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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: @@
-'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
+<span id="BackToTop"></span>
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
+[[#top|Back to Top]]
+</div>
-'''Please be aware that some regimens listed here are studies for gastric cancer, not esophageal cancer.'''  These regimens were listed as options by the NCCN, Esophageal Cancer version 2.2011, and their inclusion here reflects the overlap between treatments of esophageal and gastric cancer.
+{{#lst:Editorial board transclusions|gi}}
+''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>
+<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]]'''
+**'''[[Esophageal squamous cell carcinoma]]'''
+*'''Biomarker-specific:'''
+**'''[[Gastric_cancer,_HER2-positive|'''HER2 positive gastroesophageal cancer''']]
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
-|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
+|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
-<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
+<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 |}
 {{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]==
+*'''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]
+**'''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]
-=Neoadjuvant chemoradiation=
+==[https://www.esmo.org/ ESMO]==
-==Capecitabine, Carboplatin, Paclitaxel, RT {{#subobject:79bb5a|Regimen=1}}==
+*'''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]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+**'''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]
-|[[#toc|back to top]]
+**'''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]
-===Regimen {{#subobject:f22688|Variant=1}}===
+**'''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]
-Level of Evidence:
+**'''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]
-<span
+*'''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]
-style="background:#ff0000;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Pilot, <20 patients reported</span>
-''The primary reference did not specify whether patients were intended to proceed to surgery.''
+==NCCN==
-*[[Carboplatin (Paraplatin)]] AUC 1.5 IV on days 2, 9, 16, 23, 30
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433 NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers]
-*[[Paclitaxel (Taxol)]] 45 mg/m2 IV over 1 hour on days 2, 9, 16, 23, 30
-*[[Capecitabine (Xeloda)]] 600 mg/m2 PO BID, starting on day 1 and finishing the evening of the last day of radiation therapy
-*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy, starting on day 1
-'''6-week course'''
+*'''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]
-===References===
+=Neoadjuvant induction therapy=
-# 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.sciencedirect.com/science/article/pii/S0360301606033621 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17197129 PubMed]
+==Capecitabine & Cisplatin (CX) {{#subobject:ce2bbb|Regimen=1}}==
+CX: '''<u>C</u>'''isplatin & '''<u>X</u>'''eloda (Capecitabine)
-==Capecitabine, Cisplatin, RT {{#subobject:ae7180|Regimen=1}}==
+<br>XP: '''<u>X</u>'''eloda (Capecitabine) & '''<u>P</u>'''latinol (Cisplatin)
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1dd767|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
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:eccd56|Variant=1}}===
+''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.''
-''Note: This is listed as a neoadjuvant regimen by the NCCN, Esophageal Cancer version 2.2011, but the 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.''
+<div class="toccolours" style="background-color:#fdcdac">
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV over 1 hour on day 1; given before the first dose of capecitabine
+====Eligibility criteria====
-*[[Capecitabine (Xeloda)]] 800 mg/m2 PO BID, 5 days per week while radiation is being given
+*Stage IV disease
-*Concurrent radiation therapy, total of 54 Gy given (dose per fraction and total duration of treatment was not specified)
+</div>
+<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)'''
+</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]]
+</div></div>
 ===References===
-# 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 [http://www.ncbi.nlm.nih.gov/pubmed/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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17951334/ PubMed]
+==Cisplatin & Docetaxel (DC) {{#subobject:eed8f6|Regimen=1}}==
-==Capecitabine, Docetaxel, RT {{#subobject:ff7031|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:523945|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/10.1093/annonc/mdp045 Ruhstaller et al. 2009 (SAKK 75/02)]
+|2003-07 to 2006-06
+| style="background-color:#91cf61" |Phase 2
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1093/annonc/mdy105 Ruhstaller et al. 2018 (SAKK 75/08)]
-|}
+|2010-2013
-===Regimen {{#subobject:d49e8|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-''Note: Neither of the references cited for this regimen by the NCCN, Esophageal Cancer version 2.2011, actually contained this regimen.  No primary reference could be found for this regimen.''
+|[[#Cisplatin_.26_Docetaxel_.28DC.29_.26_Cetuximab_999|DC & Cetuximab]]
-*[[Docetaxel (Taxotere)]] 20 mg/m2 IV on days 1, 8, 15, 22, 29
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-*[[Capecitabine (Xeloda)]] 625-825 mg/m2 PO BID on days 1 to 5, 8-12, 15-19, 22-26, 29-33
-*Concurrent radiation therapy not defined
-'''5-week course'''
-==Capecitabine, Docetaxel, Oxaliplatin, RT {{#subobject:312400|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:e65189|Variant=1}}===
+''Note: SAKK 75/02 patients had 55% adenocarcinoma, 45% squamous cell histology''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
-padding:3px 6px 3px 6px;
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
-border-color:black;
+'''21-day cycle for 2 cycles'''
-border-width:2px;
+</div>
-border-style:solid;">Phase II</span>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID on days 1 to 7, 15 to 21, 29 to 35
+*Neoadjuvant [[#Cisplatin.2C_Docetaxel.2C_RT|cisplatin, docetaxel, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]
-*[[Docetaxel (Taxotere)]] 20 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29
+</div></div>
-*[[Oxaliplatin (Eloxatin)]] 40 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy.  Patients who were no longer surgical candidates received additional radiation therapy to a total dose of 64.8 Gy.
-*Endoscopy, CT scan, and--if available--endoscopic ultrasound for restaging 2 to 4 weeks after finishing chemoradiation
-*Surgical resection for appropriate candidates during weeks 9 to 12
-'''5-week course of therapy'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 4 mg PO every 12 hours before, at the time of, and after docetaxel; first dose the evening before docetaxel
-*"Routine antiemetics"
 ===References===
-# 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. [http://jco.ascopubs.org/content/28/13/2213.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20351330 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 dosing details in manuscript''' [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]
-==Capecitabine, Oxaliplatin, RT {{#subobject:e958eb|Regimen=1}}==
+==Cisplatin & Fluorouracil (CF) {{#subobject:37e6ba|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+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%"|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(02)08651-8 Girling et al. 2002 (UK MRC OE02)]
+|1992-1998
+| 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<sup>1</sup> (primary endpoint)<br>OS60: 23% vs 17.1%<br>(HR 0.84, 95% CI 0.72-0.98)
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:69d2ce|Variant=1}}===
+''<sup>1</sup>Reported efficacy for UK MRC OE02 is based on the 2009 update.''
