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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. 2007_esoph	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

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

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
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

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
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

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

References

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

References

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

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

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

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. 2007_esoph	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

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

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

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

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

References

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

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

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
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
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

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

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
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
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
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
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

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

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

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

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
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. 2007_esoph	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

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
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

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

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
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
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
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
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
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

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

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
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

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
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

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

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
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

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

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

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

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

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

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

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
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

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
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

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

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
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)
Cunningham et al. 2008 (REAL-2)	2000-2005	Phase 3 (E-RT-switch-ic)	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

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)
Cunningham et al. 2008 (REAL-2)	2000-2005	Phase 3 (E-switch-ic)	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

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

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
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

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

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

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

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
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

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
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

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

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
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
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

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

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

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
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
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

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

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
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
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

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

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:100%;"
+<span id="BackToTop"></span>
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''
+[[#top|Back to Top]]
-|-
+</div>
-| style="background-color:#F0F0F0; width:15%" |[[File:RyanNguyen.jpg|frameless|upright=0.3|center]]
+{{#lst:Editorial board transclusions|gi}}
-| style="width:35%" |<big>[[User:Ryannguyen|Ryan Nguyen, DO]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br>[https://www.linkedin.com/in/ryan-nguyen-0b12a432/ LinkedIn]
+''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Esophageal cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.<br>
-| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]
-| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big>
-|-
-|}
-''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Esophageal cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.
 <big>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.</big>
 <br>There are several related dedicated pages:
 *'''Histology-specific:'''
 **'''[[Esophageal adenocarcinoma]]'''
@@ Line 19: / Line 12: @@
 *'''Biomarker-specific:'''
 **'''[[Gastric_cancer,_HER2-positive|'''HER2 positive gastroesophageal cancer''']]
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 26: / Line 18: @@
 |}
 {{TOC limit|limit=3}}
 =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.'''
 ==[http://www.asco.org/ ASCO]==
-*'''2020:''' Shah et al. [https://doi.org/10.1200/jco.20.00866 Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline]
+*'''2023:''' Shah et al. [https://doi.org/10.1200/jco.22.02331 Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline] [https://pubmed.ncbi.nlm.nih.gov/36603169/ PubMed]
+*'''2021:''' Shah et al. [https://doi.org/10.1200/jco.21.01831 Immunotherapy in Patients With Locally Advanced Esophageal Carcinoma: ASCO Treatment of Locally Advanced Esophageal Carcinoma Guideline Rapid Recommendation Update] [https://pubmed.ncbi.nlm.nih.gov/34406872/ PubMed]
-==[http://www.esmo.org/ ESMO]==
+**'''2020:''' Shah et al. [https://doi.org/10.1200/jco.20.00866 Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/32568633 PubMed]
-*'''2016:''' Lordick et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Oesophageal-Cancer Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+==[https://www.esmo.org/ ESMO]==
+*'''2022:''' Obermannová et al. [https://doi.org/10.1016/j.annonc.2022.07.003 Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/35914638 PubMed]
+**'''2016:''' Lordick et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Oesophageal-Cancer Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/27664261 PubMed]
+**'''2013:''' Stahl et al. [https://doi.org/10.1093/annonc/mdt342 Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/24078662/ PubMed]
+**'''2010:''' Stahl et al. [https://doi.org/10.1093/annonc/mdq163 Esophageal cancer: Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555101/ PubMed]
+**'''2009:''' Stahl & Oliveira. [https://doi.org/10.1093/annonc/mdp121 Esophageal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454456/ PubMed]
+**'''2008:''' Stahl & Oliveira. [https://doi.org/10.1093/annonc/mdn074 Esophageal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456754/ PubMed]
+**'''2007:''' Stahl. [https://doi.org/10.1093/annonc/mdm018 Esophageal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491027/ PubMed]
+*'''2019:''' Muro et al. [https://doi.org/10.1093/annonc/mdy498 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] [https://pubmed.ncbi.nlm.nih.gov/30475943/ PubMed]
-==[https://www.nccn.org/ NCCN]==
+==NCCN==
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433 NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers]
-*[https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers]
+*'''2015:''' Ajani et al. [https://doi.org/10.6004/jnccn.2015.0028 Esophageal and Esophagogastric Junction Cancers, Version 1.2015] [https://pubmed.ncbi.nlm.nih.gov/25691612/ PubMed]
+*'''2011:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2011.0072 Esophageal and esophagogastric junction cancers.] [https://pubmed.ncbi.nlm.nih.gov/21900218/ PubMed]
+*'''2008:''' Ajani et al. Esophageal cancer. [https://pubmed.ncbi.nlm.nih.gov/18926093/ PubMed]
+*'''2006:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2006.0029 Esophageal Cancer Clinical Practice Guidelines.] [https://pubmed.ncbi.nlm.nih.gov/16569387/ PubMed]
+*'''2003:''' Ajani et al. [https://doi.org/10.6004/Jnccn.2003.0004 Esophageal cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19764147/ PubMed]
 =Neoadjuvant induction therapy=
 ==Capecitabine & Cisplatin (CX) {{#subobject:ce2bbb|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 CX: '''<u>C</u>'''isplatin & '''<u>X</u>'''eloda (Capecitabine)
 <br>XP: '''<u>X</u>'''eloda (Capecitabine) & '''<u>P</u>'''latinol (Cisplatin)
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:1dd767|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
 ! style="width: 50%" |Study
 ! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
@@ Line 56: / Line 58: @@
 |-
 |}
-''The study was for patients with stage IV disease.''
+''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.''
+<div class="toccolours" style="background-color:#fdcdac">
-''Patients 97% adenocarcinoma, 3% squamous cell histology; 3% with ECOG PS of 2.''
+====Eligibility criteria====
+*Stage IV disease
-*Patients with M1b disease (visceral metastases) received the chemotherapy only part until progression of disease or unacceptable toxicity.
+</div>
-*Patients with M1a or M1b (non-viscertal metastases) received 2 cycles of the chemotherapy only part, underwent treatment with chemoradiation, and then treatment continued with--presumably, but not outright specified in the paper--chemotherapy only until progression of disease or unacceptable toxicity.
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 *[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
+'''21-day cycles (see note)'''
-'''21-day cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*Lee et al. 2007<sub>esoph</sub>, patients with M1a or M1b (non-visceral) disease: Definitive [[#Capecitabine.2C_Cisplatin.2C_RT|capecitabine, cisplatin, RT]]
-*Patients with M1a or M1b disease: [[#Capecitabine.2C_Cisplatin.2C_RT|Definitive capecitabine, cisplatin, RT]]
+</div></div>
 ===References===
+#'''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. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17951334/ PubMed]
-#'''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. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17951334 PubMed]
+==Cisplatin & Docetaxel (DC) {{#subobject:eed8f6|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Cisplatin & Docetaxel {{#subobject:eed8f6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:523945|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 91: / Line 86: @@
 |-
 |[https://doi.org/10.1093/annonc/mdp045 Ruhstaller et al. 2009 (SAKK 75/02)]
-|2003-2006
+|2003-07 to 2006-06
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
@@ Line 98: / Line 93: @@
 |[https://doi.org/10.1093/annonc/mdy105 Ruhstaller et al. 2018 (SAKK 75/08)]
 |2010-2013
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Cisplatin, Docetaxel, Cetuximab
+|[[#Cisplatin_.26_Docetaxel_.28DC.29_.26_Cetuximab_999|DC & Cetuximab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
-''SAKK 75/02 patients: 55% adenocarcinoma, 45% squamous cell histology''
+''Note: SAKK 75/02 patients had 55% adenocarcinoma, 45% squamous cell histology''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
 *[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycle for 2 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*Neoadjuvant [[#Cisplatin.2C_Docetaxel.2C_RT|cisplatin, docetaxel, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]
-*[[#Cisplatin.2C_Docetaxel.2C_RT|Neoadjuvant cisplatin, docetaxel, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1093/annonc/mdp045 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19465425/ PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdp045 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19465425 PubMed]
+#'''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. [https://doi.org/10.1093/annonc/mdy105 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29635438/ PubMed] [https://clinicaltrials.gov/study/NCT01107639 NCT01107639]
-#'''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. [https://doi.org/10.1093/annonc/mdy105 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29635438 PubMed] NCT01107639
 ==Cisplatin & Fluorouracil (CF) {{#subobject:37e6ba|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
 <br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol (Cisplatin)
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, 80/4000, 4 day 5-FU infusion {{#subobject:2335c3|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08651-8/fulltext Girling et al. 2002 (UK MRC OE02)]
+|[https://doi.org/10.1016/S0140-6736(02)08651-8 Girling et al. 2002 (UK MRC OE02)]
 |1992-1998
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-| style="background-color:#91cf60" |Seems to have superior OS (*)
+| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> (primary endpoint)<br>OS60: 23% vs 17.1%<br>(HR 0.84, 95% CI 0.72-0.98)
 |-
 |}
-''Note: Reported efficacy for UK MRC OE02 is based on the 2009 update.''
+''<sup>1</sup>Reported efficacy for UK MRC OE02 is based on the 2009 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1
 *[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
 '''21-day cycle for 2 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
 *[[Surgery#Esophageal_cancer_surgery|Surgery]]
+</div></div><br>
-===Regimen variant #2, 80/4000, 5 day 5-FU infusion {{#subobject:4b5879|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 100/5000 {{#subobject:e6fe90|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://link.springer.com/article/10.1245%2Fs10434-011-2049-9 Ando et al. 2011 (JCOG 9907)]
+|[https://doi.org/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]
-|2000-2006
+|1990-1995
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29_3|Adjuvant CF]]
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#ffffbf" |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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: see note)
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+'''28-day cycle for 3 cycles'''
+</div>
-'''21-day cycle for 2 cycles'''
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*[[Surgery#Esophageal_cancer_surgery|Surgery]], then adjuvant [[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
+</div></div>
+===References===
+#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://doi.org/10.1056/NEJM199812313392704 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9869669/ PubMed]
+##'''Update:''' Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG; Radiation Therapy Oncology Group; USA Intergroup. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007 Aug 20;25(24):3719-25. [https://doi.org/10.1200/JCO.2006.10.4760 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17704421/ PubMed]
+#'''UK MRC OE02:''' Girling DJ, Bancewicz J, Clark PI, Smith DB, Donnelly RJ, Fayers PM, Weeden S, Hutchinson T, Harvey A, Lyddiard J; Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33. [https://doi.org/10.1016/S0140-6736(02)08651-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12049861/ PubMed]
+##'''Update:''' Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009 Oct 20;27(30):5062-7. Epub 2009 Sep 21. [https://doi.org/10.1200/JCO.2009.22.2083 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19770374/ PubMed]
-*[[Surgery#Esophageal_cancer_surgery|Surgery]]
+==Cisplatin & Irinotecan (IC) {{#subobject:500b44|Regimen=1}}==
+IC: '''<u>I</u>'''rinotecan & '''<u>C</u>'''isplatin
-===Regimen variant #3, 100/5000 {{#subobject:e6fe90|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+===Regimen {{#subobject:927613|Variant=1}}===
-!style="width: 20%"|Study
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 20%"|Years of enrollment
+!style="width: 33%"|Study
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Dates of enrollment
-!style="width: 20%"|Comparator
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]
-|1990-1995
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010601%2991%3A11%3C2165%3A%3AAID-CNCR1245%3E3.0.CO%3B2-H Ancona et al. 2001]
+|[https://doi.org/10.1002/cncr.26591 Ilson et al. 2011]
-|1992-1997
+|2002-12 to 2005-10
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#91cf61" |Phase 2
-|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: it is not entirely clear from Ancona et al. 2001 whether this was a 96-hour or 120-hour infusion; there was option to proceed after the 2nd cycle. In both trials, this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
+''Note: Ilson et al. 2011 patients had 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated histology; 33% gastroesophageal junction.''
+<div class="toccolours" style="background-color:#b3e2cd">
-''Ancona et al. 2001 patients: 100% squamous cell carcinoma histology''
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1
+*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
-*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: see note)
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] 20 mg IV or PO once per day on days 1 & 8, prior to chemotherapy
-'''28-day cycle for 3 cycles'''
+*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|D5NS]] or [[Normal saline|NS]] as supportive hydration
+*[[Atropine (Atropen)]] 0.5 to 1 mg IV prn cholinergic symptoms
+'''21-day cycle for 2 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*Neoadjuvant [[#Cisplatin.2C_Irinotecan.2C_RT|cisplatin, irinotecan, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]
-*RTOG 8911: [[Surgery#Esophageal_cancer_surgery|Surgery]], then [[#Cisplatin_.26_Fluorouracil_.28CF.29_3|adjuvant CF]]
+</div></div>
-*Ancona et al. 2001: [[Surgery#Esophageal_cancer_surgery|Surgery]], performed 3 to 4 weeks after the last cycle of chemotherapy
+===References===
+#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. [https://doi.org/10.1002/cncr.26591 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990000/ PubMed]
+==EOF {{#subobject:ae4e32|Regimen=1}}==
+EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e532ea|Variant=1}}===
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+====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
+*[[:Category:Serotonin_5-HT3_antagonists|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'''
+</div></div>
 ===References===
-#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9869669 PubMed]
+==EOX {{#subobject:891a3e|Regimen=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. [https://doi.org/10.1200/JCO.2006.10.4760 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17704421 PubMed]
+EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)
-#Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, Bonavina L, Peracchia A. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001 Jun 1;91(11):2165-74. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010601%2991%3A11%3C2165%3A%3AAID-CNCR1245%3E3.0.CO%3B2-H link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/11391598 PubMed]
+<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
-#'''UK MRC OE02:''' Girling DJ, Bancewicz J, Clark PI, Smith DB, Donnelly RJ, Fayers PM, Weeden S, Hutchinson T, Harvey A, Lyddiard J; Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08651-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12049861 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-##'''Update:''' Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009 Oct 20;27(30):5062-7. Epub 2009 Sep 21. [https://doi.org/10.1200/JCO.2009.22.2083 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19770374 PubMed]
+===Regimen {{#subobject:6941e|Variant=1}}===
-#'''JCOG 9907:''' Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. [https://link.springer.com/article/10.1245%2Fs10434-011-2049-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21879261 PubMed] NCT00190554
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
-==Cisplatin & Irinotecan (IC) {{#subobject:500b44|Regimen=1}}==
+====Chemotherapy====
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-|-
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-|[[#top|back to top]]
+*[[Capecitabine (Xeloda)]] 500 to 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
-|}
+====Supportive therapy====
-IC: '''<u>I</u>'''rinotecan & '''<u>C</u>'''isplatin
+*[[Dexamethasone (Decadron)]] 8 mg IV once on day 1, prior to chemotherapy, then 4 mg PO three times per day on days 2 & 3
-===Regimen {{#subobject:927613|Variant=1}}===
+*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] once on day 1, prior to chemotherapy
-{| class="wikitable" style="width: 50%; text-align:center;"
+*[[Metoclopramide (Reglan)]] 10 mg PO three times per day on days 2 to 4
-! style="width: 50%" |Study
+'''21-day cycle for up to 8 cycles; for perioperative use per some guidelines, 3 cycles preoperatively and 3 cycles postoperatively would be used'''
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+</div></div>
-|-
+===References===
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.26591/full Ilson et al. 2011]
-| style="background-color:#91cf61" |Phase II
+==FLEP {{#subobject:78eabc|Regimen=1}}==
-|-
+FLEP: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin)
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:721ee9|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1200/JCO.2005.00.034 Stahl et al. 2005]
+|1994-2002
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+|-
 |}
-''Illson et al. patients: 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated history; 33% gastroesophageal junction.''
+''Note: For historic reference.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Leucovorin (Folinic acid)]] 300 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
+'''21-day cycle for 3 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Neoadjuvant [[#Cisplatin_.26_Etoposide_.28EP.29_.26_RT_888|PE & RT]] (4000 cGy) followed by [[Surgery#Esophageal_cancer_surgery|surgery]] versus definitive [[#Cisplatin_.26_Etoposide_.28EP.29_.26_RT_888|PE & RT]] (at least 6500 cGy)
+</div></div>
-*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
+===References===
-*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
+#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. [https://doi.org/10.1200/JCO.2005.00.034 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15800321/ PubMed]
+==PCF {{#subobject:747f5e|Regimen=1}}==
-====Supportive medications====
+PCF: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Dexamethasone (Decadron)]] 20 mg IV or PO once per day on days 1 & 8, prior to chemotherapy
+===Regimen {{#subobject:2d319e|Variant=1}}===
-*One of the following:
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-**[[Granisetron]] 2 mg PO once per day on days 1 & 8, prior to chemotherapy
+!style="width: 33%"|Study
-**[[Ondansetron (Zofran)]] 32 mg IV once per day on days 1 & 8, prior to chemotherapy
+!style="width: 33%"|Dates of enrollment
-*At least 500 mL D5NS or NS as supportive hydration
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-*[[Atropine (Atropen)]] 0.5 to 1 mg IV prn cholinergic symptoms
+|-
+|[https://doi.org/10.1097/JTO.0000000000000612 Zhao et al. 2015 (ZY-01)]
-'''21-day cycle for 2 cycles'''
+|2005-2007
-====Subsequent treatment====
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-*[[#Cisplatin.2C_Irinotecan.2C_RT|Neoadjuvant cisplatin, irinotecan, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]
