 Jul;24(4):946-958. Epub 2021 Mar 20. link to original article link to PMC article 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 variant #1, 70 mg/m2, 3 out of 4 weeks===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lee et al. 2018 (KCSG ST10-01)	2011-2015 	Phase 3 (C)	Irinotecan	Inconclusive whether non-inferior PFS
====Chemotherapy====
*Paclitaxel (Taxol) 70 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
28-day cycles
===Regimen variant #2, 80 mg/m2, 3 out of 4 weeks===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hironaka et al. 2006 	2002-2004 	Non-randomized 	 	
Kodera et al. 2007 (CCOG0302) 	2003-2006 	Phase 2 	 	
Hironaka et al. 2013 (WJOG 4007) 	2007-2010 	Phase 3 (E-switch-ic)	Irinotecan 	Did not meet primary endpoint of OSMedian OS: 9.5 vs 8.4 mo(HR 0.88, 95% CI 0.67-1.16)
Wilke et al. 2014 (RAINBOW) 	2010-2012 	Phase 3 (C) 	Paclitaxel & Ramucirumab	Seems to have shorter OS (primary endpoint)Median OS: 7.4 vs 9.6 mo(HR 1.23, 95% CI 1.04-1.47)
Lorenzen et al. 2020 (RADPAC) 	2011-2015 	Phase 3 (C) 	Everolimus & Paclitaxel 	Did not meet primary endpoint of OSMedian OS: 5 vs 6.1 mo(HR 1.08, 95% CI 0.85-1.37)
Shitara et al. 2017 (ABSOLUTE) 	2013-2015 	Phase 3 (C) 	1. nab-Paclitaxel weekly	Non-inferior OS
Shitara et al. 2017 (ABSOLUTE) 	2013-2015 	Phase 3 (C) 	2. nab-Paclitaxel q3wk 	Might have longer OS
Bang et al. 2017 (GOLD) 	2013-2016 	Phase 3 (C) 	Olaparib & Paclitaxel 	Seems to have shorter OSMedian OS: 6.9 vs 8.8 mo(HR 1.27, 97.5% CI 1.00-1.59)
Shah et al. 2022 (BRIGHTER) 	2014-10-02 to 2016-12-12	Phase 3 (C) 	Napabucasin & Paclitaxel	Did not meet primary endpoint of OSMedian OS: 7.36 vs 6.93 mo(HR 0.99, 95% CI 0.83-1.16)
Shitara et al. 2018 (KEYNOTE-061) 	2015-06-04 to 2016-07-26	Phase 3 (C) 	Pembrolizumab 	Seems to have shorter OS1Median OS: 8.3 vs 9.1 mo(HR 1.23, 95% CI 1.00-1.52)
Bang et al. 2018 (JAVELIN Gastric 300)	2015-2017 	Phase 3 (C) 	Avelumab 	Did not meet primary endpoint of OSMedian OS: 5 vs 4.6 mo(HR 0.91, 95% CI 0.71-1.11)
Chung et al. 2021 (KEYNOTE-063) 	2017-02-16 to 2018-03-12	Phase 3 (C) 	Pembrolizumab 	Seems to have longer PFS (co-primary endpoint)Median PFS: 4 vs 2 mo(HR 0.62, 95% CI 0.40-0.96)Did not meet co-primary endpoint of OS
Xu et al. 2021 (RAINBOW-Asia) 	2017-2020 	Phase 3 (C) 	Paclitaxel & Ramucirumab	Seems to have shorter PFSMedian PFS: 3.15 vs 4.1 mo(HR 1.30, 95% CI 1.05-1.64)
Wang et al. 2024 (FRUTIGA) 	2017-10-18 to 2022-07-25	Phase 3 (C) 	Paclitaxel & Fruquitinib	Shorter PFS (co-primary endpoint)Median PFS: 2.7 vs 5.6 mo(HR 1.75, 95% CI 1.47-2.08)Did not meet co-primary endpoint of OSMedian OS: 8.4 vs 9.6 mo(HR 1.04, 95% CI 0.88-1.23)
1Reported efficacy for KEYNOTE-061 is based on the 2021 update, for the CPS at least 1 group.