-*[[Capecitabine (Xeloda)]] 625 mg/m2 PO BID on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV on days 1, 15, 29
+====Chemotherapy====
-*Concurrent radiation therapy, total dose of 50.4 Gy
+*[[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>)
-'''5-week course'''
+'''21-day cycle for 2 cycles'''
+</div>
-===References===
+<div class="toccolours" style="background-color:#cbd5e7">
-# 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. [http://informahealthcare.com/doi/abs/10.1080/07357900802172093 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19235592 PubMed]
+====Subsequent treatment====
+*[[Surgery#Esophageal_cancer_surgery|Surgery]]
-==Capecitabine, Paclitaxel, RT {{#subobject:17bbec|Regimen=1}}==
+</div></div><br>
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<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%"|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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]
-|}
+|1990-1995
-===Regimen {{#subobject:c6f9f5|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-''Note: Neither of the references cited for this regimen by the NCCN, Esophageal Cancer version 2.2011, actually contained this regimen.  No primary reference could be found for this regimen.''
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-*[[Capecitabine (Xeloda)]] 625 to 825 mg/m2 PO BID on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-*[[Paclitaxel (Taxol)]] 45 to 50 mg/m2 IV on days 1, 8, 15, 22, 29
-*Concurrent radiation therapy not defined
-'''5-week course'''
-==Carboplatin, Fluorouracil, RT {{#subobject:d29415|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:1c21a7|Variant=1}}===
+''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.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1
-padding:3px 6px 3px 6px;
+*[[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)
-border-color:black;
+'''28-day cycle for 3 cycles'''
-border-width:2px;
+</div>
-border-style:solid;">Non-randomized</span>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-*[[Carboplatin (Paraplatin)]] AUC 6 IV once per day on days 1 & 22
+*[[Surgery#Esophageal_cancer_surgery|Surgery]], then adjuvant [[#Cisplatin_.26_Fluorouracil_.28CF.29_3|CF]]
-*[[Fluorouracil (5-FU)]] 200 mg/m2/day IV continuous infusion on days 1 to 42
+</div></div>
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, starting on day 1, for a total dose of 45 Gy.  If surgery was contraindicated, total dose was increased to 50.4-56.8 Gy.
-*Upper endoscopy and CT chest and abdomen was performed after completion of chemoradiation
-'''42-day course'''
-''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. [http://onlinelibrary.wiley.com/doi/10.1111/j.1442-2050.2009.00984.x/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19515190 PubMed]
+#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://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]
-==Carboplatin, Paclitaxel, RT {{#subobject:93878b|Regimen=1}}==
+==Cisplatin & Irinotecan (IC) {{#subobject:500b44|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+IC: '''<u>I</u>'''rinotecan & '''<u>C</u>'''isplatin
+<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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1002/cncr.26591 Ilson et al. 2011]
-|}
+|2002-12 to 2005-10
-===Regimen {{#subobject:33b67a|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286 van Meerten et al. 2006]
-|<span
-style="background:#eeee00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-|
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1112088 van Hagen et al. 2012 (CROSS)]
-|<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Surgery_alone|Surgery alone]]
 |-
 |}
+''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">
+====Chemotherapy====
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
+*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> 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|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]]
+</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]
+==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===
-*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, 22, 29; '''given second'''
+==EOX {{#subobject:891a3e|Regimen=1}}==
-*[[Paclitaxel (Taxol)]] 50 mg/m2 IV over 1 hour once per day on days 1, 8, 15, 22, 29; '''given first'''
+EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)
-*Concurrent radiation therapy, 1.8 Gy fractions x 23 fractions given 5 days per week, starting on day 1, for a total dose of 41.4 Gy
+<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
+<div class="toccolours" style="background-color:#eeeeee">
-Supportive medications:
+===Regimen {{#subobject:6941e|Variant=1}}===
-*[[Dexamethasone (Decadron)]] 10 mg IV 30 minutes prior to paclitaxel
+''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.''
-*[[Ranitidine (Zantac)]] 50 mg IV 30 minutes prior to paclitaxel
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Clemastine (Tagevil)]] 2 mg IV 30 minutes prior to paclitaxel
+====Chemotherapy====
-*Between paclitaxel & carboplatin: 100 mL NS given over 30 minutes, then [[Ondansetron (Zofran)]] 8 mg in 100 mL NS given over 30 minutes
+*[[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
-'''5-week course'''
+*[[Capecitabine (Xeloda)]] 500 to 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
+====Supportive therapy====
-''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.''
+*[[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
+'''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===
-# 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. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286 link to PMC article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16670722 PubMed]
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1112088 link to original article] '''contains verified protocol''' [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1112088/suppl_file/nejmoa1112088_appendix.pdf link to appendix with details about administration] [http://www.ncbi.nlm.nih.gov/pubmed/22646630 PubMed]
-==Cisplatin & Docetaxel -> Cisplatin, Docetaxel, RT {{#subobject:4231cb|Regimen=1}}==
+==FLEP {{#subobject:78eabc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+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
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:6c3cc6|Variant=1}}===
+''Note: For historic reference.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 3
-padding:3px 6px 3px 6px;
+*[[Leucovorin (Folinic acid)]] 300 mg/m<sup>2</sup> IV once per day on days 1 to 3
-border-color:black;
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3
-border-width:2px;
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
-border-style:solid;">Phase II</span>
+'''21-day cycle for 3 cycles'''
+</div>
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV once on day 1
+<div class="toccolours" style="background-color:#cbd5e7">
-*[[Docetaxel (Taxotere)]] 75 mg/m2 IV once on day 1
+====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)
-'''21-day cycles x 2 cycles, followed by:'''
+</div></div>
-*[[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
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, starting on day 1, for a total dose of 45 Gy.
