Esophageal cancer

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 Ryan Nguyen, DO
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 Neeta K. Venepalli, MD, MBA
University of Illinois at Chicago
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Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.

Please be aware that some regimens listed here are studies for gastric cancer, not esophageal cancer, reflecting the overlap between treatments of esophageal and gastric cancer.
There are several related dedicated pages:

56 regimens on this page
74 variants on this page


Guidelines

ASCO

ESMO

NCCN

Neoadjuvant induction therapy

Capecitabine & Cisplatin (CX)

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CX: Cisplatin & Xeloda (Capecitabine)
XP: Xeloda (Capecitabine) & Platinol (Cisplatin)

Regimen

Study Evidence
Lee et al. 2007esoph Retrospective

The study was for patients with stage IV disease.

Patients 97% adenocarcinoma, 3% squamous cell histology; 3% with ECOG PS of 2.

  • Patients with M1b disease (visceral metastases) received the chemotherapy only part until progression of disease or unacceptable toxicity.
  • Patients with M1a or M1b (non-viscertal metastases) received 2 cycles of the chemotherapy only part, underwent treatment with chemoradiation, and then treatment continued with--presumably, but not outright specified in the paper--chemotherapy only until progression of disease or unacceptable toxicity.

Chemotherapy

21-day cycles

Subsequent treatment

References

  1. Retrospective: Lee SS, Kim SB, Park SI, Kim YH, Ryu JS, Song HY, Shin JH, Jung HY, Lee GH, Choi KD, Cho KJ, Kim JH. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regimen in patients with three different settings of stage IV esophageal cancer. Jpn J Clin Oncol. 2007 Nov;37(11):829-35. Epub 2007 Oct 19. link to original article contains verified protocol PubMed

Cisplatin & Docetaxel

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ruhstaller et al. 2009 (SAKK 75/02) 2003-2006 Phase II
Ruhstaller et al. 2018 (SAKK 75/08) 2010-2013 Phase III (C) Cisplatin, Docetaxel, Cetuximab Did not meet primary endpoint of PFS

SAKK 75/02 patients: 55% adenocarcinoma, 45% squamous cell histology

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment

References

  1. SAKK 75/02: Ruhstaller T, Widmer L, Schuller JC, Roth A, Hess V, Mingrone W, von Moos R, Borner M, Pestalozzi BC, Balmermajno S, Köberle D, Terraciano L, Schnider A, Bodis S, Popescu R; Swiss Group for Clinical Cancer Research. Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02). Ann Oncol. 2009 Sep;20(9):1522-8. Epub 2009 May 22. link to original article contains verified protocol PubMed
  2. SAKK 75/08: Ruhstaller T, Thuss-Patience P, Hayoz S, Schacher S, Knorrenschild JR, Schnider A, Plasswilm L, Budach W, Eisterer W, Hawle H, Mariette C, Hess V, Mingrone W, Montemurro M, Girschikofsky M, Schmidt SC, Bitzer M, Bedenne L, Brauchli P, Stahl M; Swiss Group for Clinical Cancer Research; German Esophageal Cancer Study Group; Arbeitsgemeinschaft Medikamentöse Tumortherapie; Fédération Francophone de Cancérologie Digestive. Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08). Ann Oncol. 2018 Jun 1;29(6):1386-1393. link to original article PubMed NCT01107639

Cisplatin & Etoposide (EP)

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Boonstra et al. 2011 1989-1996 Phase III (E-esc) Surgery alone Seems to have superior OS

Patients: 100% squamous cell histology

Chemotherapy

21-day cycle for 2 to 4 cycles

Subsequent treatment

References

  1. 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

Cisplatin & Fluorouracil (CF)

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CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol (Cisplatin)

Regimen variant #2, 80/4000, 4 day 5-FU infusion

Study Years of enrollment Evidence Comparator Comparative Efficacy
Girling et al. 2002 (UK MRC OE02) 1992-1998 Phase III (E-esc) Surgery alone Seems to have superior OS (*)

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

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment

Regimen variant #3, 80/4000, 5 day 5-FU infusion

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ando et al. 2011 (JCOG 9907) 2000-2006 Phase III (E-switch-ic) Adjuvant CF Seems to have superior OS

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment

Regimen variant #5, 100/5000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kelsen et al. 1998 (RTOG 8911) 1990-1995 Phase III (E-esc) Surgery alone Did not meet primary endpoint of OS
Ancona et al. 2001 1992-1997 Phase III (E-esc) Surgery alone Did not meet primary endpoint of OS

Note: it is not entirely clear from Ancona et al. 2001 whether this was a 96-hour or 120-hour infusion; there was option to proceed after the 2nd cycle. In both trials, this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Ancona et al. 2001 patients: 100% squamous cell carcinoma histology

Chemotherapy

28-day cycle for 3 cycles

Subsequent treatment

  • RTOG 8911: Surgery, then adjuvant CF
  • Ancona et al. 2001: Surgery, performed 3 to 4 weeks after the last cycle of chemotherapy

References

  1. 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 contains verified protocol 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
  2. 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 partial protocol PubMed
  3. 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 contains protocol 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
  4. JCOG 9907: Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. link to original article contains verified protocol PubMed NCT00190554

Cisplatin & Irinotecan (IC)

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IC: Irinotecan & Cisplatin

Regimen

Study Evidence
Ilson et al. 2011 Phase II

Illson et al. patients: 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated history; 33% gastroesophageal junction.

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 & 8, prior to chemotherapy
  • One of the following:
  • At least 500 mL D5NS or NS as supportive hydration
  • Atropine (Atropen) 0.5 to 1 mg IV prn cholinergic symptoms

21-day cycle for 2 cycles

Subsequent treatment

References

  1. Ilson DH, Minsky BD, Ku GY, Rusch V, Rizk N, Shah M, Kelsen DP, Capanu M, Tang L, Campbell J, Bains M. Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer. Cancer. 2011 Oct 11. link to original article contains verified protocol PubMed

EOF

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EOF: Epirubicin, Oxaliplatin, Fluorouracil

Regimen

Note: This regimen is sometimes listed as a perioperative option, but it is not clearly described as one by the primary reference to the REAL-2 study. Study participants could have had either locally advanced or metastatic disease, and the primary reference did not list a uniform policy about what patients underwent surgery and its timing--although a few patients were mentioned to undergo surgery.

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles; for perioperative use per some guidelines, 3 cycles preoperatively and 3 cycles postoperatively would be used

EOX

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EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)
EOC: Epirubicin, Oxaliplatin, Capecitabine

Regimen

Note: This regimen is sometimes listed as a perioperative option, but it is not clearly described as one by the primary reference to the REAL-2 study. Study participants could have had either locally advanced or metastatic disease, and the primary reference did not list a uniform policy about what patients underwent surgery and its timing--although a few patients were mentioned to undergo surgery.

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles; for perioperative use per some guidelines, 3 cycles preoperatively and 3 cycles postoperatively would be used

FLEP

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FLEP: Fluorouracil, Leucovorin, Etoposide, Platinol (Cisplatin)

Regimen

Study Evidence
Stahl et al. 2005 Non-randomized portion of RCT

For historic reference.

Chemotherapy

Subsequent treatment

  • PE & RT (40 Gy), then surgery versus PE & RT (at least 65 Gy)

References

  1. Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, Klump B, Budach W, Teichmann R, Schmitt M, Schmitt G, Franke C, Wilke H. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005 Apr 1;23(10):2310-7. Erratum in: J Clin Oncol. 2006 Jan 20;24(3):531. link to original article PubMed

PCF

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PCF: Paclitaxel, Cisplatin, Fluorouracil

Regimen

Study Evidence
Zhao et al. 2015 (ZY-01) Non-randomized portion of RCT

Chemotherapy

2 cycles

Subsequent treatment

  • Surgery, then adjuvant PCF x 2 versus no further treatment

References

  1. ZY-01: Zhao Y, Dai Z, Min W, Sui X, Kang H, Zhang Y, Ren H, Wang XJ. Perioperative versus Preoperative Chemotherapy with Surgery in Patients with Resectable Squamous Cell Carcinoma of Esophagus: A Phase III Randomized Trial. J Thorac Oncol. 2015 Sep;10(9):1349-1356. link to original article contains protocol PubMed

Neoadjuvant chemoradiotherapy

Note: while these regimens are listed as neoadjuvant (pre-operative), in some cases they are also used as definitive therapy in patients that are not surgical candidates.