-===References===
-#Ilson DH, Minsky BD, Ku GY, Rusch V, Rizk N, Shah M, Kelsen DP, Capanu M, Tang L, Campbell J, Bains M. Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer. Cancer. 2011 Oct 11. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.26591/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21990000 PubMed]
-==EOF {{#subobject:ae4e32|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
-EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
+<div class="toccolours" style="background-color:#b3e2cd">
-===Regimen {{#subobject:e532ea|Variant=1}}===
-''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====
+*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once on day 1
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 2
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Fluorouracil (5-FU)]] 700 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+'''2 cycles'''
+</div>
-====Supportive medications====
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-*[[Dexamethasone (Decadron)]] 8 mg IV once on day 1, prior to chemotherapy, then 4 mg PO three times per day on days 2 & 3
+*[[Surgery#Esophageal_cancer_surgery|Surgery]], then adjuvant [[#PCF_999|PCF]] x 2 versus [[Esophageal_cancer_-_null_regimens#Observation|no further treatment]]
-*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] once on day 1, prior to chemotherapy
+</div></div>
-*[[Metoclopramide (Reglan)]] 10 mg PO three times per day on days 2 to 4
+===References===
-*[[Warfarin (Coumadin)]] 1 mg PO once per day as thrombosis prophylaxis, started on day -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. [https://doi.org/10.1097/JTO.0000000000000612 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26287319/ PubMed] [https://clinicaltrials.gov/study/NCT01225523 NCT01225523]
+=Neoadjuvant chemoradiotherapy=
-'''21-day cycle for up to 8 cycles; for perioperative use per some guidelines, 3 cycles preoperatively and 3 cycles postoperatively would be used'''
+''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 {{#subobject:79bb5a|Regimen=1}}==
-==EOX {{#subobject:891a3e|Regimen=1}}==
+Capecitabine, Carboplatin, Paclitaxel, RT: Capecitabine, Carboplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:f22688|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1016/j.ijrobp.2006.10.027 Czito et al. 2006]
+|2003-07 to 2005-07
+| style="background-color:#ffffbe" |Pilot, fewer than 20 pts
 |-
-|[[#top|back to top]]
 |}
-EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)
+''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.''
-<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
+<div class="toccolours" style="background-color:#b3e2cd">
-===Regimen {{#subobject:6941e|Variant=1}}===
+====Chemotherapy====
-''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.''
+*[[Carboplatin (Paraplatin)]] AUC 1.5 IV once per day on days 2, 9, 16, 23, 30
+*[[Paclitaxel (Taxol)]] 45 mg/m<sup>2</sup> IV over 60 minutes once per day on days 2, 9, 16, 23, 30
+*[[Capecitabine (Xeloda)]] 600 mg/m<sup>2</sup> PO twice per day, starting on day 1 and finishing the evening of the last day of radiation therapy
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 180 cGy fractions x 28 fractions, for a total dose of 5040 cGy
+'''6-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Czito et al. 2006, surgical candidates: [[Surgery#Esophagectomy|surgery]], performed 6 to 8 weeks after chemoradiotherapy completion. Patients could receive adjuvant chemotherapy, beginning 4 to 12 weeks postoperatively
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1016/j.ijrobp.2006.10.027 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17197129/ PubMed]
+==Capecitabine, Cisplatin, RT {{#subobject:ae7180|Regimen=1}}==
+CX & RT: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:eccd56|Variant=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 50%" |Study
+! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[http://jjco.oxfordjournals.org/content/37/11/829.long Lee et al. 2007<sub>esoph</sub>]
+| style="background-color:#ffffbe" |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.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Induction [[#Capecitabine_.26_Cisplatin_.28CX.29|Capecitabine & Cisplatin]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
+*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5, '''given second'''
+'''7-day cycles until radiation therapy is complete'''
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 5400 cGy given (dose per fraction and total duration of treatment was not specified)
+'''One course'''
+</div></div>
+===References===
+#'''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. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains dosing details in manuscript'''--please see note above, as patients in this study did not undergo surgery [https://pubmed.ncbi.nlm.nih.gov/17951334/ PubMed]
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
+==Capecitabine, Docetaxel, RT {{#subobject:ff7031|Regimen=1}}==
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+Capecitabine, Docetaxel, RT: Capecitabine, Docetaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-*[[Capecitabine (Xeloda)]] 500 to 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:d49e8|Variant=1}}===
-====Supportive medications====
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
-*[[Dexamethasone (Decadron)]] 8 mg IV once on day 1, prior to chemotherapy, then 4 mg PO three times per day on days 2 & 3
+!style="width: 33%"|Dates of enrollment
-*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] once on day 1, prior to chemotherapy
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-*[[Metoclopramide (Reglan)]] 10 mg PO three times per day on days 2 to 4
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600150/ Wood et al. 2013 (D-9939)]
-'''21-day cycle for up to 8 cycles; for perioperative use per some guidelines, 3 cycles preoperatively and 3 cycles postoperatively would be used'''
+|NR
+| style="background-color:#ffffbe" |Phase 1
-==FLEP {{#subobject:78eabc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
-FLEP: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin)
+''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.''
-===Regimen {{#subobject:721ee9|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="width: 50%; text-align:center;"
+====Chemotherapy====
-! style="width: 50%" |Study
+*[[Docetaxel (Taxotere)]] 15 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+*[[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 [[External_beam_radiotherapy|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'''
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1097/JTO.0b013e3182829bf3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600150/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23370365/ PubMed] [https://clinicaltrials.gov/study/NCT00153881 NCT00153881]
+==Capecitabine, Docetaxel, Oxaliplatin, RT {{#subobject:312400|Regimen=1}}==
+Capecitabine, Docetaxel, Oxaliplatin, RT: Capecitabine, Docetaxel, Oxaliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e65189|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/JCO.2005.00.034 Stahl et al. 2005]
+|[https://doi.org/10.1200/jco.2009.24.8773 Spigel et al. 2010 (SCRI GI 57)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+|2005-2008
+| style="background-color:#91cf61" |Phase 1/2
 |-
 |}
-''For historic reference.''
+''Note: Patients had 69% adenocarcinoma, 18% squamous cell, 12% not otherwise specified. 69% distal esophagus, 16% midesophagus, 14% gastroesophageal junction.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 7, 15 to 21, 29 to 35
-*[[Fluorouracil (5-FU)]]
+*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29
-*[[Folinic acid (Leucovorin)]]
+*[[Oxaliplatin (Eloxatin)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29
-*[[Etoposide (Vepesid)]]
+====Supportive therapy====
-*[[Cisplatin (Platinol)]]
+*[[Dexamethasone (Decadron)]] 4 mg PO every 12 hours before, at the time of, and after docetaxel; first dose the evening prior to docetaxel
+*"Routine [[:Category:Emesis prevention|antiemetics]]"
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====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:
-*PE & RT (40 Gy), then [[Surgery#Esophageal_cancer_surgery|surgery]] versus PE & RT (at least 65 Gy)
+**SCRI GI 57, surgical candidates: [[Surgery#Esophagectomy|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
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1200/jco.2009.24.8773 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20351330/ PubMed] [https://clinicaltrials.gov/study/NCT00193128 NCT00193128]
-#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. [https://doi.org/10.1200/JCO.2005.00.034 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15800321 PubMed]
+==Capecitabine, Oxaliplatin, RT {{#subobject:e958eb|Regimen=1}}==
+CapeOx & RT: '''<u>Cape</u>'''citabine, '''<u>Ox</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-==PCF {{#subobject:747f5e|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:69d2ce|Variant=1}}===
-|-
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-|[[#top|back to top]]
+!style="width: 33%"|Study
-|}
+!style="width: 33%"|Dates of enrollment
-PCF: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-===Regimen {{#subobject:2d319e|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.jto.org/article/S1556-0864(15)33583-8/fulltext Zhao et al. 2015 (ZY-01)]
+|[https://doi.org/10.1080/07357900802172093 Javle et al. 2009]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+|NR in abstract
+| style="background-color:#ffffbe" |Phase 1b
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
-*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 2
+====Radiotherapy====
-*[[Fluorouracil (5-FU)]] 700 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
+*Concurrent [[External_beam_radiotherapy|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'''
-'''2 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*[[Surgery#Esophagectomy|Surgery]]
-*[[Surgery#Esophageal_cancer_surgery|Surgery]], then adjuvant PCF x 2 versus no further treatment
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1080/07357900802172093 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19235592/ PubMed]
-#'''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. [https://www.jto.org/article/S1556-0864(15)33583-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26287319 PubMed]
+==Capecitabine, Paclitaxel, RT {{#subobject:17bbec|Regimen=1}}==
+Capecitabine, Paclitaxel, RT: Capecitabine, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-=Neoadjuvant chemoradiotherapy=
+<div class="toccolours" style="background-color:#eeeeee">
-''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.''
+===Regimen {{#subobject:c6f9f5|Variant=1}}===
-==Capecitabine, Carboplatin, Paclitaxel, RT {{#subobject:79bb5a|Regimen=1}}==
+''Note: No primary reference could be found for this regimen.''
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 625 to 825 mg/m<sup>2</sup> 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/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] not defined on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+'''5-week course'''
+</div></div>
+===References===
+==Carboplatin, Fluorouracil, RT {{#subobject:d29415|Regimen=1}}==
+Carboplatin, Fluorouracil, RT: Carboplatin, Fluorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1c21a7|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1111/j.1442-2050.2009.00984.x Zemanoa et al. 2009]
-|}
+|2001-01 to 2005-08
-Capecitabine, Carboplatin, Paclitaxel, RT: Capecitabine, Carboplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+| style="background-color:#91cf61" |Non-randomized
-===Regimen {{#subobject:f22688|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.redjournal.org/article/S0360-3016(06)03362-1/abstract Czito et al. 2006]
-| style="background-color:#ffffbe" |Pilot, <20 pts
 |-
 |}
-''The primary reference did not specify whether patients were intended to proceed to surgery.''
+''Note: Patients had 86% squamous cell, 8% adenocarcinoma, 6% other histology. 3% ECOG PS of 2.''
+<div class="toccolours" style="background-color:#b3e2cd">
-''Patients: 77% adenocarcinoma, 23% squamous cell histology. 54% lower thoracic, 23% midthoracic, 23% gastroesophageal junction.''
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 6 IV once per day on days 1 & 22
-*[[Carboplatin (Paraplatin)]] AUC 1.5 IV once per day on days 2, 9, 16, 23, 30
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on days 1 & 22 (total dose: 8400 mg/m<sup>2</sup>)
-*[[Paclitaxel (Taxol)]] 45 mg/m<sup>2</sup> IV over 60 minutes once per day on days 2, 9, 16, 23, 30
-*[[Capecitabine (Xeloda)]] 600 mg/m<sup>2</sup> PO twice per day, starting on day 1 and finishing the evening of the last day of radiation therapy
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] by the following criteria:
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy
+**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.
-'''6-week course'''
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*Upper endoscopy and CT chest and abdomen was performed after completion of chemoradiation
-*Patients were evaluated for [[Surgery#Esophagectomy|surgery]], performed 6 to 8 weeks after chemoradiotherapy completion. Patients could receive adjuvant chemotherapy, beginning 4 to 12 weeks postoperatively
+*[[Surgery#Esophagectomy|Surgery]] planned to be done 4 to 6 weeks after finishing chemoradiation
+</div></div>
 ===References===
+#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. [https://doi.org/10.1111/j.1442-2050.2009.00984.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19515190/ PubMed]
-#'''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. [http://www.redjournal.org/article/S0360-3016(06)03362-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17197129 PubMed]
+==Carboplatin & Paclitaxel (CP) & RT {{#subobject:93878b|Regimen=1}}==
+CP & RT: '''<u>C</u>'''arboplatin, '''<u>P</u>'''aclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-==Capecitabine, Cisplatin, RT {{#subobject:ae7180|Regimen=1}}==
+{| class="wikitable" style="color:black; background-color:#42f584"
-{| class="wikitable" style="float:right; margin-left: 5px;"
+|<small>'''ESMO-preferred for squamous cell carcinoma (I-A, 2016)'''</small>
 |-
-|[[#top|back to top]]
 |}
-CX & RT: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:eccd56|Variant=1}}===
+===Regimen variant #1, 5 weeks of chemotherapy {{#subobject:33b67a|Variant=1}}===
-''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.''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-''Patients: 3% adenocarcinoma, 97% squamous cell histology; 3% with ECOG PS of 2.''
+!style="width: 20%"|Dates of enrollment
-====Preceding treatment====
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-*[[#Capecitabine_.26_Cisplatin_.28CX.29|Capecitabine & Cisplatin]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
-====Chemotherapy====
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286 van Meerten et al. 2006]
+|2001-2004
-*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
+| style="background-color:#91cf61" |Phase 2
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5, '''given second'''
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
-'''7-day cycles until radiation therapy is complete'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 54 Gy given (dose per fraction and total duration of treatment was not specified)
-'''One course'''
-===References===
-#'''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. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains verified protocol'''--please see note above, as patients in this study did not undergo surgery [https://pubmed.ncbi.nlm.nih.gov/17951334 PubMed]
-==Capecitabine, Docetaxel, RT {{#subobject:ff7031|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1056/NEJMoa1112088 van Hagen et al. 2012 (CROSS)]
-|}
+|2004-2008
-Capecitabine, Docetaxel, RT: Capecitabine, Docetaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-===Regimen {{#subobject:d49e8|Variant=1}}===
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-{| class="wikitable" style="width: 50%; text-align:center;"
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>OS120: 38% vs 25%<br>(HR 0.70, 95% CI 0.55-0.89)
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600150/ Wood et al. 2013 (D-9939)]
-| style="background-color:#ffffbe" |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.''
+''<sup>1</sup>Reported efficacy for CROSS is based on the 2021 update.''<br>
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, 22, 29, '''given second'''
-*[[Docetaxel (Taxotere)]] 15 mg/m<sup>2</sup> IV once on day 1
+*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29 '''given first'''
-*[[Capecitabine (Xeloda)]] 3500 mg PO once per day on days 1 to 5, '''given prior to radiation'''
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] 10 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to paclitaxel
-'''7-day cycle for 5 cycles'''
+*[[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 [[Normal saline|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 [[External_beam_radiotherapy|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)
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] to 50.4 Gy in 28 fractions
 '''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Esophagectomy|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
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===References===
+===Regimen variant #2, 6 weeks of chemotherapy {{#subobject:ug717a|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#'''Phase 1:''' Wood MD, Zaki BI, Gordon SR, Sutton JE Jr, Lisovsky M, Gui J, Bubis JA, Dragnev KH, Rigas JR. Trimodality therapy for stage II-III carcinoma of the esophagus: a dose-ranging study of concurrent capecitabine, docetaxel, and thoracic radiotherapy. J Thorac Oncol. 2013 Apr;8(4):487-94. [https://www.jto.org/article/S1556-0864(15)32794-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600150/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23370365 PubMed]
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-==Capecitabine, Docetaxel, Oxaliplatin, RT {{#subobject:312400|Regimen=1}}==
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903071/ Safran et al. 2022 (RTOG 1010)]
+|2010-2015
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Carboplatin.2C_Paclitaxel.2C_Trastuzumab.2C_RT_999|CP, Trastuzumab, RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[[#top|back to top]]
 |}
-Capecitabine, Docetaxel, Oxaliplatin, RT: Capecitabine, Docetaxel, Oxaliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#fdcdac">
-===Regimen {{#subobject:e65189|Variant=1}}===
+====Biomarker eligibility criteria====
-{| class="wikitable sortable" style="width: 75%; text-align:center;"
+*HER2+
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div></div>
+===References===
+#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. [https://doi.org/10.1038/sj.bjc.6603134 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16670722/ PubMed]
+#'''CROSS:''' van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. [https://doi.org/10.1056/NEJMoa1112088 link to original article] '''contains dosing details in manuscript''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1112088/suppl_file/nejmoa1112088_appendix.pdf link to appendix with details about administration] [https://pubmed.ncbi.nlm.nih.gov/22646630/ PubMed] NTR487
+##'''Update:''' Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. Epub 2015 Aug 5. [https://doi.org/10.1016/S1470-2045(15)00040-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26254683/ PubMed]
+##'''Update:''' Eyck BM, van Lanschot JJB, Hulshof MCCM, van der Wilk BJ, Shapiro J, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch OR, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Spillenaar Bilgen EJ, van der Sangen MJC, Rozema T, Ten Kate FJW, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS Study Group. Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol. 2021 Jun 20;39(18):1995-2004. Epub 2021 Apr 23. [https://doi.org/10.1200/jco.20.03614 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33891478/ PubMed]
+#'''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. [https://doi.org/10.1016/s1470-2045(21)00718-x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903071/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35038433/ PubMed] [https://clinicaltrials.gov/study/NCT01196390 NCT01196390]
+==Cisplatin, Docetaxel, RT {{#subobject:4231cb|Regimen=1}}==
+DC & RT: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:6c3cc6|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 33%"|Dates of enrollment
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.2009.24.8773 Spigel et al. 2010 (SCRI GI 57)]
+|[https://doi.org/10.1093/annonc/mdp045 Ruhstaller et al. 2009 (SAKK 75/02)]
-|2005-2008
+|2003-07 to 2006-06
-| style="background-color:#91cf61" |Phase I/II
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Patients: 69% adenocarcinoma, 18% squamous cell, 12% not otherwise specified. 69% distal esophagus, 16% midesophagus, 14% gastroesophageal junction.''
+''Note: Patients had 55% adenocarcinoma, 45% squamous cell histology''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Induction [[#Cisplatin_.26_Docetaxel_.28DC.29|Cisplatin & Docetaxel]] x 2
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 7, 15 to 21, 29 to 35
+*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29
-*[[Oxaliplatin (Eloxatin)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29
-====Supportive medications====
-*[[Dexamethasone (Decadron)]] 4 mg PO every 12 hours before, at the time of, and after [[Docetaxel (Taxotere)]]; first dose the evening before [[Docetaxel (Taxotere)]]
-*"Routine antiemetics"
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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)
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy
 '''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*[[Surgery#Esophagectomy|Surgery]], 3 to 8 weeks after finishing chemoradiation
-*Endoscopy, CT scan, and--if available--endoscopic ultrasound for restaging 2 to 4 weeks after finishing chemoradiation, with subsequent treatment as follows:
+</div></div>
-**Appropriate candidates: [[Surgery#Esophagectomy|Surgical resection]] sometime during weeks 9 to 12
-**Patients who were no longer surgical candidates: Additional radiation therapy to a total dose of 64.8 Gy
 ===References===
+#'''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. [https://doi.org/10.1093/annonc/mdp045 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19465425/ PubMed]
-#'''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. [https://doi.org/10.1200/jco.2009.24.8773 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20351330 PubMed] NCT00193128
+==Cisplatin & Fluorouracil (CF) & RT {{#subobject:17919|Regimen=1}}==
+CF & RT: '''C'''isplatin, '''<u>F</u>'''luourouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-==Capecitabine, Oxaliplatin, RT {{#subobject:e958eb|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen variant #1, 75/3200 x 2 {{#subobject:e20717|Variant=1}}===
-|-
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|[[#top|back to top]]
+!style="width: 20%"|Study
-|}
+!style="width: 20%"|Dates of enrollment
-CapeOx & RT: '''<u>Cape</u>'''citabine, '''<u>Ox</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-===Regimen {{#subobject:69d2ce|Variant=1}}===
+!style="width: 20%"|Comparator
-{| class="wikitable" style="width: 50%; text-align:center;"
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.tandfonline.com/doi/full/10.1080/07357900802172093 Javle et al. 2009]
+|[https://doi.org/10.1200/JCO.2013.53.6532 Mariette et al. 2014 (FFCD 9901)]
-| style="background-color:#ffffbe" |Phase I
+|2000-2009
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+| style="background-color:#ffffbf" |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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once per day on either day 1 or 2 & 29
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on days 1 & 29 (total dose: 6400 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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)
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], total dose of 50.4 Gy
 '''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
 *[[Surgery#Esophagectomy|Surgery]]
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 75/4000 x 2 {{#subobject:a49842|Variant=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. [https://www.tandfonline.com/doi/full/10.1080/07357900802172093 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19235592 PubMed]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
