Esophageal cancer

Section editor
	Travis Zack, MD, PhD University of California San Francisco San Francisco, CA, USA LinkedIn

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:

• Histology-specific:
  • Esophageal adenocarcinoma
  • Esophageal squamous cell carcinoma
• Biomarker-specific:
  • HER2 positive gastroesophageal cancer

56 regimens on this page 74 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

• 2023: Shah et al. Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline PubMed
• 2021: Shah et al. Immunotherapy in Patients With Locally Advanced Esophageal Carcinoma: ASCO Treatment of Locally Advanced Esophageal Carcinoma Guideline Rapid Recommendation Update PubMed
  • 2020: Shah et al. Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline PubMed

ESMO

• 2022: Obermannová et al. Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed
  • 2016: Lordick et al. Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2013: Stahl et al. Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2010: Stahl et al. Esophageal cancer: Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2009: Stahl & Oliveira. Esophageal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2008: Stahl & Oliveira. Esophageal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2007: Stahl. Esophageal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
• 2019: Muro et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS PubMed

NCCN

• NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers

• 2015: Ajani et al. Esophageal and Esophagogastric Junction Cancers, Version 1.2015 PubMed
• 2011: Ajani et al. Esophageal and esophagogastric junction cancers. PubMed
• 2008: Ajani et al. Esophageal cancer. PubMed
• 2006: Ajani et al. Esophageal Cancer Clinical Practice Guidelines. PubMed
• 2003: Ajani et al. Esophageal cancer. Clinical practice guidelines in oncology. PubMed

Neoadjuvant induction therapy

Capecitabine & Cisplatin (CX)

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

Regimen

Study	Evidence
Lee et al. 2007esoph	Retrospective

Note: Patients had 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-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.

Eligibility criteria

• Stage IV disease

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Cisplatin (Platinol) 60 mg/m² IV over 60 minutes once on day 1, given first

21-day cycles (see note)

Subsequent treatment

• Lee et al. 2007_esoph, patients with M1a or M1b (non-visceral) disease: Definitive capecitabine, cisplatin, RT

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 dosing details in manuscript PubMed

Cisplatin & Docetaxel (DC)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ruhstaller et al. 2009 (SAKK 75/02)	2003-07 to 2006-06	Phase 2
Ruhstaller et al. 2018 (SAKK 75/08)	2010-2013	Phase 3 (C)	DC & Cetuximab	Did not meet primary endpoint of PFS

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for 2 cycles

Subsequent treatment

• Neoadjuvant cisplatin, docetaxel, RT, then surgery

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 dosing details in manuscript 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 contains dosing details in manuscript PubMed NCT01107639

Cisplatin & Fluorouracil (CF)

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

Regimen variant #1, 80/4000, 4 day 5-FU infusion

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Girling et al. 2002 (UK MRC OE02)	1992-1998	Phase 3 (E-esc)	Surgery alone	Seems to have superior OS1 (primary endpoint) OS60: 23% vs 17.1% (HR 0.84, 95% CI 0.72-0.98)

¹Reported efficacy for UK MRC OE02 is based on the 2009 update.

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

21-day cycle for 2 cycles

Subsequent treatment

• Surgery

Regimen variant #2, 100/5000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kelsen et al. 1998 (RTOG 8911)	1990-1995	Phase 3 (E-esc)	Surgery alone	Did not meet primary endpoint of OS

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

Chemotherapy

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

28-day cycle for 3 cycles

Subsequent treatment

• Surgery, then adjuvant CF

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 dosing details in manuscript 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. 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 dosing details in abstract 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

Cisplatin & Irinotecan (IC)

IC: Irinotecan & Cisplatin

Regimen

Study	Dates of enrollment	Evidence
Ilson et al. 2011	2002-12 to 2005-10	Phase 2

Note: Ilson et al. 2011 patients had 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated histology; 33% gastroesophageal junction.

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV over 30 minutes once per day on days 1 & 8, given first
• Irinotecan (Camptosar) 65 mg/m² IV over 30 minutes once per day on days 1 & 8, given second

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 & 8, prior to chemotherapy
• One of the following:
  • Granisetron 2 mg PO once per day on days 1 & 8, prior to chemotherapy
  • Ondansetron (Zofran) 32 mg IV once per day on days 1 & 8, prior to chemotherapy
• 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

• Neoadjuvant cisplatin, irinotecan, RT, then surgery

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. 2012 Jun 1;118(11):2820-7. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed

EOF

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

• Epirubicin (Ellence) 50 mg/m² IV bolus once on day 1
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m²)

Supportive therapy

• Dexamethasone (Decadron) 8 mg IV once on day 1, prior to chemotherapy, then 4 mg PO three times per day on days 2 & 3
• 5-HT3 antagonist once on day 1, prior to chemotherapy
• Metoclopramide (Reglan) 10 mg PO three times per day on days 2 to 4
• Warfarin (Coumadin) 1 mg PO once per day as thrombosis prophylaxis, started on day -1

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

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

• Epirubicin (Ellence) 50 mg/m² IV bolus once on day 1
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1
• Capecitabine (Xeloda) 500 to 625 mg/m² PO twice per day on days 1 to 21

Supportive therapy

• Dexamethasone (Decadron) 8 mg IV once on day 1, prior to chemotherapy, then 4 mg PO three times per day on days 2 & 3
• 5-HT3 antagonist once on day 1, prior to chemotherapy
• Metoclopramide (Reglan) 10 mg PO three times per day on days 2 to 4

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

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

Regimen

Study	Dates of enrollment	Evidence
Stahl et al. 2005	1994-2002	Non-randomized part of phase 3 RCT

Note: For historic reference.

