Gastric cancer - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main gastric cancer page for regimens that include active anticancer treatment.


Neoadjuvant chemotherapy

No neoadjuvant therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schuhmacher et al. 2010 (EORTC 40954) 1999-2004 Phase 3 (C) FULV & Cisplatin Did not meet primary endpoint of OS
Iwasaki et al. 2020 (JCOG0501) 2005-2013 Phase 3 (C) Cisplatin & S-1 Did not meet primary endpoint of OS
Kang et al. 2021 (PRODIGY) 2012-2017 Phase 3 (C) DOS Seems to have inferior PFS

No antineoplastic treatment prior to surgery.

Subsequent treatment

References

  1. EORTC 40954: Schuhmacher C, Gretschel S, Lordick F, Reichardt P, Hohenberger W, Eisenberger CF, Haag C, Mauer ME, Hasan B, Welch J, Ott K, Hoelscher A, Schneider PM, Bechstein W, Wilke H, Lutz MP, Nordlinger B, Van Cutsem E, Siewert JR, Schlag PM. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol. 2010 Dec 10;28(35):5210-8. Epub 2010 Nov 8. link to original article link to PMC article PubMed NCT00004099
  2. JCOG0501: Iwasaki Y, Terashima M, Mizusawa J, Katayama H, Nakamura K, Katai H, Yoshikawa T, Ito S, Kaji M, Kimura Y, Hirao M, Yamada M, Kurita A, Takagi M, Lee SW, Takagane A, Yabusaki H, Hihara J, Boku N, Sano T, Sasako M. Gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer (JCOG0501): an open-label, phase 3, randomized controlled trial. Gastric Cancer. 2021 Mar;24(2):492-502. Epub 2020 Nov 16. link to original article PubMed NCT00252161
  3. 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 link to PMC article PubMed NCT01515748

Adjuvant therapy

Observation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Allum et al. 1989 1976-NR Phase 3 (C) 5-FU & Mitomycin Did not meet primary endpoint of OS
Macdonald et al. 1995 (SWOG-7804) 1978-1991 Phase 3 (C) FAM Did not meet primary endpoint of OS
Lise et al. 1995 (EORTC 40813) 1980-1989 Phase 3 (C) FAM2 Might have inferior DFS
Coombes et al. 1990 1981-1984 Phase 3 (C) FAM Did not meet efficacy endpoints of DFS/OS
Hallissey et al. 1994 1981-1986 Phase 3 (C) 1. FAM
2. Radiation therapy 		Did not meet primary endpoint of OS
Nakajima et al. 1999 (JCOG8801) 1988-1992 Phase 3 (C) 5-FU & Mitomycin, then UFT Did not meet primary endpoint of OS
Cirera et al. 1999 1988-1994 Phase 3 (C) Mitomycin & Tegafur Seems to have inferior OS
Bouché et al. 2005 (FFCD 8801) 1989-1997 Phase 3 (C) Cisplatin & 5-FU Did not meet primary endpoint of OS
Nitti et al. 2005 1990-1998 Phase 3 (C) 1. FAMTX
2. FEMTX 		Did not meet primary endpoint of OS
Macdonald et al. 2001 (INT-0116) 1991-1998 Phase 3 (C) FULV & RT Inferior OS
Nashimoto et al. 2003 (JCOG 9206-1) 1993-01 to 1994-12 Phase 3 (C) 5-FU, Ara-C, Mitomycin, then 5-FU Did not meet primary endpoint of RFS
Miyashiro et al. 2011 (JCOG 9206-2) 1993-1998 Phase 3 (C) IV/IP Cisplatin, then UFT Did not meet primary endpoint of OS
Kulig et al. 2010 1995-1999 Phase 3 (C) EAP Did not meet primary endpoint of OS
Di Costanzo et al. 2008 1995-2000 Phase 3 (C) PELF Did not meet primary endpoint of OS
De Vita et al. 2007 (GOIM 9602) 1996-2001 Phase 3 (C) ELFE Did not meet primary endpoint of OS
Nakajima et al. 2007 (NSAS-GC) 1997-2001 Phase 3 (C) UFT Inferior OS
Sakuramoto et al. 2007 (ACTS-GC) 2001-2004 Phase 3 (C) S-1 Inferior OS

No further treatment after surgery.