-==Capecitabine, Paclitaxel, RT {{#subobject:17bbec|Regimen=1}}==
+!style="width: 33%"|Dates of enrollment
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1200/jco.2005.04.7118 Bedenne et al. 2007 (FFCD 9102)]
+|1993-2000
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|[[#top|back to top]]
 |}
-Capecitabine, Paclitaxel, RT: Capecitabine, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+''Note: Patients had 89% epidermoid, 11% glandular histology.''
-===Regimen {{#subobject:c6f9f5|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, 22 to 26
-*[[Capecitabine (Xeloda)]] 625 to 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1 & 22 (total dose: 8000 mg/m<sup>2</sup>)
-*[[Paclitaxel (Taxol)]] 45 to 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Supportive therapy====
+*1 liter [[Normal saline|NS]] IV over 2 hours twice per day on days 1 to 5, 22 to 26, before and after cisplatin
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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)
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] not defined
+**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'''
-===References===
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
-#No primary reference could be found for this regimen.
+====Subsequent treatment====
+*Definitive [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|Cisplatin, Fluorouracil, RT (no surgery)]] x 3 (5 cycles total) versus [[Surgery#Esophagectomy|surgery]], 50 to 60 days after start of chemoradiation
-==Carboplatin, Fluorouracil, RT {{#subobject:d29415|Regimen=1}}==
+</div></div><br>
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 80/3200 {{#subobject:b4cc81|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(05)70288-6 Burmeister et al. 2005]
+|1994-2000
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
-|[[#top|back to top]]
 |}
-Carboplatin, Fluorouracil, RT: Carboplatin, Fluorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+''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.''
-===Regimen {{#subobject:1c21a7|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="width: 50%; text-align:center;"
+====Chemotherapy====
-! style="width: 50%" |Study
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 3200 mg/m<sup>2</sup>)
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Esophagectomy|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 100/4000 x 2 {{#subobject:45f8a2|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1111/j.1442-2050.2009.00984.x/full Zemanoa et al. 2009]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ Tepper et al. 2008 (CALGB 9781)]
-| style="background-color:#91cf61" |Non-randomized
+|1997-2000
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 4.48 vs 1.79 y<br>(HR NR, 95% CI 0.18-0.68)
 |-
 |}
-''Patients: 86% squamous cell, 8% adenocarcinoma, 6% other histology. 3% ECOG PS of 2.''
+''Note: Patients had 75% adenocarcinoma, 25% squamous cell histology. 5% with ECOG PS of 2.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 29, '''given first'''
-*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on days 1 & 29, '''given second''' (total dose: 8000 mg/m<sup>2</sup>)
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
-'''21-day cycle for 2 cycles'''
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy.
+'''5-week course'''
-**If surgery was contraindicated, total dose was increased to 50.4 to 56.8 Gy.
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
-'''42-day 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#Esophagectomy|surgery]]. Surgery was planned to be done 3 to 8 weeks after finishing chemoradiation.
+</div></div>
+===References===
+#Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, Denham JW; Trans-Tasman Radiation Oncology Group; Australasian Gastro-Intestinal Trials Group. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005 Sep;6(9):659-68. [https://doi.org/10.1016/S1470-2045(05)70288-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16129366/ PubMed]
+#'''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. [https://doi.org/10.1200/jco.2005.04.7118 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17401004/ PubMed]
+#'''CALGB 9781:''' Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086-92. [https://doi.org/10.1200/jco.2007.12.9593 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18309943/ PubMed] [https://clinicaltrials.gov/study/NCT00003118 NCT00003118]
+#'''FFCD 9901:''' Mariette C, Dahan L, Mornex F, Maillard E, Thomas PA, Meunier B, Boige V, Pezet D, Robb WB, Le Brun-Ly V, Bosset JF, Mabrut JY, Triboulet JP, Bedenne L, Seitz JF. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol. 2014 Aug 10;32(23):2416-22. Epub 2014 Jun 30. [https://doi.org/10.1200/JCO.2013.53.6532 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24982463/ PubMed] [https://clinicaltrials.gov/study/NCT00047112 NCT00047112]
+#'''KEYNOTE-975:''' [https://clinicaltrials.gov/study/NCT04210115 NCT04210115]
-*Upper endoscopy and CT chest and abdomen was performed after completion of chemoradiation
+==Cisplatin, Irinotecan, RT {{#subobject:4932b1|Regimen=1}}==
-*[[Surgery#Esophagectomy|Surgery]] planned to be done 4 to 6 weeks after finishing chemoradiation
+Cisplatin, Irinotecan, RT: Cisplatin, Irinotecan, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:927613|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1002/cncr.26591 Ilson et al. 2011]
+|2002-12 to 2005-10
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+''Note: Patients had 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated history; 33% gastroesophageal junction.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#Cisplatin_.26_Irinotecan_.28IC.29|IC]] induction x 2
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 22, 29 '''given first'''
+*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 22, 29, '''given second'''
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Esophagectomy|Surgery]], performed 4 to 8 weeks after chemoradiation
+</div></div>
 ===References===
+#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. [https://doi.org/10.1002/cncr.26591 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990000/ PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/10.1111/j.1442-2050.2009.00984.x/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19515190 PubMed]
+==Cisplatin, Paclitaxel, RT {{#subobject:3d8eaa|Regimen=1}}==
+Cisplatin, Paclitaxel, RT: Cisplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-==Carboplatin, Paclitaxel, RT {{#subobject:93878b|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:32166d|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1002/cncr.11759 Urba et al. 2003]
+|1995-01 to 1997-09
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#top|back to top]]
 |}
-Carboplatin, Paclitaxel, RT: Carboplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+''Note: Patients had 83% adenocarcinoma, 14% squamous cell, 3% undifferentiated histology''
-===Regimen {{#subobject:33b67a|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+====Chemotherapy====
-!style="width: 20%"|Study
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 2 hours once on day 1
-!style="width: 20%"|Years of enrollment
+*[[Paclitaxel (Taxol)]] 60 mg/m<sup>2</sup> IV over 3 hours once per day on days 1, 8, 15, 22
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+====Supportive therapy====
-!style="width: 20%"|Comparator
+*[[Dexamethasone (Decadron)]] 20 mg PO twice per day on days 1, 8, 15, 22; 12 and 6 hours prior to paclitaxel
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+*[[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 [[External_beam_radiotherapy|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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Barium swallow and CT chest and abdomen done about 1 week prior to surgery to rule out metastatic disease. [[Surgery#Esophagectomy|Surgery]] to be done on approximately day 50
+</div></div>
+===References===
+#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. [https://doi.org/10.1002/cncr.11759 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14601087/ PubMed]
+==Docetaxel, Fluorouracil, RT {{#subobject:956374|Regimen=1}}==
+Docetaxel, Fluorouracil, RT: Docetaxel, Fluorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 15/4000 x 2 {{#subobject:c112ab|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286 van Meerten et al. 2006]
+|[http://ar.iiarjournals.org/content/27/4C/2597.long Hihara et al. 2007]
-|2001-2004
+|2004-04-21 to 2005-04-07
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#ffffbe" |Phase 1
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1112088 van Hagen et al. 2012 (CROSS)]
-|2004-2008
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-| style="background-color:#1a9850" |Superior OS
 |-
 |}
-''van Meerten et al. Patients: 76% adenocarcinoma, 22% squamous cell, 2% large cell histology. 91% lower esophagus, 9% thoracic esophagus''
+''Note: Patients had 86% squamous cell, 14% carcinosarcoma histology''
+<div class="toccolours" style="background-color:#b3e2cd">
-''van Hagen et al. Patients: 75% adenocarcinoma, 23% squamous cell, 2% other. 24% gastroesophageal junction''
+====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 7.5 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 29, 36
+*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 29, 36, 43 (total dose: 8000 mg/m<sup>2</sup>)
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] 8 mg IV once per day on days 1, 8, 29, 36; 30 minutes prior to docetaxel
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:8dd58b|Variant=1}}===
+''Note: No primary reference could be found for this regimen.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, 22, 29, '''given second'''
+*[[Fluorouracil (5-FU)]] 200 to 300 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 22, 29 (total dose: 5000 to 7500 mg/m<sup>2</sup>)
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29, '''given first'''
-====Supportive medications====
-*[[Dexamethasone (Decadron)]] 10 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Ranitidine (Zantac)]] 50 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Clemastine (Tavist)]] 2 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*Between paclitaxel & carboplatin: 100 mL NS given over 30 minutes, then [[Ondansetron (Zofran)]] 8 mg in 100 mL NS given over 30 minutes
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] not defined on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 23 fractions, for a total dose of 41.4 Gy
 '''5-week course'''
-====Subsequent treatment====
+</div></div>
-*[[Surgery#Esophagectomy|Surgery]] planned to be done within 6 weeks of finishing chemoradiation; van Hagen et al. 2012 said surgery was done as soon as possible after finishing chemoradiotherapy, preferably within 4 to 6 weeks
 ===References===
+#'''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. [http://ar.iiarjournals.org/content/27/4C/2597.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17695421/ PubMed]
-#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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16670722 PubMed]
+==Fluorouracil, Oxaliplatin, RT {{#subobject:94b79a|Regimen=1}}==
-#'''CROSS:''' van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa1112088 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1112088/suppl_file/nejmoa1112088_appendix.pdf link to appendix with details about administration] [https://pubmed.ncbi.nlm.nih.gov/22646630 PubMed]
+Fluorouracil, Oxaliplatin, RT: Fluorouracil, Oxaliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-##'''Update:''' Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. Epub 2015 Aug 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00040-6/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26254683 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 5040 cGy, bi-weekly oxaliplatin {{#subobject:ae22de|Variant=1}}===
-==Cisplatin, Docetaxel, RT {{#subobject:4231cb|Regimen=1}}==
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1200/jco.2002.12.032 Khushalani et al. 2002]
+|2000-02 to 2001-05
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#top|back to top]]
 |}
-DC & RT: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+''Note: 58% of patients had stage IV disease''
-===Regimen {{#subobject:6c3cc6|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="width: 50%; text-align:center;"
+====Chemotherapy====
-! style="width: 50%" |Study
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Fluorouracil (5-FU)]] 180 mg/m<sup>2</sup>/day IV continuous infusion over 35 days, started on day 8 (total dose: 6300 mg/m<sup>2</sup>)
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====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#Esophagectomy|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.
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 5040 cGy, weekly oxaliplatin {{#subobject:aa7e55|Variant=1}}===
+{| class="wikitable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1093/annonc/mdp045 Ruhstaller et al. 2009 (SAKK 75/02)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937600/ Ajani et al. 2013 (MDACC 2004-0703)]
-| style="background-color:#91cf61" |Phase II
+|2005-2011
+| style="background-color:#91cf61" |Non-randomized part of phase 2 RCT
 |-
 |}
-''Patients: 55% adenocarcinoma, 45% squamous cell histology''
+''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.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[#FUOX_999|FUOX]] versus [[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|no induction chemotherapy]]
-*[[#Cisplatin_.26_Docetaxel|Cisplatin & Docetaxel]] x 2
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Oxaliplatin (Eloxatin)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22, 29 (total dose: 5000 mg/m<sup>2</sup>)
-*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 5040 cGy of proton or photon (intensity modulated) radiation in 28 fractions
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy
 '''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*[[Surgery#Esophagectomy|Surgery]]
-*[[Surgery#Esophagectomy|Surgery]], 3 to 8 weeks after finishing chemoradiation
+</div></div>
 ===References===
+#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. [https://doi.org/10.1200/jco.2002.12.032 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12065561/ PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdp045 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19465425 PubMed]
+#'''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. [https://doi.org/10.1093/annonc/mdt339 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937600/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23975663/ PubMed] [https://clinicaltrials.gov/study/NCT00525915 NCT00525915]
+=Definitive therapy=
-==Cisplatin, Fluorouracil, RT {{#subobject:17919|Regimen=1}}==
+==Capecitabine, Cisplatin, RT {{#subobject:dfe688|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+CX & RT: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-|-
+<div class="toccolours" style="background-color:#eeeeee">
-|[[#top|back to top]]
+===Regimen variant #1, 1250/60/50 {{#subobject:4beb7f|Variant=1}}===
-|}
-CF & RT: '''C'''isplatin, '''<u>F</u>'''luourouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-===Regimen variant #1, 75/3200 x 2 {{#subobject:e20717|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/JCO.2013.53.6532 Mariette et al. 2014 (FFCD 9901)]
+|[https://doi.org/10.1016/S1470-2045(13)70136-0 Crosby et al. 2013 (SCOPE-1)]
-|2000-2009
+|2008-2012
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+|[[Stub#Capecitabine.2C_Cisplatin.2C_Cetuximab.2C_RT|Capecitabine, Cisplatin, Cetuximab, RT]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
 |-
 |}
-''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
+''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br>
+''Note: Patients had 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Capecitabine (Xeloda)]] as follows:
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on either day 1 or 2
+**Cycles 1 & 2: 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3200 mg/m<sup>2</sup>)
+**Cycle 3 (chemoradiation): 625 mg/m<sup>2</sup> PO twice per day on days 1 to 42
+*[[Cisplatin (Platinol)]] as follows:
-'''28-day cycle for 2 cycles'''
+**Cycles 1 & 2: 60 mg/m<sup>2</sup> IV once on day 1
+**Cycle 3 (chemoradiation): 60 mg/m<sup>2</sup> IV once per day on days 1 & 22
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.80 Gy fractions x 25 fractions, for a total dose of 45 Gy
+**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'''
-'''5-week course'''
+</div></div><br>
-====Subsequent treatment====
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 1600/30/54 {{#subobject:f7a6c1|Variant=1}}===
-*[[Surgery#Esophagectomy|Surgery]]
+{| class="wikitable" style="width: 40%; text-align:center;"
-===Regimen variant #2, 75/4000 x 2 {{#subobject:a49842|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
 ! style="width: 50%" |Study
 ! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.2005.04.7118 Bedenne et al. 2007 (FFCD 9102)]
+|[http://jjco.oxfordjournals.org/content/37/11/829.long Lee et al. 2007<sub>esoph</sub>]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#ffffbe" |Retrospective
 |-
 |}
-''Patients: 89% epidermoid, 11% glandular histology.''
+''Note: Patients had 97% adenocarcinoma, 3% squamous cell histology; 3% with ECOG PS of 2.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Induction [[#Capecitabine_.26_Cisplatin_.28CX.29|XP]] x 2
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+'''7-day cycles until radiation therapy is complete'''
-====Supportive medications====
-*1 liter NS IV over 2 hours before and after [[Cisplatin (Platinol)]]
-'''21-day cycle for 2 cycles'''
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div></div>
+===References===
+#'''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. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17951334/ PubMed]
+#'''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. [https://doi.org/10.1016/S1470-2045(13)70136-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23623280/ PubMed] ISRCTN47718479
+##'''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. [https://doi.org/10.1038/bjc.2017.21 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28196063/ PubMed]
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 23 fractions, for a total dose of 46 Gy
+==Cisplatin, Docetaxel, RT {{#subobject:21719f|Regimen=1}}==
-**Earlier in the study, some patients instead received split-course radiation therapy, 3 Gy fractions x 5 fractions given on days 1 to 5. 15 Gy per cycle; total dose after 2 cycles is 30 Gy.
+DC & RT: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
-'''4.5-week course'''
+===Regimen variant #1 {{#subobject:f4800d|Variant=1}}===
-====Subsequent treatment====
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
-*[[#Cisplatin.2C_Fluorouracil.2C_RT_2|Cisplatin, Fluorouracil, RT (no surgery)]] x 3 (5 cycles total) versus [[Surgery#Esophagectomy|surgery]], 50 to 60 days after start of chemoradiation
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-===Regimen variant #3, 80/3200 {{#subobject:b4cc81|Variant=1}}===
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031899 Day et al. 2010]
+|2001-05 to 2007-01
+| style="background-color:#ffffbe" |Phase 1
+|-
+|}
+''Note: Patients had 46% squamous cell, 54% adenocarcinoma histology. Some guidelines suggest a wider dose range of 20 to 30 mg/m<sup>2</sup> for both cisplatin and docetaxel. The primary reference also investigated these dose levels, but ultimately recommended 30 mg/m<sup>2</sup> dosages for both cisplatin and docetaxel.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Supportive therapy====
+*"Steroid and anti-emetic pre-medication"
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1038/sj.bjc.6606051 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031899/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21157450/ PubMed]
+==Cisplatin & Fluorouracil (CF) & RT {{#subobject:2b3dbc|Regimen=1}}==
+CF & RT: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br>
+FP & RT: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 60/4725 x 4 (5000 cGy) {{#subobject:4dab7f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70288-6/fulltext Burmeister et al. 2005]
+|[https://doi.org/10.1016/S1470-2045(13)70136-0 Crosby et al. 2013 (SCOPE-1)]
-|1994-2000
+|2008-2012
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+|[[Stub#Capecitabine.2C_Cisplatin.2C_Cetuximab.2C_RT|Capecitabine, Cisplatin, Cetuximab, RT]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
 |-
 |}
-''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
+''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br>
+''Note: This regimen was an alternative for patients who could not swallow pills. Patients had 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] as follows:
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1
+**Cycles 1 & 2: 60 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 3200 mg/m<sup>2</sup>)
+**Cycle 3 (chemoradiation): 60 mg/m<sup>2</sup> IV once per day on days 1 & 22
+*[[Fluorouracil (5-FU)]] as follows:
+**Cycles 1 & 2: 225 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4725 mg/m<sup>2</sup>)
+**Cycle 3 (chemoradiation): 225 mg/m<sup>2</sup>/day IV continuous infusion over 42 days, started on day 1 (total dose during chemoradiation: 9450 mg/m<sup>2</sup>)
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.33 Gy fractions x 15 fractions for a total dose of 35 Gy
+**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'''
-'''3-week course'''
+</div></div><br>
-====Subsequent treatment====
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 75/4000 x 2 (5040 cGy) {{#subobject:3272d5|Variant=1}}===
-*[[Surgery#Esophagectomy|Surgery]]
-===Regimen variant #4, 100/4000 x 2 {{#subobject:45f8a2|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ Tepper et al. 2008 (CALGB 9781)]
+|[https://doi.org/10.1200/jco.2002.20.5.1167 Minsky et al. 2002 (RTOG 94-05)]
-|1997-2000
+|1995-1999
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]; high-dose RT
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS24
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70028-2 Conroy et al. 2014 (PRODIGE5/ACCORD17)]
+|2004-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
+| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
 |-
 |}
-''Patients: 75% adenocarcinoma, 25% squamous cell histology. 5% with ECOG PS of 2.''
+''Note: Patients had RTOG 94-05 included both adenocarcinoma and squamous cell histology''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 29
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on days 1 & 29 (total dose: 8000 mg/m<sup>2</sup>)
-*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)
-'''28-day cycle for 2 cycles'''
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] by the following study-specific criteria:
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, then a 5.4 Gy final boost, for a total dose of 50.4 Gy, '''starting within 24 hours of start of chemotherapy'''
+**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-week course'''
+'''5- to 5.5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*[[#Cisplatin_.26_Fluorouracil_.28CF.29_2|CF]] consolidation
-*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#Esophagectomy|surgery]]. Surgery was planned to be done 3 to 8 weeks after finishing chemoradiation.
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===References===
+===Regimen variant #3, 75/4000 x 3 (6600 cGy) {{#subobject:0d8520|Variant=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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70288-6/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16129366 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#'''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. [https://doi.org/10.1200/jco.2005.04.7118 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17401004 PubMed]
+!style="width: 20%"|Study
-#'''CALGB 9781:''' Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086-92. [https://doi.org/10.1200/jco.2007.12.9593 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18309943 PubMed]
+!style="width: 20%"|Dates of enrollment
-#'''FFCD 9901:''' Mariette C, Dahan L, Mornex F, Maillard E, Thomas PA, Meunier B, Boige V, Pezet D, Robb WB, Le Brun-Ly V, Bosset JF, Mabrut JY, Triboulet JP, Bedenne L, Seitz JF. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol. 2014 Aug 10;32(23):2416-22. Epub 2014 Jun 30. [https://doi.org/10.1200/JCO.2013.53.6532 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24982463 PubMed]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-==Cisplatin, Irinotecan, RT {{#subobject:4932b1|Regimen=1}}==