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 to 3
• Leucovorin (Folinic acid) 300 mg/m² IV once per day on days 1 to 3
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3
• Cisplatin (Platinol) 30 mg/m² IV once per day on days 1 to 3

21-day cycle for 3 cycles

Subsequent treatment

• Neoadjuvant PE & RT (4000 cGy) followed by surgery versus definitive PE & RT (at least 6500 cGy)

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 contains dosing details in manuscript PubMed

PCF

PCF: Paclitaxel, Cisplatin, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence
Zhao et al. 2015 (ZY-01)	2005-2007	Non-randomized part of phase 3 RCT

Chemotherapy

• Paclitaxel (Taxol) 100 mg/m² IV once on day 1
• Cisplatin (Platinol) 60 mg/m² IV once on day 2
• Fluorouracil (5-FU) 700 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3500 mg/m²)

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 dosing details in abstract PubMed NCT01225523

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

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

Regimen

Study	Dates of enrollment	Evidence
Czito et al. 2006	2003-07 to 2005-07	Pilot, fewer than 20 pts

Note: The primary reference did not specify whether patients were intended to proceed to surgery. Patients had 77% adenocarcinoma, 23% squamous cell histology. 54% lower thoracic, 23% midthoracic, 23% gastroesophageal junction.

Chemotherapy

• Carboplatin (Paraplatin) AUC 1.5 IV once per day on days 2, 9, 16, 23, 30
• Paclitaxel (Taxol) 45 mg/m² IV over 60 minutes once per day on days 2, 9, 16, 23, 30
• Capecitabine (Xeloda) 600 mg/m² PO twice per day, starting on day 1 and finishing the evening of the last day of radiation therapy

Radiotherapy

• Concurrent radiation therapy: 180 cGy fractions x 28 fractions, for a total dose of 5040 cGy

6-week course

Subsequent treatment

• Czito et al. 2006, surgical candidates: 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 dosing details in manuscript PubMed

Capecitabine, Cisplatin, RT

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

Regimen

Study	Evidence
Lee et al. 2007esoph	Retrospective

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

Preceding treatment

• Induction Capecitabine & Cisplatin

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV over 60 minutes once on day 1, given first
• Capecitabine (Xeloda) 800 mg/m² PO twice per day on days 1 to 5, given second

7-day cycles until radiation therapy is complete

Radiotherapy

• Concurrent radiation therapy, total of 5400 cGy 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 dosing details in manuscript--please see note above, as patients in this study did not undergo surgery PubMed

Capecitabine, Docetaxel, RT

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

Regimen

Study	Dates of enrollment	Evidence
Wood et al. 2013 (D-9939)	NR	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

• Docetaxel (Taxotere) 15 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Capecitabine (Xeloda) 3500 mg PO once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 given prior to radiation

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5040 cGy in 28 fractions)

5-week course

References

1. D-9939: 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 dosing details in manuscript PubMed NCT00153881

Capecitabine, Docetaxel, Oxaliplatin, RT

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

Regimen

Study	Dates of enrollment	Evidence
Spigel et al. 2010 (SCRI GI 57)	2005-2008	Phase 1/2

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 7, 15 to 21, 29 to 35
• Docetaxel (Taxotere) 20 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29
• Oxaliplatin (Eloxatin) 40 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29

Supportive therapy

• Dexamethasone (Decadron) 4 mg PO every 12 hours before, at the time of, and after docetaxel; first dose the evening prior to docetaxel
• "Routine antiemetics"

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)

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 by the following response-based criteria:
  • SCRI GI 57, surgical candidates: Surgical resection sometime during weeks 9 to 12
  • SCRI GI 57, patients who were no longer surgical candidates: Additional radiation therapy to a total dose of 6480 cGy

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 dosing details in manuscript PubMed NCT00193128

Capecitabine, Oxaliplatin, RT

CapeOx & RT: Capecitabine, Oxaliplatin, Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence
Javle et al. 2009	NR in abstract	Phase 1b

Chemotherapy

• Capecitabine (Xeloda) 625 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
• Oxaliplatin (Eloxatin) 85 mg/m² IV once per day on days 1, 15, 29

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (total dose of 5040 cGy)

5-week course

Subsequent treatment

• Surgery

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 dosing details in abstract PubMed

Capecitabine, Paclitaxel, RT

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

Regimen

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

Chemotherapy

• Capecitabine (Xeloda) 625 to 825 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
• Paclitaxel (Taxol) 45 to 50 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

• Concurrent radiation therapy not defined on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

5-week course

Carboplatin, Fluorouracil, RT

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

Regimen

Study	Dates of enrollment	Evidence
Zemanoa et al. 2009	2001-01 to 2005-08	Non-randomized

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

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once per day on days 1 & 22
• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion, started on days 1 & 22 (total dose: 8400 mg/m²)

Radiotherapy

• Concurrent radiation therapy by the following criteria:
  • Surgery indicated: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)
  • If surgery was contraindicated: total dose was increased to 5040 to 5680 cGy.

5-week 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 dosing details in manuscript PubMed

Carboplatin & Paclitaxel (CP) & RT

CP & RT: Carboplatin, Paclitaxel, Radiation Therapy

ESMO-preferred for squamous cell carcinoma (I-A, 2016)

Regimen variant #1, 5 weeks of chemotherapy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van Meerten et al. 2006	2001-2004	Phase 2
van Hagen et al. 2012 (CROSS)	2004-2008	Phase 3 (E-esc)	Surgery alone	Superior OS1 (primary endpoint) OS120: 38% vs 25% (HR 0.70, 95% CI 0.55-0.89)

¹Reported efficacy for CROSS is based on the 2021 update.
Note: van Meerten et al. patients had 76% adenocarcinoma, 22% squamous cell, 2% large cell histology. 91% lower esophagus, 9% thoracic esophagus. CROSS patients had 75% adenocarcinoma, 23% squamous cell, 2% other histology. 24% gastroesophageal junction.

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, 22, 29, given second
• Paclitaxel (Taxol) 50 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22, 29 given first

Supportive therapy

• Dexamethasone (Decadron) 10 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to paclitaxel
• Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to paclitaxel
• Clemastine (Tavist) 2 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to paclitaxel
• 100 mL NS given over 30 minutes once per day on days 1, 8, 15, 22, 29, between paclitaxel & carboplatin
• Ondansetron (Zofran) 8 mg in 100 mL NS given over 30 minutes once per day on days 1, 8, 15, 22, 29, between paclitaxel & carboplatin

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 31 (23 fractions, for a total dose of 4140 cGy)

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

Regimen variant #2, 6 weeks of chemotherapy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Safran et al. 2022 (RTOG 1010)	2010-2015	Phase 3 (C)	CP, Trastuzumab, RT	Did not meet primary endpoint of DFS