Capecitabine, Carboplatin, Paclitaxel, RT

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Capecitabine, Carboplatin, Paclitaxel, RT: Capecitabine, Carboplatin, Paclitaxel, Radiation Therapy

Regimen

Study Evidence
Czito et al. 2006 Pilot, <20 pts

The primary reference did not specify whether patients were intended to proceed to surgery.

Patients: 77% adenocarcinoma, 23% squamous cell histology. 54% lower thoracic, 23% midthoracic, 23% gastroesophageal junction.

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy

6-week course

Subsequent treatment

  • Patients were evaluated for surgery, performed 6 to 8 weeks after chemoradiotherapy completion. Patients could receive adjuvant chemotherapy, beginning 4 to 12 weeks postoperatively

References

  1. Phase I: Czito BG, Kelsey CR, Hurwitz HI, Willett CG, Morse MA, Blobe GC, Fernando NH, D'Amico TA, Harpole DH, Honeycutt W, Yu D, Bendell JC. A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma. Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1002-7. Epub 2006 Dec 29. link to original article contains verified protocol PubMed

Capecitabine, Cisplatin, RT

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CX & RT: Cisplatin, Xeloda (Capecitabine), Radiation Therapy

Regimen

Note: This study was for patients with stage IV disease. Please reference the original paper, as there were no patients who only received this neoadjuvant treatment, and they did not undergo surgical resection of disease.

Patients: 3% adenocarcinoma, 97% squamous cell histology; 3% with ECOG PS of 2.

Preceding treatment

Chemotherapy

7-day cycles until radiation therapy is complete

Radiotherapy

  • Concurrent radiation therapy, total of 54 Gy given (dose per fraction and total duration of treatment was not specified)

One course

References

  1. Retrospective: Lee SS, Kim SB, Park SI, Kim YH, Ryu JS, Song HY, Shin JH, Jung HY, Lee GH, Choi KD, Cho KJ, Kim JH. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regimen in patients with three different settings of stage IV esophageal cancer. Jpn J Clin Oncol. 2007 Nov;37(11):829-35. Epub 2007 Oct 19. link to original article contains verified protocol--please see note above, as patients in this study did not undergo surgery PubMed

Capecitabine, Docetaxel, RT

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Capecitabine, Docetaxel, RT: Capecitabine, Docetaxel, Radiation Therapy

Regimen

Study Evidence
Wood et al. 2013 (D-9939) Phase 1

Note: Some guidelines recommend different dosing but this is the only publication that we could locate with dosing details. Treatment is assumed to begin on a Monday.

Chemotherapy

7-day cycle for 5 cycles

Radiotherapy

5-week course

References

  1. Phase 1: Wood MD, Zaki BI, Gordon SR, Sutton JE Jr, Lisovsky M, Gui J, Bubis JA, Dragnev KH, Rigas JR. Trimodality therapy for stage II-III carcinoma of the esophagus: a dose-ranging study of concurrent capecitabine, docetaxel, and thoracic radiotherapy. J Thorac Oncol. 2013 Apr;8(4):487-94. link to original article link to PMC article contains verified protocol PubMed

Capecitabine, Docetaxel, Oxaliplatin, RT

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Capecitabine, Docetaxel, Oxaliplatin, RT: Capecitabine, Docetaxel, Oxaliplatin, Radiation Therapy

Regimen

Study Years of enrollment Evidence
Spigel et al. 2010 (SCRI GI 57) 2005-2008 Phase I/II

Patients: 69% adenocarcinoma, 18% squamous cell, 12% not otherwise specified. 69% distal esophagus, 16% midesophagus, 14% gastroesophageal junction.

Chemotherapy

Supportive medications

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy

5-week course

Subsequent treatment

  • Endoscopy, CT scan, and--if available--endoscopic ultrasound for restaging 2 to 4 weeks after finishing chemoradiation, with subsequent treatment as follows:
    • Appropriate candidates: Surgical resection sometime during weeks 9 to 12
    • Patients who were no longer surgical candidates: Additional radiation therapy to a total dose of 64.8 Gy

References

  1. SCRI GI 57: Spigel DR, Greco FA, Meluch AA, Lane CM, Farley C, Gray JR, Clark BL, Burris HA 3rd, Hainsworth JD. Phase I/II trial of preoperative oxaliplatin, docetaxel, and capecitabine with concurrent radiation therapy in localized carcinoma of the esophagus or gastroesophageal junction. J Clin Oncol. 2010 May 1;28(13):2213-9. Epub 2010 Mar 29. link to original article contains verified protocol PubMed NCT00193128

Capecitabine, Oxaliplatin, RT

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CapeOx & RT: Capecitabine, Oxaliplatin, Radiation Therapy

Regimen

Study Evidence
Javle et al. 2009 Phase I

Chemotherapy

Radiotherapy

5-week course

Subsequent treatment

References

  1. Phase I: Javle MM, Yang G, Nwogu CE, Wilding GE, O'Malley L, Vinjamaram S, Schiff MD, Nava HR, LeVea C, Clark KR, Prey JD, Smith PF, Pendyala L. Capecitabine, oxaliplatin and radiotherapy: a phase IB neoadjuvant study for esophageal cancer with gene expression analysis. Cancer Invest. 2009 Feb;27(2):193-200. link to original article contains protocol PubMed

Capecitabine, Paclitaxel, RT

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Capecitabine, Paclitaxel, RT: Capecitabine, Paclitaxel, Radiation Therapy

Regimen

Chemotherapy

Radiotherapy

5-week course

References

  1. No primary reference could be found for this regimen.

Carboplatin, Fluorouracil, RT

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Carboplatin, Fluorouracil, RT: Carboplatin, Fluorouracil, Radiation Therapy

Regimen

Study Evidence
Zemanoa et al. 2009 Non-randomized

Patients: 86% squamous cell, 8% adenocarcinoma, 6% other histology. 3% ECOG PS of 2.

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy.
    • If surgery was contraindicated, total dose was increased to 50.4 to 56.8 Gy.

42-day course

Subsequent treatment

  • Upper endoscopy and CT chest and abdomen was performed after completion of chemoradiation
  • Surgery planned to be done 4 to 6 weeks after finishing chemoradiation

References

  1. Zemanova M, Petruzelka L, Pazdro A, Kralova D, Smejkal M, Pazdrova G, Honova H. Prospective non-randomized study of preoperative concurrent platinum plus 5-fluorouracil-based chemoradiotherapy with or without paclitaxel in esophageal cancer patients: long-term follow-up. Dis Esophagus. 2010 Feb;23(2):160-7. Epub 2009 Jun 9. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, RT

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Carboplatin, Paclitaxel, RT: Carboplatin, Paclitaxel, Radiation Therapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
van Meerten et al. 2006 2001-2004 Phase II
van Hagen et al. 2012 (CROSS) 2004-2008 Phase III (E-esc) Surgery alone Superior OS

van Meerten et al. Patients: 76% adenocarcinoma, 22% squamous cell, 2% large cell histology. 91% lower esophagus, 9% thoracic esophagus

van Hagen et al. Patients: 75% adenocarcinoma, 23% squamous cell, 2% other. 24% gastroesophageal junction

Chemotherapy

Supportive medications

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 23 fractions, for a total dose of 41.4 Gy

5-week course

Subsequent treatment

  • Surgery planned to be done within 6 weeks of finishing chemoradiation; van Hagen et al. 2012 said surgery was done as soon as possible after finishing chemoradiotherapy, preferably within 4 to 6 weeks

References

  1. van Meerten E, Muller K, Tilanus HW, Siersema PD, Eijkenboom WM, van Dekken H, Tran TC, van der Gaast A. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer. 2006 May 22;94(10):1389-94. link to PMC article contains verified protocol link to PMC article contains verified protocol PubMed
  2. 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 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

