Esophageal cancer - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the main esophageal cancer page for current regimens.


Neoadjuvant induction therapy

No neoadjuvant therapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Urba et al. 2001 1989-1994 Randomized Phase II (C) Cisplatin, 5-FU, Vinblastine, RT Did not meet primary endpoint of OS
Bosset et al. 1997 1989-1995 Phase III (C) Cisplatin & RT Did not meet primary endpoint of OS60
Boonstra et al. 2011 1989-1996 Phase III (C) EP Seems to have inferior OS
Walsh et al. 1996 1990-1995 Randomized Phase II (C) CF & RT Inferior OS
Kelsen et al. 1998 (RTOG 8911) 1990-1995 Phase III (C) CF Did not meet primary endpoint of OS
Ancona et al. 2001 1992-1997 Phase III (C) CF Did not meet primary endpoint of OS
Girling et al. 2002 (UK MRC OE02) 1992-1998 Phase III (C) CF Seems to have inferior OS (*)
Burmeister et al. 2005 1994-2000 Phase III (C) CF & RT Did not meet primary endpoint of PFS
Cunningham et al. 2006 (MAGIC) 1994-2002 Phase III (C) Perioperative ECF Inferior OS
Ychou et al. 2011 (ACCORD 07) 1995-2003 Phase III (C) Perioperative CF Seems to have inferior OS
Tepper et al. 2008 (CALGB 9781) 1997-2000 Phase III (C) CF & RT Inferior OS
Lee et al. 2004 1999-2002 Phase III (C) CF & RT Did not meet primary endpoint of OS50%
Mariette et al. 2014 (FFCD 9901) 2000-2009 Phase III (C) CF & RT Did not meet primary endpoint of OS
van Hagen et al. 2012 (CROSS) 2004-2008 Phase III (C) Carboplatin, Paclitaxel, RT Inferior OS
Yang et al. 2018 (NEOCRTEC5010) 2007-2014 Phase III (C) Cisplatin, Vinorelbine, RT Seems to have inferior OS

Note: Reported efficacy for UK MRC OE02 is based on the 2009 update.

Surgery as primary therapy; i.e., no induction chemotherapy or chemoradiotherapy, and no adjuvant therapy.

MAGIC patients: 100% adenocarcinoma of the stomach or lower third of the esophagus. 74% gastric, 15% lower esophagus, 11% gastroesophageal junction.

CALGB 9781 patients: 75% adenocarcinoma, 25% squamous cell histology. 5% with ECOG PS of 2.

CROSS patients: 75% adenocarcinoma, 23% squamous cell, 2% other. 24% gastroesophageal junction.

Subsequent treatment

References

  1. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996 Aug 15;335(7):462-7. Erratum in: N Engl J Med 1999 Jul 29;341(5):384. link to original article contains verified protocol PubMed
  2. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, Lozach P, Ollier JC, Pavy JJ, Mercier M, Sahmoud T. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997 Jul 17;337(3):161-7. link to original article PubMed
  3. RTOG 8911: Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. link to original article PubMed
    1. Update: Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG; Radiation Therapy Oncology Group; USA Intergroup. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007 Aug 20;25(24):3719-25. link to original article PubMed
  4. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001 Jan 15;19(2):305-13. link to original article contains protocol PubMed
  5. Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, Bonavina L, Peracchia A. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001 Jun 1;91(11):2165-74. link to original article contains protocol PubMed
  6. UK MRC OE02: Girling DJ, Bancewicz J, Clark PI, Smith DB, Donnelly RJ, Fayers PM, Weeden S, Hutchinson T, Harvey A, Lyddiard J; Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33. link to original article PubMed
    1. Update: Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009 Oct 20;27(30):5062-7. Epub 2009 Sep 21. link to original article PubMed
  7. Lee JL, Park SI, Kim SB, Jung HY, Lee GH, Kim JH, Song HY, Cho KJ, Kim WK, Lee JS, Kim SH, Min YI. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol. 2004 Jun;15(6):947-54. link to original article PubMed
  8. Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, Denham JW; Trans-Tasman Radiation Oncology Group; Australasian Gastro-Intestinal Trials Group. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005 Sep;6(9):659-68. link to original article contains protocol PubMed
  9. MAGIC: Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. link to original article contains verified protocol PubMed
  10. CALGB 9781: Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086-92. link to original article contains verified protocol link to PMC article PubMed
  11. ACCORD 07: Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. link to original article contains verified protocol PubMed
  12. Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, Siersema PD, Dinjens WN, van Lanschot JJ, Tilanus HW, van der Gaast A. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011 May 19;11:181. link to original article contains verified protocol link to PMC article PubMed
  13. CROSS: van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. link to original article contains verified protocol link to appendix with details about administration contains verified protocol PubMed
    1. Update: Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. Epub 2015 Aug 5. link to original article PubMed
  14. FFCD 9901: Mariette C, Dahan L, Mornex F, Maillard E, Thomas PA, Meunier B, Boige V, Pezet D, Robb WB, Le Brun-Ly V, Bosset JF, Mabrut JY, Triboulet JP, Bedenne L, Seitz JF. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol. 2014 Aug 10;32(23):2416-22. Epub 2014 Jun 30. link to original article contains protocol PubMed
  15. NEOCRTEC5010: Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Lordick F, D'Journo XB, Cerfolio RJ, Korst RJ, Novoa NM, Swanson SJ, Brunelli A, Ismail M, Fernando HC, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J; AME Thoracic Surgery Collaborative Group. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial. J Clin Oncol. 2018 Sep 20;36(27):2796-2803. Epub 2018 Aug 8. link to original article link to PMC article PubMed

