Latest revision as of 00:54, 27 January 2024

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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 esophageal cancer page for regimens that include active anticancer treatment.

Neoadjuvant induction therapy

No neoadjuvant therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Urba et al. 2001	1989-1994	Randomized Phase 2 (C)	Cisplatin, 5-FU, Vinblastine, RT	Did not meet primary endpoint of OS
Kelsen et al. 1998 (RTOG 8911)	1990-1995	Phase 3 (C)	CF	Did not meet primary endpoint of OS
Girling et al. 2002 (UK MRC OE02)	1992-1998	Phase 3 (C)	CF	Seems to have inferior OS¹
Burmeister et al. 2005	1994-2000	Phase 3 (C)	CF & RT	Did not meet primary endpoint of PFS
Tepper et al. 2008 (CALGB 9781)	1997-2000	Phase 3 (C)	CF & RT	Inferior OS
Mariette et al. 2014 (FFCD 9901)	2000-2009	Phase 3 (C)	CF & RT	Did not meet primary endpoint of OS
van Hagen et al. 2012 (CROSS)	2004-2008	Phase 3 (C)	Carboplatin, Paclitaxel, RT	Inferior OS

¹Reported 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.

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

Surgery

References

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
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 PubMed
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
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 PubMed
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 link to PMC article PubMed NCT00003118
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 link to supplement PubMed NTR487
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, Spillenaar Bilgen EJ, 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
2. Update: Eyck BM, van Lanschot JJB, Hulshof MCCM, van der Wilk BJ, Shapiro J, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch OR, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Spillenaar Bilgen EJ, van der Sangen MJC, Rozema T, Ten Kate FJW, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS Study Group. Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol. 2021 Jun 20;39(18):1995-2004. Epub 2021 Apr 23. link to original article PubMed
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 PubMed NCT00047112

Adjuvant therapy

Placebo

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kelly et al. 2021 (CheckMate 577)	2016-2019	Phase 3 (C)	Nivolumab	Inferior DFS

No active antineoplastic treatment.

Preceding treatment

Neoadjuvant chemoradiotherapy (not specified), then Surgery, with residual pathologic disease

References

CheckMate 577: Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 Investigators. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021 Apr 1;384(13):1191-1203. link to original article PubMed NCT02743494

Metastatic or locally advanced disease, subsequent lines of therapy

Placebo

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dutton et al. 2014 (COG-esoph)	2009-2011	Phase 3 (C)	Gefitinib	Did not meet primary endpoint of OS

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

No active antineoplastic treatment.

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

References

COG-esoph: 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 NCT01243398

Difference between revisions of "Esophageal cancer - null regimens"