Biomarker eligibility criteria

• HER2+

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 30 to 60 minutes once per day on days 1, 8, 15, 22, 29, 36
• Paclitaxel (Taxol) 50 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38 (28 fractions, for a total dose of 5040 cGy)

6-week course

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 original article contains dosing details in manuscript link to PMC article contains dosing details in manuscript 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 dosing details in manuscript link to appendix with details about administration PubMed NTR487
   1. Update: Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. Epub 2015 Aug 5. link to original article PubMed
   2. Update: Eyck BM, van Lanschot JJB, Hulshof MCCM, van der Wilk BJ, Shapiro J, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch OR, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Spillenaar Bilgen EJ, van der Sangen MJC, Rozema T, Ten Kate FJW, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS Study Group. Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol. 2021 Jun 20;39(18):1995-2004. Epub 2021 Apr 23. link to original article PubMed
3. RTOG 1010: Safran HP, Winter K, Ilson DH, Wigle D, DiPetrillo T, Haddock MG, Hong TS, Leichman LP, Rajdev L, Resnick M, Kachnic LA, Seaward S, Mamon H, Diaz Pardo DA, Anderson CM, Shen X, Sharma AK, Katz AW, Salo J, Leonard KL, Moughan J, Crane CH. Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):259-269. Epub 2022 Jan 14. link to original article link to PMC article contains dosing details in abstract PubMed NCT01196390

Cisplatin, Docetaxel, RT

DC & RT: Docetaxel, Cisplatin, Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence
Ruhstaller et al. 2009 (SAKK 75/02)	2003-07 to 2006-06	Phase 2

Note: Patients had 55% adenocarcinoma, 45% squamous cell histology

Preceding treatment

• Induction Cisplatin & Docetaxel x 2

Chemotherapy

• Cisplatin (Platinol) 25 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Docetaxel (Taxotere) 20 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)

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 dosing details in manuscript PubMed

Cisplatin & Fluorouracil (CF) & RT

CF & RT: Cisplatin, Fluourouracil, Radiation Therapy

Regimen variant #1, 75/3200 x 2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mariette et al. 2014 (FFCD 9901)	2000-2009	Phase 3 (E-esc)	Surgery alone	Did not meet primary endpoint of OS

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once per day on either day 1 or 2 & 29
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 96 hours, started on days 1 & 29 (total dose: 6400 mg/m²)

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)

5-week course

Subsequent treatment

• Surgery

Regimen variant #2, 75/4000 x 2

Study	Dates of enrollment	Evidence
Bedenne et al. 2007 (FFCD 9102)	1993-2000	Non-randomized part of phase 3 RCT

Note: Patients had 89% epidermoid, 11% glandular histology.

Chemotherapy

• Cisplatin (Platinol) 15 mg/m² IV over 60 minutes once per day on days 1 to 5, 22 to 26
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on days 1 & 22 (total dose: 8000 mg/m²)

Supportive therapy

• 1 liter NS IV over 2 hours twice per day on days 1 to 5, 22 to 26, before and after cisplatin

Radiotherapy

• Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 31 (23 fractions, for a total dose of 4600 cGy)
  • Earlier in the study, some patients instead received split-course radiation therapy, 300 cGy fractions x 5 fractions given on days 1 to 5. 1500 cGy per cycle; total dose after 2 cycles is 3000 cGy.

5-week course

Subsequent treatment

• Definitive Cisplatin, Fluorouracil, RT (no surgery) x 3 (5 cycles total) versus surgery, 50 to 60 days after start of chemoradiation

Regimen variant #3, 80/3200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Burmeister et al. 2005	1994-2000	Phase 3 (E-esc)	Surgery alone	Did not meet primary endpoint of PFS

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

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 3200 mg/m²)

Radiotherapy

• Concurrent radiation therapy 233 cGy per day on days 1 to 5, 8 to 12, 15 to 19 (15 fractions for a total dose of 3500 cGy)

3-week course

Subsequent treatment

• Surgery

Regimen variant #4, 100/4000 x 2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tepper et al. 2008 (CALGB 9781)	1997-2000	Phase 3 (E-esc)	Surgery alone	Superior OS (primary endpoint) Median OS: 4.48 vs 1.79 y (HR NR, 95% CI 0.18-0.68)

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

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 30 minutes once per day on days 1 & 29, given first
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on days 1 & 29, given second (total dose: 8000 mg/m²)

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, then a 540 cGy final boost, for a total dose of 5040 cGy), 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 dosing details in abstract 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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed NCT00003118
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 NCT00047112
5. KEYNOTE-975: NCT04210115

Cisplatin, Irinotecan, RT

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

Regimen

Study	Dates of enrollment	Evidence
Ilson et al. 2011	2002-12 to 2005-10	Phase 2

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

Preceding treatment

• IC induction x 2

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV over 30 minutes once per day on days 1, 8, 22, 29 given first
• Irinotecan (Camptosar) 65 mg/m² IV over 30 minutes once per day on days 1, 8, 22, 29, given second

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38 (28 fractions, for a total of 5040 cGy)

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. 2012 Jun 1;118(11):2820-7. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed

Cisplatin, Paclitaxel, RT

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

Regimen

Study	Dates of enrollment	Evidence
Urba et al. 2003	1995-01 to 1997-09	Phase 2

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 2 hours once on day 1
• Paclitaxel (Taxol) 60 mg/m² IV over 3 hours once per day on days 1, 8, 15, 22

Supportive therapy

• Dexamethasone (Decadron) 20 mg PO twice per day on days 1, 8, 15, 22; 12 and 6 hours prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to paclitaxel
• 1 liter D5NS and mannitol 12.5 g bolus IV once on day 1, prior to cisplatin
• Mannitol 25 g in 1 liter D5NS IV over 4 hours once on day 1, after cisplatin
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 23, continuing until ANC greater than 10,000/μL

Radiotherapy

• Concurrent radiation therapy, 150 cGy 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 4500 cGy

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 dosing details in manuscript PubMed

Docetaxel, Fluorouracil, RT

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

Regimen variant #1, 15/4000 x 2

Study	Dates of enrollment	Evidence
Hihara et al. 2007	2004-04-21 to 2005-04-07	Phase 1

Note: Patients had 86% squamous cell, 14% carcinosarcoma histology

Chemotherapy

• Docetaxel (Taxotere) 7.5 mg/m² IV over 60 minutes once per day on days 1, 8, 29, 36
• Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 29, 36, 43 (total dose: 8000 mg/m²)