Cisplatin, Docetaxel, RT

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DC & RT: Docetaxel, Cisplatin, Radiation Therapy

Regimen

Study Evidence
Ruhstaller et al. 2009 (SAKK 75/02) Phase II

Patients: 55% adenocarcinoma, 45% squamous cell histology

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy

5-week course

Subsequent treatment

  • Surgery, 3 to 8 weeks after finishing chemoradiation

References

  1. SAKK 75/02: Ruhstaller T, Widmer L, Schuller JC, Roth A, Hess V, Mingrone W, von Moos R, Borner M, Pestalozzi BC, Balmermajno S, Köberle D, Terraciano L, Schnider A, Bodis S, Popescu R; Swiss Group for Clinical Cancer Research. Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02). Ann Oncol. 2009 Sep;20(9):1522-8. Epub 2009 May 22. link to original article contains verified protocol PubMed

Cisplatin, Fluorouracil, RT

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CF & RT: Cisplatin, Fluourouracil, Radiation Therapy

Regimen variant #1, 75/3200 x 2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mariette et al. 2014 (FFCD 9901) 2000-2009 Phase III (E-esc) Surgery alone Did not meet primary endpoint of OS

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.80 Gy fractions x 25 fractions, for a total dose of 45 Gy

5-week course

Subsequent treatment

Regimen variant #2, 75/4000 x 2

Study Evidence
Bedenne et al. 2007 (FFCD 9102) Non-randomized portion of RCT

Patients: 89% epidermoid, 11% glandular histology.

Chemotherapy

  • Cisplatin (Platinol) 15 mg/m2 IV over 60 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)

Supportive medications

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 2 Gy fractions x 23 fractions, for a total dose of 46 Gy
    • Earlier in the study, some patients instead received split-course radiation therapy, 3 Gy fractions x 5 fractions given on days 1 to 5. 15 Gy per cycle; total dose after 2 cycles is 30 Gy.

4.5-week course

Subsequent treatment

Regimen variant #3, 80/3200

Study Years of enrollment Evidence Comparator Comparative Efficacy
Burmeister et al. 2005 1994-2000 Phase III (E-esc) Surgery alone Did not meet primary endpoint of PFS

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 2.33 Gy fractions x 15 fractions for a total dose of 35 Gy

3-week course

Subsequent treatment

Regimen variant #4, 100/4000 x 2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Tepper et al. 2008 (CALGB 9781) 1997-2000 Phase III (E-esc) Surgery alone Superior OS

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

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV over 30 minutes once on day 1, given first
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1, given second (total dose per cycle: 4000 mg/m2)

28-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, then a 5.4 Gy final boost, for a total dose of 50.4 Gy, starting within 24 hours of start of chemotherapy

5-week course

Subsequent treatment

  • EGD and CT chest and abdomen done within 4 weeks after finishing radiation therapy. Only patients who still had resectable disease that was stable or responded would proceed to surgery. Surgery was planned to be done 3 to 8 weeks after finishing chemoradiation.

References

  1. 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
  2. FFCD 9102: Bedenne L, Michel P, Bouché O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007 Apr 1;25(10):1160-8. link to original article contains verified protocol PubMed
  3. 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
  4. 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

Cisplatin, Irinotecan, RT

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Cisplatin, Irinotecan, RT: Cisplatin, Irinotecan, Radiation Therapy

Regimen

Study Evidence
Ilson et al. 2011 Phase II

Patients: 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated history; 33% gastroesophageal junction.

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions, for a total of 50.4 Gy

5.5-week course

Subsequent treatment

  • Surgery, performed 4 to 8 weeks after chemoradiation

References

  1. Ilson DH, Minsky BD, Ku GY, Rusch V, Rizk N, Shah M, Kelsen DP, Capanu M, Tang L, Campbell J, Bains M. Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer. Cancer. 2011 Oct 11. link to original article contains verified protocol PubMed

Cisplatin, Paclitaxel, RT

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Cisplatin, Paclitaxel, RT: Cisplatin, Paclitaxel, Radiation Therapy

Regimen

Study Evidence
Urba et al. 2003 Phase II

Patients: 83% adenocarcinoma, 14% squamous cell, 3% undifferentiated histology

Chemotherapy

Supportive medications

Radiotherapy

  • Concurrent radiation therapy, 1.5 Gy fractions given twice per day on days 1 to 5, 8 to 12, 15 to 19, with at least 6 hours between fractions, for a total dose of 45 Gy

4-week course

Subsequent treatment

  • Barium swallow and CT chest and abdomen done about 1 week prior to surgery to rule out metastatic disease. Surgery to be done on approximately day 50

References

  1. Urba SG, Orringer MB, Ianettonni M, Hayman JA, Satoru H. Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. Cancer. 2003 Nov 15;98(10):2177-83. link to original article contains verified protocol PubMed

Cisplatin, Vinorelbine, RT

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Cisplatin, Vinorelbine, RT: Cisplatin, Vinorelbine, Radiation Therapy

Regimen variant #1, standard cisplatin

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2018 (NEOCRTEC5010) 2007-2014 Phase III (E-esc) No neoadjuvant therapy Seems to have superior OS

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 2.0 Gy fractions x 20 fractions, for a total dose of 40 Gy

4-week course

Subsequent treatment

Regimen variant #2, split-dose cisplatin

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2018 (NEOCRTEC5010) 2007-2014 Phase III (E-esc) No neoadjuvant therapy Seems to have superior OS

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 2.0 Gy fractions x 20 fractions, for a total dose of 40 Gy

4-week course

Subsequent treatment

References

  1. 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

Docetaxel, Fluorouracil, RT

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Docetaxel, Fluorouracil, RT: Docetaxel, Fluorouracil, Radiation Therapy

Regimen variant #1, 15/4000 x 2

Study Evidence
Hihara et al. 2007 Phase II

Patients: 86% squamous cell, 14% carcinosarcoma histology

Chemotherapy

  • Docetaxel (Taxotere) 7.5 mg/m2 IV over 60 minutes once per day on days 1 & 8
  • Fluorouracil (5-FU) 250 mg/m2/day IV continuous infusion over 120 hours, started on days 1, 8, 15 (total dose per cycle: 4000 mg/m2)

Supportive medications

28-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 2 Gy fractions x 30 to 33 fractions, for a total dose of 60 to 66 Gy

6- to 6.5-week course

Regimen variant #2

Note: No primary reference could be found for this regimen.

Chemotherapy

Radiotherapy

7-day cycle for 5 cycles

References

  1. Phase I: Hihara J, Yoshida K, Hamai Y, Emi M, Yamaguchi Y, Wadasaki K. Phase I study of docetaxel (TXT) and 5-fluorouracil (5-FU) with concurrent radiotherapy in patients with advanced esophageal cancer. Anticancer Res. 2007 Jul-Aug;27(4C):2597-603. link to original article contains verified protocol PubMed

Fluorouracil, Oxaliplatin, RT

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Fluorouracil, Oxaliplatin, RT: Fluorouracil, Oxaliplatin, Radiation Therapy

Regimen variant #1, 45 Gy

Study Evidence
Lorenzen et al. 2008 Phase I/II

Patients: 100% squamous cell etiology, 65% poor differentiated or undifferentiated

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy

35-day course

Subsequent treatment

  • Surgery, 4 to 6 weeks after finishing chemoradiation

Regimen variant #2, 50.4 Gy, bi-weekly oxaliplatin

Study Evidence
Khushalani et al. 2002 Phase II

58% patients were classified as stage IV disease

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 20 to 22 fractions, for an initial total dose of 36 to 39.6 Gy, started on day 8
    • Followed by off-cord conformal oblique fields, 5.4 to 9 Gy given to the clinical target volume (CTV). A second off-cord phase to the gross tumor volume (GTV) of 5.4 Gy was then given, for a total dose delivered of 50.4 Gy to the GTV.