Adjuvant therapy

Observation

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ando et al. 1997 (JCOG8806) 1988-1991 Phase III (C) Cisplatin & Vindesine Did not meet primary endpoint of OS60
Macdonald et al. 2001 (INT-0116) 1991-1998 Phase III (C) FULV/FULV & RT Inferior OS
Ando et al. 2003 (JCOG 9204) 1992-1997 Phase III (C) CF Seems to have inferior DFS
Cunningham et al. 2006 (MAGIC) 1994-2002 Phase III (C) Perioperative ECF Inferior OS
Ychou et al. 2011 (ACCORD 07) 1995-2003 Phase III (C) Perioperative CF Seems to have inferior OS

Surgery as primary therapy; i.e., no induction chemotherapy or chemoradiotherapy, and no adjuvant therapy.

McDonald et al. patients: 100% adenocarcinoma histology, originating from the stomach or gastroesophageal junction. MAGIC patients: 100% adenocarcinoma of the stomach or lower third of the esophagus. 74% gastric, 15% lower esophagus, 11% gastroesophageal junction.

Preceding treatment

References

  1. JCOG8806: Ando N, Iizuka T, Kakegawa T, Isono K, Watanabe H, Ide H, Tanaka O, Shinoda M, Takiyama W, Arimori M, Ishida K, Tsugane S. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg. 1997 Aug;114(2):205-9. link to original article PubMed
  2. INT-0116: Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. link to original article contains verified protocol PubMed
  3. JCOG 9204: Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, Takiyama W, Watanabe H, Isono K, Aoyama N, Makuuchi H, Tanaka O, Yamana H, Ikeuchi S, Kabuto T, Nagai K, Shimada Y, Kinjo Y, Fukuda H; JCOG. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. J Clin Oncol. 2003 Dec 15;21(24):4592-6. link to original article contains verified protocol PubMed
  4. MAGIC: Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. link to original article contains verified protocol PubMed
  5. ACCORD 07: Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. link to original article contains verified protocol PubMed

Metastatic or locally advanced disease, subsequent lines of therapy

Best supportive care

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ford et al. 2013 (COUGAR-02) 2008-2012 Phase III (C) Docetaxel Inferior OS

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

References

  1. 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

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dutton et al. 2014 (COG-esoph) 2009-2011 Phase III (C) Gefitinib Did not meet primary endpoint of OS
Fuchs et al. 2013 (REGARD) 2009-2012 Phase III (C) Ramucirumab Seems to have inferior OS
Li et al. 2016 2011-2012 Phase III (C) Apatinib Seems to have inferior OS
Kang et al. 2017 (ATTRACTION-2) 2014-2016 Phase III (C) Nivolumab Inferior OS

Note: 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." COG is renamed as COG-esoph so as not to confuse with the Children's Oncology Group.

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

Fuchs patients: 100% adenocarcinoma histology (25% gastroesophageal junction, 75% gastric origin).

Dutton patients: 24% squamous cell, 76% adenocarcinoma histology. 78% esophageal, 22% gastroesophageal junction

Li patients: 100% adenocarcinoma histology (70% gastric origin, 22% gastroesophageal junction, 8% unknown). All patients with at least two prior lines of treatment.

ATTRACTION-2: 100% adenocarcinoma. Patients had progression on two prior lines of systemic 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 contains verified protocol PubMed
  2. COG: Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W, Thompson J, Harrison M, Chatterjee A, Falk S, Garcia-Alonso A, Fyfe DW, Hubner RA, Gamble T, Peachey L, Davoudianfar M, Pearson SR, Julier P, Jankowski J, Kerr R, Petty RD. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 2014 Jul;15(8):894-904. Epub 2014 Jun 17. link to original article PubMed
  3. Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R, Wang Z, Wang Q, Ouyang X, Yang Y, Ba Y, Liang J, Lin X, Luo D, Zheng R, Wang X, Sun G, Wang L, Zheng L, Guo H, Wu J, Xu N, Yang J, Zhang H, Cheng Y, Wang N, Chen L, Fan Z, Sun P, Yu H. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016 May 1;34(13):1448-54. Epub 2016 Feb 16. link to original article PubMed
  4. ATTRACTION-2: Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Kato K, Satoh T, Muro K, Yoshikawa T, Tamura T, Hamamoto Y, Chin K, Minashi K, Tsuda M, Yamaguchi K, Machida N, Esaki T, Goto M, Komatsu Y, Nakajima TE, Sugimoto N, Yoshida K, Oki E, Nishina T, Tsuji A, Fujii H, Kunieda K, Saitoh S, Omuro Y, Azuma M, Iwamoto Y, Taku K, Fushida S, Chen LT, Kang YK, Boku N. A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2). Gastric Cancer. 2019 Mar;22(2):344-354. Epub 2018 Dec 1. link to original article link to original article PubMed