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1200/jco.2005.04.7118 Bedenne et al. 2007 (FFCD 9102)]
-|}
+|1993-2000
-Cisplatin, Irinotecan, RT: Cisplatin, Irinotecan, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
-===Regimen {{#subobject:927613|Variant=1}}===
+|[[Surgery#Esophageal_cancer_surgery|Surgery]]
-{| class="wikitable" style="width: 50%; text-align:center;"
+| style="background-color:#eeee01" |Equivalent OS (primary endpoint)
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.26591/full Ilson et al. 2011]
-| style="background-color:#91cf61" |Phase II
 |-
 |}
-''Patients: 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated history; 33% gastroesophageal junction.''
+''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.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*Induction [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]] x 2
-*[[#Cisplatin_.26_Irinotecan_.28IC.29|IC induction]] x 2
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] as follows:
+**Cycle 1: 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+**Cycles 2 & 3: 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+*[[Fluorouracil (5-FU)]] as follows:
+**Cycle 1: 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+**Cycles 2 & 3: 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+====Supportive therapy====
+*1 liter [[Normal saline|NS]] IV over 2 hours before and after cisplatin
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
+===Regimen variant #4, 75/4000 x 4 (5000 cGy) {{#subobject:ca1b71|Variant=1}}===
-*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-'''21-day cycle for 2 cycles'''
+!style="width: 20%"|Dates of enrollment
-====Radiotherapy====
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions, for a total of 50.4 Gy
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-'''5.5-week course'''
-====Subsequent treatment====
-*[[Surgery#Esophagectomy|Surgery]], performed 4 to 8 weeks after chemoradiation
-===References===
-#Ilson DH, Minsky BD, Ku GY, Rusch V, Rizk N, Shah M, Kelsen DP, Capanu M, Tang L, Campbell J, Bains M. Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer. Cancer. 2011 Oct 11. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.26591/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21990000 PubMed]
-==Cisplatin, Paclitaxel, RT {{#subobject:3d8eaa|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1056/NEJM199206113262403 Herskovic et al. 1992 (RTOG 85-01)]
-|}
+|1986-1990
-Cisplatin, Paclitaxel, RT: Cisplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-===Regimen {{#subobject:32166d|Variant=1}}===
+|[[#Radiation_therapy|Radiation therapy]]
-{| class="wikitable" style="width: 50%; text-align:center;"
+| style="background-color:#1a9850" |Superior OS
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.11759/full Urba et al. 2003]
-| style="background-color:#91cf61" |Phase II
 |-
 |}
-''Patients: 83% adenocarcinoma, 14% squamous cell, 3% undifferentiated histology''
+''Note: Patients had 88% squamous cell, 12% adenocarcinoma histology. 7% karnofsky performance scale of 50-60.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] as follows:
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 2 hours once on day 1
+**Cycle 1 (chemoradiation): 75 mg/m<sup>2</sup> IV once per day on days 1 & 29
-*[[Paclitaxel (Taxol)]] 60 mg/m<sup>2</sup> IV over 3 hours once per day on days 1, 8, 15, 22
+**Cycles 2 & 3: 75 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] as follows:
-====Supportive medications====
+**Cycle 1 (chemoradiation): 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on days 1 & 29 (total dose during chemoradiation: 8000 mg/m<sup>2</sup>)
+**Cycles 2 & 3: 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-*[[Dexamethasone (Decadron)]] 20 mg PO twice per day on days 1, 8, 15, 22; 12 and 6 hours before [[Paclitaxel (Taxol)]]
-*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*1 liter D5NS and mannitol 12.5 g bolus IV once on day 1, prior to [[Cisplatin (Platinol)]]
-*Mannitol 25 g in 1 liter D5NS IV over 4 hours once on day 1, after [[Cisplatin (Platinol)]]
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 23, continuing until ANC greater than 10,000/uL
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions given twice per day on days 1 to 5, 8 to 12, 15 to 19, with at least 6 hours between fractions, for a total dose of 45 Gy
+**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'''
-'''4-week course'''
+</div></div>
-====Subsequent treatment====
-*Barium swallow and CT chest and abdomen done about 1 week prior to surgery to rule out metastatic disease. [[Surgery#Esophagectomy|Surgery]] to be done on approximately day 50
 ===References===
+#'''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. [https://doi.org/10.1056/NEJM199206113262403 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1584260/ PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.11759/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14601087 PubMed]
+##'''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. [https://doi.org/10.1200/jco.1997.15.1.277 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8996153/ PubMed]
+##'''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. [http://jama.jamanetwork.com/article.aspx?articleid=189737 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10235156/ PubMed]
-==Cisplatin, Vinorelbine, RT {{#subobject:d72171|Regimen=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. [https://doi.org/10.1200/jco.2002.20.5.1167 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11870157/ PubMed] [https://clinicaltrials.gov/study/NCT00002631 NCT00002631]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+#'''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. [https://doi.org/10.1200/jco.2005.04.7118 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17401004/ PubMed]
-|-
+#'''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. [https://doi.org/10.1016/S1470-2045(13)70136-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23623280/ PubMed] ISRCTN47718479
-|[[#top|back to top]]
+##'''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. [https://doi.org/10.1038/bjc.2017.21 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28196063/ PubMed]
-|}
+#'''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. [https://doi.org/10.1016/S1470-2045(14)70028-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24556041/ PubMed] [https://clinicaltrials.gov/study/NCT00861094 NCT00861094]
-Cisplatin, Vinorelbine, RT: Cisplatin, Vinorelbine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+##'''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. [https://doi.org/10.1016/j.ejca.2017.07.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28829992/ PubMed]
-===Regimen variant #1, standard cisplatin {{#subobject:ddf0ee|Variant=1}}===
+#'''KEYNOTE-975:''' [https://clinicaltrials.gov/study/NCT04210115 NCT04210115]
+==Cisplatin, Paclitaxel, RT {{#subobject:5ef1ea|Regimen=1}}==
+TP & RT: '''<u>T</u>'''axol (Paclitaxel), '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:8f0c89|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145832/ Yang et al. 2018 (NEOCRTEC5010)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5710193/ Suntharalingam et al. 2017 (RTOG 0436)]
-|2007-2014
+|2008-2013
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
+|[[#Cisplatin.2C_Paclitaxel.2C_Cetuximab.2C_RT_999|Cisplatin, Paclitaxel, Cetuximab, RT]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#ffffbf" |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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
+*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
-'''21-day cycle for 2 cycles'''
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div></div>
+===References===
+#'''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. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2643119 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5710193/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28687830/ PubMed] [https://clinicaltrials.gov/study/NCT00655876 NCT00655876]
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.0 Gy fractions x 20 fractions, for a total dose of 40 Gy
+==FOLFOX4 & RT {{#subobject:1f91c5|Regimen=1}}==
+FOLFOX4 & RT: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-'''4-week course'''
+<div class="toccolours" style="background-color:#eeeeee">
-====Subsequent treatment====
+===Regimen {{#subobject:e2fc30|Variant=1}}===
-*[[Surgery#Esophagectomy|Surgery]]
-===Regimen variant #2, split-dose cisplatin {{#subobject:672470|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145832/ Yang et al. 2018 (NEOCRTEC5010)]
+|[https://doi.org/10.1016/S1470-2045(14)70028-2 Conroy et al. 2014 (PRODIGE5/ACCORD17)]
-|2007-2014
+|2004-2011
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
+|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
 |-
 |}
+''Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m<sup>2</sup>. Despite being a non-superior experimental arm, this regimen is recommended by some guidelines such as ESMO.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1, 15, 29, then 1600 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on days 1, 15, 29 '''given third''' (total dose: 6000 mg/m<sup>2</sup>)
-*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 4
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29
-*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29
-'''21-day cycle for 2 cycles'''
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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)
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.0 Gy fractions x 20 fractions, for a total dose of 40 Gy
+'''5-week course'''
+</div>
-'''4-week course'''
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*[[#FOLFOX4|FOLFOX4]] consolidation x 3
-*[[Surgery#Esophagectomy|Surgery]]
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1016/S1470-2045(14)70028-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24556041/ PubMed] [https://clinicaltrials.gov/study/NCT00861094 NCT00861094]
-#'''NEOCRTEC5010:''' Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Lordick F, D'Journo XB, Cerfolio RJ, Korst RJ, Novoa NM, Swanson SJ, Brunelli A, Ismail M, Fernando HC, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J; AME Thoracic Surgery Collaborative Group. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial. J Clin Oncol. 2018 Sep 20;36(27):2796-2803. Epub 2018 Aug 8. [https://doi.org/10.1200/JCO.2018.79.1483 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145832/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30089078 PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2017.07.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28829992/ PubMed]
+#'''KEYNOTE-975:''' [https://clinicaltrials.gov/study/NCT04210115 NCT04210115]
-==Docetaxel, Fluorouracil, RT {{#subobject:956374|Regimen=1}}==
+==Radiation therapy {{#subobject:16tea6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 5000 cGy {{#subobject:adu3cd|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJM199206113262403 Herskovic et al. 1992 (RTOG 85-01)]
+|1986-1990
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT]]
+| style="background-color:#d73027" |Inferior OS
 |-
-|[[#top|back to top]]
 |}
-Docetaxel, Fluorouracil, RT: Docetaxel, Fluorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+''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.''
-===Regimen variant #1, 15/4000 x 2 {{#subobject:c112ab|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="width: 50%; text-align:center;"
+====Radiotherapy====
-! style="width: 50%" |Study
+*[[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
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+'''6.4-week course'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 6000 cGy {{#subobject:adu60d|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://ar.iiarjournals.org/content/27/4C/2597.long Hihara et al. 2007]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343504/ Ji et al. 2021 (ZJCH-E-E)]
-| style="background-color:#91cf61" |Phase II
+|2016-06-01 to 2018-08-31
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#S-1_.26_RT|S-1 & RT]]
+| style="background-color:#d73027" |Inferior OS24
 |-
 |}
-''Patients: 86% squamous cell, 14% carcinosarcoma histology''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
+*[[External beam radiotherapy]] 200 cGy per day, 5 days per week, for 30 fractions (total dose of 6000 cGy)
+'''One course'''
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1056/NEJM199206113262403 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1584260/ PubMed]
+##'''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. [https://doi.org/10.1200/jco.1997.15.1.277 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8996153/ PubMed]
+##'''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. [http://jama.jamanetwork.com/article.aspx?articleid=189737 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10235156/ PubMed]
+#'''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. [https://doi.org/10.1001/jamaoncol.2021.2705 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343504/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34351356/ PubMed] [https://clinicaltrials.gov/study/NCT02813967 NCT02813967]
+==S-1 & RT {{#subobject:cff3w6|Regimen=1}}==
+S-1 & RT: '''<u>S-1</u>''' & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:9134b2|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343504/ Ji et al. 2021 (ZJCH-E-E)]
+|2016-06-01 to 2018-08-31
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Radiation_therapy|RT]] x 6000 cGy
+| style="background-color:#1a9850" |Superior OS24 (primary endpoint)<br>OS24: 53.2% vs 35.8%<br>(HR 0.63, 95% CI 0.47-0.85)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Tegafur, gimeracil, oteracil (S-1)]] 70 mg/m<sup>2</sup>/day PO on days 1 to 14, 29 to 42 (rounded down to the nearest 20 mg)
-*[[Docetaxel (Taxotere)]] 7.5 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
-*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1, 8, 15 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-====Supportive medications====
-*[[Dexamethasone (Decadron)]] 8 mg IV once per day on days 1 & 8; 30 minutes prior to [[Docetaxel (Taxotere)]]
-'''28-day cycle for 2 cycles'''
 ====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'''
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1001/jamaoncol.2021.2705 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343504/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34351356/ PubMed] [https://clinicaltrials.gov/study/NCT02813967 NCT02813967]
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 30 to 33 fractions, for a total dose of 60 to 66 Gy
+=Consolidation after definitive therapy=
+==Cisplatin & Fluorouracil (CF) {{#subobject:cf23a6|Regimen=1}}==
-'''6- to 6.5-week course'''
+CF: '''<u>C</u>'''isplatin & '''<u>F</u>'''luorouracil
-===Regimen variant #2 {{#subobject:8dd58b|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-''Note: No primary reference could be found for this regimen.''
+===Regimen {{#subobject:ade242|Variant=1}}===
-====Chemotherapy====
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV once on day 1
+!style="width: 20%"|Dates of enrollment
-*[[Fluorouracil (5-FU)]] 200 to 300 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-====Radiotherapy====
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] not defined
-'''7-day cycle for 5 cycles'''
-===References===
-#'''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. [http://ar.iiarjournals.org/content/27/4C/2597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17695421 PubMed]
-==Fluorouracil, Oxaliplatin, RT {{#subobject:94b79a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1200/jco.2002.20.5.1167 Minsky et al. 2002 (RTOG 94-05)]
-|}
+|1995-1999
-Fluorouracil, Oxaliplatin, RT: Fluorouracil, Oxaliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-===Regimen variant #1, 50.4 Gy, bi-weekly oxaliplatin {{#subobject:ae22de|Variant=1}}===
+| style="background-color:#d3d3d3" |
-{| class="wikitable" style="width: 50%; text-align:center;"
+| style="background-color:#d3d3d3" |
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.2002.12.032 Khushalani et al. 2002]
+|[https://doi.org/10.1016/S1470-2045(14)70028-2 Conroy et al. 2014 (PRODIGE5/ACCORD17)]
-| style="background-color:#91cf61" |Phase II
+|2004-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
+| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
 |-
 |}
-''58% patients were classified as stage IV disease''
+''Note: study included both adenocarcinoma and squamous cell histology''
+<div class="toccolours" style="background-color:#cbd5e8">
-====Chemotherapy====
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29
-*[[Fluorouracil (5-FU)]] 180 mg/m<sup>2</sup>/day IV continuous infusion over 35 days, started on day 8 (total dose: 6300 mg/m<sup>2</sup>)
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 20 to 22 fractions, for an initial total dose of 36 to 39.6 Gy, '''started on day 8'''
-**Followed by off-cord conformal oblique fields, 5.4 to 9 Gy given to the clinical target volume (CTV). A second off-cord phase to the gross tumor volume (GTV) of 5.4 Gy was then given, for a total dose delivered of 50.4 Gy to the GTV.
-'''6-week course'''
-====Subsequent treatment====
-*Upper GI endoscopy and CT chest, abdomen, and pelvis were done after completion of chemoradiation, and patients without progressive stage II-III disease were offered [[Surgery#Esophagectomy|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, 50.4 Gy, weekly oxaliplatin {{#subobject:aa7e55|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937600/ Ajani et al. 2013 (MDACC 2004-0703)]
-|2005-2011
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-''Note: it is unclear how long the 5-FU continuous infusions were in this regimen; the authors have been contacted for clarification. Treatment is assumed to start on a Monday.''
 ====Preceding treatment====
+*RTOG 94-05: Definitive [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT]]; standard dose versus [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT]]; high-dose
-*FUOX versus [[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|no induction chemotherapy]]
+*PRODIGE5/ACCORD17: Definitive [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once on day 1
-*[[Oxaliplatin (Eloxatin)]] 40 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1000 mg/m<sup>2</sup>)
+'''28-day cycle for 2 cycles'''
+</div></div>
-'''7-day cycle for 5 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 50.4 Gy of proton or photon (intensity modulated) radiation in 28 fractions
-'''5-week course'''
-====Subsequent treatment====
-*[[Surgery#Esophagectomy|Surgery]]
 ===References===
+#'''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. [https://doi.org/10.1200/jco.2002.20.5.1167 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11870157/ PubMed] [https://clinicaltrials.gov/study/NCT00002631 NCT00002631]
-#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. [https://doi.org/10.1200/jco.2002.12.032 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12065561 PubMed]
+#'''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. [https://doi.org/10.1016/S1470-2045(14)70028-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24556041/ PubMed] [https://clinicaltrials.gov/study/NCT00861094 NCT00861094]
-#'''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. [https://doi.org/10.1093/annonc/mdt339 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937600/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23975663 PubMed] NCT00525915
+##'''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. [https://doi.org/10.1016/j.ejca.2017.07.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28829992/ PubMed]
+==FOLFOX4 {{#subobject:a8048e|Regimen=1}}==
-=Definitive therapy=
+FOLFOX4: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin 4
+<div class="toccolours" style="background-color:#eeeeee">
-==Capecitabine, Cisplatin, RT {{#subobject:dfe688|Regimen=1}}==
+===Regimen {{#subobject:f200f1|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CX & RT: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-===Regimen variant #1, 1250/60/50 {{#subobject:4beb7f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70136-0/abstract Crosby et al. 2013 (SCOPE-1)]
+|[https://doi.org/10.1016/S1470-2045(14)70028-2 Conroy et al. 2014 (PRODIGE5/ACCORD17)]
-|2008-2012
+|2004-2011
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[Stub#Capecitabine.2C_Cisplatin.2C_Cetuximab.2C_RT|Capecitabine, Cisplatin, Cetuximab, RT]]
+|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
+| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
 |-
 |}
-''Note: Reported efficacy is based on the 2017 update.''
+''Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m<sup>2</sup>. Despite being a non-superior experimental arm, this regimen is recommended by some guidelines such as ESMO.''
+<div class="toccolours" style="background-color:#cbd5e8">
-''Patients: 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology''
+====Preceding treatment====
+*Definitive [[#FOLFOX4_.26_RT|FOLFOX4 & RT]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1600 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
+'''14-day cycle for 3 cycles'''
-'''21-day cycle for 4 cycles'''
+</div></div>
-====Radiotherapy====
+===References===
+#'''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. [https://doi.org/10.1016/S1470-2045(14)70028-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24556041/ PubMed] [https://clinicaltrials.gov/study/NCT00861094 NCT00861094]
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 50 Gy given in 25 fractions with cycles 3 & 4
+##'''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. [https://doi.org/10.1016/j.ejca.2017.07.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28829992/ PubMed]
+=Adjuvant therapy=
-'''5-week course'''
+==Cisplatin & Fluorouracil (CF) {{#subobject:e35a6c|Regimen=1}}==
+CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-===Regimen variant #2, 1600/30/54 {{#subobject:f7a6c1|Variant=1}}===
+<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol
-{| class="wikitable" style="width: 50%; text-align:center;"
+<div class="toccolours" style="background-color:#eeeeee">
-! style="width: 50%" |Study
+===Regimen {{#subobject:fc3c70|Variant=1}}===
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+{| class="wikitable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://jjco.oxfordjournals.org/content/37/11/829.long Lee et al. 2007<sub>esoph</sub>]
+|[https://doi.org/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]
-| style="background-color:#ffffbe" |Retrospective
+|1990-1995
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
 |}
-''Patients: 97% adenocarcinoma, 3% squamous cell histology; 3% with ECOG PS of 2.''
+''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.''
+<div class="toccolours" style="background-color:#cbd5e8">
-''The study was for patients with stage IV disease.''
-*Patients with M1b disease (visceral metastases) received the chemotherapy only part until progression of disease or unacceptable toxicity.
-*Patients with M1a or M1b (non-visceral metastases) received 2 cycles of the chemotherapy only part, underwent treatment with chemoradiation, and then treatment continued with--presumably, but not outright specified in the paper--chemotherapy only until progression of disease or unacceptable toxicity.
 ====Preceding treatment====
+*Neoadjuvant [[#Cisplatin_.26_Fluorouracil_.28CF.29|CF]], then [[Surgery#Esophageal_cancer_surgery|surgery]]
-*[[#Capecitabine_.26_Cisplatin_.28CX.29|XP]] x 2
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: see note)
-*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
+'''28-day cycle for 3 cycles'''
+</div></div>
-'''7-day cycles until radiation therapy is complete'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 54 Gy given. Dose per fraction and total duration of treatment were not specified, but based on other regimens, it is suspected to be either 1.8 Gy x 30 fractions or 2 Gy x 27 fractions.
-'''One course'''
 ===References===
+#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://doi.org/10.1056/NEJM199812313392704 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9869669/ PubMed]
-#'''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. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17951334 PubMed]
+==Nivolumab monotherapy {{#subobject:e3u15c|Regimen=1}}==
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70136-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23623280 PubMed] ISCRTN47718479
+<div class="toccolours" style="background-color:#eeeeee">
-##'''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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28196063 PubMed]