-*Surgery planned to be done 3-8 weeks after finishing chemoradiation
-'''5-week course'''
 ===References===
-# 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 (SAKK). 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. [http://annonc.oxfordjournals.org/content/20/9/1522.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19465425 PubMed]
+#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}}==
-==Cisplatin, Fluorouracil, RT {{#subobject:17919|Regimen=1}}==
+PCF: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:2d319e|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/10.1097/JTO.0000000000000612 Zhao et al. 2015 (ZY-01)]
+|2005-2007
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1 {{#subobject:45f8a2|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| border="1" style="text-align:center;" !align="left"
+====Chemotherapy====
-|'''Study'''
+*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once on day 1
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 2
-|'''Comparator'''
+*[[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>)
+'''2 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Esophageal_cancer_surgery|Surgery]], then adjuvant [[#PCF_999|PCF]] x 2 versus [[Esophageal_cancer_-_null_regimens#Observation|no further treatment]]
+</div></div>
+===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. [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=
+''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}}==
+Capecitabine, Carboplatin, Paclitaxel, RT: Capecitabine, Carboplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<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]]
 |-
-|[http://jco.ascopubs.org/content/26/7/1086.long Tepper et al. 2008 (CALGB 9781)]
+|[https://doi.org/10.1016/j.ijrobp.2006.10.027 Czito et al. 2006]
-|<span
+|2003-07 to 2005-07
-style="background:#00CD00;
+| style="background-color:#ffffbe" |Pilot, fewer than 20 pts
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Surgery_alone|Surgery alone]]
 |-
 |}
+''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.''
-*[[Cisplatin (Platinol)]] 100 mg/m2 IV over 30 minutes once per day on days 1 & 29; '''given first'''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Fluorouracil (5-FU)]] 1000 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4, 29 to 32; '''given after cisplatin''' (total dose 8000 mg/m2)
+====Chemotherapy====
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, then a 5.4 Gy final boost, for a total dose of 50.4 Gy, starting within 24 hours of chemotherapy
+*[[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
-'''5.5-week course'''
+*[[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====
-''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.''
+*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 180 cGy fractions x 28 fractions, for a total dose of 5040 cGy
+'''6-week course'''
-===Regimen #2 {{#subobject:a49842|Variant=1}}===
+</div>
-{| border="1" style="text-align:center;" !align="left"
+<div class="toccolours" style="background-color:#cbd5e7">
-|'''Study'''
+====Subsequent treatment====
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+*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
-|'''Comparator'''
+</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://jco.ascopubs.org/content/25/10/1160.long Bedenne et al. 2007 (FFCD 9102)]
+|[http://jjco.oxfordjournals.org/content/37/11/829.long Lee et al. 2007<sub>esoph</sub>]
-|<span
+| style="background-color:#ffffbe" |Retrospective
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Cisplatin.2C_Fluorouracil.2C_RT_2|Cisplatin, Fluorouracil, RT (no surgery)]]
 |-
 |}
+''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">
-''Study did not show a benefit of surgery after 2 cycles of chemoradiation as compared to additional chemoradiation.''
+====Chemotherapy====
-*[[Cisplatin (Platinol)]] 15 mg/m2 IV over 1 hour 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/m2/day IV continuous infusion over 120 hours on days 1 to 5 (total dose 4000 mg/m2)
+*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5, '''given second'''
-*Conventional radiation therapy, 2 Gy fractions x 23 fractions given 5 days per week, for a total dose of 46 Gy
+'''7-day cycles until radiation therapy is complete'''
-**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.
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 5400 cGy given (dose per fraction and total duration of treatment was not specified)
-Supportive hydration:
+'''One course'''
-*1 liter NS IV over 2 hours before and after cisplatin
+</div></div>
-'''21-day cycle x 2 cycles'''
-''Surgery to be done 50 to 60 days after start of chemoradiation.''
 ===References===
-# 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. [http://jco.ascopubs.org/content/25/10/1160.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17401004 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 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]
-# 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. [http://jco.ascopubs.org/content/26/7/1086.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18309943 PubMed]
-==Cisplatin & Fluorouracil -> Fluorouracil, Paclitaxel, RT {{#subobject:52e768|Regimen=1}}==
+==Capecitabine, Docetaxel, RT {{#subobject:ff7031|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+Capecitabine, Docetaxel, RT: Capecitabine, Docetaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:d49e8|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/PMC3600150/ Wood et al. 2013 (D-9939)]
+|NR
+| style="background-color:#ffffbe" |Phase 1
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:f8576f|Variant=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.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Docetaxel (Taxotere)]] 15 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-padding:3px 6px 3px 6px;
+*[[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'''
-border-color:black;
+====Radiotherapy====
-border-width:2px;
+*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)
-border-style:solid;">Phase II</span>
-*[[Cisplatin (Platinol)]] 20 mg/m2 IV once per day on days 1 & 5
-*[[Fluorouracil (5-FU)]] 200 mg/m2/day IV continous infusion on days 1 to 21 (total dose 4200 mg/m2)
-'''28-day cycle x 2 cycles, followed by:'''
-*[[Paclitaxel (Taxol)]] 45 mg/m2 IV once per day on days 1, 8, 15, 22, 29
-*[[Fluorouracil (5-FU)]] 300 mg/m2/day IV continuous infusion on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy
 '''5-week course'''
+</div></div>
 ===References===
-# Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, Greskovich JF, Anne PR, Bradley JD, Willett C, Rich TA. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006 Aug 20;24(24):3953-8. [http://jco.ascopubs.org/content/24/24/3953.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16921048 PubMed]
+#'''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}}==
-==Cisplatin & Irinotecan -> Cisplatin, Irinotecan, RT {{#subobject:500b44|Regimen=1}}==
+Capecitabine, Docetaxel, Oxaliplatin, RT: Capecitabine, Docetaxel, Oxaliplatin, '''<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: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.2009.24.8773 Spigel et al. 2010 (SCRI GI 57)]
+|2005-2008
+| style="background-color:#91cf61" |Phase 1/2
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Ilson et al. 2011 {{#subobject:927613|Variant=1}}===
+''Note: Patients had 69% adenocarcinoma, 18% squamous cell, 12% not otherwise specified. 69% distal esophagus, 16% midesophagus, 14% gastroesophageal junction.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 7, 15 to 21, 29 to 35
-padding:3px 6px 3px 6px;
+*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29
-border-color:black;
+*[[Oxaliplatin (Eloxatin)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29
-border-width:2px;
+====Supportive therapy====
-border-style:solid;">Phase II</span>
+*[[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]]"
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV over 30 minutes once per day on days 1 & 8; '''given before irinotecan'''
+====Radiotherapy====
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV over 30 minutes once per day on days 1 & 8; '''given after cisplatin'''
+*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)
-'''21-day cycle x 2 cycles, followed by:'''
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV over 30 minutes once per day on days 1 & 8; '''given before irinotecan'''
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV over 30 minutes once per day on days 1 & 8; '''given after cisplatin'''
-*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total of 50.4 Gy given
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 20 mg PO/IV prior to chemotherapy
-*[[Granisetron (Kytril)]] 2 mg PO or [[Ondansetron (Zofran)]] 32 mg IV prior to chemotherapy
-*At least 500 mL D5NS or NS as supportive hydration
-*Atropine 0.5 to 1 mg IV prn cholinergic symptoms
-'''21-day cycle x 2 cycles'''
-''Surgery performed 4 to 8 weeks after chemoradiation.''