Supportive therapy

• Dexamethasone (Decadron) 8 mg IV once per day on days 1, 8, 29, 36; 30 minutes prior to docetaxel

Radiotherapy

• Concurrent radiation therapy 200 cGy fractions x 30 to 33 fractions, for a total dose of 60 to 6600 cGy

6- to 6.5-week course

Regimen variant #2

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

Chemotherapy

• Docetaxel (Taxotere) 20 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Fluorouracil (5-FU) 200 to 300 mg/m²/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 22, 29 (total dose: 5000 to 7500 mg/m²)

Radiotherapy

• Concurrent radiation therapy not defined on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

5-week course

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 dosing details in manuscript PubMed

Fluorouracil, Oxaliplatin, RT

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

Regimen variant #1, 5040 cGy, bi-weekly oxaliplatin

Study	Dates of enrollment	Evidence
Khushalani et al. 2002	2000-02 to 2001-05	Phase 2

Note: 58% of patients had stage IV disease

Chemotherapy

• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once per day on days 1, 15, 29
• Fluorouracil (5-FU) 180 mg/m²/day IV continuous infusion over 35 days, started on day 8 (total dose: 6300 mg/m²)

Radiotherapy

• Concurrent radiation therapy, 180 cGy fractions x 20 to 22 fractions, for an initial total dose of 36 to 3960 cGy, started on day 8
  • Followed by off-cord conformal oblique fields, 540 to 900 cGy given to the clinical target volume (CTV). A second off-cord phase to the gross tumor volume (GTV) of 540 cGy was then given, for a total dose delivered of 5040 cGy 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 #2, 5040 cGy, weekly oxaliplatin

Study	Dates of enrollment	Evidence
Ajani et al. 2013 (MDACC 2004-0703)	2005-2011	Non-randomized part of phase 2 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

• FUOX versus no induction chemotherapy

Chemotherapy

• Oxaliplatin (Eloxatin) 40 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22, 29 (total dose: 5000 mg/m²)

Radiotherapy

• Concurrent radiation therapy: 5040 cGy of proton or photon (intensity modulated) radiation in 28 fractions

5-week course

Subsequent treatment

• Surgery

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 dosing details in manuscript PubMed
2. 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 dosing details in manuscript PubMed NCT00525915

Definitive therapy

Capecitabine, Cisplatin, RT

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

Regimen variant #1, 1250/60/50

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Crosby et al. 2013 (SCOPE-1)	2008-2012	Phase 3 (C)	Capecitabine, Cisplatin, Cetuximab, RT	Did not meet primary endpoint of OS1

¹Reported efficacy is based on the 2017 update.
Note: Patients had 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology

Chemotherapy

• Capecitabine (Xeloda) as follows:
  • Cycles 1 & 2: 625 mg/m² PO twice per day on days 1 to 21
  • Cycle 3 (chemoradiation): 625 mg/m² PO twice per day on days 1 to 42
• Cisplatin (Platinol) as follows:
  • Cycles 1 & 2: 60 mg/m² IV once on day 1
  • Cycle 3 (chemoradiation): 60 mg/m² IV once per day on days 1 & 22

Radiotherapy

• Concurrent radiation therapy as follows:
  • Cycle 3 (chemoradiation): 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (total of 5000 cGy given in 25 fractions)

21-day cycle for 2 cycles, then 6-week course

Regimen variant #2, 1600/30/54

Study	Evidence
Lee et al. 2007esoph	Retrospective

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

Preceding treatment

• Induction XP x 2

Chemotherapy

• Capecitabine (Xeloda) 800 mg/m² PO twice per day on days 1 to 5
• Cisplatin (Platinol) 30 mg/m² IV over 60 minutes once on day 1, given first

7-day cycles until radiation therapy is complete

Radiotherapy

• Concurrent radiation therapy, total of 5400 cGy given. Dose per fraction and total duration of treatment were not specified, but based on other regimens, it is suspected to be either 180 cGy x 30 fractions or 200 cGy 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 dosing details in manuscript 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. Epub 2013 Apr 25. link to original article contains dosing details in manuscript PubMed ISRCTN47718479
   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 dosing details in manuscript link to PMC article contains dosing details in manuscript PubMed

Cisplatin, Docetaxel, RT

DC & RT: Docetaxel, Cisplatin, Radiation Therapy

Regimen variant #1

Study	Dates of enrollment	Evidence
Day et al. 2010	2001-05 to 2007-01	Phase 1

Note: Patients had 46% squamous cell, 54% adenocarcinoma histology. 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

• Cisplatin (Platinol) 30 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Docetaxel (Taxotere) 30 mg/m² IV once per day on days 1, 8, 15, 22, 29

Supportive therapy

• "Steroid and anti-emetic pre-medication"

Radiotherapy

• Concurrent radiation therapy, 200 cGy fractions x 25 fractions, for a total dose of 5000 cGy, to start within 4 hours after the first dose of chemotherapy.

5-week course

References

1. 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 dosing details in manuscript link to PMC article PubMed

Cisplatin & Fluorouracil (CF) & RT

CF & RT: Cisplatin, Fluorouracil, Radiation Therapy
FP & RT: Fluorouracil, Platinol (Cisplatin), Radiation Therapy

Regimen variant #1, 60/4725 x 4 (5000 cGy)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Crosby et al. 2013 (SCOPE-1)	2008-2012	Phase 3 (C)	Capecitabine, Cisplatin, Cetuximab, RT	Did not meet primary endpoint of OS1

¹Reported efficacy is based on the 2017 update.
Note: This regimen was an alternative for patients who could not swallow pills. Patients had 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology

Chemotherapy

• Cisplatin (Platinol) as follows:
  • Cycles 1 & 2: 60 mg/m² IV once on day 1
  • Cycle 3 (chemoradiation): 60 mg/m² IV once per day on days 1 & 22
• Fluorouracil (5-FU) as follows:
  • Cycles 1 & 2: 225 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4725 mg/m²)
  • Cycle 3 (chemoradiation): 225 mg/m²/day IV continuous infusion over 42 days, started on day 1 (total dose during chemoradiation: 9450 mg/m²)