+===Regimen {{#subobject:e4f654|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-==Cisplatin, Docetaxel, RT {{#subobject:21719f|Regimen=1}}==
+!style="width: 20%"|Study
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/nejmoa2032125 Kelly et al. 2021 (CheckMate 577)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-279-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
+|-
+|} -->
+|2016-2019
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Esophageal_cancer_-_null_regimens#Placebo_2|Placebo]]
+| style="background-color:#1a9850" |Superior DFS (primary endpoint)<br>Median DFS: 22.4 vs 11 mo<br>(HR 0.69, 96.4% CI 0.56-0.86)
 |-
-|[[#top|back to top]]
 |}
-DC & RT: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#cbd5e8">
-===Regimen variant #1 {{#subobject:f4800d|Variant=1}}===
+====Preceding treatment====
-{| class="wikitable" style="width: 50%; text-align:center;"
+*Neoadjuvant [[Regimen_classes#Chemoradiotherapy-based_regimen|chemoradiotherapy (not specified)]], then [[Surgery#Esophageal_cancer_surgery|surgery]], with residual pathologic disease
-! style="width: 50%" |Study
+</div>
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+<div class="toccolours" style="background-color:#b3e2cd">
+====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)'''
+</div></div>
+===References===
+#'''CheckMate 577:''' Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 Investigators. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021 Apr 1;384(13):1191-1203. [https://doi.org/10.1056/nejmoa2032125 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33789008/ PubMed] [https://clinicaltrials.gov/study/NCT02743494 NCT02743494]
+=Metastatic or locally advanced disease, first-line=
+==Carboplatin & Paclitaxel (CP) {{#subobject:4df570|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:9725d8|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031899 Day et al. 2010]
+|[https://pubmed.ncbi.nlm.nih.gov/9427274 Philip et al. 1997]
-| style="background-color:#ffffbe" |Phase I
+|NR in abstract
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Patients: 46% squamous cell, 54% adenocarcinoma histology''
+''Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6.''
+<div class="toccolours" style="background-color:#fdcdac">
-''Note: some guidelines suggest a wider dose range of 20 to 30 mg/m<sup>2</sup> for both cisplatin and docetaxel. The primary reference also investigated these dose levels, but ultimately recommended 30 mg/m<sup>2</sup> dosages for both cisplatin and docetaxel.''
+====Eligibility criteria====
+*Locally advanced metastatic or recurrent esophageal or gastric cancer
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1, '''given second'''
-*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+'''21-day cycles'''
+</div></div>
-====Supportive medications====
+===References===
+#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''' [https://pubmed.ncbi.nlm.nih.gov/9427274/ PubMed]
-*"Steroid and anti-emetic pre-medication"
+==Cisplatin & Fluorouracil (CF) {{#subobject:cjuc2x|Regimen=1}}==
+CF: '''<u>C</u>'''isplatin & '''<u>F</u>'''luorouracil
-====Radiotherapy====
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:cf5acj2|Variant=1}}===
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 25 fractions, for a total dose of 50 Gy, to start within 4 hours after the first dose of chemotherapy.
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-'''5-week course'''
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s0140-6736(21)01234-4 Sun et al. 2021 (KEYNOTE-590)]
+|2017-2019
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab|CF & Pembrolizumab]]
+| style="background-color:#d73027" |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.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+'''21-day cycle for up to 35 cycles (2 years)'''
+</div></div>
 ===References===
-#'''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. [https://www.nature.com/articles/6606051 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031899/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21157450 PubMed]
+#'''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. [https://doi.org/10.1016/s0140-6736(21)01234-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34454674/ PubMed] [https://clinicaltrials.gov/study/NCT03189719 NCT03189719]
+==Cisplatin & Fluorouracil (CF) & Pembrolizumab {{#subobject:c798a3|Regimen=1}}==
-==Cisplatin, Fluorouracil, RT {{#subobject:2b3dbc|Regimen=1}}==
+CF & Pembrolizumab: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, Pembrolizumab
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:d18acj2|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
 |-
-|[[#top|back to top]]
 |}
-CF & RT: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===Regimen variant #1, 60/4725 x 4 (50 Gy) {{#subobject:4dab7f|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70136-0/abstract Crosby et al. 2013 (SCOPE-1)]
+|[https://doi.org/10.1016/s0140-6736(21)01234-4 Sun et al. 2021 (KEYNOTE-590)]
-|2008-2012
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase III (C)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-308-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
-|[[Stub#Capecitabine.2C_Cisplatin.2C_Cetuximab.2C_RT|Capecitabine, Cisplatin, Cetuximab, RT]]
+|-
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
+|} -->
+|2017-2019
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_4|CF]]
+| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>Median OS: 12.4 vs 9.8 mo<br>(HR 0.73, 95% CI 0.62-0.86)
 |-
 |}
-''Note: This regimen was an alternative for patients who could not swallow pills. Reported efficacy is based on the 2017 update.''
+''Note: 73% of patients had squamous histology. MCBS score is for all patients, regardless of CPS status.''
+<div class="toccolours" style="background-color:#b3e2cd">
-''Patients: 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology''
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+'''21-day cycle for up to 35 cycles (2 years)'''
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1016/s0140-6736(21)01234-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34454674/ PubMed] [https://clinicaltrials.gov/study/NCT03189719 NCT03189719]
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+==Cisplatin & Irinotecan (IC) {{#subobject:ec60da|Regimen=1}}==
-*[[Fluorouracil (5-FU)]] 225 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4725 mg/m<sup>2</sup>)
+IC: '''<u>I</u>'''rinotecan & '''<u>C</u>'''isplatin
+<br>CI: '''<u>C</u>'''isplatin & '''<u>I</u>'''rinotecan
-'''21-day cycle for 4 cycles'''
+<div class="toccolours" style="background-color:#eeeeee">
-====Radiotherapy====
+===Regimen variant #1 {{#subobject:8f624d|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 50 Gy given in 25 fractions with cycles 3 & 4
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
-'''5-week course'''
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-===Regimen variant #2, 75/4000 x 2 (50.4 Gy) {{#subobject:3272d5|Variant=1}}===
+|-
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+|[https://www.cancernetwork.com/view/phase-ii-trial-weekly-irinotecancisplatin-advanced-esophageal-cancer Ilson 2004]
-!style="width: 20%"|Study
+|NR
-!style="width: 20%"|Years of enrollment
+| style="background-color:#91cf61" |Phase 2
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2002.20.5.1167 Minsky et al. 2002 (RTOG 94-05)]
+|}
-|1995-1999
+''Note: In contrast to the original reference, some guidelines list cisplatin 25 mg/m<sup>2</sup> as an alternate dosage. Patients had 26% squamous cell, 74% adenocarcinoma histology. 85% metastatic disease.''
-| style="background-color:#1a9851" |Phase III (C)
+<div class="toccolours" style="background-color:#b3e2cd">
-|Cisplatin, 5-FU, high-dose RT
+====Chemotherapy====
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS24
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
+*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV once per day on days 1 & 8
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:219a1|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract Conroy et al. 2014 (PRODIGE5/ACCORD17)]
+|[https://doi.org/10.1200/jco.1999.17.10.3270 Ilson et al. 1999]
-|2004-2011
+|1997-07 to 1998-09
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#91cf61" |Phase 2
-|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
 |-
 |}
-''Patients: RTOG 94-05 included both adenocarcinoma and squamous cell histology''
+''Note: Patients had 66% adenocarcinoma, 34% squamous cell histology. Did not receive any prior chemotherapy. 97% with metastatic disease.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once on day 1
+*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22
-*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] 20 mg IV once per day on days 1, 8, 15, 22, prior to chemotherapy
-'''28-day cycle for 2 cycles'''
+*[[Granisetron]] 2 mg PO once per day on days 1, 8, 15, 22, prior to chemotherapy
-====Radiotherapy====
+*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
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
+'''42-day cycles'''
-**RTOG 94-05: 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy
+</div></div>
-**PRODIGE5/ACCORD17: 2.0 Gy fractions x 25 fractions, for a total dose of 50 Gy
+===References===
+#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. [https://doi.org/10.1200/jco.1999.17.10.3270 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10506629/ PubMed]
-'''5- to 5.5-week course'''
+#Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park). 2004 Dec;18(14 Suppl 14):22-5. [https://www.cancernetwork.com/view/phase-ii-trial-weekly-irinotecancisplatin-advanced-esophageal-cancer link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15685830/ PubMed]
+==Cisplatin & Paclitaxel {{#subobject:5d50ee|Regimen=1}}==
-====Subsequent treatment====
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:ffaa05|Variant=1}}===
-*[[#Cisplatin_.26_Fluorouracil_.28CF.29_2|CF consolidation]]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
-===Regimen variant #3, 75/4000 x 3 (66 Gy) {{#subobject:0d8520|Variant=1}}===
+!style="width: 33%"|Dates of enrollment
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2005.04.7118 Bedenne et al. 2007 (FFCD 9102)]
+|[https://pubmed.ncbi.nlm.nih.gov/11079171 Ilson et al. 2000]
-|1993-2000
+|NR in abstract
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
+| style="background-color:#91cf61" |Phase 2
-|[[Surgery#Esophageal_cancer_surgery|Surgery]]
-| style="background-color:#eeee01" |Equivalent OS
 |-
 |}
-''Patients: 89% epidermoid, 11% glandular histology. Note that this was not a formal non-inferiority study but the study met its primary endpoint of equivalence.''
+''Note: In contrast to the original reference, some guidelines list the paclitaxel dose as 135 mg/m<sup>2</sup>. No primary reference could be found for the 135 mg/m<sup>2</sup> dosage. The protocol reported here was amended to change the original dose of 250 mg/m<sup>2</sup> to 200 mg/m<sup>2</sup> 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.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]] x 2
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 2, '''given second'''
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+====Supportive therapy====
+*"Granulocyte colony stimulating factor support"
-====Supportive medications====
+'''21-day cycles'''
+</div></div><br>
-*1 liter NS IV over 2 hours before and after [[Cisplatin (Platinol)]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:a5b523|Variant=1}}===
-'''21-day cycle for 1 cycle, then 28-day cycle for 2 cycles'''
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-====Radiotherapy====
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 10 fractions, for a total dose of 66 Gy (including the initial 46 Gy)
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-**Earlier in the study, some patients instead received split-course radiation therapy
-'''2-week course'''
-===Regimen variant #4, 75/4000 x 4 (50 Gy) {{#subobject:ca1b71|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199206113262403 Herskovic et al. 1992 (RTOG 85-01)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063082 Petrasch et al. 1998]
-|1986-1990
+|NR
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#91cf61" |Phase 2
-|[[#Radiation_therapy|Radiation therapy]]
-| style="background-color:#1a9850" |Superior OS
 |-
 |}
-''Patients: 88% squamous cell, 12% adenocarcinoma histology. 7% karnofsky performance scale of 50-60.''
+''Note: Patients had 25% adenocarcinoma, 75% squamous cell histology. Consisting of unresectable stage III disease, recurrent or metastatic tumors of esophageal origin.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
+*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] 20 mg IV once on day 1; 30 minutes prior to paclitaxel
-'''28-day cycle for 1 cycle, then 21-day cycle for 3 cycles'''
+*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 minutes prior to paclitaxel
-====Radiotherapy====
+*[[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
-*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 2.0 Gy fractions x 15 fractions, then 2.0 Gy fractions x 10 fractions to the initial tumor length plus a 5 cm margin, for a total dose of 50.0 Gy
+*"Adequate pre- and post- [[:Category:Hydration|hydration]]" for cisplatin
+'''14-day cycles'''
-'''5-week course'''
+</div></div>
 ===References===
+#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. [https://doi.org/10.1038/bjc.1998.524 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063082 link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9716036/ PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJM199206113262403 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1584260 PubMed]
+#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''' [https://pubmed.ncbi.nlm.nih.gov/11079171/ PubMed]
-##'''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. [https://doi.org/10.1200/jco.1997.15.1.277 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8996153 PubMed]
+==Docetaxel & Irinotecan {{#subobject:96e013|Regimen=1}}==
-##'''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. [http://jama.jamanetwork.com/article.aspx?articleid=189737 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10235156 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-#'''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. [https://doi.org/10.1200/jco.2002.20.5.1167 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11870157 PubMed]
+===Regimen {{#subobject:38cdd0|Variant=1}}===
-#'''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. [https://doi.org/10.1200/jco.2005.04.7118 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17401004 PubMed]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70136-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23623280 PubMed] ISCRTN47718479
+!style="width: 33%"|Study
-##'''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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28196063 PubMed]
+!style="width: 33%"|Dates of enrollment
-#'''PRODIGE5/ACCORD17:''' Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24556041 PubMed] NCT00861094
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-##'''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. [https://www.ejcancer.com/article/S0959-8049(17)31158-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28829992 PubMed]
-==Cisplatin, Paclitaxel, RT {{#subobject:5ef1ea|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ Burtness et al. 2009]
-|}
+|2001-12 to 2004-10
-TP & RT: '''<u>T</u>'''axol (Paclitaxel), '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+| style="background-color:#91cf61" |Phase 2
-===Regimen {{#subobject:8f0c89|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2643119 Suntharalingam et al. 2017 (RTOG 0436)]
-|2008-2013
-| style="background-color:#1a9851" |Phase III (C)
-|Cisplatin, Paclitaxel, Cetuximab, RT
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-Patients: 62% ''adenocarcinoma, 38% squamous cell histology. 14% with M1a disease. 6% with Zubrod PS score 2.''
+''Note: Patients had 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''
-*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+*[[Irinotecan (Camptosar)]] 50 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] as follows:
-====Radiotherapy====
+**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
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy
+**8 mg PO once per day on days 1 & 8; 12 hour afters chemotherapy
+*[[:Category:Serotonin 5-HT3 antagonists|Serotonin 5-HT3 antagonist]] IV once per day on days 1 & 8, within 1 hour before chemotherapy
-'''5-week course'''
+*"Oral antiemetic therapy prescribed"
+*[[Loperamide (Imodium)]] as needed
+'''21-day cycles'''
+</div></div>
 ===References===
+#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. [https://doi.org/10.1093/annonc/mdn787 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19429872/ PubMed]
-#'''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. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2643119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28687830 PubMed] NCT00655876
+==ECF {{#subobject:6325cb|Regimen=1}}==
+ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-==FOLFOX4 & RT {{#subobject:1f91c5|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:e5ede0|Variant=1}}===
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4 & RT: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-===Regimen {{#subobject:e2fc30|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract Conroy et al. 2014 (PRODIGE5/ACCORD17)]
+|[https://doi.org/10.1200/jco.2002.08.105 Ross et al. 2002]
-|2004-2011
+|1995-1998
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
+|[[#MCF|MCF]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
+| style="background-color:#eeee01" |Seems to have non-inferior OS
+|-
+| rowspan="3" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+|rowspan=3|2000-2005
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#ECX_2|ECX]]
+| style="background-color:#eeee01" |Non-inferior OS
+|-
+|2. [[#EOF_2|EOF]]
+| style="background-color:#eeee01" |Non-inferior OS
+|-
+|3. [[#EOX_2|EOX]]
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-''Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m<sup>2</sup>. Despite being a non-superior experimental arm, this regimen is recommended by some guidelines such as ESMO.''
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1600 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
+====Supportive therapy====
+*(varied depending on reference):
-'''14-day cycle for 3 cycles'''
+*3 liters per day "hyperhydration"
-====Radiotherapy====
+*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis
+*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 25 fractions, for a total dose of 50 Gy
+*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
+'''21-day cycle for up to 8 cycles'''
-'''5-week course'''
+</div></div>
-====Subsequent treatment====
-*[[#FOLFOX4|FOLFOX4]] x 3
 ===References===
+#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. [https://doi.org/10.1200/jco.2002.08.105 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11956258/ PubMed]
-#'''PRODIGE5/ACCORD17:''' Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24556041 PubMed] NCT00861094
+#'''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. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
-##'''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. [https://www.ejcancer.com/article/S0959-8049(17)31158-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28829992 PubMed]
+==ECX {{#subobject:bb95b5|Regimen=1}}==
+ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
-==Radiation therapy==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:e965c5|Variant=1}}===
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199206113262403 Herskovic et al. 1992 (RTOG 85-01)]
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|1986-1990
+|rowspan=2|2000-2005
-| style="background-color:#1a9851" |Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-|[[#Cisplatin.2C_Fluorouracil.2C_RT_2|Cisplatin, 5-FU, RT]]
+|1. [[#ECF_2|ECF]]
-| style="background-color:#d73027" |Inferior OS
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+|-
+|2. [[#EOF_2|EOF]]<br> 3. [[#EOX_2|EOX]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
 |-
 |}
-''Patients: 88% squamous cell, 12% adenocarcinoma histology. 7% Karnofsky performance scale of 50-60''
+''Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric primary site. 11% ECOG PS of 2.''
+<div class="toccolours" style="background-color:#b3e2cd">
-''Radiation as primary therapy; used as a comparator arm and here for reference purposes only.''
+====Chemotherapy====
-====Radiotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1
-*[[External beam radiotherapy]] total of 32 fractions: 50 Gy of regional treatment and 14 Gy to the boost field, for total dose of 64 Gy
+*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
+'''21-day cycle for up to 8 cycles'''
-'''6.4-week course'''
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJM199206113262403 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1584260 PubMed]
+==EOF {{#subobject:a6390c|Regimen=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. [https://doi.org/10.1200/jco.1997.15.1.277 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8996153 PubMed]
+EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
-##'''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. [http://jama.jamanetwork.com/article.aspx?articleid=189737 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10235156 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:abf19f|Variant=1}}===
-=Consolidation after definitive therapy=
-==Cisplatin & Fluorouracil (CF) {{#subobject:cf23a6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CF: '''<u>C</u>'''isplatin & '''<u>F</u>'''luorouracil
-===Regimen {{#subobject:ade242|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2002.20.5.1167 Minsky et al. 2002 (RTOG 94-05)]
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|1995-1999
+|rowspan=2|2000-2005
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-| style="background-color:#d3d3d3" |
+|1. [[#ECF_2|ECF]]<br>2. [[#ECX_2|ECX]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract Conroy et al. 2014 (PRODIGE5/ACCORD17)]
+|3. [[#EOX_2|EOX]]
-|2004-2011
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
 |-
 |}
-''Patients: study included both adenocarcinoma and squamous cell histology''
+''Note: Patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*RTOG 94-05: [[#Cisplatin.2C_Fluorouracil.2C_RT_2|Definitive CF & RT]] versus definitive CF & high-dose RT
-*PRODIGE5/ACCORD17: [[#Cisplatin.2C_Fluorouracil.2C_RT_2|Definitive CF & RT]]
 ====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once on day 1
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+====Supportive therapy====
-'''28-day cycle for 2 cycles'''
+*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
+'''21-day cycle for up to 8 cycles'''
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
-#'''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. [https://doi.org/10.1200/jco.2002.20.5.1167 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11870157 PubMed]
+==EOX {{#subobject:438182|Regimen=1}}==
-#'''PRODIGE5/ACCORD17:''' Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24556041 PubMed] NCT00861094
+EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)
-##'''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. [https://www.ejcancer.com/article/S0959-8049(17)31158-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28829992 PubMed]
+<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
+<div class="toccolours" style="background-color:#eeeeee">
-==FOLFOX4 {{#subobject:a8048e|Regimen=1}}==
+===Regimen {{#subobject:339609|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin 4
-===Regimen {{#subobject:f200f1|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract Conroy et al. 2014 (PRODIGE5/ACCORD17)]
+| rowspan="3" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|2004-2011
+|rowspan=3|2000-2005
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
+|1. [[#ECF_2|ECF]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
+| style="background-color:#91cf60" |Seems to have superior OS
+|-
+|2. [[#ECX_2|ECX]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+|-
+|3. [[#EOF_2|EOF]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669518/ Waddell et al. 2013 (REAL3)]
+|2008-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#mEOC.2BP_999|mEOC+P]]
+| style="background-color:#91cf60" |Seems to have superior OS
 |-
 |}
-''Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m<sup>2</sup>. Despite being a non-superior experimental arm, this regimen is recommended by some guidelines such as ESMO.''