-===Regimen #2, Rivera et al. 2009 {{#subobject:1a3475|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV on days 1, 8, 22, 29
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV on days 1, 8, 22, 29
-'''21-day cycles x 2 cycles, THEN'''
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV on days 1, 8, 15, 22
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV on days 1, 8, 15, 22
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.
-*Surgery done 5-8 weeks after finishing chemoradiation
 '''5-week course'''
+</div>
-===Regimen #3, Yoon et al. 2011 {{#subobject:55fb6e|Variant=1}}===
+<div class="toccolours" style="background-color:#cbd5e7">
-''Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011, lists the dosage of preoperative irinotecan as 50 mg/m2.''
+====Subsequent treatment====
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV on days 1, 8, 22, 29
+*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:
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV on days 1, 8, 22, 29
+**SCRI GI 57, surgical candidates: [[Surgery#Esophagectomy|Surgical resection]] sometime during weeks 9 to 12
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.
+**SCRI GI 57, patients who were no longer surgical candidates: Additional radiation therapy to a total dose of 6480 cGy
+</div></div>
-'''5-week course, THEN'''
-*Surgery done at least 28 days after finishing chemoradiation, then begin adjuvant chemotherapy at least 28 days after surgical resection:
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV on days 1 & 8
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV on days 1 & 8
-'''21-day cycles x 3 cycles'''
-===Regimen #4, Sharma et al. 2009 {{#subobject:3a82b6|Variant=1}}===
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV on days 1 & 8
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV on days 1 & 8
-*Concurrent radiation therapy, 1.8 Gy fractions x 25-28 fractions, for a total of 45-50.4 Gy given
-'''21-day cycles x 2 cycles''' (2 cycles per NCCN, Esophageal Cancer version 2.2011; abstract did not specify number of cycles)
 ===References===
-# R. Sharma, G. Y. Yang, H. R. Nava, T. L. Demmy, C. E. Nwogu, S. S. Yendamuri, D. Lamonica, W. Tan, R. V. Iyer, N. I. Khushalani. A single institution experience with neoadjuvant chemoradiation (CRT) with irinotecan (I) and cisplatin (C) in locally advanced esophageal carcinoma (LAEC). 2009 ASCO Annual Meeting abstract e15619. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34782 link to abstract]
+#'''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]
-# [http://clinicaltrials.gov/ct2/show/NCT00033657 Radiation Therapy and Chemotherapy Before and After Surgery in Treating Patients With Esophageal Cancer] (Regimen #2, Rivera et al. 2009, clinicaltrials.gov)
+==Capecitabine, Oxaliplatin, RT {{#subobject:e958eb|Regimen=1}}==
-# Rivera F, Galán M, Tabernero J, Cervantes A, Vega-Villegas ME, Gallego J, Laquente B, Rodríguez E, Carrato A, Escudero P, Massutí B, Alonso-Orduña V, Cardenal A, Sáenz A, Giralt J, Yuste AL, Antón A, Aranda E; Spanish Cooperative Group for Digestive Tumor Therapy. Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric junction adenocarcinoma. Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1430-6. Epub 2009 Jun 18. [http://www.sciencedirect.com/science/article/pii/S0360301609003629 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19540072 PubMed]
+CapeOx & RT: '''<u>Cape</u>'''citabine, '''<u>Ox</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-# 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. doi: 10.1002/cncr.26591. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.26591/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21990000 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-# Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. [http://www.springerlink.com/content/v4g0257025185531/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21286719 PubMed]
+===Regimen {{#subobject:69d2ce|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-==Cisplatin, Paclitaxel, RT {{#subobject:3d8eaa|Regimen=1}}==
+!style="width: 33%"|Study
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1080/07357900802172093 Javle et al. 2009]
+|NR in abstract
+| style="background-color:#ffffbe" |Phase 1b
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Urba et al. 2003 {{#subobject:32166d|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-Level of Evidence:
+====Chemotherapy====
-<span
+*[[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
-style="background:#EEEE00;
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
-padding:3px 6px 3px 6px;
+====Radiotherapy====
-border-color:black;
+*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)
-border-width:2px;
+'''5-week course'''
-border-style:solid;">Phase II</span>
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 2 hours on day 1
+====Subsequent treatment====
-*[[Paclitaxel (Taxol)]] 60 mg/m2 IV over 3 hours on days 1, 8, 15, 22
+*[[Surgery#Esophagectomy|Surgery]]
-*Concurrent radiation therapy, 1.5 Gy fractions given twice per day on days 1 to 5, 8-12, 15-19, with at least 6 hours between fractions, for a total dose of 45 Gy
+</div></div>
-*Barium swallow and CT chest and abdomen done about 1 week prior to surgery to rule out metastatic disease
+===References===
-*Surgery to be done on approximately day 50
+#'''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]
+==Capecitabine, Paclitaxel, RT {{#subobject:17bbec|Regimen=1}}==
-'''4-week course of therapy'''
+Capecitabine, Paclitaxel, RT: Capecitabine, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
-Supportive medications:
+===Regimen {{#subobject:c6f9f5|Variant=1}}===
-*[[Dexamethasone (Decadron)]] 20 mg PO given 12 and 6 hours before paclitaxel
+''Note: No primary reference could be found for this regimen.''