6-week course

Subsequent treatment

  • Upper GI endoscopy and CT chest, abdomen, and pelvis were done after completion of chemoradiation, and patients without progressive stage II-III disease were offered surgery followed by another cycle of oxaliplatin and 5-FU. Patients who could not proceed to surgery were given another 1 to 2 cycles of oxaliplatin and 5-FU within 2 weeks.

Regimen variant #3, 50.4 Gy, weekly oxaliplatin

Study Years of enrollment Evidence
Ajani et al. 2013 (MDACC 2004-0703) 2005-2011 Non-randomized portion of RCT

Note: it is unclear how long the 5-FU continuous infusions were in this regimen; the authors have been contacted for clarification. Treatment is assumed to start on a Monday.

Preceding treatment

Chemotherapy

7-day cycle for 5 cycles

Radiotherapy

  • Concurrent radiation therapy: 50.4 Gy of proton or photon (intensity modulated) radiation in 28 fractions

5-week course

Subsequent treatment

References

  1. Khushalani NI, Leichman CG, Proulx G, Nava H, Bodnar L, Klippenstein D, Litwin A, Smith J, Nava E, Pendyala L, Smith P, Greco W, Berdzik J, Douglass H, Leichman L. Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol. 2002 Jun 15;20(12):2844-50. link to original article contains verified protocol PubMed
  2. Lorenzen S, Brücher B, Zimmermann F, Geinitz H, Riera J, Schuster T, Roethling N, Höfler H, Ott K, Peschel C, Siewert JR, Molls M, Lordick F. Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial. Br J Cancer. 2008 Oct 7;99(7):1020-6. Epub 2008 Sep 16. link to PMC article contains verified protocol link to PMC article PubMed
  3. MDACC 2004-0703: Ajani JA, Xiao L, Roth JA, Hofstetter WL, Walsh G, Komaki R, Liao Z, Rice DC, Vaporciyan AA, Maru DM, Lee JH, Bhutani MS, Eid A, Yao JC, Phan AP, Halpin A, Suzuki A, Taketa T, Thall PF, Swisher SG. A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer. Ann Oncol. 2013 Nov;24(11):2844-9. Epub 2013 Aug 23. link to original article link to PMC article contains verified protocol PubMed NCT00525915

Definitive therapy

Capecitabine, Cisplatin, RT

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CX & RT: Cisplatin, Xeloda (Capecitabine), Radiation Therapy

Regimen variant #1, 1250/60/50

Study Years of enrollment Evidence Comparator Comparative Efficacy
Crosby et al. 2013 (SCOPE-1) 2008-2012 Phase III (C) Capecitabine, Cisplatin, Cetuximab, RT Did not meet primary endpoint of OS (*)

Note: Reported efficacy is based on the 2017 update.

Patients: 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology

Chemotherapy

21-day cycle for 4 cycles

Radiotherapy

5-week course

Regimen variant #2, 1600/30/54

Study Evidence
Lee et al. 2007esoph Retrospective

Patients: 97% adenocarcinoma, 3% squamous cell histology; 3% with ECOG PS of 2.

The study was for patients with stage IV disease.

  • Patients with M1b disease (visceral metastases) received the chemotherapy only part until progression of disease or unacceptable toxicity.
  • Patients with M1a or M1b (non-visceral metastases) received 2 cycles of the chemotherapy only part, underwent treatment with chemoradiation, and then treatment continued with--presumably, but not outright specified in the paper--chemotherapy only until progression of disease or unacceptable toxicity.

Preceding treatment

Chemotherapy

7-day cycles until radiation therapy is complete

Radiotherapy

  • Concurrent radiation therapy, total of 54 Gy given. Dose per fraction and total duration of treatment were not specified, but based on other regimens, it is suspected to be either 1.8 Gy x 30 fractions or 2 Gy x 27 fractions.

One course

References

  1. Retrospective: Lee SS, Kim SB, Park SI, Kim YH, Ryu JS, Song HY, Shin JH, Jung HY, Lee GH, Choi KD, Cho KJ, Kim JH. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regimen in patients with three different settings of stage IV esophageal cancer. Jpn J Clin Oncol. 2007 Nov;37(11):829-35. Epub 2007 Oct 19. link to original article contains verified protocol PubMed
  2. SCOPE-1: Crosby T, Hurt CN, Falk S, Gollins S, Mukherjee S, Staffurth J, Ray R, Bashir N, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol. 2013 Jun;14(7):627-37. link to original article contains verified protocol PubMed ISCRTN47718479
    1. Update: Crosby T, Hurt CN, Falk S, Gollins S, Staffurth J, Ray R, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G, Mukherjee S. Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer. Br J Cancer. 2017 Mar 14;116(6):709-716. Epub 2017 Feb 14. link to original article contains verified protocol link to PMC article contains verified protocol PubMed

Cisplatin, Docetaxel, RT

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DC & RT: Docetaxel, Cisplatin, Radiation Therapy

Regimen variant #1, 80/60 x 2

Study Evidence
Li et al. 2009 Phase II

Patients: 100% squamous cell histology, 5% gastroesophageal junction. 44% of patients had stage IV disease

Chemotherapy

Supportive medications

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.8 to 2.0 Gy fractions, to start within 24 hours of the start of chemotherapy
    • Patients with stage I to III disease received a total dose of 60 to 64 Gy over 4 to 6 weeks
    • Patients with stage IV disease (lymph node only) received a total dose of 50 to 56 Gy

Note, dose reductions were permitted, see article for specifications

One course

Regimen variant #2

Study Evidence
Day et al. 2010 Phase I

Patients: 46% squamous cell, 54% adenocarcinoma histology

Note: some guidelines suggest a wider dose range of 20 to 30 mg/m2 for both cisplatin and docetaxel. The primary reference also investigated these dose levels, but ultimately recommended 30 mg/m2 dosages for both cisplatin and docetaxel.

Chemotherapy

Supportive medications

  • "Steroid and anti-emetic pre-medication"

Radiotherapy

  • Concurrent radiation therapy, 2 Gy fractions x 25 fractions, for a total dose of 50 Gy, to start within 4 hours after the first dose of chemotherapy.

5-week course

References

  1. Li QQ, Liu MZ, Hu YH, Liu H, He ZY, Lin HX. Definitive concomitant chemoradiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus. 2010 Apr;23(3):253-9. Epub 2009 Aug 28. link to original article contains verified protocol PubMed
  2. Phase I: Day FL, Leong T, Ngan S, Thomas R, Jefford M, Zalcberg JR, Rischin D, McKendick J, Milner AD, Di Iulio J, Matera A, Michael M. Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer. Br J Cancer. 2011 Jan 18;104(2):265-71. Epub 2010 Dec 14. link to original article contains verified protocol link to PMC article PubMed

Cisplatin, Fluorouracil, RT

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CF & RT: Cisplatin, Fluorouracil, Radiation Therapy

Regimen variant #1, 60/4725 x 4 (50 Gy)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Crosby et al. 2013 (SCOPE-1) 2008-2012 Phase III (C) Capecitabine, Cisplatin, Cetuximab, RT Did not meet primary endpoint of OS (*)

Note: This regimen was an alternative for patients who could not swallow pills. Reported efficacy is based on the 2017 update.

Patients: 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology

Chemotherapy

21-day cycle for 4 cycles

Radiotherapy

5-week course

Regimen variant #2, 75/4000 x 2 (50.4 Gy)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Minsky et al. 2002 (RTOG 94-05) 1995-1999 Phase III (C) Cisplatin, 5-FU, high-dose RT Did not meet primary endpoint of OS24
Conroy et al. 2014 (PRODIGE5/ACCORD17) 2004-2011 Phase III (C) See link See link

Patients: RTOG 94-05 included both adenocarcinoma and squamous cell histology

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy as follows:
    • RTOG 94-05: 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy
    • PRODIGE5/ACCORD17: 2.0 Gy fractions x 25 fractions, for a total dose of 50 Gy

5- to 5.5-week course

Subsequent treatment

Regimen variant #3, 75/4000 x 3 (66 Gy)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bedenne et al. 2007 (FFCD 9102) 1993-2000 Phase III (E-switch-ooc) Surgery Equivalent OS

Patients: 89% epidermoid, 11% glandular histology. Note that this was not a formal non-inferiority study but the study met its primary endpoint of equivalence.