+''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.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[#FOLFOX4_.26_RT|FOLFOX4 & RT]]
 ====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1600 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
+'''21-day cycle for up to 8 cycles'''
+</div></div>
-'''14-day cycle for 3 cycles'''
+===References===
+#'''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. [https://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] content property of [https://hemonc.org HemOnc.org] ISRCTN51678883
-===References===
+#'''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. [https://doi.org/10.1016/s1470-2045(13)70096-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669518/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23594787/ PubMed] [https://clinicaltrials.gov/study/NCT00824785 NCT00824785]
+==mFOLFOX6 & Cetuximab {{#subobject:e51095|Regimen=1}}==
-#'''PRODIGE5/ACCORD17:''' Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24556041 PubMed] NCT00861094
+mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
-##'''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. [https://www.ejcancer.com/article/S0959-8049(17)31158-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28829992 PubMed]
+<br>FOLFOX-C: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>C</u>'''etuximab
+<div class="toccolours" style="background-color:#eeeeee">
-=Adjuvant therapy=
+===Regimen {{#subobject:2a9d10|Variant=1}}===
-==Cisplatin & Fluorouracil (CF) {{#subobject:e35a6c|Regimen=1}}==
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019745/ Enziger et al. 2016 (CALGB 80403/ECOG E1206)]
-|}
+|2006-2009
-CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
-<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol
+|1. [[#ECF_.26_Cetuximab_888|ECF-C]]<br>2. [[#Cisplatin_.26_Irinotecan_.28IC.29_.26_Cetuximab_888|IC-C]]
-===Regimen variant #1, 75/5000 {{#subobject:fc3c70|Variant=1}}===
+| style="background-color:#d3d3d3" |Not powered to draw conclusions
-{| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]
-|1990-1995
-| style="background-color:#91cf61" |Non-randomized portion of RCT
 |-
 |}
-''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+''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.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[#Cisplatin_.26_Fluorouracil_.28CF.29|Neoadjuvant CF]], then [[Surgery#Esophageal_cancer_surgery|surgery]]
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with oxaliplatin'''
-*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: see note)
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with leucovorin'''
+====Targeted therapy====
-'''28-day cycle for 3 cycles'''
+*[[Cetuximab (Erbitux)]] as follows, '''given first''':
+**Cycle 1: 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 250 mg/m<sup>2</sup> IV over 60 minutes once on day 8
-===Regimen variant #2, 80/4000 {{#subobject:e4f654|Variant=1}}===
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+'''14-day cycles'''
-!style="width: 20%"|Study
+</div></div>
-!style="width: 20%"|Years of enrollment
+===References===
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+<!--
-!style="width: 20%"|Comparator
+# P. C. Enzinger, B. Burtness, D. Hollis, D. Niedzwiecki, D. Ilson, A. B. Benson, R. J. Mayer, R. M. Goldberg. CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer. 2010 ASCO Annual Meeting abstract 4006. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=44487 link to abstract] -->
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+#'''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. [https://doi.org/10.1200/jco.2015.65.5092 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019745/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27382098/ PubMed] [https://clinicaltrials.gov/study/NCT00381706 NCT00381706]
+==FULV & Gemcitabine {{#subobject:876cd7|Regimen=1}}==
+FULV & Gemcitabine: 5-'''<u>FU</u>''', '''<u>L</u>'''euco'''<u>V</u>'''orin, Gemcitabine
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:173a91|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/JCO.2003.12.095 Ando et al. 2003 (JCOG 9204)]
+|[https://doi.org/10.1159/000087815 Morgan-Meadows et al. 2005]
-|1992-1997
+|1998-06 to 2001-11
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#91cf61" |Phase 2
-|[[Esophageal_cancer_-_null_regimens#Observation|Observation]]
-| style="background-color:#91cf60" |Seems to have superior DFS
-|-
-|[https://link.springer.com/article/10.1245%2Fs10434-011-2049-9 Ando et al. 2011 (JCOG 9907)]
-|2000-2006
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29|Neoadjuvant CF]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-====Preceding treatment====
+''Note: Patients had 100% esophageal cancer (both squamous and adenocarcinoma histology). Patients received no prior therapy.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Surgery#Esophageal_cancer_surgery|Surgery]]
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 (total dose per cycle: 1800 mg/m<sup>2</sup>)
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Leucovorin (Folinic acid)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+'''28-day cycles'''
-'''21-day cycle for 2 cycles'''
+</div></div>
 ===References===
+<!-- # Michelle Pipp, Daniel Mulkerin, Deb Warren, Wesley Hotchkis, Jordan Berlin, James P Thomas. A Phase II Trial of Gemcitabine and 5-Fluoruracil in Advanced Esophageal Cancer. 2001 ASCO Annual Meeting abstract 630. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=10&abstractID=630 link to abstract] -->
-#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9869669 PubMed]
+#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. [https://doi.org/10.1159/000087815 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16118509/ PubMed]
-#'''JCOG 9204:''' Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, Takiyama W, Watanabe H, Isono K, Aoyama N, Makuuchi H, Tanaka O, Yamana H, Ikeuchi S, Kabuto T, Nagai K, Shimada Y, Kinjo Y, Fukuda H; [[Study_Groups#JCOG|JCOG]]. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. J Clin Oncol. 2003 Dec 15;21(24):4592-6. [https://doi.org/10.1200/JCO.2003.12.095 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14673047 PubMed]
+==LdCF {{#subobject:f31fcc|Regimen=1}}==
-#'''JCOG 9907:''' Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. [https://link.springer.com/article/10.1245%2Fs10434-011-2049-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21879261 PubMed] NCT00190554
+LdCF: '''<u>L</u>'''iposomal '''<u>d</u>'''oxorubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+<div class="toccolours" style="background-color:#eeeeee">
-=Metastatic or locally advanced disease, first-line=
+===Regimen {{#subobject:1b58a0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-==Carboplatin & Paclitaxel (CP) {{#subobject:4df570|Regimen=1}}==
+!style="width: 20%"|Study
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1007/s00280-010-1424-8 Cascinu et al. 2010]
-|}
+|2002-2005
-===Regimen {{#subobject:9725d8|Variant=1}}===
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
-{| class="wikitable" style="width: 50%; text-align:center;"
+|[[#MCF|MCF]]
-! style="width: 50%" |Study
+| style="background-color:#91cf60" |Seems to have superior OS
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://pubmed.ncbi.nlm.nih.gov/9427274 Philip et al. 1997]
-| style="background-color:#91cf61" |Phase II
 |-
 |}
-''Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6.''
+''Note: Patients had 11% gastroesophageal junction, 89% gastric origin. 90% metastatic. 6% with ECOG PS of 2.''
+<div class="toccolours" style="background-color:#b3e2cd">
-''Philip et al. Patients: locally advanced metastatic or recurrent esophageal or gastric cancer''
 ====Chemotherapy====
+*[[Pegylated liposomal doxorubicin (Doxil)]] 20 mg/m<sup>2</sup> IV once on day 1
-*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1, '''given second'''
+*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once on day 1
-*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup>)
+'''14-day cycles'''
-'''21-day cycles'''
+</div></div>
 ===References===
+#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. [https://doi.org/10.1007/s00280-010-1424-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20821330/ PubMed]
-#Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9427274 PubMed]
+==MCF {{#subobject:d3775b|Regimen=1}}==
+MCF: '''<u>M</u>'''itomycin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-==Cisplatin & Fluorouracil (CF) & Pembrolizumab {{#subobject:c798a3|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:47b99f|Variant=1}}===
-|-
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|[[#top|back to top]]
-|}
-CF & Pembrolizumab: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, Pembrolizumab
-===Regimen {{#subobject:d18acj2|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/pembrolizumab-plus-chemotherapy-versus-chemotherapy-as-first-line-therapy-in-patients-with-advanced-esophageal-cancer-the-phase-3-keynote-590-study Kato et al. 2020 (KEYNOTE-590)]
+|[https://doi.org/10.1200/jco.2002.08.105 Ross et al. 2002]
-|2017-2020
+|1995-1998
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Cisplatin_.26_Fluorouracil_.28CF.29_4|CF]]
+|[[#ECF_2|ECF]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#eeee01" |Seems to have non-inferior OS (primary endpoint)
+|-
+|[https://doi.org/10.1007/s00280-010-1424-8 Cascinu et al. 2010]
+|2002-2005
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#LdCF|LdCF]]
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-''73% squamous histology.''
+''Note: Cascinu et al. patients had 11% gastroesophageal junction, 89% gastric primary site. 90% metastatic. 6% with ECOG PS of 2.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Immunotherapy====
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 ====Chemotherapy====
+*[[Mitomycin (Mutamycin)]] 7 mg/m<sup>2</sup> (maximum dose of 14 mg) IV once on day 1
-*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 22
-*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 12,600 mg/m<sup>2</sup>)
+====Supportive therapy====
-'''21-day cycle for up to 35 cycles (2 years)'''
+*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
+'''42-day cycle for up to 5 cycles (6 months)'''
+</div></div>
 ===References===
+#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. [https://doi.org/10.1200/jco.2002.08.105 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11956258/ PubMed]
+#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. [https://doi.org/10.1007/s00280-010-1424-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20821330/ PubMed]
-#'''Abstract:''' Kato et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study Annals of Oncology (2020) 31 (suppl_4): S1142-S1215.  [https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/pembrolizumab-plus-chemotherapy-versus-chemotherapy-as-first-line-therapy-in-patients-with-advanced-esophageal-cancer-the-phase-3-keynote-590-study link to abstract] NCT03189719
+==Paclitaxel monotherapy {{#subobject:ed008a|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Cisplatin & Irinotecan (IC) {{#subobject:ec60da|Regimen=1}}==
+===Regimen variant #1, weekly {{#subobject:dd30a4|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1093/annonc/mdm004 Ilson et al. 2007]
-|}
+|1998-01 to 2000-04
-IC: '''<u>I</u>'''rinotecan & '''<u>C</u>'''isplatin
+| style="background-color:#91cf61" |Phase 2
-<br>CI: '''<u>C</u>'''isplatin & '''<u>I</u>'''rinotecan
-===Regimen variant #1 {{#subobject:8f624d|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.cancernetwork.com/esophageal-cancer/phase-ii-trial-weekly-irinotecancisplatin-advanced-esophageal-cancer Ilson 2004]
-| style="background-color:#91cf61" |Phase II
 |-
 |}
-''Note: In contrast to the original reference, some guidelines list cisplatin 25 mg/m<sup>2</sup> as an alternate dosage.''
+''Note: Patients had 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.''
+<div class="toccolours" style="background-color:#b3e2cd">
-''Patients: 26% squamous cell, 74% adenocarcinoma histology. 85% metastatic disease.''
 ====Chemotherapy====
+*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22
-*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
+====Supportive therapy====
-*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV once per day on days 1 & 8
+*[[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
-'''21-day cycles'''
+*[[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 {{#subobject:219a1|Variant=1}}===
+</div></div><br>
-{| class="wikitable" style="width: 50%; text-align:center;"
+<div class="toccolours" style="background-color:#eeeeee">
-! style="width: 50%" |Study
+===Regimen variant #2, CI {{#subobject:1d24a4|Variant=1}}===
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.1999.17.10.3270 Ilson et al. 1999]
+|[http://jnci.oxfordjournals.org/content/86/14/1086.long Ajani et al. 1994]
-| style="background-color:#91cf61" |Phase II
+|1992-08 to 1993-12
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Patients: 66% adenocarcinoma, 34% squamous cell histology. Did not receive any prior chemotherapy. 97% with metastatic disease.''
+''Note: In contrast to the original reference, some guidelines list the dosage of paclitaxel as 135 to 175 mg/m<sup>2</sup>. Patients had 100% esophageal cancer. 36% squamous cell, 64% adenocarcinoma histology.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Paclitaxel (Taxol)]] 250 mg/m<sup>2</sup> 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'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
-*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
+====Dose and schedule modifications====
-*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22
+*[[Paclitaxel (Taxol)]] dosage adjusted based on toxicity down to 150 or 200 mg/m<sup>2</sup>, or up to 280 mg/m<sup>2</sup>
+</div></div>
-====Supportive medications====
-*[[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 (Platinol)]]
-*[[Atropine (Atropen)]] used as pretreatment medication if there was diarrhea or abdominal cramps within 1 hour of [[Irinotecan (Camptosar)]]
-'''42-day cycles'''
 ===References===
+#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. [http://jnci.oxfordjournals.org/content/86/14/1086.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7912736/ PubMed]
+#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. [https://doi.org/10.1093/annonc/mdm004 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17351256/ PubMed]
-#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. [https://doi.org/10.1200/jco.1999.17.10.3270 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10506629 PubMed]
+=Metastatic or locally advanced disease, subsequent lines of therapy=
-#Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park). 2004 Dec;18(14 Suppl 14):22-5. [http://www.cancernetwork.com/esophageal-cancer/phase-ii-trial-weekly-irinotecancisplatin-advanced-esophageal-cancer link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15685830 PubMed]
+==CAPIRI {{#subobject:c699c3|Regimen=1}}==
+CapeIRI: '''<u>Cape</u>'''citabine and '''<u>IRI</u>'''notecan
-==Cisplatin & Paclitaxel {{#subobject:5d50ee|Regimen=1}}==
+<br>CAPIRI: '''<u>CAP</u>'''ecitabine and '''<u>IRI</u>'''notecan
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<br>XELIRI: '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan
+<br>XI: '''<u>X</u>'''eloda (Capecitabine) and '''<u>I</u>'''rinotecan
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:d233c0|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1007/s00280-008-0893-5 Leary et al. 2008]
-|}
+|2003-10 to 2005-09
-===Regimen variant #1 {{#subobject:ffaa05|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://pubmed.ncbi.nlm.nih.gov/11079171 Ilson et al. 2000]
-| style="background-color:#91cf61" |Phase II
 |-
 |}
-''Note: In contrast to the original reference, some guidelines list the paclitaxel dose as 135 mg/m<sup>2</sup>. No primary reference could be found for the 135 mg/m<sup>2</sup> dosage. The protocol reported here was amended to change the original dose of 250 mg/m<sup>2</sup> to 200 mg/m<sup>2</sup> based on toxicity and treatment-related deaths.''
+<div class="toccolours" style="background-color:#b3e2cd">
-''Patients: 87% adenocarcinoma, 13% squamous cell histology. Included both gastroesophageal junction and esophageal patients. 95% with metastatic disease. None had received prior chemotherapy.''
 ====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 2, '''given second'''
+*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1
-*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
+====Supportive therapy====
+*[[Atropine (Atropen)]] 0.25 mg SC once on day 1, given prior to irinotecan
-====Supportive medications====
+*[[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
-*"Granulocyte colony stimulating factor support"
+'''21-day cycle for up to 8 cycles'''
+</div></div>
+===References===
+#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. [https://doi.org/10.1007/s00280-008-0893-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19104814/ PubMed]
+==Docetaxel monotherapy {{#subobject:421f5e|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 75 mg/m<sup>2</sup>, indefinite {{#subobject:abe193|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
+|-
+|}
+''<sup>1</sup>Reported 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.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 '''21-day cycles'''
+</div></div><br>
-===Regimen variant #2 {{#subobject:a5b523|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 50%; text-align:center;"
+===Regimen variant #2, 100 mg/m<sup>2</sup> {{#subobject:b279a5|Variant=1}}===
-! style="width: 50%" |Study
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063082 Petrasch et al. 1998]
+|[https://doi.org/10.1007/s12032-007-0028-6 Albertsson et al. 2007]
-| style="background-color:#91cf61" |Phase II
+|1997-2003
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Patients: 25% adenocarcinoma, 75% squamous cell histology. Consisting of unresectable stage III disease, recurrent or metastatic tumors of esophageal origin.''
+''Note: Patients had squamous cell or adenocarcinoma histology of the esophagus or gastric cardia.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
+'''21-day cycles'''
-*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+</div></div>
-====Supportive medications====
-*[[Dexamethasone (Decadron)]] 20 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Clemastine (Tavist)]] 2 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Ondansetron (Zofran)]] 8 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*"Adequate pre- and posthydration" for [[Cisplatin (Platinol)]]
-'''14-day cycles'''
 ===References===
+#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. [https://doi.org/10.1007/s12032-007-0028-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17917090/ PubMed]
-#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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063082 link to PMC article] '''contains verified protocol'''  [https://pubmed.ncbi.nlm.nih.gov/9716036 PubMed]
+<!-- #'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://doi.org/10.1200/JCO.2019.37.4_suppl.2 link to abstract] -->
-#Ilson DH, Forastiere A, Arquette M, Costa F, Heelan R, Huang Y, Kelsen DP. A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J. 2000 Sep-Oct;6(5):316-23. '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11079171 PubMed]
+#'''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. [https://doi.org/10.1200/jco.20.01888 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33026938/ PubMed] [https://clinicaltrials.gov/study/NCT02564263 NCT02564263]
+#'''INTEGRATE IIb:''' [https://clinicaltrials.gov/study/NCT04879368 NCT04879368]
-==Docetaxel & Irinotecan {{#subobject:96e013|Regimen=1}}==
+==Docetaxel & Irinotecan {{#subobject:96f053|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen {{#subobject:38cff0|Variant=1}}===
-|[[#top|back to top]]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-|}
+!style="width: 33%"|Study
-===Regimen {{#subobject:38cdd0|Variant=1}}===
+!style="width: 33%"|Dates of enrollment
-{| class="wikitable" style="width: 50%; text-align:center;"
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ Burtness et al. 2009]
-| style="background-color:#91cf61" |Phase II
+|2001-12 to 2004-10
+| style="background-color:#ffffbe" |Phase 2, fewer than 20 pts in this subgroup
 |-
 |}
-''Patients: 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.''
+''Note: Patients had 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''
 *[[Irinotecan (Camptosar)]] 50 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
+====Supportive therapy====
-====Supportive medications====
 *[[Dexamethasone (Decadron)]] as follows:
-**8 mg PO once per day on days 1 & 8; 12 hours before [[Docetaxel (Taxotere)]]
+**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
@@ Line 1,867: / Line 2,088: @@
 *"Oral antiemetic therapy prescribed"
 *[[Loperamide (Imodium)]] as needed
 '''21-day cycles'''
+</div></div>
 ===References===
+#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. [https://doi.org/10.1093/annonc/mdn787 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19429872/ PubMed]
-#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. [https://doi.org/10.1093/annonc/mdn787 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19429872 PubMed]
+==Erlotinib monotherapy {{#subobject:5efb4d|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==ECF {{#subobject:6325cb|Regimen=1}}==
+===Regimen {{#subobject:eaf7de|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116987/ Ilson et al. 2010]
+|2002-07 to 2005-09
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#top|back to top]]
 |}
-ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+''Note: Patients had 57% adenocarcinoma, 43% squamous cell histology. 6% proximal esophagus, 35% distal esophagus, 59% gastroesophageal junction.''
-===Regimen {{#subobject:e5ede0|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div></div>
+===References===
+#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. [https://doi.org/10.1002/cncr.25602 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116987/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21425140/ PubMed]
+==Irinotecan monotherapy {{#subobject:6df2c0|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 14-day cycles {{#subobject:9b9303|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2002.08.105 Ross et al. 2002]
+|[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
-|1995-1998
+|2015-2017
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#MCF|MCF]]
+|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#eeee01" |Seems to have non-inferior OS
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
 |-
-| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+|}
-|rowspan=3|2000-2005
+''<sup>1</sup>Reported 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.''
-| rowspan="3" style="background-color:#1a9851" |Phase III (C)
+<div class="toccolours" style="background-color:#b3e2cd">
-|1. [[#ECX_2|ECX]]
+====Chemotherapy====
-| style="background-color:#eeee01" |Non-inferior OS
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
+'''14-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 4 out of 6 weeks {{#subobject:9fb427|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|2. [[#EOF_2|EOF]]
+|[https://doi.org/10.1007/s00384-002-0464-x Mühr-Wilkenshoff et al. 2003]
-| style="background-color:#eeee01" |Non-inferior OS
+|1999-2000
-|-
+| style="background-color:#ffffbe" |Phase 2, fewer than 20 patients
-|3. [[#EOX_2|EOX]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
+''Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m<sup>2</sup> IV once per day on days 1 & 8, with 21-day cycles. Ten patients had esophageal squamous cell carcinoma, three with esophageal adenocarcinoma''
-''Ross et al. Patients: adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer.''
+<div class="toccolours" style="background-color:#b3e2cd">
-''REAL-2 Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
 ====Chemotherapy====
+*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22
+'''42-day cycles'''
+</div></div>
+===References===
+#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. [https://doi.org/10.1007/s00384-002-0464-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/12774248/ PubMed]
+<!-- #'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://doi.org/10.1200/JCO.2019.37.4_suppl.2 link to abstract] -->
+#'''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. [https://doi.org/10.1200/jco.20.01888 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33026938/ PubMed] [https://clinicaltrials.gov/study/NCT02564263 NCT02564263]