-*[[Diphenhydramine (Benadryl)]] 50 mg IV 30 minutes prior to paclitaxel
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Cimetidine (Tagamet)]] 300 mg IV 30 minutes prior to paclitaxel
+====Chemotherapy====
-*1 liter D5NS and mannitol 12.5 g bolus IV prior to cisplatin
+*[[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
-*Mannitol 25 g in 1 liter D5NS IV over 4 hours after cisplatin
+*[[Paclitaxel (Taxol)]] 45 to 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC daily, starting 24 hours after the fourth dose of paclitaxel, continuing until absolute neutrophil count >10,000
+====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
-===Regimen #2, Yoon et al. 2011 {{#subobject:5a433d|Variant=1}}===
+'''5-week course'''
-Level of Evidence:
+</div></div>
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV on days 1, 8, 15, 22, 29
-*[[Paclitaxel (Taxol)]] 50 mg/m2 IV over 1 hour on days 1, 8, 15, 22, 29
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.
-'''5-week course, THEN'''
-*Surgery done at least 28 days after finishing chemoradiation, then begin adjuvant chemotherapy at least 28 days after surgical resection:
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV on day 1
-*[[Paclitaxel (Taxol)]] 175 mg/m2 IV on day 1
-'''21-day cycles x 3 cycles'''
 ===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. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.11759/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/14601087 PubMed]
+==Carboplatin, Fluorouracil, RT {{#subobject:d29415|Regimen=1}}==
-# [http://clinicaltrials.gov/ct2/show/NCT00033657 Radiation Therapy and Chemotherapy Before and After Surgery in Treating Patients With Esophageal Cancer] (Regimen #2, Yoon et al. 2011, clinicaltrials.gov)
+Carboplatin, Fluorouracil, RT: Carboplatin, Fluorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-# Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. [http://www.springerlink.com/content/v4g0257025185531/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21286719 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1c21a7|Variant=1}}===
-==Docetaxel, Fluorouracil, RT {{#subobject:956374|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/10.1111/j.1442-2050.2009.00984.x Zemanoa et al. 2009]
+|2001-01 to 2005-08
+| style="background-color:#91cf61" |Non-randomized
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Hihara et al. 2007 {{#subobject:c112ab|Variant=1}}===
+''Note: Patients had 86% squamous cell, 8% adenocarcinoma, 6% other histology. 3% ECOG PS of 2.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Docetaxel (Taxotere)]] 7.5 mg/m2 IV over 1 hour once per day on days 1, 8, 22, 29
+====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 250 mg/m2/day IV continuous infusion on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 45
+*[[Carboplatin (Paraplatin)]] AUC 6 IV once per day on days 1 & 22
-*Concurrent radiation therapy, 2 Gy fractions x 30-33 fractions given 5 days per week (i.e. on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 45), for a total dose of 60 to 66 Gy, starting on day 1
+*[[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>)
+====Radiotherapy====
-Supportive medications:
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] by the following criteria:
-*[[Dexamethasone (Decadron)]] 8 mg IV 30 minutes prior to docetaxel
+**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.
-'''7-week course'''
-===Regimen #2 {{#subobject:8dd58b|Variant=1}}===
-''Note: Neither of the references cited for this regimen by the NCCN, Esophageal Cancer version 2.2011, actually contained this regimen.  No primary reference could be found for this regimen.''
-*[[Docetaxel (Taxotere)]] 20 mg/m2 IV on days 1, 8, 15, 22, 29
-*[[Fluorouracil (5-FU)]] 200-300 mg/m2/day IV continuous infusion on days 1 to 5, 8-12, 15-19, 22-26, 29-33
-*Concurrent radiation therapy not defined
 '''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
+*[[Surgery#Esophagectomy|Surgery]] planned to be done 4 to 6 weeks after finishing chemoradiation
+</div></div>
 ===References===
-# 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''' [http://www.ncbi.nlm.nih.gov/pubmed/17695421 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://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]
+==Carboplatin & Paclitaxel (CP) & RT {{#subobject:93878b|Regimen=1}}==
-==Fluorouracil, Oxaliplatin, RT {{#subobject:94b79a|Regimen=1}}==
+CP & RT: '''<u>C</u>'''arboplatin, '''<u>P</u>'''aclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable" style="color:black; background-color:#42f584"
+|<small>'''ESMO-preferred for squamous cell carcinoma (I-A, 2016)'''</small>
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Lorenzen et al. 2008 {{#subobject:bbd435|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-Level of Evidence:
+===Regimen variant #1, 5 weeks of chemotherapy {{#subobject:33b67a|Variant=1}}===
-<span
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-style="background:#EEEE00;
+!style="width: 20%"|Study
-padding:3px 6px 3px 6px;
+!style="width: 20%"|Dates of enrollment
-border-color:black;
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-border-width:2px;
+!style="width: 20%"|Comparator
-border-style:solid;">Phase II</span>
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
-*[[Oxaliplatin (Eloxatin)]] 45 mg/m2 IV over 2 hours on days 1, 8, 15, 22, 29
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286 van Meerten et al. 2006]
-*[[Fluorouracil (5-FU)]] 225 mg/m2/day IV continuous infusion over days 1-33
+|2001-2004
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy
+| style="background-color:#91cf61" |Phase 2
-*Surgery 4-6 weeks after finishing chemoradiation
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
-'''35-day course'''
-===Regimen #2, Khushalani et al. 2002 {{#subobject:ae22de|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-''Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011 lists [[Fluorouracil (5-FU)]] as being given on days 1 to 33.''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV over 2 hours on days 1, 15, 29
-*[[Fluorouracil (5-FU)]] 180 mg/m2/day IV continuous infusion over days 8-42
-*Concurrent radiation therapy, 1.8 Gy fractions x 20-22 fractions, for an initial total dose of 36-39.6 Gy, started on day 8
-**Followed by off-cord conformal oblique fields, 5.4-9 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.