Preceding treatment

Chemotherapy

  • Cisplatin (Platinol) 15 mg/m2 IV over 60 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)

Supportive medications

21-day cycle for 1 cycle, then 28-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 2 Gy fractions x 10 fractions, for a total dose of 66 Gy (including the initial 46 Gy)
    • Earlier in the study, some patients instead received split-course radiation therapy

2-week course

Regimen variant #4, 75/4000 x 4 (50 Gy)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Herskovic et al. 1992 (RTOG 85-01) 1986-1990 Phase III (E-esc) Radiation therapy Superior OS

Patients: 88% squamous cell, 12% adenocarcinoma histology. 7% karnofsky performance scale of 50-60.

Chemotherapy

28-day cycle for 1 cycle, then 21-day cycle for 3 cycles

Radiotherapy

  • Concurrent radiation therapy: 2.0 Gy fractions x 15 fractions, then 2.0 Gy fractions x 10 fractions to the initial tumor length plus a 5 cm margin, for a total dose of 50.0 Gy

5-week course

References

  1. RTOG 85-01: Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992 Jun 11;326(24):1593-8. link to original article contains verified protocol PubMed
    1. Update: al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J, Byhardt R, Davis L, Emami B. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol. 1997 Jan;15(1):277-84. link to original article contains verified protocol PubMed
    2. Update: Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL; Radiation Therapy Oncology Group. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA. 1999 May 5;281(17):1623-7. link to original article contains verified protocol PubMed
  2. RTOG 94-05: Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002 Mar 1;20(5):1167-74. link to original article contains verified protocol PubMed
  3. FFCD 9102: Bedenne L, Michel P, Bouché O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007 Apr 1;25(10):1160-8. link to original article contains verified protocol PubMed
  4. SCOPE-1: Crosby T, Hurt CN, Falk S, Gollins S, Mukherjee S, Staffurth J, Ray R, Bashir N, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol. 2013 Jun;14(7):627-37. link to original article contains verified protocol PubMed ISCRTN47718479
    1. Update: Crosby T, Hurt CN, Falk S, Gollins S, Staffurth J, Ray R, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G, Mukherjee S. Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer. Br J Cancer. 2017 Mar 14;116(6):709-716. Epub 2017 Feb 14. link to original article contains verified protocol link to PMC article contains verified protocol PubMed
  5. PRODIGE5/ACCORD17: Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article contains protocol PubMed NCT00861094
    1. HRQoL analysis: Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. link to original article PubMed

Cisplatin, Paclitaxel, RT

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TP & RT: Taxol (Paclitaxel), Platinol (Cisplatin), Radiation Therapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Suntharalingam et al. 2017 (RTOG 0436) 2008-2013 Phase III (C) Cisplatin, Paclitaxel, Cetuximab, RT Did not meet primary endpoint of OS

Patients: 62% adenocarcinoma, 38% squamous cell histology. 14% with M1a disease. 6% with Zubrod PS score 2.

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy

5-week course

References

  1. RTOG 0436: Suntharalingam M, Winter K, Ilson D, Dicker AP, Kachnic L, Konski A, Chakravarthy AB, Anker CJ, Thakrar H, Horiba N, Dubey A, Greenberger JS, Raben A, Giguere J, Roof K, Videtic G, Pollock J, Safran H, Crane CH. Effect of the addition of cetuximab to paclitaxel, cisplatin, and radiation therapy for patients with esophageal cancer: The NRG Oncology RTOG 0436 phase 3 randomized clinical trial. JAMA Oncol. 2017 Nov 1;3(11):1520-1528. link to original article contains verified protocol PubMed NCT00655876

Fluorouracil, Paclitaxel, RT

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Chen et al. 2019 (ESO-Shanghai1) 2012-2015 Phase III (E-switch-ic) Cisplatin, Flourouracil, RT Did not meet primary endpoint of OS36

Inclusion criteria: Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated. The total dose of 5-FU for this portion of the protocol is unclear in the manuscript; dosing here is as clarified by the authors.

Chemotherapy

7-day cycle for 5 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 34 fractions, for a total dose of 61.2 Gy

7-week course

Subsequent treatment

References

  1. ESO-Shanghai1: Chen Y, Ye J, Zhu Z, Zhao W, Zhou J, Wu C, Tang H, Fan M, Li L, Lin Q, Xia Y, Li Y, Li J, Jia H, Lu S, Zhang Z, Zhao K. Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial. J Clin Oncol. 2019 Jul 10;37(20):1695-1703. Epub 2019 Mar 28. link to original article PubMed NCT01591135

FOLFOX4 & RT

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FOLFOX4 & RT: FOLinic acid, Fluorouracil, OXaliplatin, Radiation Therapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Conroy et al. 2014 (PRODIGE5/ACCORD17) 2004-2011 Phase III (E-switch-ic) See link See link

Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m2. Despite being a non-superior experimental arm, this regimen is recommended by some guidelines such as ESMO.

Chemotherapy

14-day cycle for 3 cycles

Radiotherapy

  • Concurrent radiation therapy, 2 Gy fractions x 25 fractions, for a total dose of 50 Gy

5-week course

Subsequent treatment

References

  1. PRODIGE5/ACCORD17: Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article contains protocol PubMed NCT00861094
    1. HRQoL analysis: Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. link to original article PubMed

Radiation therapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Herskovic et al. 1992 (RTOG 85-01) 1986-1990 Phase III (C) Cisplatin, 5-FU, RT Inferior OS

Patients: 88% squamous cell, 12% adenocarcinoma histology. 7% Karnofsky performance scale of 50-60

Radiation as primary therapy; used as a comparator arm and here for reference purposes only.

Radiotherapy

  • External beam radiotherapy total of 32 fractions: 50 Gy of regional treatment and 14 Gy to the boost field, for total dose of 64 Gy

6.4-week course

References

  1. RTOG 85-01: Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992 Jun 11;326(24):1593-8. link to original article contains verified protocol PubMed
    1. Update: al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J, Byhardt R, Davis L, Emami B. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol. 1997 Jan;15(1):277-84. link to original article contains verified protocol PubMed
    2. Update: Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL; Radiation Therapy Oncology Group. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA. 1999 May 5;281(17):1623-7. link to original article contains verified protocol PubMed

Consolidation after definitive therapy

Cisplatin & Fluorouracil (CF)

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CF: Cisplatin & Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Minsky et al. 2002 (RTOG 94-05) 1995-1999 Non-randomized portion of RCT
Conroy et al. 2014 (PRODIGE5/ACCORD17) 2004-2011 Phase III (C) See link See link

Patients: study included both adenocarcinoma and squamous cell histology

Preceding treatment

Chemotherapy

28-day cycle for 2 cycles

References

  1. RTOG 94-05: Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002 Mar 1;20(5):1167-74. link to original article contains verified protocol PubMed
  2. PRODIGE5/ACCORD17: Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article contains protocol PubMed NCT00861094
    1. HRQoL analysis: Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. link to original article PubMed

Fluorouracil & Paclitaxel

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Chen et al. 2019 (ESO-Shanghai1) 2012-2015 Phase III (E-switch-ic) Cisplatin & Flourouracil Did not meet primary endpoint of OS36

Inclusion criteria: Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated

Preceding treatment

Chemotherapy

28-day cycle for 2 cycles

References

  1. ESO-Shanghai1: Chen Y, Ye J, Zhu Z, Zhao W, Zhou J, Wu C, Tang H, Fan M, Li L, Lin Q, Xia Y, Li Y, Li J, Jia H, Lu S, Zhang Z, Zhao K. Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial. J Clin Oncol. 2019 Jul 10;37(20):1695-1703. Epub 2019 Mar 28. link to original article contains verified protocol PubMed NCT01591135

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin 4

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Conroy et al. 2014 (PRODIGE5/ACCORD17) 2004-2011 Phase III (E-switch-ic) See link See link

Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m2. Despite being a non-superior experimental arm, this regimen is recommended by some guidelines such as ESMO.