Radiotherapy

• Concurrent radiation therapy as follows:
  • Cycle 3 (chemoradiation): 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (total of 5000 cGy given in 25 fractions)

21-day cycle for 2 cycles, then 5-week course

Regimen variant #2, 75/4000 x 2 (5040 cGy)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Minsky et al. 2002 (RTOG 94-05)	1995-1999	Phase 3 (C)	CF & RT; high-dose RT	Did not meet primary endpoint of OS24
Conroy et al. 2014 (PRODIGE5/ACCORD17)	2004-2011	Phase 3 (C)	See link	See link

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 30 minutes once per day on days 1 & 29
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on days 1 & 29 (total dose: 8000 mg/m²)

Radiotherapy

• Concurrent radiation therapy by the following study-specific criteria:
  • RTOG 94-05: 180 cGy fractions x 28 fractions, for a total dose of 5040 cGy
  • PRODIGE5/ACCORD17: 200 cGy fractions x 25 fractions, for a total dose of 5000 cGy

5- to 5.5-week course

Subsequent treatment

• CF consolidation

Regimen variant #3, 75/4000 x 3 (6600 cGy)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bedenne et al. 2007 (FFCD 9102)	1993-2000	Phase 3 (E-switch-ooc)	Surgery	Equivalent OS (primary endpoint)

Note: Patients had 89% epidermoid, 11% glandular histology. Note that this was not a formal non-inferiority study but the study met its primary endpoint of equivalence. Earlier in the study, some patients instead received split-course radiation therapy.

Preceding treatment

• Induction CF & RT x 2

Chemotherapy

• Cisplatin (Platinol) as follows:
  • Cycle 1: 15 mg/m² IV over 60 minutes once per day on days 1 to 5
  • Cycles 2 & 3: 15 mg/m² IV over 60 minutes once per day on days 1 to 5
• Fluorouracil (5-FU) as follows:
  • Cycle 1: 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)
  • Cycles 2 & 3: 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

Supportive therapy

• 1 liter NS IV over 2 hours before and after cisplatin

Radiotherapy

• Concurrent radiation therapy as follows:
  • Cycle 1: 200 cGy per day on days 1 to 5, 8 to 12 (10 fractions, for a total dose of 6600 cGy, including the initial 4600 cGy)

3-week course, then 28-day cycle for 2 cycles

Regimen variant #4, 75/4000 x 4 (5000 cGy)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Herskovic et al. 1992 (RTOG 85-01)	1986-1990	Phase 3 (E-esc)	Radiation therapy	Superior OS

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

Chemotherapy

• Cisplatin (Platinol) as follows:
  • Cycle 1 (chemoradiation): 75 mg/m² IV once per day on days 1 & 29
  • Cycles 2 & 3: 75 mg/m² IV once on day 1
• Fluorouracil (5-FU) as follows:
  • Cycle 1 (chemoradiation): 1000 mg/m²/day IV continuous infusion over 96 hours, started on days 1 & 29 (total dose during chemoradiation: 8000 mg/m²)
  • Cycles 2 & 3: 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

Radiotherapy

• Concurrent radiation therapy as follows:
  • Cycle 1 (chemoradiation): 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19 to the tumor, then 200 cGy per day on days 22 to 26, 29 to 33 to the initial tumor length plus a 5 cm margin (25 fractions for a total dose of 5000 cGy)

7-week course, then 21-day cycle for 2 cycles

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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00002631
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 dosing details in manuscript 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. Epub 2013 Apr 25. link to original article contains dosing details in manuscript PubMed ISRCTN47718479
   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 dosing details in manuscript link to PMC article contains dosing details in manuscript 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. Epub 2014 Feb 18. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article contains dosing details in abstract 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
6. KEYNOTE-975: NCT04210115

Cisplatin, Paclitaxel, RT

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Suntharalingam et al. 2017 (RTOG 0436)	2008-2013	Phase 3 (C)	Cisplatin, Paclitaxel, Cetuximab, RT	Did not meet primary endpoint of OS

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

Chemotherapy

• Cisplatin (Platinol) 25 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Paclitaxel (Taxol) 50 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

• Concurrent radiation therapy, 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 35 to 37 (28 fractions, for a total dose of 5040 cGy)

6-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 dosing details in manuscript link to PMC article PubMed NCT00655876

FOLFOX4 & RT

FOLFOX4 & RT: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Conroy et al. 2014 (PRODIGE5/ACCORD17)	2004-2011	Phase 3 (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

• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1, 15, 29, then 1600 mg/m² IV continuous infusion over 46 hours, started on days 1, 15, 29 given third (total dose: 6000 mg/m²)
• Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once per day on days 1, 15, 29
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once per day on days 1, 15, 29

Radiotherapy

• Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 5000 cGy)

5-week course

Subsequent treatment

• FOLFOX4 consolidation x 3

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. Epub 2014 Feb 18. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article contains dosing details in abstract 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
2. KEYNOTE-975: NCT04210115

Radiation therapy

Regimen variant #1, 5000 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Herskovic et al. 1992 (RTOG 85-01)	1986-1990	Phase 3 (C)	CF & RT	Inferior OS

Note: Patients had 88% squamous cell, 12% adenocarcinoma histology. 7% Karnofsky performance scale of 50-60. Radiation was used as primary therapy; used as a comparator arm and here for reference purposes only.

Radiotherapy

• External beam radiotherapy total of 32 fractions: 5000 cGy of regional treatment and 1400 cGy to the boost field, for total dose of 6400 cGy

6.4-week course

Regimen variant #2, 6000 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ji et al. 2021 (ZJCH-E-E)	2016-06-01 to 2018-08-31	Phase 3 (C)	S-1 & RT	Inferior OS24

Radiotherapy

• External beam radiotherapy 200 cGy per day, 5 days per week, for 30 fractions (total dose of 6000 cGy)