-*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 1-2 cycles of oxaliplatin and 5-FU within 2 weeks.
-'''6-week cycle x 1 initial cycle (see above)'''
-===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. [http://jco.ascopubs.org/content/20/12/2844.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12065561 PubMed]
-# Lorenzen S, Brücher B, Zimmermann F, Geinitz H, Riera J, Schuster T, Roethling N, Höfler H, Ott K, Peschel C, Siewert JR, Molls M, Lordick F. Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial. Br J Cancer. 2008 Oct 7;99(7):1020-6. Epub 2008 Sep 16. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567089 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18797462 PubMed]
-=Perioperative chemotherapy=
-==ECF {{#subobject:87a09a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1056/NEJMoa1112088 van Hagen et al. 2012 (CROSS)]
-|}
+|2004-2008
-ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-===Regimen, Sumpter et al. 2005 & Cunningham et al. 2006 (MAGIC) {{#subobject:d40982|Variant=1}}===
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-Level of Evidence:
+| 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)
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV bolus once on day 1
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV once on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m2/day IV continuous infusion on days 1 to 21
-'''21-day cycles x 3 cycles preoperatively, with surgery 3 to 6 weeks after completing cycle 3. The 3 cycles of postoperative chemotherapy are started 6 to 12 weeks after surgery.'''
-Supportive medications:
-*[[Warfarin (Coumadin)]] 1 mg PO once per day recommended for thrombosis prophylaxis
-===References===
-# Sumpter K, Harper-Wynne C, Cunningham D, Rao S, Tebbutt N, Norman AR, Ward C, Iveson T, Nicolson M, Hickish T, Hill M, Oates J. Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer. 2005 Jun 6;92(11):1976-83. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361798 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15928658 PubMed]
-# Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [http://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]
-==ECX {{#subobject:c8ab0e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda
+''<sup>1</sup>Reported efficacy for CROSS is based on the 2021 update.''<br>
-===Regimen {{#subobject:27f848|Variant=1}}===
+''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.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#00CD00;
+*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, 22, 29, '''given second'''
-padding:3px 6px 3px 6px;
+*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29 '''given first'''
-border-color:black;
+====Supportive therapy====
-border-width:2px;
+*[[Dexamethasone (Decadron)]] 10 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to paclitaxel
-border-style:solid;">Phase III</span>
+*[[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
-''Note: This regimen is listed as a perioperative option by the NCCN, Esophageal Cancer version 2.2011, but it is not clearly described as one by the primary reference.  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.  No follow-up report for this trial or its additional participants could be found.''
+*100 mL [[Normal saline|NS]] given over 30 minutes once per day on days 1, 8, 15, 22, 29, between paclitaxel & carboplatin
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV bolus on day 1
+*[[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
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV on day 1
+====Radiotherapy====
-*[[Capecitabine (Xeloda)]] 500-625 mg/m2 PO BID on days 1 to 21
+*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)
+'''5-week course'''
-'''21-day cycles x up to 8 cycles; for perioperative use per NCCN, 3 cycles preoperatively and 3 cycles postoperatively would be used'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
-Supportive medications:
+====Subsequent treatment====
-*[[Dexamethasone (Decadron)]] 8 mg IV prior to day 1 chemotherapy and 4 mg PO TID x 2 days thereafter
+*[[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
-*"5HT3 antagonist" prior to chemotherapy
+</div></div><br>
-*Metoclopramide (Reglan) 10 mg PO TID x 3 days after day 1 chemotherapy
+<div class="toccolours" style="background-color:#eeeeee">
-*"Standard hydration" for cisplatin
-*[[Warfarin (Coumadin)]] 1 mg PO daily as thrombosis prophylaxis, started on day -1
-===References===
-# Sumpter K, Harper-Wynne C, Cunningham D, Rao S, Tebbutt N, Norman AR, Ward C, Iveson T, Nicolson M, Hickish T, Hill M, Oates J. Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer. 2005 Jun 6;92(11):1976-83. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361798 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15928658 PubMed]
-==EOF {{#subobject:ae4e32|Regimen=1}}==
+===Regimen variant #2, 6 weeks of chemotherapy {{#subobject:ug717a|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| 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]]
 |-
-|[[#toc|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903071/ Safran et al. 2022 (RTOG 1010)]
-|}
+|2010-2015
-EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
+| style="background-color:#1a9851" |Phase 3 (C)
-===Regimen {{#subobject:e532ea|Variant=1}}===
+|[[#Carboplatin.2C_Paclitaxel.2C_Trastuzumab.2C_RT_999|CP, Trastuzumab, RT]]
-Level of Evidence:
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-''Note: This regimen is listed as a perioperative option by the NCCN, Esophageal Cancer version 2.2011, but it is not clearly described as one by the primary reference.  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.  No follow-up report for this trial or its additional participants could be found.''
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV bolus on day 1
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m2 IV over 2 hours on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m2/day IV continuous infusion on days 1 to 21
-'''21-day cycles x up to 8 cycles; for perioperative use per NCCN, 3 cycles preoperatively and 3 cycles postoperatively would be used'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 8 mg IV prior to day 1 chemotherapy and 4 mg PO TID x 2 days thereafter
-*"5HT3 antagonist" prior to chemotherapy
-*Metoclopramide (Reglan) 10 mg PO TID x 3 days after day 1 chemotherapy
-*[[Warfarin (Coumadin)]] 1 mg PO daily as thrombosis prophylaxis, started on day -1
-===References===
-# Sumpter K, Harper-Wynne C, Cunningham D, Rao S, Tebbutt N, Norman AR, Ward C, Iveson T, Nicolson M, Hickish T, Hill M, Oates J. Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer. 2005 Jun 6;92(11):1976-83. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361798 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15928658 PubMed]
-==EOX {{#subobject:891a3e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda
+<div class="toccolours" style="background-color:#fdcdac">
-===Regimen {{#subobject:6941e|Variant=1}}===
+====Biomarker eligibility criteria====
-Level of Evidence:
+*HER2+
-<span
+</div>
-style="background:#00CD00;
+<div class="toccolours" style="background-color:#b3e2cd">
-padding:3px 6px 3px 6px;
+====Chemotherapy====
-border-color:black;
+*[[Carboplatin (Paraplatin)]] AUC 2 IV over 30 to 60 minutes once per day on days 1, 8, 15, 22, 29, 36
-border-width:2px;
+*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36
-border-style:solid;">Phase III</span>
+====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)
-''Note: This regimen is listed as a perioperative option by the NCCN, Esophageal Cancer version 2.2011, but it is not clearly described as one by the primary reference.  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.  No follow-up report for this trial or its additional participants could be found.''