Note: RAINBOW included patients with GE junction malignancy (79% gastric, 21% GE junction). Satoh et al. patients had 98.5% gastric, 1.5% other. WJOG 4007 had 3.7% patients with a PFS of 2.
====Prior treatment criteria====
*RAINBOW: documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV over 60 to 90 minutes once per day on days 1, 8, 15
====Supportive therapy====
*Dexamethasone (Decadron) 20 mg IV once per day on days 1, 8, 15, given 30 minutes prior to paclitaxel
*Diphenhydramine (Benadryl) 25 mg PO once per day on days 1, 8, 15, given 30 minutes prior to paclitaxel
*Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, given 30 minutes prior to paclitaxel
28-day cycle for varying durations: 6 cycles (FRUTIGA); indefinitely (all others)
===Regimen variant #3, 175 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kang et al. 2018 (DREAM)	2013-2015 	Phase 3 (C)	DHP-107 	Non-inferior PFS
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycles
===References===
#Hironaka S, Zenda S, Boku N, Fukutomi A, Yoshino T, Onozawa Y. Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer. 2006;9(1):14-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#CCOG0302: Kodera Y, Ito S, Mochizuki Y, Fujitake S, Koshikawa K, Kanyama Y, Matsui T, Kojima H, Takase T, Ohashi N, Fujiwara M, Sakamoto J, Akimasa N; Chubu Clinical Cancer Group. A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric cancer (CCOG0302 study). Anticancer Res. 2007 Jul-Aug;27(4C):2667-71. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#WJOG 4007: Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. link to original artile dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000001252
#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
#ABSOLUTE: Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. Epub 2017 Jan 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-132059
#GOLD: Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, Shen L, Qin S, Xu N, Im SA, Locker G, Rowe P, Shi X, Hodgson D, Liu YZ, Boku N. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1637-1651. Epub 2017 Nov 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01924533
#DREAM: Kang YK, Ryu MH, Park SH, Kim JG, Kim JW, Cho SH, Park YI, Park SR, Rha SY, Kang MJ, Cho JY, Kang SY, Roh SY, Ryoo BY, Nam BH, Jo YW, Yoon KE, Oh SC. Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus IV paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann Oncol. 2018 May 1;29(5):1220-1226. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01839773
#KEYNOTE-061: Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo MD, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. Epub 2018 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02370498
##HRQoL analysis: Van Cutsem E, Amonkar M, Fuchs CS, Alsina M, Özgüroğlu M, Bang YJ, Chung HC, Muro K, Goekkurt E, Benson AB 3rd, Sun W, Wainberg ZA, Norquist JM, Chen X, Shih CS, Shitara K. Health-related quality of life in advanced gastric/gastroesophageal junction cancer with second-line pembrolizumab in KEYNOTE-061. Gastric Cancer. 2021 Nov;24(6):1330-1340. Epub 2021 Aug 7. Erratum in: Gastric Cancer. 2021 Nov;24(6):1341. link to original article link to PMC article EuroPMC