Preceding treatment

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

References

  1. Allum WH, Hallissey MT, Kelly KA; British Stomach Cancer Group. Adjuvant chemotherapy in operable gastric cancer: 5 year follow-up of first British Stomach Cancer Group trial. Lancet. 1989 Mar 18;1(8638):571-4. link to original article PubMed
  2. Coombes RC, Schein PS, Chilvers CE, Wils J, Beretta G, Bliss JM, Rutten A, Amadori D, Cortes-Funes H, Villar-Grimalt A, McArdle C, Rauschecker HF, Boven E, Vassilopoulos P, Welvaart K, Pinto Ferreira E, Wiig J, Gisselbrecht C, Rougier P, Woods EMA; International Collaborative Cancer Group. A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. J Clin Oncol. 1990 Aug;8(8):1362-9. link to original article PubMed
  3. Hallissey MT, Dunn JA, Ward LC, Allum WH; British Stomach Cancer Group. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet. 1994 May 28;343(8909):1309-12. link to original article PubMed
  4. EORTC 40813: Lise M, Nitti D, Marchet A, Sahmoud T, Buyse M, Duez N, Fiorentino M, Dos Santos JG, Labianca R, Rougier P, Gignoux M. Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer. J Clin Oncol. 1995 Nov;13(11):2757-63. link to original article PubMed
  5. SWOG-7804: Macdonald JS, Fleming TR, Peterson RF, Berenberg JL, McClure S, Chapman RA, Eyre HJ, Solanki D, Cruz AB Jr, Gagliano R, Estes NC, Tangen CM, Rivkin S. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study. Ann Surg Oncol. 1995 Nov;2(6):488-94. link to original article PubMed
  6. JCOG8801: Nakajima T, Nashimoto A, Kitamura M, Kito T, Iwanaga T, Okabayashi K, Goto M; Gastric Cancer Surgical Study Group. Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Lancet. 1999 Jul 24;354(9175):273-7. link to original article PubMed
  7. Cirera L, Balil A, Batiste-Alentorn E, Tusquets I, Cardona T, Arcusa A, Jolis L, Saigí E, Guasch I, Badia A, Boleda M. Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol. 1999 Dec;17(12):3810-5. link to original article PubMed
  8. INT-0116: Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. link to original article PubMed
    1. Update: Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. link to original article link to PMC article PubMed
  9. JCOG 9206-1: Nashimoto A, Nakajima T, Furukawa H, Kitamura M, Kinoshita T, Yamamura Y, Sasako M, Kunii Y, Motohashi H, Yamamoto S; Gastric Cancer Surgical Study Group, Japan Clinical Oncology Group. Randomized trial of adjuvant chemotherapy with mitomycin, Fluorouracil, and Cytosine arabinoside followed by oral Fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1. J Clin Oncol. 2003 Jun 15;21(12):2282-7. link to original article PubMed
  10. FFCD 8801: Bouché O, Ychou M, Burtin P, Bedenne L, Ducreux M, Lebreton G, Baulieux J, Nordlinger B, Martin C, Seitz JF, Tigaud JM, Echinard E, Stremsdoerfer N, Milan C, Rougier P; Fédération Francophone de Cancérologie Digestive Group. Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Ann Oncol. 2005 Sep;16(9):1488-97. Epub 2005 Jun 6. link to original article PubMed
  11. Nitti D, Wils J, Dos Santos JG, Fountzilas G, Conte PF, Sava C, Tres A, Coombes RC, Crivellari D, Marchet A, Sanchez E, Bliss JM, Homewood J, Couvreur ML, Hall E, Baron B, Woods E, Emson M, Van Cutsem E, Lise M; EORTC GI Group; ICCG. Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer: a combined analysis of the EORTC GI Group and the ICCG. Ann Oncol. 2006 Feb;17(2):262-9. Epub 2005 Nov 17. link to original article PubMed
  12. GOIM 9602: De Vita F, Giuliani F, Orditura M, Maiello E, Galizia G, Di Martino N, Montemurro F, Cartenì G, Manzione L, Romito S, Gebbia V, Ciardiello F, Catalano G, Colucci G; Gruppo Oncologico Italia Meridionale. Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study). Ann Oncol. 2007 Aug;18(8):1354-8. Epub 2007 May 24. link to original article PubMed
  13. 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 PubMed NCT00152217
    1. Update: Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. link to original article PubMed
  14. 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 PubMed NCT00152243
  15. Di Costanzo F, Gasperoni S, Manzione L, Bisagni G, Labianca R, Bravi S, Cortesi E, Carlini P, Bracci R, Tomao S, Messerini L, Arcangeli A, Torri V, Bilancia D, Floriani I, Tonato M; Italian Oncology Group for Cancer Research. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst. 2008 Mar 19;100(6):388-98. Epub 2008 Mar 11. link to original article PubMed
  16. Kulig J, Kolodziejczyk P, Sierzega M, Bobrzynski L, Jedrys J, Popiela T, Dadan J, Drews M, Jeziorski A, Krawczyk M, Starzynska T, Wallner G. Adjuvant chemotherapy with etoposide, adriamycin and cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial. Oncology. 2010;78(1):54-61. Epub 2010 Mar 6. link to original article PubMed
  17. JCOG 9206-2: Miyashiro I, Furukawa H, Sasako M, Yamamoto S, Nashimoto A, Nakajima T, Kinoshita T, Kobayashi O, Arai K; Gastric Cancer Surgical Study Group in the Japan Clinical Oncology Group. Randomized clinical trial of adjuvant chemotherapy with intraperitoneal and intravenous cisplatin followed by oral fluorouracil (UFT) in serosa-positive gastric cancer versus curative resection alone: final results of the Japan Clinical Oncology Group trial JCOG9206-2. Gastric Cancer. 2011 Aug;14(3):212-8. Epub 2011 Feb 19. link to original article PubMed NCT00147147