Preceding treatment

Chemotherapy

14-day cycle for 3 cycles

References

  1. PRODIGE5/ACCORD17: Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article contains protocol PubMed NCT00861094
    1. HRQoL analysis: Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. link to original article PubMed

Adjuvant therapy

Cisplatin & Fluorouracil (CF)

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CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen variant #1, 75/5000

Study Years of enrollment Evidence
Kelsen et al. 1998 (RTOG 8911) 1990-1995 Non-randomized portion of RCT

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Chemotherapy

28-day cycle for 3 cycles

Regimen variant #2, 80/4000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ando et al. 2003 (JCOG 9204) 1992-1997 Phase III (E-esc) Observation Seems to have superior DFS
Ando et al. 2011 (JCOG 9907) 2000-2006 Phase III (C) Neoadjuvant CF Seems to have inferior OS

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. 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 contains verified protocol PubMed
  2. 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
  3. JCOG 9907: Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. link to original article contains verified protocol PubMed NCT00190554

Metastatic or locally advanced disease, first-line

Carboplatin & Paclitaxel (CP)

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Regimen

Study Evidence
Philip et al. 1997 Phase II

Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6.

Philip et al. Patients: locally advanced metastatic or recurrent esophageal or gastric cancer

Chemotherapy

21-day cycles

References

  1. 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. contains protocol PubMed

Cisplatin & Docetaxel

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DC: Docetaxel, Cisplatin
TC: Taxotere (Docetaxel), Cisplatin

Regimen

Study Evidence
Kim et al. 2009 Phase II

Patients: 100% squamous cell histology. 5% with ECOG PS of 2.

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

References

  1. Kim JY, Do YR, Park KU, Kim MK, Lee KH, Bae SH, Ryoo HM, Baek JH, Song HS. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010 May;66(1):31-6. Epub 2009 Sep 18. link to original article contains verified protocol PubMed

Cisplatin & Fluorouracil (CF)

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CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen variant #1, 80/4000, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moehler et al. 2019 (POWER) 2012-2015 Phase III (C) CFP Did not meet primary endpoint of OS

Note: this was the dosing after a mid-protocol amendment.

Chemotherapy

28-day cycles

Regimen variant #2, 100/5000 x 6

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lorenzen et al. 2009 2004-2006 Randomized Phase II (C) CF & Cetuximab Did not meet primary endpoint of ORR

Patients: 100% squamous cell histology. 87% with metastatic disease. No patients with ECOG PS greater than 1.

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes 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 medications

29-day cycle for up to 6 cycles

References

  1. Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article contains verified protocol PubMed
  2. POWER: Moehler M, Maderer A, Thuss-Patience PC, Brenner B, Meiler J, Ettrich TJ, Hofheinz RD, Al-Batran SE, Vogel A, Mueller L, Lutz MP, Lordick F, Alsina M, Borchert K, Greil R, Eisterer W, Schad A, Slotta-Huspenina J, Van Cutsem E, Lorenzen S. Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER). Ann Oncol. 2020 Feb;31(2):228-235. Epub 2019 Dec 16. link to original article contains verified protocol PubMed NCT01627379

Cisplatin, Fluorouracil, Cetuximab

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CF-C: Cisplatin, Fluorouracil, Cetuximab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lorenzen et al. 2009 2004-2006 Randomized Phase II (E-esc) CF Did not meet primary endpoint of ORR

Patients: 100% squamous cell histology. 87% with metastatic disease. No patients with ECOG PS greater than 1.

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1, given first
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2 )

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8, 15, 22
    • Cycles 2 to 6: 250 mg/m2 IV once per day on days 1, 8, 15, 22

Supportive medications

29-day cycle for up to 6 cycles

References

  1. Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article contains verified protocol PubMed

Cisplatin & Fluorouracil (CF) & Pembrolizumab

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CF & Pembrolizumab: Cisplatin, Fluorouracil, Pembrolizumab

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Kato et al. 2020 (KEYNOTE-590) 2017-2020 Phase III (E-esc) CF Superior OS

73% squamous histology.

Immunotherapy

Chemotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. Abstract: Kato et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. link to abstract NCT03189719

Cisplatin & Irinotecan (IC)

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IC: Irinotecan & Cisplatin
CI: Cisplatin & Irinotecan

Regimen variant #1

Study Evidence
Ilson 2004 Phase II

Note: In contrast to the original reference, some guidelines list cisplatin 25 mg/m2 as an alternate dosage.

Patients: 26% squamous cell, 74% adenocarcinoma histology. 85% metastatic disease.

Chemotherapy

21-day cycles

Regimen variant #2

Study Evidence
Ilson et al. 1999 Phase II

Patients: 66% adenocarcinoma, 34% squamous cell histology. Did not receive any prior chemotherapy. 97% with metastatic disease.

Chemotherapy

Supportive medications

42-day cycles

References

  1. Ilson DH, Saltz L, Enzinger P, Huang Y, Kornblith A, Gollub M, O'Reilly E, Schwartz G, DeGroff J, Gonzalez G, Kelsen DP. Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol. 1999 Oct;17(10):3270-5. link to original article contains verified protocol PubMed
  2. Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park). 2004 Dec;18(14 Suppl 14):22-5. link to original article contains protocol PubMed

Cisplatin & Paclitaxel

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Regimen variant #1

Study Evidence
Zhang et al. 2008 Phase II

Patients: 100% squamous cell carcinoma with advanced or metastatic disease. 18% ECOG PS of 2.

Chemotherapy

21-day cycles

Regimen variant #2

Study Evidence
Ilson et al. 2000 Phase II

Note: In contrast to the original reference, some guidelines list the paclitaxel dose as 135 mg/m2. No primary reference could be found for the 135 mg/m2 dosage. The protocol reported here was amended to change the original dose of 250 mg/m2 to 200 mg/m2 based on toxicity and treatment-related deaths.

Patients: 87% adenocarcinoma, 13% squamous cell histology. Included both gastroesophageal junction and esophageal patients. 95% with metastatic disease. None had received prior chemotherapy.

Chemotherapy

Supportive medications

  • "Granulocyte colony stimulating factor support"

21-day cycles

Regimen variant #3

Study Evidence
Petrasch et al. 1998 Phase II

Patients: 25% adenocarcinoma, 75% squamous cell histology. Consisting of unresectable stage III disease, recurrent or metastatic tumors of esophageal origin.

Chemotherapy

Supportive medications

14-day cycles

References

  1. Petrasch S, Welt A, Reinacher A, Graeven U, König M, Schmiegel W. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer. Br J Cancer. 1998 Aug;78(4):511-4. link to PMC article contains verified protocol PubMed
  2. Ilson DH, Forastiere A, Arquette M, Costa F, Heelan R, Huang Y, Kelsen DP. A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J. 2000 Sep-Oct;6(5):316-23. contains protocol PubMed
  3. Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 2008 Feb;31(1):29 to 33. link to original article contains protocol PubMed

Docetaxel & Irinotecan

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Regimen

Study Evidence
Burtness et al. 2009 Phase II

Patients: 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.

Chemotherapy

Supportive medications

21-day cycles

References

  1. Burtness B, Gibson M, Egleston B, Mehra R, Thomas L, Sipples R, Quintanilla M, Lacy J, Watkins S, Murren JR, Forastiere AA. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009 Jul;20(7):1242-8. Epub 2009 May 8. link to original article contains verified protocol link to PMC article PubMed

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ross et al. 2002 1995-1998 Phase III (C) MCF Seems to have non-inferior OS
Cunningham et al. 2008 (REAL-2) 2000-2005 Phase III (C) 1. ECX Non-inferior OS
2. EOF Non-inferior OS
3. EOX Seems to have inferior OS

Ross et al. Patients: adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer.