+'''6-week course'''
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV bolus on day 1
+</div></div>
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m2 IV over 2 hours on day 1
-*[[Capecitabine (Xeloda)]] 500-625 mg/m2 PO BID on days 1 to 21
-'''21-day cycles x up to 8 cycles; for perioperative use per NCCN, 3 cycles preoperatively and 3 cycles postoperatively would be used'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 8 mg IV prior to day 1 chemotherapy and 4 mg PO TID x 2 days thereafter
-*"5HT3 antagonist" prior to chemotherapy
-*Metoclopramide (Reglan) 10 mg PO TID x 3 days after day 1 chemotherapy
-*[[Warfarin (Coumadin)]] 1 mg PO daily as thrombosis prophylaxis, started on day -1
 ===References===
-# Sumpter K, Harper-Wynne C, Cunningham D, Rao S, Tebbutt N, Norman AR, Ward C, Iveson T, Nicolson M, Hickish T, Hill M, Oates J. Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer. 2005 Jun 6;92(11):1976-83. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361798 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15928658 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://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
-=Adjuvant chemoradiation=
+##'''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]
-==Fluorouracil (5-FU), Folinic acid (Leucovorin), RT {{#subobject:f6b345|Regimen=1}}==
+##'''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]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+#'''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%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1093/annonc/mdp045 Ruhstaller et al. 2009 (SAKK 75/02)]
-|}
+|2003-07 to 2006-06
-===Regimen #1, Macdonald et al. 2001 {{#subobject:5cd826|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-Cycles 1, 3, 4:
-*[[Fluorouracil (5-FU)]] 425 mg/m2 IV bolus on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 20 mg/m2 IV bolus on days 1 to 5
-'''28-day cycles x 3 total cycles, interrupted by cycle 2 as described below'''
-Cycle 2:
-*[[Fluorouracil (5-FU)]] 400mg/m2 IV bolus on days 1 to 4 and the last 3 days of radiation therapy
-*[[Folinic acid (Leucovorin)]] 20 mg/m2 IV bolus on days 1 to 4 and the last 3 days of radiation therapy
-*Concurrent radiation therapy starting cycle 2 day 1 with 180 cGy, 5 days per week; 25 fractions given over 5 weeks for a total of 4500 cGy
-'''35-day cycle x 1 cycle, to be followed by cycle 3 as described above'''
-===Regimen #2 {{#subobject:c3cc1c|Variant=1}}===
-''Note: This regimen was listed by the NCCN, Esophageal Cancer version 2.2011, but the reference cited, [http://jco.ascopubs.org/content/25/24/3732.long André T et al. 2007] ([http://www.ncbi.nlm.nih.gov/pubmed/17704423 PubMed]), was for colon cancer, did not include radiation, and did not match this regimen.  No primary reference could be found for this regimen.''
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus on EITHER days 1 & 15 OR days 1, 2, 15, 16
-*[[Fluorouracil (5-FU)]] 1200 mg/m2 IV continuous infusion on days 1, 2, 15, 16
-*[[Folinic acid (Leucovorin)]] 400 mg/m2 IV on EITHER days 1 & 15 OR days 1, 2, 15, 16
-'''28-day cycles x 3 total cycles (1 cycle given before radiation, and 2 cycles to be given after radiation)'''
-===References===
-# Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [http://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11547741 PubMed]
-==FP -> Capecitabine (Xeloda) & RT -> FP {{#subobject:778727|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol
+''Note: Patients had 55% adenocarcinoma, 45% squamous cell histology''
-===Regimen {{#subobject:20ea7f|Variant=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
-Level of Evidence:
+====Preceding treatment====
-<span
+*Induction [[#Cisplatin_.26_Docetaxel_.28DC.29|Cisplatin & Docetaxel]] x 2
-style="background:#EEEE00;
+</div>
-padding:3px 6px 3px 6px;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-color:black;
+====Chemotherapy====
-border-width:2px;
+*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-border-style:solid;">Phase II</span>
+*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Radiotherapy====
-''Note: In contrast to the primary reference, the NCCN, Esophageal Cancer version 2.2011 listed this regimen without FP cycles 1, 3, 4, 5.  Dosage of [[Capecitabine (Xeloda)]] was listed as 625-825 mg/m2 PO BID on days 1 to 5 or 1-7 while radiation is being given.''
+*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)
-''FP starts 3 weeks after surgery.''  Cycles 1, 3, 4, 5:
+'''5-week course'''
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV on day 1
+</div>
-*[[Fluorouracil (5-FU)]] 1000 mg/m2/day IV continuous infusion on days 1 to 5
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-'''21-day cycles x 4 total cycles (1 cycle prior to radiation and 3 cycles after chemoradiation, with cycle 2 starting 4 weeks after radiation is finished)'''
+*[[Surgery#Esophagectomy|Surgery]], 3 to 8 weeks after finishing chemoradiation
+</div></div>
-Cycle 2, chemoradiation:
-*[[Capecitabine (Xeloda)]] 825 mg/m2 (1650 mg/m2/day) PO every 12 hours
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy
-'''5-week course, to begin immediately after cycle 1'''
 ===References===
-# Lee HS, Choi Y, Hur WJ, Kim HJ, Kwon HC, Kim SH, Kim JS, Lee JH, Jung GJ, Kim MC. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006 Jan 28;12(4):603-7. [http://www.wjgnet.com/1007-9327/full/v12/i4/603.htm link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16489675 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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19465425/ PubMed]
+==Cisplatin & Fluorouracil (CF) & RT {{#subobject:17919|Regimen=1}}==
-==ECF -> 5-FU & RT -> ECF {{#subobject:7f3e93|Regimen=1}}==
+CF & RT: '''C'''isplatin, '''<u>F</u>'''luourouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===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%"|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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1200/JCO.2013.53.6532 Mariette et al. 2014 (FFCD 9901)]
-|}
+|2000-2009
-ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-===Regimen {{#subobject:53c380|Variant=1}}===
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-Level of Evidence:
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-''Note: In contrast to the primary reference, the NCCN, Esophageal Cancer version 2.2011 listed this regimen without ECF cycles 1, 3, 4.  Dosage of [[Fluorouracil (5-FU)]] was listed as 200-250 mg/m2/day IV continuous infusion on days 1 to 5 or 1-7 while radiation is being given.''