+#'''INTEGRATE IIb:''' [https://clinicaltrials.gov/study/NCT04879368 NCT04879368]
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
+==IRIS {{#subobject:252c51|Regimen=1}}==
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1
+IRIS: '''<u>IRI</u>'''notecan & '''<u>S</u>'''-1
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:cdcc15|Variant=1}}===
-====Supportive medications====
-*(varied depending on reference):
-*3 liters per day "hyperhydration"
-*[[:Category:Serotonin_5-HT3_antagonists|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===
-#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. [https://doi.org/10.1200/jco.2002.08.105 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11956258 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18172173 PubMed]
-==ECX {{#subobject:bb95b5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
-===Regimen {{#subobject:e965c5|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|rowspan=2|2000-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#ECF_2|ECF]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|2. [[#EOF_2|EOF]]<br> 3. [[#EOX_2|EOX]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-''REAL-2 patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
-====Chemotherapy====
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
-'''21-day cycle for up to 8 cycles'''
-===References===
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18172173 PubMed]
-==EOF {{#subobject:a6390c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
-===Regimen {{#subobject:abf19f|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|rowspan=2|2000-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#ECF_2|ECF]]<br> 2. [[#ECX_2|ECX]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|3. [[#EOX_2|EOX]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-''Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
-====Chemotherapy====
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
-====Supportive medications====
-*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
-'''21-day cycle for up to 8 cycles'''
-===References===
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18172173 PubMed]
-==EOX {{#subobject:438182|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)
-<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
-===Regimen {{#subobject:339609|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|rowspan=3|2000-2005
-| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#ECF_2|ECF]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|2. [[#ECX_2|ECX]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|3. [[#EOF_2|EOF]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669518/ Waddell et al. 2013 (REAL3)]
-|2008-2011
-| style="background-color:#1a9851" |Phase III (C)
-|mEOC+P
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''REAL-2 patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
-''REAL3 patients: 99% adenocarcinoma, 1% undifferentiated histology. 39% esophagus, 31% ''gastroesophageal'' junction, 30% gastric. 6% ECOF PS of 2. 89% metastatic disease.''
-====Chemotherapy====
-*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
-'''21-day cycle for up to 8 cycles'''
-===References===
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18172173 PubMed] content property of [http://hemonc.org HemOnc.org]
-#'''REAL3:''' Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, Wotherspoon A, Saffery C, Middleton G, Wadsley J, Ferry D, Mansoor W, Crosby T, Coxon F, Smith D, Waters J, Iveson T, Falk S, Slater S, Peckitt C, Barbachano Y. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):481-9. Epub 2013 Apr 15. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669518/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23594787 PubMed] NCT00824785
-==mFOLFOX6 & Cetuximab {{#subobject:e51095|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
-<br>FOLFOX-C: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>C</u>'''etuximab
-===Regimen {{#subobject:2a9d10|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019745/ Enziger et al. 2016 (CALGB 80403/ECOG E1206)]
-|2006-2009
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
-|1. ECF-C<br> 2. IC-C
-| style="background-color:#d3d3d3" |Not powered to draw conclusions
-|-
-|}
-''Patients: 91% adenocarcinoma, 9% squamous cell histology. 56% esophageal, 43% gastroesophageal tumors.''
-''To receive full-dose therapy in this trial, patients were required to have an absolute neutrophil count of 1,000/µL or greater, platelets of 75,000/µL or greater, and no other grade 2 or higher treatment-related toxicity.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with leucovorin'''
-====Targeted therapy====
-*[[Cetuximab (Erbitux)]] as follows, '''given first''':
-**Cycle 1: 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 250 mg/m<sup>2</sup> IV over 60 minutes once on day 8
-**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
-'''14-day cycles'''
-===References===
-<!--
-# P. C. Enzinger, B. Burtness, D. Hollis, D. Niedzwiecki, D. Ilson, A. B. Benson, R. J. Mayer, R. M. Goldberg. CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer. 2010 ASCO Annual Meeting abstract 4006. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=44487 link to abstract] -->
-#'''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. [https://doi.org/10.1200/jco.2015.65.5092 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019745/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27382098 PubMed] NCT00381706
-==FULV & Gemcitabine {{#subobject:876cd7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FULV & Gemcitabine: 5-'''<u>FU</u>''', '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid), Gemcitabine
-===Regimen {{#subobject:173a91|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.karger.com/Article/Abstract/87815 Morgan-Meadows et al. 2005]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-''Patients: 100% esophageal cancer (both squamous and adenocarcinoma histology). Patients received no prior therapy.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 (total dose per cycle: 1800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-'''28-day cycles'''
-===References===
-<!-- # Michelle Pipp, Daniel Mulkerin, Deb Warren, Wesley Hotchkis, Jordan Berlin, James P Thomas. A Phase II Trial of Gemcitabine and 5-Fluoruracil in Advanced Esophageal Cancer. 2001 ASCO Annual Meeting abstract 630. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=10&abstractID=630 link to abstract] -->
-#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. [http://www.karger.com/Article/Abstract/87815 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16118509 PubMed]
-==LdCF {{#subobject:f31fcc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-LdCF: '''<u>L</u>'''iposomal '''<u>d</u>'''oxorubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-===Regimen {{#subobject:1b58a0|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1007/s00280-010-1424-8 Cascinu et al. 2010]
-|2002-2005
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
-|[[#MCF|MCF]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Patients: 11% gastroesophageal junction, 89% gastric origin. 90% metastatic. 6% with ECOG PS of 2.''
-====Chemotherapy====
-*[[Pegylated liposomal doxorubicin (Doxil)]] 20 mg/m<sup>2</sup> IV once on day 1
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup> )
-'''14-day cycles'''
-===References===
-#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. [https://doi.org/10.1007/s00280-010-1424-8 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20821330 PubMed]
-==MCF {{#subobject:d3775b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-MCF: '''<u>M</u>'''itomycin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-===Regimen {{#subobject:47b99f|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2002.08.105 Ross et al. 2002]
-|1995-1998
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#ECF_2|ECF]]
-| style="background-color:#eeee01" |Seems to have non-inferior OS
-|-
-|[https://doi.org/10.1007/s00280-010-1424-8 Cascinu et al. 2010]
-|2002-2005
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[#LdCF|LdCF]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-''Cascinu Patients: 11% gastroesophageal junction, 89% gastric origin. 90% metastatic. 6% with ECOG PS of 2.''
-====Chemotherapy====
-*[[Mitomycin (Mutamycin)]] 7 mg/m<sup>2</sup> (maximum dose of 14 mg) IV once on day 1
-*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 22
-*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 12,600 mg/m<sup>2</sup>)
-====Supportive medications====
-*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
-'''42-day cycle for up to 5 cycles (6 months)'''
-===References===
-#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. [https://doi.org/10.1200/jco.2002.08.105 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11956258 PubMed]
-#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. [https://doi.org/10.1007/s00280-010-1424-8 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20821330 PubMed]
-==Paclitaxel monotherapy {{#subobject:ed008a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, weekly {{#subobject:dd30a4|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1093/annonc/mdm004 Ilson et al. 2007]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-''Patients: 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.''
-====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22
-====Supportive medications====
-*[[Dexamethasone (Decadron)]] 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]
-'''28-day cycles'''
-===Regimen variant #2, CI {{#subobject:1d24a4|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://jnci.oxfordjournals.org/content/86/14/1086.long Ajani et al. 1994]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-''Note: In contrast to the original reference, some guidelines list the dosage of paclitaxel as 135 to 175 mg/m<sup>2</sup>.''
-''Patients: 100% esophageal cancer. 36% squamous cell, 64% adenocarcinoma histology.''
-====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 250 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-**Dosage adjusted based on toxicity down to 150 or 200 mg/m<sup>2</sup>, or up to 280 mg/m<sup>2</sup>
-====Supportive medications====
-*[[Dexamethasone (Decadron)]] 20 mg PO for 2 doses on day 1; 14 hours and 7 hours prior to [[Paclitaxel (Taxol)]]
-*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 60 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Diphenhydramine (Benadryl)]] 50 mg IV once on day 1; 60 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 hours after the [[Paclitaxel (Taxol)]] infusion finishes
-'''21-day cycles'''
-===References===
-#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. [http://jnci.oxfordjournals.org/content/86/14/1086.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/7912736 PubMed]
-#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. [https://doi.org/10.1093/annonc/mdm004 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17351256 PubMed]
-=Metastatic or locally advanced disease, subsequent lines of therapy=
-==Camrelizumab monotherapy {{#subobject:c701c3|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:d1dde0|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1016/s1470-2045(20)30110-8 Huang et al. 2020 (ESCORT)]
-|2017-2018
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-| 1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Irinotecan_monotherapy_2|Irinotecan]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====Immunotherapy====
-*[[Camrelizumab (AiRuiKa)]] 200 mg IV once on day 1
-'''14-day cycles'''
-===References===
-# '''ESCORT:''' Huang J, Xu J, Chen Y, Zhang Y, Chen Z, Chen J, Niu Z, Fan Q, Lin L, Gu K, Liu Y, Ba Y, Miao Z, Jiang X, Chen J, Fu Z, Gan L, Wang J, Zhan X, Liu T, Li Z. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2020;21(6):832-842. [https://doi.org/10.1016/s1470-2045(20)30110-8 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416073/ PubMed] NCT03099382
-==CAPIRI {{#subobject:c699c3|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeIRI: '''<u>Cape</u>'''citabine and '''<u>IRI</u>'''notecan
-<br>CAPIRI: '''<u>CAP</u>'''ecitabine and '''<u>IRI</u>'''notecan
-<br>XELIRI: '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan
-<br>XI: '''<u>X</u>'''eloda (Capecitabine) and '''<u>I</u>'''rinotecan
-===Regimen {{#subobject:d233c0|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1007/s00280-008-0893-5 Leary et al. 2008]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1
-====Supportive medications====
-*[[Atropine (Atropen)]] 0.25 mg SC once on day 1, given before [[Irinotecan (Camptosar)]]
-*[[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===
-#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. [https://doi.org/10.1007/s00280-008-0893-5 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19104814 PubMed]
-==Docetaxel monotherapy {{#subobject:421f5e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, 75 mg/m<sup>2</sup>, indefinite {{#subobject:abe193|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
-|2015-2017
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d73027" |Inferior OS (*)
-|-
-|}
-''Note: efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.''
-====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-'''21-day cycles'''
-===Regimen variant #2, 100 mg/m<sup>2</sup> {{#subobject:b279a5|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://link.springer.com/article/10.1007/s12032-007-0028-6 Albertsson et al. 2007]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-''Patients: squamous cell or adenocarcinoma histology of the esophagus or gastric cardia.''
-====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-'''21-day cycles'''
-===References===
-#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. [http://link.springer.com/article/10.1007/s12032-007-0028-6 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17917090 PubMed]
-<!-- #'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://doi.org/10.1200/JCO.2019.37.4_suppl.2 link to abstract] -->
-#'''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. [https://doi.org/10.1200/jco.20.01888 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33026938 PubMed] NCT02564263
-==Docetaxel & Irinotecan {{#subobject:96f053|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:38cff0|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ Burtness et al. 2009]
-| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup
-|-
-|}
-''Patients: 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.''
-====Chemotherapy====
-*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''
-*[[Irinotecan (Camptosar)]] 50 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
-====Supportive medications====
-*[[Dexamethasone (Decadron)]] as follows:
-**8 mg PO once per day on days 1 & 8; 12 hours before [[Docetaxel (Taxotere)]]
-**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
-*[[:Category:Serotonin 5-HT3 antagonists|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===
-#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. [https://doi.org/10.1093/annonc/mdn787 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19429872 PubMed]
-==Erlotinib monotherapy {{#subobject:5efb4d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:eaf7de|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116987/ Ilson et al. 2010]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-''Patients: 57% adenocarcinoma, 43% squamous cell histology. 6% proximal esophagus, 35% distal esophagus, 59% gastroesophageal junction.''
-====Targeted therapy====
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day, at least 1 hour before a meal, or 2 hours after a meal
-'''28-day cycles'''
-===References===
-#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. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25602/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116987/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21425140 PubMed]
-==Irinotecan monotherapy {{#subobject:6df2c0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, 14-day cycles {{#subobject:9b9303|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
-|2015-2017
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d73027" |Inferior OS (*)
-|-
-|}
-''Note: efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-'''14-day cycles'''
-===Regimen variant #2, 4 out of 6 weeks {{#subobject:9fb427|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://link.springer.com/article/10.1007/s00384-002-0464-x Mühr-Wilkenshoff et al. 2003]
-| style="background-color:#ffffbe" |Phase II, <20 patients
-|-
-|}
-''Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m<sup>2</sup> IV once per day on days 1 & 8, with 21-day cycles.''
-''Patients: Ten with esophageal squamous cell carcinoma, three with esophageal adenocarcinoma''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===References===
-#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. [https://link.springer.com/article/10.1007/s00384-002-0464-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/12774248 PubMed]
-<!-- #'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://doi.org/10.1200/JCO.2019.37.4_suppl.2 link to abstract] -->
-#'''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. [https://doi.org/10.1200/jco.20.01888 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33026938 PubMed] NCT02564263
-==Irinotecan & Mitomycin {{#subobject:dfc95f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:3213a7|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.jchemother.it/cgi-bin/digisuite.exe/product?ID=252&IDCategory=30 Bamias et al. 2003a]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-''Patients: Advanced gastric and colorectal cancers. All previously received 5-fluorouracil-based chemotherapy.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV once on day 1
-*[[Mitomycin (Mutamycin)]] 5 mg/m<sup>2</sup> IV once on day 1
-'''14-day cycles'''
-===References===
-#Bamias A, Papamichael D, Syrigos K, Pavlidis N. Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother. 2003 Jun;15(3):275-81. [http://www.jchemother.it/cgi-bin/digisuite.exe/product?ID=252&IDCategory=30 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12868555 PubMed]
-==IRIS {{#subobject:252c51|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IRIS: '''<u>IRI</u>'''notecan & '''<u>S</u>'''-1
-===Regimen {{#subobject:cdcc15|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 2,553: / Line 2,174: @@
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ Huang et al. 2019 (ESWN 01)]
 |2014-2016
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 |[[#S-1_monotherapy|S-1]]
-| style="background-color:#1a9850" |Superior PFS
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 3.8 vs 1.7 mo<br>(HR 0.58, 95% CI 0.38-0.86)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Irinotecan (Camptosar)]] 160 mg/m<sup>2</sup> IV once on day 1, '''given first'''
-*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 10
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 10
-**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 10
+**Between 1.25 m<sup>2</sup> and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 10
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 10
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 10
 '''14-day cycles'''
+</div></div>
 ===References===
+#'''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. [https://cancercommun.biomedcentral.com/articles/10.1186/s40880-019-0359-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30940189/ PubMed] [https://clinicaltrials.gov/study/NCT02319187 NCT02319187]
-#'''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. [https://cancercommun.biomedcentral.com/articles/10.1186/s40880-019-0359-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30940189 PubMed] NCT02319187
+==Paclitaxel monotherapy {{#subobject:ec998a|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Paclitaxel monotherapy {{#subobject:ec998a|Regimen=1}}==
+===Regimen variant #1, weekly {{#subobject:aa30a4|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-|-
+!style="width: 33%"|Study
-|[[#top|back to top]]
+!style="width: 33%"|Dates of enrollment
-|}
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-===Regimen variant #1, weekly {{#subobject:aa30a4|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://doi.org/10.1093/annonc/mdm004 Ilson et al. 2007]
-| style="background-color:#91cf61" |Phase II
+|1998-01 to 2000-04
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Patients: 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.''
+''Note: Patients had 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22
+====Supportive therapy====
-====Supportive medications====
+*[[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
-*[[Dexamethasone (Decadron)]] 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]
+*[[Diphenhydramine (Benadryl)]] 50 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 (Taxol)]]
-*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]
 '''28-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 80 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:cc40a4|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 2,610: / Line 2,224: @@
 |[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
 |2015-2017
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d73027" |Inferior OS (*)
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
 |-
 |}
-''Note: efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS. This is the lower bound of dosing specified in KEYNOTE-181.''
+''<sup>1</sup>Reported 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.''<br>
+''Note: This is the lower bound of dosing specified in KEYNOTE-181.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 '''28-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #3, 100 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:99h0a4|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 2,632: / Line 2,247: @@
 |[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
 |2015-2017
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d73027" |Inferior OS (*)
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
 |-
 |}
-''Note: efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS. This is the upper bound of dosing specified in the protocol.''
+''<sup>1</sup>Reported 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.''<br>
+''Note: This is the upper bound of dosing specified in the protocol.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 '''28-day cycles'''
+</div></div>
 ===References===
+#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. [https://doi.org/10.1093/annonc/mdm004 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17351256/ PubMed]
-#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. [https://doi.org/10.1093/annonc/mdm004 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17351256 PubMed]
 <!-- #'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://doi.org/10.1200/JCO.2019.37.4_suppl.2 link to abstract] -->
-#'''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. [https://doi.org/10.1200/jco.20.01888 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33026938 PubMed] NCT02564263
+#'''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. [https://doi.org/10.1200/jco.20.01888 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33026938/ PubMed] [https://clinicaltrials.gov/study/NCT02564263 NCT02564263]
+#'''INTEGRATE IIb:''' [https://clinicaltrials.gov/study/NCT04879368 NCT04879368]
 ==S-1 monotherapy {{#subobject:387c51|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:cdff15|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 2,664: / Line 2,276: @@
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ Huang et al. 2019 (ESWN 01)]
 |2014-2016
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#IRIS|IRIS]]
 | style="background-color:#d73027" |Inferior PFS
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
-**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
+**Between 1.25 m<sup>2</sup> and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
-**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
+**1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14
 '''21-day cycles'''
+</div></div>
 ===References===
+#'''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. [https://cancercommun.biomedcentral.com/articles/10.1186/s40880-019-0359-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30940189/ PubMed] [https://clinicaltrials.gov/study/NCT02319187 NCT02319187]
-#'''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. [https://cancercommun.biomedcentral.com/articles/10.1186/s40880-019-0359-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30940189 PubMed] NCT02319187
 [[Category:Esophageal cancer regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Gastroesophageal cancers]]