REAL-2 Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles

References

  1. 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 contains verified protocol PubMed
  2. 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 contains verified protocol PubMed

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2008 (REAL-2) 2000-2005 Phase III (E-switch-ic) 1. ECF Non-inferior OS
2. EOF
3. EOX 		Non-inferior OS

REAL-2 patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. 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 contains verified protocol PubMed

EOF

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EOF: Epirubicin, Oxaliplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2008 (REAL-2) 2000-2005 Phase III (E-switch-ic) 1. ECF
2. ECX 		Non-inferior OS
3. EOX Non-inferior OS

Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles

References

  1. 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 contains verified protocol PubMed

EOX

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EOX: Epirubicin, Oxaliplatin, Xeloda (Capecitabine)
EOC: Epirubicin, Oxaliplatin, Capecitabine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2008 (REAL-2) 2000-2005 Phase III (E-switch-ic) 1. ECF Seems to have superior OS
2. ECX Non-inferior OS
3. EOF Non-inferior OS
Waddell et al. 2013 (REAL3) 2008-2011 Phase III (C) mEOC+P Seems to have superior OS

REAL-2 patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.

REAL3 patients: 99% adenocarcinoma, 1% undifferentiated histology. 39% esophagus, 31% gastroesophageal junction, 30% gastric. 6% ECOF PS of 2. 89% metastatic disease.

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. 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 contains verified protocol PubMed content property of HemOnc.org
  2. 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. contains verified protocol link to PMC article PubMed NCT00824785

Etoposide monotherapy

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Regimen

Study Evidence
Harstrick et al. 1992 Phase II

Note: this is higher than the dose usually employed in modern settings.

Patients: metastatic 100% squamous cell carcinoma of the esophagus, with ECOG PS range 1-2.

Chemotherapy

21-day cycles

References

  1. Harstrick A, Bokemeyer C, Preusser P, Köhne-Wömpner CH, Meyer HJ, Stahl M, Knipp H, Schmoll HJ, Wilke H. Phase II study of single-agent etoposide in patients with metastatic squamous-cell carcinoma of the esophagus. Cancer Chemother Pharmacol. 1992;29(4):321-2. link to original article contains protocol PubMed

mFOLFOX6 & Cetuximab

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mFOLFOX6 & Cetuximab: modified FOLinic acid, Fluorouracil, OXaliplatin, Cetuximab
FOLFOX-C: FOLinic acid, Fluorouracil, OXaliplatin, Cetuximab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Enziger et al. 2016 (CALGB 80403/ECOG E1206) 2006-2009 Randomized Phase II (E-switch-ic) 1. ECF-C
2. IC-C 		Not powered to draw conclusions

Patients: 91% adenocarcinoma, 9% squamous cell histology. 56% esophageal, 43% gastroesophageal tumors.

To receive full-dose therapy in this trial, patients were required to have an absolute neutrophil count of 1,000/µL or greater, platelets of 75,000/µL or greater, and no other grade 2 or higher treatment-related toxicity.

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given third (total dose per cycle: 2800 mg/m2)
  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given second, with oxaliplatin
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given second, with leucovorin

Targeted therapy

  • Cetuximab (Erbitux) as follows, given first:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once on day 8
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

  1. CALGB 80403/ECOG E1206: Enzinger PC, Burtness BA, Niedzwiecki D, Ye X, Douglas K, Ilson DH, Villaflor VM, Cohen SJ, Mayer RJ, Venook A, Benson AB 3rd, Goldberg RM. CALGB 80403 (Alliance)/E1206: a randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers. J Clin Oncol. 2016 Aug 10;34(23):2736-42. Epub 2016 Jul 5. link to original article contains verified protocol link to PMC article PubMed NCT00381706

FULV & Gemcitabine

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FULV & Gemcitabine: 5-FU, LeucoVorin (Folinic acid), Gemcitabine

Regimen

Study Evidence
Morgan-Meadows et al. 2005 Phase II

Patients: 100% esophageal cancer (both squamous and adenocarcinoma histology). Patients received no prior therapy.

Chemotherapy

28-day cycles

References

  1. Morgan-Meadows S, Mulkerin D, Berlin JD, Kim K, Bailey H, Saphner T, Jumonville A, Hansen R, Ahuja H, McFarland T, Thomas JP. A phase II trial of gemcitabine, 5-fluorouracil and leucovorin in advanced esophageal carcinoma. Oncology. 2005;69(2):130-4. Epub 2005 Aug 23. link to original article contains protocol PubMed

LdCF

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LdCF: Liposomal doxorubicin, Cisplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cascinu et al. 2010 2002-2005 Randomized Phase II (E-switch-ic) MCF Seems to have superior OS

Patients: 11% gastroesophageal junction, 89% gastric origin. 90% metastatic. 6% with ECOG PS of 2.

Chemotherapy

14-day cycles

References

  1. Cascinu S, Galizia E, Labianca R, Ferraù F, Pucci F, Silva RR, Luppi G, Beretta GD, Berardi R, Scartozzi M. Pegylated liposomal doxorubicin, 5-fluorouracil and cisplatin versus mitomycin-C, 5-fluorouracil and cisplatin for advanced gastric cancer: a randomized phase II trial. Cancer Chemother Pharmacol. 2011 Jul;68(1):37-43. Epub 2010 Sep 7. link to original article contains verified protocol PubMed

MCF

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MCF: Mitomycin, Cisplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ross et al. 2002 1995-1998 Phase III (E-switch-ic) ECF Seems to have non-inferior OS
Cascinu et al. 2010 2002-2005 Randomized Phase II (C) LdCF Seems to have inferior OS

Cascinu Patients: 11% gastroesophageal junction, 89% gastric origin. 90% metastatic. 6% with ECOG PS of 2.

Chemotherapy

Supportive medications

42-day cycle for up to 5 cycles (6 months)

References

  1. 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 contains verified protocol PubMed
  2. Cascinu S, Galizia E, Labianca R, Ferraù F, Pucci F, Silva RR, Luppi G, Beretta GD, Berardi R, Scartozzi M. Pegylated liposomal doxorubicin, 5-fluorouracil and cisplatin versus mitomycin-C, 5-fluorouracil and cisplatin for advanced gastric cancer: a randomized phase II trial. Cancer Chemother Pharmacol. 2011 Jul;68(1):37-43. Epub 2010 Sep 7. link to original article contains verified protocol PubMed

Paclitaxel monotherapy

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Regimen variant #1, weekly

Study Evidence
Ilson et al. 2007 Phase II

Patients: 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.

Chemotherapy

Supportive medications

28-day cycles

Regimen variant #2, CI

Study Evidence
Ajani et al. 1994 Phase II

Note: In contrast to the original reference, some guidelines list the dosage of paclitaxel as 135 to 175 mg/m2.

Patients: 100% esophageal cancer. 36% squamous cell, 64% adenocarcinoma histology.

Chemotherapy

  • Paclitaxel (Taxol) 250 mg/m2 IV continuous infusion over 24 hours, started on day 1
    • Dosage adjusted based on toxicity down to 150 or 200 mg/m2, or up to 280 mg/m2

Supportive medications

21-day cycles

References

  1. Ajani JA, Ilson DH, Daugherty K, Pazdur R, Lynch PM, Kelsen DP. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst. 1994 Jul 20;86(14):1086-91. link to original article contains verified protocol PubMed
  2. Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-902. Epub 2007 Mar 9. link to original article contains verified protocol PubMed

Metastatic or locally advanced disease, subsequent lines of therapy

Camrelizumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Huang et al. 2020 (ESCORT) 2017-2018 Phase III (E-switch-ooc) 1. Docetaxel
2. Irinotecan 		Superior OS

Immunotherapy

14-day cycles

References

  1. ESCORT: Huang J, Xu J, Chen Y, Zhang Y, Chen Z, Chen J, Niu Z, Fan Q, Lin L, Gu K, Liu Y, Ba Y, Miao Z, Jiang X, Chen J, Fu Z, Gan L, Wang J, Zhan X, Liu T, Li Z. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2020;21(6):832-842. link to original article contains protocol PubMed NCT03099382

CAPIRI

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CapeIRI: Capecitabine and IRInotecan
CAPIRI: CAPecitabine and IRInotecan
XELIRI: XELox (Capecitabine) and IRInotecan
XI: Xeloda (Capecitabine) and Irinotecan

Regimen

Study Evidence
Leary et al. 2008 Phase II

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles

References

  1. Leary A, Assersohn L, Cunningham D, Norman AR, Chong G, Brown G, Ross PJ, Costello C, Higgins L, Oates J. A phase II trial evaluating capecitabine and irinotecan as second line treatment in patients with oesophago-gastric cancer who have progressed on, or within 3 months of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2009 Aug;64(3):455-62. Epub 2008 Dec 23. link to original article contains verified protocol PubMed

Docetaxel monotherapy

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Regimen variant #2, 75 mg/m2, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase III (C) Pembrolizumab Inferior OS (*)

Note: efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.