##Update: Fuchs CS, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Van Cutsem E, Elme A, Thuss-Patience P, Chau I, Ohtsu A, Bhagia P, Wang A, Shih CS, Shitara K. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2022 Jan;25(1):197-206. Epub 2021 Sep 1. link to original article link to PMC article EuroPMC
#KCSG ST10-01: Lee KW, Maeng CH, Kim TY, Zang DY, Kim YH, Hwang IG, Oh SC, Chung JS, Song HS, Kim JW, Jeong SJ, Cho JY. A phase III study to compare the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer who failed in first-line therapy (KCSG ST10-01). Oncologist. 2019 Jan;24(1):18-e24. Epub 2018 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01224652
#JAVELIN Gastric 300: Bang YJ, Yanez Ruiz E, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, Al-Batran SE, Park SH, Lichinitser M, Boku N, Moehler MH, Hong J, Xiong H, Hallwachs R, Conti I, Taieb J. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018 Oct 1;29(10):2052-2060. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02625623
#RADPAC: Lorenzen S, Knorrenschild JR, Pauligk C, Hegewisch-Becker S, Seraphin J, Thuss-Patience P, Kopp HG, Dechow T, Vogel A, Luley KB, Pink D, Stahl M, Kullmann F, Hebart H, Siveke J, Egger M, Homann N, Probst S, Goetze TO, Al-Batran SE. Phase III randomized, double-blind study of paclitaxel with and without everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC). Int J Cancer. 2020 Nov 1;147(9):2493-2502. Epub 2020 May 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01248403
#RAINBOW-Asia: Xu RH, Zhang Y, Pan H, Feng J, Zhang T, Liu T, Qin Y, Qin S, Yin X, Liu B, Ba Y, Yang N, Voon PJ, Tanasanvimon S, Zhou C, Zhang WL, Shen L. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Dec;6(12):1015-1024. Epub 2021 Oct 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02898077
#KEYNOTE-063: Chung HC, Kang YK, Chen Z, Bai Y, Wan Ishak WZ, Shim BY, Park YL, Koo DH, Lu J, Xu J, Chon HJ, Bai LY, Zeng S, Yuan Y, Chen YY, Gu K, Zhong WY, Kuang S, Shih CS, Qin SK. Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients. Cancer. 2022 Mar 1;128(5):995-1003. Epub 2021 Dec 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03019588
#BRIGHTER: Shah MA, Shitara K, Lordick F, Bang YJ, Tebbutt NC, Metges JP, Muro K, Lee KW, Shen L, Tjulandin S, Hays JL, Starling N, Xu RH, Sturtz K, Fontaine M, Oh C, Brooks EM, Xu B, Li W, Li CJ, Borodyansky L, Van Cutsem E. Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma. Clin Cancer Res. 2022 Sep 2;28(17):3686–3694. Epub 2022 Jul 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02178956
#FRUTIGA: Wang F, Shen L, Guo W, Liu T, Li J, Qin S, Bai Y, Chen Z, Wang J, Pan Y, Shu Y, Zhao F, Cheng Y, Ye F, Gu K, Zhang T, Pan H, Zhong H, Zhou F, Qin Y, Yang L, Mao W, Li Q, Dai W, Li W, Wang S, Tang Y, Ma D, Yin X, Deng Y, Yuan Y, Li M, Hu W, Chen D, Li G, Liu Q, Tan P, Fan S, Shi M, Su W, Xu RH. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial. Nat Med. 2024 Aug;30(8):2189-2198. Epub 2024 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03223376
#INTEGRATEIIb: NCT04879368
==nab-Paclitaxel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shitara et al. 2017 (ABSOLUTE)	2013-2015 	Phase 3 (E-switch-ic)	1. Paclitaxel; weekly 	Non-inferior OS (primary endpoint)Median OS: 11.1 vs 10.9 mo(HR 0.97, 97.5% CI 0.76-1.23)
Shitara et al. 2017 (ABSOLUTE)	2013-2015 	Phase 3 (E-switch-ic)	2. nab-Paclitaxel; q3wk	Not reported