One 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed
2. ZJCH-E-E: Ji Y, Du X, Zhu W, Yang Y, Ma J, Zhang L, Li J, Tao H, Xia J, Yang H, Huang J, Bao Y, Du D, Liu D, Wang X, Li C, Yang X, Zeng M, Liu Z, Zheng W, Pu J, Chen J, Hu W, Li P, Wang J, Xu Y, Zheng X, Chen J, Wang W, Tao G, Cai J, Zhao J, Zhu J, Jiang M, Yan Y, Xu G, Bu S, Song B, Xie K, Huang S, Zheng Y, Sheng L, Lai X, Chen Y, Cheng L, Hu X, Ji W, Fang M, Kong Y, Yu X, Li H, Li R, Shi L, Shen W, Zhu C, Lv J, Huang R, He H, Chen M. Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1459-1466. link to original article link to PMC article PubMed NCT02813967

S-1 & RT

S-1 & RT: S-1 & Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ji et al. 2021 (ZJCH-E-E)	2016-06-01 to 2018-08-31	Phase 3 (E-esc)	RT x 6000 cGy	Superior OS24 (primary endpoint) OS24: 53.2% vs 35.8% (HR 0.63, 95% CI 0.47-0.85)

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) 70 mg/m²/day PO on days 1 to 14, 29 to 42 (rounded down to the nearest 20 mg)

Radiotherapy

• External beam radiotherapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40 (30 fractions for a total dose of 5400 cGy)

6-week course

References

1. ZJCH-E-E: Ji Y, Du X, Zhu W, Yang Y, Ma J, Zhang L, Li J, Tao H, Xia J, Yang H, Huang J, Bao Y, Du D, Liu D, Wang X, Li C, Yang X, Zeng M, Liu Z, Zheng W, Pu J, Chen J, Hu W, Li P, Wang J, Xu Y, Zheng X, Chen J, Wang W, Tao G, Cai J, Zhao J, Zhu J, Jiang M, Yan Y, Xu G, Bu S, Song B, Xie K, Huang S, Zheng Y, Sheng L, Lai X, Chen Y, Cheng L, Hu X, Ji W, Fang M, Kong Y, Yu X, Li H, Li R, Shi L, Shen W, Zhu C, Lv J, Huang R, He H, Chen M. Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1459-1466. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02813967

Consolidation after definitive therapy

Cisplatin & Fluorouracil (CF)

CF: Cisplatin & Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Minsky et al. 2002 (RTOG 94-05)	1995-1999	Non-randomized part of phase 3 RCT
Conroy et al. 2014 (PRODIGE5/ACCORD17)	2004-2011	Phase 3 (C)	See link	See link

Note: study included both adenocarcinoma and squamous cell histology

Preceding treatment

• RTOG 94-05: Definitive CF & RT; standard dose versus CF & RT; high-dose
• PRODIGE5/ACCORD17: Definitive CF & RT

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 30 minutes once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

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 dosing details in manuscript PubMed NCT00002631
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. Epub 2014 Feb 18. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article contains dosing details in abstract 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

FOLFOX4

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin 4

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Conroy et al. 2014 (PRODIGE5/ACCORD17)	2004-2011	Phase 3 (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

• Definitive FOLFOX4 & RT

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1600 mg/m² IV continuous infusion over 46 hours, given third (total dose per cycle: 2000 mg/m²)
• Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

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. Epub 2014 Feb 18. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article contains dosing details in abstract 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)

CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen

Study	Dates of enrollment	Evidence
Kelsen et al. 1998 (RTOG 8911)	1990-1995	Non-randomized part of phase 3 RCT

Note: This was 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

• Neoadjuvant CF, then surgery

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion, started on day 1 (total dose per cycle: see note)

28-day cycle for 3 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 dosing details in manuscript PubMed

Nivolumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kelly et al. 2021 (CheckMate 577)	2016-2019	Phase 3 (E-RT-esc)	Placebo	Superior DFS (primary endpoint) Median DFS: 22.4 vs 11 mo (HR 0.69, 96.4% CI 0.56-0.86)

Preceding treatment

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

Immunotherapy

• Nivolumab (Opdivo) as follows:
  • Cycles 1 to 8: 240 mg IV over 30 minutes once on day 1
  • Cycles 9 to 17: 480 mg IV over 30 minutes once on day 1

14-day cycle for 8 cycles, then 28-day cycle for 9 cycles (1 year total)

References

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

Metastatic or locally advanced disease, first-line

Carboplatin & Paclitaxel (CP)

Regimen

Study	Dates of enrollment	Evidence
Philip et al. 1997	NR in abstract	Phase 2

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

Eligibility criteria

• Locally advanced metastatic or recurrent esophageal or gastric cancer

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycles

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 dosing details in abstract PubMed

Cisplatin & Fluorouracil (CF)

CF: Cisplatin & Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sun et al. 2021 (KEYNOTE-590)	2017-2019	Phase 3 (C)	CF & Pembrolizumab	Inferior OS (co-primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. 73% of patients had squamous histology.

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

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

References

1. KEYNOTE-590: Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, Cho BC, Mansoor W, Li SH, Sunpaweravong P, Maqueda MA, Goekkurt E, Hara H, Antunes L, Fountzilas C, Tsuji A, Oliden VC, Liu Q, Shah S, Bhagia P, Kato K; KEYNOTE-590 Investigators. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021 Aug 28;398(10302):759-771. link to original article PubMed NCT03189719

Cisplatin & Fluorouracil (CF) & Pembrolizumab

CF & Pembrolizumab: Cisplatin, Fluorouracil, Pembrolizumab

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sun et al. 2021 (KEYNOTE-590)	2017-2019	Phase 3 (E-RT-esc)	CF	Superior OS (co-primary endpoint) Median OS: 12.4 vs 9.8 mo (HR 0.73, 95% CI 0.62-0.86)

Note: 73% of patients had squamous histology. MCBS score is for all patients, regardless of CPS status.

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

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

References

1. KEYNOTE-590: Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, Cho BC, Mansoor W, Li SH, Sunpaweravong P, Maqueda MA, Goekkurt E, Hara H, Antunes L, Fountzilas C, Tsuji A, Oliden VC, Liu Q, Shah S, Bhagia P, Kato K; KEYNOTE-590 Investigators. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021 Aug 28;398(10302):759-771. link to original article PubMed NCT03189719

Cisplatin & Irinotecan (IC)

IC: Irinotecan & Cisplatin
CI: Cisplatin & Irinotecan

Regimen variant #1

Study	Dates of enrollment	Evidence
Ilson 2004	NR	Phase 2

Note: In contrast to the original reference, some guidelines list cisplatin 25 mg/m² as an alternate dosage. Patients had 26% squamous cell, 74% adenocarcinoma histology. 85% metastatic disease.