Latest revision as of 00:54, 27 January 2024

Contents

Neoadjuvant induction therapy

No neoadjuvant therapy

Regimen

Subsequent treatment

References

Adjuvant therapy

Placebo

Regimen

Preceding treatment

References

Metastatic or locally advanced disease, subsequent lines of therapy

Placebo

Regimen

References

Navigation menu

Search

@@ Line 1: / Line 1: @@
-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 [[Esophageal cancer|main esophageal cancer page]] for current regimens.
+<span id="BackToTop"></span>
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
+[[#top|Back to Top]]
+</div>
+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 [[Esophageal cancer|main esophageal cancer page]] for regimens that include active anticancer treatment.
 {{TOC limit|limit=3}}
@@ Line 5: / Line 9: @@
 =Neoadjuvant induction therapy=
 ==No neoadjuvant therapy==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 20: / Line 21: @@
 |1989-1994
 | style="background-color:#1a9851" |Randomized Phase 2 (C)
-|[[#Cisplatin.2C_Fluorouracil.2C_Vinblastine.2C_RT_99|Cisplatin, 5-FU, Vinblastine, RT]]
+|[[#Cisplatin.2C_Fluorouracil.2C_Vinblastine.2C_RT_999|Cisplatin, 5-FU, Vinblastine, RT]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199707173370304 Bosset et al. 1997]
+|[https://doi.org/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]
-|1989-1995
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_RT_99|Cisplatin & RT]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123658/ Boonstra et al. 2011]
-|1989-1996
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_cancer#Cisplatin_.26_Etoposide_.28EP.29|EP]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199608153350702 Walsh et al. 1996]
-|1990-1995
-| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|[[Esophageal_cancer#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]
 |1990-1995
 | style="background-color:#1a9851" |Phase 3 (C)
@@ Line 47: / Line 30: @@
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010601%2991%3A11%3C2165%3A%3AAID-CNCR1245%3E3.0.CO%3B2-H Ancona et al. 2001]
+|[https://doi.org/10.1016/S0140-6736(02)08651-8 Girling et al. 2002 (UK MRC OE02)]
-|1992-1997
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_cancer#Cisplatin_.26_Fluorouracil_.28CF.29|CF]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08651-8/fulltext Girling et al. 2002 (UK MRC OE02)]
 |1992-1998
 | style="background-color:#1a9851" |Phase 3 (C)
@@ Line 59: / Line 36: @@
 | style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70288-6/fulltext Burmeister et al. 2005]
+|[https://doi.org/10.1016/S1470-2045(05)70288-6 Burmeister et al. 2005]
 |1994-2000
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[Esophageal_cancer#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]
-|1994-2002
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Complex_multipart_regimens#MAGIC|Perioperative ECF]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://doi.org/10.1200/jco.2010.33.0597 Ychou et al. 2011 (ACCORD 07)]
-|1995-2003
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Complex_multipart_regimens#ACCORD_07|Perioperative CF]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ Tepper et al. 2008 (CALGB 9781)]
@@ Line 82: / Line 47: @@
 |[[Esophageal_cancer#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]
 | style="background-color:#d73027" |Inferior OS
-|-
-|[https://doi.org/10.1093/annonc/mdh219 Lee et al. 2004]
-|1999-2002
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_cancer#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
 |-
 |[https://doi.org/10.1200/JCO.2013.53.6532 Mariette et al. 2014 (FFCD 9901)]
@@ Line 95: / Line 54: @@
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1112088 van Hagen et al. 2012 (CROSS)]
+|[https://doi.org/10.1056/NEJMoa1112088 van Hagen et al. 2012 (CROSS)]
 |2004-2008
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[Esophageal_cancer#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|Carboplatin, Paclitaxel, RT]]
 | style="background-color:#d73027" |Inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145832/ Yang et al. 2018 (NEOCRTEC5010)]
-|2007-2014
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_cancer#Cisplatin.2C_Vinorelbine.2C_RT|Cisplatin, Vinorelbine, RT]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
@@ Line 111: / Line 64: @@
 ''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.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Subsequent treatment====
 *[[Surgery#Esophagectomy|Surgery]]
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1056/NEJM199812313392704 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9869669/ PubMed]
-#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. [https://www.nejm.org/doi/full/10.1056/NEJM199608153350702 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8672151 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.2006.10.4760 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17704421/ PubMed]
-#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. [https://www.nejm.org/doi/full/10.1056/NEJM199707173370304 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9219702 PubMed]
+#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. [https://doi.org/10.1200/JCO.2001.19.2.305 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11208820/ PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9869669 PubMed]
+#'''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. [https://doi.org/10.1016/S0140-6736(02)08651-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12049861/ PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2006.10.4760 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17704421 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.2009.22.2083 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19770374/ PubMed]
-#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. [https://doi.org/10.1200/JCO.2001.19.2.305 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11208820 PubMed]
+#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. [https://doi.org/10.1016/S1470-2045(05)70288-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16129366/ PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010601%2991%3A11%3C2165%3A%3AAID-CNCR1245%3E3.0.CO%3B2-H link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11391598 PubMed]
+#'''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. [https://doi.org/10.1200/jco.2007.12.9593 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18309943/ PubMed] [https://clinicaltrials.gov/study/NCT00003118 NCT00003118]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08651-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12049861 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1112088 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1112088/suppl_file/nejmoa1112088_appendix.pdf link to supplement] [https://pubmed.ncbi.nlm.nih.gov/22646630/ PubMed] NTR487
-##'''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. [https://doi.org/10.1200/JCO.2009.22.2083 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19770374 PubMed]
+##'''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, Spillenaar Bilgen EJ, 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. [https://doi.org/10.1016/S1470-2045(15)00040-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26254683/ PubMed]
-#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. [https://doi.org/10.1093/annonc/mdh219 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15151953 PubMed]
-#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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70288-6/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16129366 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16822992 PubMed] ISRCTN93793971
-#'''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. [https://doi.org/10.1200/jco.2007.12.9593 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18309943 PubMed] NCT00003118
-#'''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. [https://doi.org/10.1200/jco.2010.33.0597 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21444866 PubMed] NCT00002883