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
===References===
#ABSOLUTE: Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. Epub 2017 Jan 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-132059
==Paclitaxel & Fruquitinib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wang et al. 2024 (FRUTIGA)	2017-10-18 to 2022-07-25	Phase 3 (E-esc)	Paclitaxel x 6	Longer PFS (co-primary endpoint)Median PFS: 5.6 vs 2.7 mo(HR 0.57, 95% CI 0.48-0.68)Did not meet co-primary endpoint of OSMedian OS: 9.6 vs 8.4 mo(HR 0.96, 95% CI 0.81-1.13)
====Chemotherapy====
*Paclitaxel (Taxol) as follows:
**Cycles 1 to 6: 80 mg/m2 IV once per day on days 1, 8, 15
====Targeted therapy====
*Fruquintinib (Elunate) 4 mg PO once per day on days 1 to 21
28-day cycles
===References===
#FRUTIGA: Wang F, Shen L, Guo W, Liu T, Li J, Qin S, Bai Y, Chen Z, Wang J, Pan Y, Shu Y, Zhao F, Cheng Y, Ye F, Gu K, Zhang T, Pan H, Zhong H, Zhou F, Qin Y, Yang L, Mao W, Li Q, Dai W, Li W, Wang S, Tang Y, Ma D, Yin X, Deng Y, Yuan Y, Li M, Hu W, Chen D, Li G, Liu Q, Tan P, Fan S, Shi M, Su W, Xu RH. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial. Nat Med. 2024 Aug;30(8):2189-2198. Epub 2024 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03223376
==Paclitaxel & Ramucirumab==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Wilke et al. 2014 (RAINBOW) 	2010-2012 	Phase 3 (E-RT-esc)	Paclitaxel	Seems to have longer OS (primary endpoint)Median OS: 9.6 vs 7.4 mo(HR 0.81, 95% CI 0.68-0.96)
Xu et al. 2021 (RAINBOW-Asia)	2017-2020 	Phase 3 (E-esc) 	Paclitaxel	Seems to have longer PFS (co-primary endpoint)Median PFS: 4.1 vs 3.15 mo(HR 0.77, 95% CI 0.61-0.955)
Note: RAINBOW included patients with GE junction malignancy (79% gastric, 21% GE junction).
====Prior treatment criteria====
*RAINBOW: documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline
====Targeted therapy====
*Ramucirumab (Cyramza) 8 mg/kg IV over 60 minutes once per day on days 1 & 15, given first
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15, given second
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
#RAINBOW-Asia: Xu RH, Zhang Y, Pan H, Feng J, Zhang T, Liu T, Qin Y, Qin S, Yin X, Liu B, Ba Y, Yang N, Voon PJ, Tanasanvimon S, Zhou C, Zhang WL, Shen L. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Dec;6(12):1015-1024. Epub 2021 Oct 6. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02898077
#RAMIRIS: NCT03081143
==Pembrolizumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Fuchs et al. 2018 (KEYNOTE-059) 	2015-03-02 to 2016-05-26	Phase 2 (RT) 	 	ORR: 12% (95% CI 8-16)
Shitara et al. 2018 (KEYNOTE-061)	2015-06-04 to 2016-07-26	Phase 3 (E-switch-ooc)	Paclitaxel	Seems to have longer OS1 (co-primary endpoint)Median OS: 9.1 vs 8.3 mo(HR 0.81, 95% CI 0.66-1.00)
1Reported efficacy is based on the 2021 update, for the CPS at least 1 group.
Note: Both studies included patients with GE junction malignancy:
*KEYNOTE-059: 48.3% gastric, 51.4% GE junction and 57.1% of patients had a PD-L1 CPS score of at least 1
*KEYNOTE-061: 68.8% gastric, 31.2% GE junction and 66% of all patients receiving pembrolizumab had a PD-L1 CPS score of at least 1
====Biomarker eligibility criteria====
PD-L1 (combined positive score > 1%) as determined by an FDA-approved test.