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV once per day on days 1 & 8
• Irinotecan (Camptosar) 65 mg/m² IV once per day on days 1 & 8

21-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence
Ilson et al. 1999	1997-07 to 1998-09	Phase 2

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

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV bolus once per day on days 1, 8, 15, 22
• Irinotecan (Camptosar) 65 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV once per day on days 1, 8, 15, 22, prior to chemotherapy
• Granisetron 2 mg PO once per day on days 1, 8, 15, 22, prior to chemotherapy
• At least 500 mL D5NS IV over 30 to 60 minutes once per day on days 1, 8, 15, 22, prior to cisplatin
• Atropine (Atropen) used as pretreatment medication if there was diarrhea or abdominal cramps within 1 hour of irinotecan

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 dosing details in manuscript 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 dosing details in abstract PubMed

Cisplatin & Paclitaxel

Regimen variant #1

Study	Dates of enrollment	Evidence
Ilson et al. 2000	NR in abstract	Phase 2

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 2, given second
• Paclitaxel (Taxol) 200 mg/m² IV continuous infusion over 24 hours, started on day 1

Supportive therapy

• "Granulocyte colony stimulating factor support"

21-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence
Petrasch et al. 1998	NR	Phase 2

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

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV over 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 90 mg/m² IV over 3 hours once on day 1, given first

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV once on day 1; 30 minutes prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once on day 1; 30 minutes prior to paclitaxel
• Clemastine (Tavist) 2 mg IV once on day 1; 30 minutes prior to paclitaxel
• Ondansetron (Zofran) 8 mg IV once on day 1; 30 minutes prior to paclitaxel
• "Adequate pre- and post- hydration" for cisplatin

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 original article link to PMC article contains dosing details in manuscript 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 dosing details in abstract PubMed

Docetaxel & Irinotecan

Regimen

Study	Dates of enrollment	Evidence
Burtness et al. 2009	2001-12 to 2004-10	Phase 2

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

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV over 60 minutes once per day on days 1 & 8, given first
• Irinotecan (Camptosar) 50 mg/m² IV over 30 minutes once per day on days 1 & 8, given second

Supportive therapy

• Dexamethasone (Decadron) as follows:
  • 8 mg PO once per day on days 1 & 8; 12 hours prior to docetaxel
  • 10 mg IV once per day on days 1 & 8, within 1 hour of chemotherapy
  • 8 mg PO once per day on days 1 & 8; 12 hour afters chemotherapy
• Serotonin 5-HT3 antagonist IV once per day on days 1 & 8, within 1 hour before chemotherapy
• "Oral antiemetic therapy prescribed"
• Loperamide (Imodium) as needed

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 dosing details in manuscript link to PMC article PubMed

ECF

ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

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

Note: Ross et al. patients had adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer. REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric primary site. 11% ECOG PS of 2.

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV bolus once on day 1
• Cisplatin (Platinol) 60 mg/m² IV over 4 hours once on day 1
• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m²)

Supportive therapy

• (varied depending on reference):
• 3 liters per day "hyperhydration"
• 5-HT3 antagonist for emesis prophylaxis
• Growth factor support allowed, such as with Filgrastim (Neupogen)
• Warfarin (Coumadin) 1 mg PO once per day for catheter thrombosis prophylaxis

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 dosing details in manuscript 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 dosing details in manuscript PubMed ISRCTN51678883

ECX

ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

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

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

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV bolus once on day 1
• Cisplatin (Platinol) 60 mg/m² IV over 4 hours once on day 1
• Capecitabine (Xeloda) 625 mg/m² PO twice per day on days 1 to 21

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 dosing details in manuscript PubMed ISRCTN51678883

EOF

EOF: Epirubicin, Oxaliplatin, Fluorouracil

Regimen

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

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

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV bolus once on day 1
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m²)

Supportive therapy

• Warfarin (Coumadin) 1 mg PO once per day for catheter thrombosis prophylaxis

21-day cycle for up to 8 cycles

References

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 dosing details in manuscript PubMed ISRCTN51678883

EOX

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

Regimen

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

Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric primary site. 11% ECOG PS of 2. REAL3 patients had 99% adenocarcinoma, 1% undifferentiated histology. 39% esophagus, 31% gastroesophageal junction, 30% gastric primary site. 6% ECOG PS of 2. 89% metastatic disease.

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1
• Capecitabine (Xeloda) 625 mg/m² PO twice per day on days 1 to 21

21-day cycle for up to 8 cycles

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 dosing details in manuscript PubMed content property of HemOnc.org ISRCTN51678883
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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00824785

mFOLFOX6 & Cetuximab

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

Regimen

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

Note: Patients had 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)
• Leucovorin (Folinic acid) 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 dosing details in manuscript link to PMC article PubMed NCT00381706

FULV & Gemcitabine

FULV & Gemcitabine: 5-FU, LeucoVorin, Gemcitabine

Regimen

Study	Dates of enrollment	Evidence
Morgan-Meadows et al. 2005	1998-06 to 2001-11	Phase 2

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

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1, 8, 15 (total dose per cycle: 1800 mg/m²)
• Leucovorin (Folinic acid) 25 mg/m² IV once per day on days 1, 8, 15
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

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 dosing details in abstract PubMed

LdCF

LdCF: Liposomal doxorubicin, Cisplatin, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cascinu et al. 2010	2002-2005	Randomized Phase 2 (E-switch-ic)	MCF	Seems to have superior OS

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

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 20 mg/m² IV once on day 1
• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1200 mg/m² IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m²)

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 dosing details in manuscript PubMed

MCF

MCF: Mitomycin, Cisplatin, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ross et al. 2002	1995-1998	Phase 3 (E-switch-ic)	ECF	Seems to have non-inferior OS (primary endpoint)
Cascinu et al. 2010	2002-2005	Randomized Phase 2 (C)	LdCF	Seems to have inferior OS

Note: Cascinu et al. patients had 11% gastroesophageal junction, 89% gastric primary site. 90% metastatic. 6% with ECOG PS of 2.