Difference between revisions of "Esophageal cancer"

Latest revision as of 19:32, 23 June 2024

Guidelines

ASCO

ESMO

NCCN

Neoadjuvant induction therapy

Capecitabine & Cisplatin (CX)

Regimen

Eligibility criteria

Chemotherapy

Subsequent treatment

References

Cisplatin & Docetaxel (DC)

Regimen

Chemotherapy

Subsequent treatment

References

Cisplatin & Fluorouracil (CF)

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

Chemotherapy

Subsequent treatment

Regimen variant #2, 100/5000

Chemotherapy

Subsequent treatment

References

Cisplatin & Irinotecan (IC)

Regimen

Chemotherapy

Supportive therapy

Subsequent treatment

References

EOF

Regimen

Chemotherapy

Supportive therapy

References

EOX

Regimen

Chemotherapy

Supportive therapy

References

FLEP

Regimen

Chemotherapy

Subsequent treatment

References

PCF

Regimen

Chemotherapy

Subsequent treatment

References

Neoadjuvant chemoradiotherapy

Capecitabine, Carboplatin, Paclitaxel, RT

Regimen

Chemotherapy

Radiotherapy

Subsequent treatment

References

Capecitabine, Cisplatin, RT

Regimen

Preceding treatment

Chemotherapy

Radiotherapy

References

Capecitabine, Docetaxel, RT

Regimen

Chemotherapy

Radiotherapy

References

Capecitabine, Docetaxel, Oxaliplatin, RT

Regimen

Chemotherapy

Supportive therapy

Radiotherapy

Subsequent treatment

References

Capecitabine, Oxaliplatin, RT

Regimen

Chemotherapy