Metastatic or locally advanced disease, first-line

Best supportive care

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pyrhönen et al. 1995 1986-1992 Phase 3 (C) FEMTX Inferior OS

No antineoplastic treatment.

References

  1. Pyrhönen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer. 1995 Mar;71(3):587-91. link to original article link to PMC article PubMed

Metastatic or locally advanced disease, subsequent lines of therapy

Best supportive care

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thuss-Patience et al. 2011 2002-2006 Phase 3 (C) Irinotecan Seems to have inferior OS
Kang et al. 2012 (SMC 2008-08-055) 2008-2010 Phase 3 (C) 1a. Docetaxel
1b. Irinotecan 		Inferior OS
Ford et al. 2014 (COUGAR-02) 2008-2012 Phase 3 (C) Docetaxel Inferior OS
Ohtsu et al. 2013 (GRANITE-1) 2009-07 to 2010-11 Phase 3 (C) Everolimus Did not meet primary endpoint of OS

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

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

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

References

  1. Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. link to original article PubMed NCT00144378
  2. SMC 2008-08-055: Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. link to original article PubMed NCT00821990
  3. COUGAR-02: Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. link to original article PubMed NCT00978549
  4. GRANITE-1: Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, Muro K, Kim YH, Ferry D, Tebbutt NC, Al-Batran SE, Smith H, Costantini C, Rizvi S, Lebwohl D, Van Cutsem E. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013 Nov 1;31(31):3935-43. Epub 2013 Sep 16. link to original article link to PMC article PubMed NCT00879333

Placebo

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fuchs et al. 2013 (REGARD) 2009-2012 Phase 3 (C) Ramucirumab Seems to have inferior OS
Pavlakis et al. 2016 (INTEGRATE) 2012-2014 Randomized Phase 2 (C) Regorafenib Inferior PFS
Kang et al. 2017 (ATTRACTION-2) 2014-2016 Phase 3 (C) Nivolumab Inferior OS
Shitara et al. 2018 (TAGS) 2016-2018 Phase 3 (C) Trifluridine/tipiracil Inferior OS
Kang et al. 2024 (ANGEL) 2017-03-14 to 2018-10-31 Phase 3 (C) Apatinib Did not meet primary endpoint of OS

All studies included patients with GE junction malignancy:

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

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

No active antineoplastic treatment.

References

  1. REGARD: Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3.link to original article PubMed NCT00917384
  2. INTEGRATE: Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, Bang YJ, Alcindor T, O'Callaghan CJ, Burnell MJ, Tebbutt NC, Rha SY, Lee J, Cho JY, Lipton LR, Wong M, Strickland A, Kim JW, Zalcberg JR, Simes J, Goldstein D. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II trial. J Clin Oncol. 2016 Aug 10;34(23):2728-35. Epub 2016 Jun 20. link to original article link to PMC article PubMed ANZCTR12612000239864
  3. ATTRACTION-2: Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. link to original article PubMed NCT02267343
  4. TAGS: Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov 1;19(11):1437-48. Epub 2018 Oct 18. link to original article PubMed NCT02500043
  5. ANGEL: Kang YK, Ryu MH, Di Bartolomeo M, Chau I, Yoon H, Kim JG, Lee KW, Oh SC, Takashima A, Kryzhanivska A, Chao Y, Evesque L, Schenker M, McGinn A, Zhao Y, Lee J, Wyrwicz L, Boku N. Rivoceranib, a VEGFR-2 inhibitor, monotherapy in previously treated patients with advanced or metastatic gastric or gastroesophageal junction cancer (ANGEL study): an international, randomized, placebo-controlled, phase 3 trial. Gastric Cancer. 2024 Mar;27(2):375-386. Epub 2024 Jan 28. link to original article link to PMC article PubMed NCT03042611
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