Chemotherapy

21-day cycles

Regimen variant #3, 100 mg/m2

Study Evidence
Albertsson et al. 2007 Phase II

Patients: squamous cell or adenocarcinoma histology of the esophagus or gastric cardia.

Chemotherapy

21-day cycles

References

  1. Albertsson M, Johansson B, Friesland S, Kadar L, Letocha H, Frykholm G, Wagenius G. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol. 2007;24(4):407-12. link to original article contains protocol PubMed
  2. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains verified protocol PubMed NCT02564263

Docetaxel & Irinotecan

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Regimen

Study Evidence
Burtness et al. 2009 Phase II, <20 pts in this subgroup

Patients: 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.

Chemotherapy

Supportive medications

21-day cycles

References

  1. Burtness B, Gibson M, Egleston B, Mehra R, Thomas L, Sipples R, Quintanilla M, Lacy J, Watkins S, Murren JR, Forastiere AA. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009 Jul;20(7):1242-8. Epub 2009 May 8. link to original article contains verified protocol link to PMC article PubMed

Erlotinib monotherapy

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Regimen

Study Evidence
Ilson et al. 2010 Phase II

Patients: 57% adenocarcinoma, 43% squamous cell histology. 6% proximal esophagus, 35% distal esophagus, 59% gastroesophageal junction.

Targeted therapy

  • Erlotinib (Tarceva) 150 mg PO once per day, at least 1 hour before a meal, or 2 hours after a meal

28-day cycles

References

  1. Ilson DH, Kelsen D, Shah M, Schwartz G, Levine DA, Boyd J, Capanu M, Miron B, Klimstra D. A phase 2 trial of erlotinib in patients with previously treated squamous cell and adenocarcinoma of the esophagus. Cancer. 2011 Apr 1;117(7):1409-14. Epub 2010 Nov 8. link to original article contains verified protocol link to PMC article PubMed

Irinotecan monotherapy

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Regimen variant #1, 14-day cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase III (C) Pembrolizumab Inferior OS (*)

Note: efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.

Chemotherapy

14-day cycles

Regimen variant #2, 4 out of 6 weeks

Study Evidence
Mühr-Wilkenshoff et al. 2003 Phase II, <20 patients

Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m2 IV once per day on days 1 & 8, with 21-day cycles.

Patients: Ten with esophageal squamous cell carcinoma, three with esophageal adenocarcinoma

Chemotherapy

42-day cycles

References

  1. Mühr-Wilkenshoff F, Hinkelbein W, Ohnesorge I, Wolf KJ, Riecken EO, Zeitz M, Scherübl H. A pilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or metastatic esophageal carcinoma. Int J Colorectal Dis. 2003 Jul;18(4):330-4. Epub 2003 Feb 1. link to original article PubMed
  2. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains verified protocol PubMed NCT02564263

Irinotecan & Mitomycin

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Regimen

Study Evidence
Bamias et al. 2003a Phase II

Patients: Advanced gastric and colorectal cancers. All previously received 5-fluorouracil-based chemotherapy.

Chemotherapy

14-day cycles

References

  1. 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 contains protocol PubMed

IRIS

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IRIS: IRInotecan & S-1

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Huang et al. 2019 (ESWN 01) 2014-2016 Phase III (E-switch-ic) S-1 Superior PFS

Chemotherapy

  • Irinotecan (Camptosar) 160 mg/m2 IV once on day 1, given first
  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA less than 1.25 m2: 40 mg PO twice per day on days 1 to 10
    • BSA at least 1.25 m2 and less than 1.5 m2: 50 mg PO twice per day on days 1 to 10
    • BSA 1.5 m2 or more: 60 mg PO twice per day on days 1 to 10

14-day cycles

References

  1. ESWN 01: Huang J, Xu B, Liu Y, Huang J, Lu P, Ba Y, Wu L, Bai Y, Zhang S, Feng J, Cheng Y, Li J, Wen L, Yuan X, Ma C, Hu C, Fan Q, Wang X. Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer (ESWN 01): a prospective randomized, multicenter, open-labeled phase 3 trial. Cancer Commun (Lond). 2019 Apr 2;39(1):16. link to original article link to PMC article contains verified protocol PubMed NCT02319187

Nivolumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kato et al. 2019 (ATTRACTION-3) 2016-2017 Phase III (E-RT-switch-ooc) 1. Docetaxel
2. Paclitaxel 		Seems to have superior OS

Inclusion Criteria: Unresectable advanced or recurrent esophageal SCC regardless of PDL1 expression, ECOG 0-1, refractory or intolerance to one prior 5-FU or platinum-based chemotherapy

Immunotherapy

14-day cycles

References

  1. ATTRACTION-3: Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Nov;20(11):1506-1517. Epub 2019 Sep 30. link to original article PubMed NCT02569242

Paclitaxel monotherapy

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Regimen variant #1, weekly

Study Evidence
Ilson et al. 2007 Phase II

Patients: 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.

Chemotherapy

Supportive medications

28-day cycles

Regimen variant #2, 80 mg/m2, 3 out of 4 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase III (C) Pembrolizumab Inferior OS (*)

Note: efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS. This is the lower bound of dosing specified in KEYNOTE-181.

Chemotherapy

28-day cycles

Regimen variant #3, 100 mg/m2, 3 out of 4 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase III (C) Pembrolizumab Inferior OS (*)

Note: efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS. This is the upper bound of dosing specified in the protocol.

Chemotherapy

28-day cycles

References

  1. Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-902. Epub 2007 Mar 9. link to original article contains verified protocol PubMed
  2. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains verified protocol PubMed NCT02564263

Pembrolizumab monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase III (E-RT-switch-ooc) Investigator's choice of:
1. Docetaxel
2. Irinotecan
3. Paclitaxel 		Superior OS (*)
Shah et al. 2019 (KEYNOTE-180) 2016-2017 Phase II (RT)

Note: Efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the experimental arm might have superior OS. Patients in KEYNOTE-180 had 100% squamous histology.

Biomarker eligibility criteria

  • PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-180: Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, Lordick F, Kim SB, Tajika M, Kim HT, Lockhart AC, Arkenau HT, El-Hajbi F, Gupta M, Pfeiffer P, Liu Q, Lunceford J, Kang SP, Bhagia P, Kato K. Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study. JAMA Oncol. 2019 Apr 1;5(4):546-550. link to original article PubMed
  2. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains verified protocol PubMed NCT02564263

S-1 monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Huang et al. 2019 (ESWN 01) 2014-2016 Phase III (C) IRIS Inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
    • BSA at least 1.25 m2 and less than 1.5 m2: 50 mg PO twice per day on days 1 to 14
    • BSA 1.5 m2 or more: 60 mg PO twice per day on days 1 to 14

21-day cycles

References

  1. ESWN 01: Huang J, Xu B, Liu Y, Huang J, Lu P, Ba Y, Wu L, Bai Y, Zhang S, Feng J, Cheng Y, Li J, Wen L, Yuan X, Ma C, Hu C, Fan Q, Wang X. Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer (ESWN 01): a prospective randomized, multicenter, open-labeled phase 3 trial. Cancer Commun (Lond). 2019 Apr 2;39(1):16. link to original article link to PMC article contains verified protocol PubMed NCT02319187
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