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
#KEYNOTE-059: Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018 May 10;4(5):e180013. Epub 2018 May 10. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02335411
#KEYNOTE-061: Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo MD, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. Epub 2018 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02370498
##HRQoL analysis: Van Cutsem E, Amonkar M, Fuchs CS, Alsina M, Özgüroğlu M, Bang YJ, Chung HC, Muro K, Goekkurt E, Benson AB 3rd, Sun W, Wainberg ZA, Norquist JM, Chen X, Shih CS, Shitara K. Health-related quality of life in advanced gastric/gastroesophageal junction cancer with second-line pembrolizumab in KEYNOTE-061. Gastric Cancer. 2021 Nov;24(6):1330-1340. Epub 2021 Aug 7. Erratum in: Gastric Cancer. 2021 Nov;24(6):1341. link to original article link to PMC article EuroPMC
##Update: Fuchs CS, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Van Cutsem E, Elme A, Thuss-Patience P, Chau I, Ohtsu A, Bhagia P, Wang A, Shih CS, Shitara K. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2022 Jan;25(1):197-206. Epub 2021 Sep 1. link to original article link to PMC article EuroPMC
==Ramucirumab monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Fuchs et al. 2013 (REGARD)	2009-2012 	Phase 3 (E-RT-esc)	Placebo 	Seems to have longer OS (primary endpoint)Median OS: 5.2 vs 3.8 mo(HR 0.78, 95% CI 0.60-0.998)
Note: this study included patients with GE junction malignancy (75% gastric, 25% GE junction).
====Prior treatment criteria====
*REGARD: Disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment
====Targeted therapy====
*Ramucirumab (Cyramza) 8 mg/kg IV over 60 minutes 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
==Regorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Pavlakis et al. 2016 (INTEGRATE) 	2012-2014 	Randomized Phase 2 (E-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: 2.6 vs 0.9 mo(HR 0.40, 95% CI 0.28-0.59)
Pavlakis et al. 2025 (INTEGRATE IIa)	2016-10 to 2021-09 	Phase 3 (E-esc) 	Placebo 	Longer OS (primary endpoint)Median OS: 4.5 vs 4 mo(HR 0.68, 95% CI 0.52-0.90)
Note: INTEGRATE included patients with GEJ malignancy: 62% stomach or other, 38% GEJ
====Targeted therapy====
*Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21
28-day cycles
===References===
#INTEGRATE: Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, Bang YJ, Alcindor T, O'Callaghan CJ, Burnell MJ, Tebbutt NC, Rha SY, Lee J, Cho JY, Lipton LR, Wong M, Strickland A, Kim JW, Zalcberg JR, Simes J, Goldstein D. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II trial. J Clin Oncol. 2016 Aug 10;34(23):2728-35. Epub 2016 Jun 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ANZCTR12612000239864
#INTEGRATE IIa: Pavlakis N, Shitara K, Sjoquist K, Martin A, Jaworski A, Tebbutt N, Bang YJ, Alcindor T, O'Callaghan C, Strickland A, Rha SY, Lee KW, Kim JS, Bai LY, Hara H, Oh DY, Yip S, Zalcberg J, Price T, Simes J, Goldstein D. INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer. J Clin Oncol. 2025 Feb;43(4):453-463. link to original article dosing details in manuscript have been reviewed by our editors link to EuroPMC NCT02773524
==Trifluridine and tipiracil monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Shitara et al. 2018 (TAGS)	2016-2018 	Phase 3 (E-RT-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 5.7 vs 3.6 mo(HR 0.69, 95% CI 0.56-0.85)
====Chemotherapy====
*Trifluridine and tipiracil (Lonsurf) 35 mg/m2 PO twice per day on days 1 to 5, 8 to 12
28-day cycles
===References===
#TAGS: Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov 1;19(11):1437-48. Epub 2018 Oct 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02500043
##HRQoL analysis: Tabernero J, Alsina M, Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Ando T, Yalçın Ş, Van Cutsem E, Sabater J, Skanji D, Leger C, Amellal N, Ilson DH. Health-related quality of life associated with trifluridine/tipiracil in heavily pretreated metastatic gastric cancer: results from TAGS. Gastric Cancer. 2020 Jul;23(4):689-698. Epub 2020 Mar 4. link to original article link to PMC article EuroPMC
#INTEGRATEIIb: NCT04879368
Category:Gastric cancer regimens
Category:Disease-specific pages
Category:Gastroesophageal cancers