-#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. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-181 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123658/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21595951 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1112088 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1112088/suppl_file/nejmoa1112088_appendix.pdf link to appendix with details about administration] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22646630 PubMed] NTR487
-##'''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, Spillenaar Bilgen EJ, 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00040-6/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26254683 PubMed]
 ##'''Update:''' Eyck BM, van Lanschot JJB, Hulshof MCCM, van der Wilk BJ, Shapiro J, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch OR, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Spillenaar Bilgen EJ, van der Sangen MJC, Rozema T, Ten Kate FJW, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS Study Group. Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol. 2021 Jun 20;39(18):1995-2004. Epub 2021 Apr 23. [https://doi.org/10.1200/jco.20.03614 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33891478/ PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2013.53.6532 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24982463 PubMed] NCT00047112
+#'''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. [https://doi.org/10.1200/JCO.2013.53.6532 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24982463/ PubMed] [https://clinicaltrials.gov/study/NCT00047112 NCT00047112]
-#'''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. [https://doi.org/10.1200/JCO.2018.79.1483 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145832/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30089078 PubMed] NCT01216527
-##'''Update:''' 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, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J. Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial. JAMA Surg. 2021 Aug 1;156(8):721-729. [https://doi.org/10.1001/jamasurg.2021.2373 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8223138/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34160577/ PubMed]
 =Adjuvant therapy=
-==Observation==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.jtcvs.org/article/S0022-5223(97)70146-6/fulltext Ando et al. 1997 (JCOG8806)]
-|1988-1991
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_Vindesine_99|Cisplatin & Vindesine]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]
-|1991-1998
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#FULV.2FFULV_.26_RT|FULV/FULV & RT]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://doi.org/10.1200/JCO.2003.12.095 Ando et al. 2003 (JCOG 9204)]
-|1992-1997
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
-| style="background-color:#fc8d59" |Seems to have inferior DFS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]
-|1994-2002
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Complex_multipart_regimens#MAGIC|Perioperative ECF]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://doi.org/10.1200/jco.2010.33.0597 Ychou et al. 2011 (ACCORD 07)]
-|1995-2003
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Complex_multipart_regimens#ACCORD_07|Perioperative CF]]
-| style="background-color:#fc8d59" |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====
-*[[Surgery#Esophageal_cancer_surgery|Surgery]]
-===References===
-#'''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. [https://www.jtcvs.org/article/S0022-5223(97)70146-6/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/9270637 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11547741 PubMed]
-#'''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; [[Study_Groups#JCOG|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. [https://doi.org/10.1200/JCO.2003.12.095 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14673047 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16822992 PubMed] ISRCTN93793971
-#'''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. [https://doi.org/10.1200/jco.2010.33.0597 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21444866 PubMed] NCT00002883
 ==Placebo==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 227: / Line 106: @@
 |}
 ''No active antineoplastic treatment.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*Neoadjuvant chemoradiotherapy (not specified), then [[Surgery#Esophageal_cancer_surgery|Surgery]], with residual pathologic disease
+*Neoadjuvant [[Regimen_classes#Chemoradiotherapy-based_regimen|chemoradiotherapy (not specified)]], then [[Surgery#Esophageal_cancer_surgery|Surgery]], with residual pathologic disease
+</div></div>
 ===References===
-#'''CheckMate 577:''' Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 Investigators. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021 Apr 1;384(13):1191-1203. [https://doi.org/10.1056/nejmoa2032125 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33789008/ PubMed] NCT02743494
+#'''CheckMate 577:''' Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 Investigators. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021 Apr 1;384(13):1191-1203. [https://doi.org/10.1056/nejmoa2032125 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33789008/ PubMed] [https://clinicaltrials.gov/study/NCT02743494 NCT02743494]
 =Metastatic or locally advanced disease, subsequent lines of therapy=
-==Best supportive care==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext Ford et al. 2013 (COUGAR-02)]
-|2008-2012
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Docetaxel_monotherapy|Docetaxel]]
-| style="background-color:#d73027" |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===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext link to original article]  [https://pubmed.ncbi.nlm.nih.gov/24332238 PubMed] ISRCTN13366390
 ==Placebo==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70024-5/fulltext Dutton et al. 2014 (COG-esoph)]
+|[https://doi.org/10.1016/S1470-2045(14)70024-5 Dutton et al. 2014 (COG-esoph)]
 |2009-2011
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Gefitinib_monotherapy_99|Gefitinib]]
+|[[#Gefitinib_monotherapy_999|Gefitinib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext Fuchs et al. 2013 (REGARD)]
-|2009-2012
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_adenocarcinoma#Ramucirumab_monotherapy|Ramucirumab]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://doi.org/10.1200/jco.2015.63.5995 Li et al. 2016]
-|2011-2012
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_adenocarcinoma#Apatinib_monotherapy|Apatinib]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext Kang et al. 2017 (ATTRACTION-2)]
-|2014-2016
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_adenocarcinoma#Nivolumab_monotherapy|Nivolumab]]
-| style="background-color:#d73027" |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.''
+''Note: 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.''
+''No active antineoplastic treatment.''
-''Fuchs patients: 100% adenocarcinoma histology (25% gastroesophageal junction, 75% gastric origin).''
+''COG-esoph patients: 24% squamous cell, 76% adenocarcinoma histology. 78% esophageal, 22% gastroesophageal junction''
-''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.''
+</div>
 ===References===
+#'''COG-esoph:''' 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. [https://doi.org/10.1016/S1470-2045(14)70024-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24950987/ PubMed] [https://clinicaltrials.gov/study/NCT01243398 NCT01243398]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24094768 PubMed] NCT00917384
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70024-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24950987 PubMed] NCT01243398
-#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. [https://doi.org/10.1200/jco.2015.63.5995 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26884585 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28993052 PubMed] 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. [https://link.springer.com/article/10.1007%2Fs10120-018-0899-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394726/ link to original article] [https://pubmed.ncbi.nlm.nih.gov/30506519 PubMed]
 [[Category:Esophageal cancer regimens]]