Chemotherapy

• Mitomycin (Mutamycin) 7 mg/m² (maximum dose of 14 mg) IV once on day 1
• Cisplatin (Platinol) 60 mg/m² IV once per day on days 1 & 22
• Fluorouracil (5-FU) 300 mg/m²/day IV continuous infusion, started on day 1 (total dose per cycle: 12,600 mg/m²)

Supportive therapy

• Warfarin (Coumadin) 1 mg PO once per day for catheter thrombosis prophylaxis

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 dosing details in manuscript 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 dosing details in manuscript PubMed

Paclitaxel monotherapy

Regimen variant #1, weekly

Study	Dates of enrollment	Evidence
Ilson et al. 2007	1998-01 to 2000-04	Phase 2

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

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel

28-day cycles

Regimen variant #2, CI

Study	Dates of enrollment	Evidence
Ajani et al. 1994	1992-08 to 1993-12	Phase 2

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

Supportive therapy

• Dexamethasone (Decadron) 20 mg PO for 2 doses on day 1; 14 hours and 7 hours prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once on day 1; 60 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1; 60 minutes prior to paclitaxel
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 hours after the paclitaxel infusion finishes

21-day cycles

Dose and schedule modifications

• Paclitaxel (Taxol) dosage adjusted based on toxicity down to 150 or 200 mg/m², or up to 280 mg/m²

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 dosing details in manuscript 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 dosing details in manuscript PubMed

Metastatic or locally advanced disease, subsequent lines of therapy

CAPIRI

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

Regimen

Study	Dates of enrollment	Evidence
Leary et al. 2008	2003-10 to 2005-09	Phase 2

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Irinotecan (Camptosar) 250 mg/m² IV over 30 to 90 minutes once on day 1

Supportive therapy

• Atropine (Atropen) 0.25 mg SC once on day 1, given prior to irinotecan
• Loperamide (Imodium) 4 mg PO prn first unformed stool, then 2 mg PO Q2H x at least 12 hours, or for 12 hours after last liquid stool
• Ciprofloxacin (Cipro) 250 mg PO twice per day prn diarrhea lasting longer than 24 hours despite loperamide

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 dosing details in manuscript PubMed

Docetaxel monotherapy

Regimen variant #1, 75 mg/m², indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017	Phase 3 (C)	Pembrolizumab	Inferior OS1

¹Reported 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

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

21-day cycles

Regimen variant #2, 100 mg/m²

Study	Dates of enrollment	Evidence
Albertsson et al. 2007	1997-2003	Phase 2

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

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

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 dosing details in abstract 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 dosing details in manuscript PubMed NCT02564263
3. INTEGRATE IIb: NCT04879368

Docetaxel & Irinotecan

Regimen

Study	Dates of enrollment	Evidence
Burtness et al. 2009	2001-12 to 2004-10	Phase 2, fewer than 20 pts in this subgroup

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

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV over 60 minutes once per day on days 1 & 8, given first
• Irinotecan (Camptosar) 50 mg/m² IV over 30 minutes once per day on days 1 & 8, given second

Supportive therapy

• Dexamethasone (Decadron) as follows:
  • 8 mg PO once per day on days 1 & 8; 12 hours prior to docetaxel
  • 10 mg IV once per day on days 1 & 8, within 1 hour of chemotherapy
  • 8 mg PO once per day on days 1 & 8; 12 hour afters chemotherapy
• Serotonin 5-HT3 antagonist IV once per day on days 1 & 8, within 1 hour before chemotherapy
• "Oral antiemetic therapy prescribed"
• Loperamide (Imodium) as needed

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 dosing details in manuscript link to PMC article PubMed

Erlotinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Ilson et al. 2010	2002-07 to 2005-09	Phase 2

Note: Patients had 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 on days 1 to 28, taken 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 dosing details in manuscript link to PMC article PubMed

Irinotecan monotherapy

Regimen variant #1, 14-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017	Phase 3 (C)	Pembrolizumab	Inferior OS1

¹Reported 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

• Irinotecan (Camptosar) 180 mg/m² IV once on day 1

14-day cycles

Regimen variant #2, 4 out of 6 weeks

Study	Dates of enrollment	Evidence
Mühr-Wilkenshoff et al. 2003	1999-2000	Phase 2, fewer than 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. Ten patients had esophageal squamous cell carcinoma, three with esophageal adenocarcinoma

Chemotherapy

• Irinotecan (Camptosar) 125 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22

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 dosing details in manuscript PubMed NCT02564263
3. INTEGRATE IIb: NCT04879368

IRIS

IRIS: IRInotecan & S-1

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Huang et al. 2019 (ESWN 01)	2014-2016	Phase 3 (E-switch-ic)	S-1	Superior PFS (primary endpoint) Median PFS: 3.8 vs 1.7 mo (HR 0.58, 95% CI 0.38-0.86)

Chemotherapy

• Irinotecan (Camptosar) 160 mg/m² IV once on day 1, given first
• Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
  • Less than 1.25 m²: 40 mg PO twice per day on days 1 to 10
  • Between 1.25 m² and 1.5 m²: 50 mg PO twice per day on days 1 to 10
  • 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 dosing details in manuscript PubMed NCT02319187

Paclitaxel monotherapy

Regimen variant #1, weekly

Study	Dates of enrollment	Evidence
Ilson et al. 2007	1998-01 to 2000-04	Phase 2

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

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel

28-day cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017	Phase 3 (C)	Pembrolizumab	Inferior OS1

¹Reported 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.
Note: This is the lower bound of dosing specified in KEYNOTE-181.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

28-day cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017	Phase 3 (C)	Pembrolizumab	Inferior OS1

¹Reported 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.
Note: This is the upper bound of dosing specified in the protocol.

Chemotherapy

• Paclitaxel (Taxol) 100 mg/m² IV once per day on days 1, 8, 15

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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT02564263
3. INTEGRATE IIb: NCT04879368

S-1 monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Huang et al. 2019 (ESWN 01)	2014-2016	Phase 3 (C)	IRIS	Inferior PFS

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

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
  • Less than 1.25 m²: 40 mg PO twice per day on days 1 to 14
  • Between 1.25 m² and 1.5 m²: 50 mg PO twice per day on days 1 to 14
  • 1.5 m² or more: 60 mg PO twice per day on days 1 to 14

21-day cycles

References

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 dosing details in manuscript PubMed NCT02319187