-Cycles 1, 3, 4:
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV bolus on day 1
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m2/day IV continuous infusion on days 1 to 21
-'''21-day cycles x 3 total cycles (1 cycle prior to radiation and 2 cycles after radiation, with cycle 2 starting 1 month after radiation is finished)
-Cycle 2, chemoradiation:
-*[[Fluorouracil (5-FU)]] 225 mg/m2/day IV continuous infusion on days 1 to 35
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week for a total dose of 45 Gy, starting on day 1
-'''5-week course, to begin immediately after cycle 1, to be followed by cycles 3-5 as described above'''
-===References===
-# Leong T, Joon DL, Willis D, Jayamoham J, Spry N, Harvey J, Di Iulio J, Milner A, Mann GB, Michael M. Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin, and 5-fluorouracil before and after three-dimensional conformal radiotherapy with concurrent infusional 5-fluorouracil: a multicenter study of the Trans-Tasman Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2011 Mar 1;79(3):690-5. Epub 2010 May 14. [http://www.sciencedirect.com/science/article/pii/S036030160903613X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20472363 PubMed]
-=Definitive chemoradiation (no surgery)=
-==Capecitabine & Cisplatin -> Capecitabine, Cisplatin, RT {{#subobject:ce2bbb|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:f7a6c1|Variant=1}}===
+''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.''
-''The study was for patients with stage IV disease.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*Patients with M1b disease (visceral metastases) received the chemotherapy only part until  progression of disease or unacceptable toxicity.
+====Chemotherapy====
-*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.
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once per day on either day 1 or 2 & 29
+*[[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>)
-Chemotherapy only part:
+====Radiotherapy====
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV over 1 hour on day 1; given before the first dose of capecitabine
+*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)
-*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID on days 1 to 14
+'''5-week course'''
+</div>
-'''21-day cycles'''
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-Chemoradiation part:
+*[[Surgery#Esophagectomy|Surgery]]
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV over 1 hour on day 1; given before the first dose of capecitabine
+</div></div><br>
-*[[Capecitabine (Xeloda)]] 800 mg/m2 PO BID, 5 days per week while radiation is being given
+<div class="toccolours" style="background-color:#eeeeee">
-*Concurrent radiation therapy, total of 54 Gy given.  Dose per fraction and total duration of treatment were not specified, but based on other regimens, it is suspected to be either 1.8 Gy x 30 fractions or 2 Gy x 27 fractions.
+===Regimen variant #2, 75/4000 x 2 {{#subobject:a49842|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-'''1-week cycles until radiation therapy is complete'''
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
-===References===
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-# 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''' [http://www.ncbi.nlm.nih.gov/pubmed/17951334 PubMed]
-==Capecitabine, Docetaxel, RT {{#subobject:9fbb10|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1200/jco.2005.04.7118 Bedenne et al. 2007 (FFCD 9102)]
-|}
+|1993-2000
-See [[#Docetaxel_.28Taxotere.29_.26_Capecitabine_.28Xeloda.29|Docetaxel (Taxotere) & Capecitabine (Xeloda)]].
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-==Capecitabine, Docetaxel, Oxaliplatin, RT {{#subobject:6c2946|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-See [[#Oxaliplatin_.28Eloxatin.29.2C_Docetaxel_.28Taxotere.29.2C_Capecitabine_.28Xeloda.29|Oxaliplatin (Eloxatin), Docetaxel (Taxotere), Capecitabine (Xeloda)]].
+''Note: Patients had 89% epidermoid, 11% glandular histology.''
+<div class="toccolours" style="background-color:#b3e2cd">
-==Capecitabine, Oxaliplatin, RT {{#subobject:22577b|Regimen=1}}==
+====Chemotherapy====
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, 22 to 26
+*[[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>)
+====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)
+**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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====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
+</div></div><br>
+<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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1016/S1470-2045(05)70288-6 Burmeister et al. 2005]
-|}
+|1994-2000
-See [[#Oxaliplatin_.28Eloxatin.29_.26_Capecitabine_.28Xeloda.29|Oxaliplatin (Eloxatin) & Capecitabine (Xeloda)]].
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-==Capecitabine, Paclitaxel, RT {{#subobject:56dddf|Regimen=1}}==
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-See [[#Paclitaxel_.28Taxol.29_.26_Capecitabine_.28Xeloda.29|Paclitaxel (Taxol) & Capecitabine (Xeloda)]].
+''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">
-==Carboplatin, Paclitaxel, RT {{#subobject:d4831|Regimen=1}}==
+====Chemotherapy====
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Cisplatin (Platinol)]] 80 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>)
+====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]]
 |-
-|[[#toc|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ Tepper et al. 2008 (CALGB 9781)]
-|}
+|1997-2000
-See [[#Carboplatin.2C_Paclitaxel.2C_RT|Carboplatin, Paclitaxel, RT]], except patients did not undergo surgery.
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
-==Cisplatin, Docetaxel, RT {{#subobject:21719f|Regimen=1}}==
+| 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)
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Li et al. 2009 {{#subobject:7b3f9c|Variant=1}}===
+''Note: Patients had 75% adenocarcinoma, 25% squamous cell histology. 5% with ECOG PS of 2.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 29, '''given first'''
-padding:3px 6px 3px 6px;
+*[[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>)
-border-color:black;
+====Radiotherapy====
-border-width:2px;
+*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'''
-border-style:solid;">Phase II</span>
-*[[Cisplatin (Platinol)]] 80 mg/m2 IV once per day on days 1 & 22
-*[[Docetaxel (Taxotere)]] 60 mg/m2 IV once per day on days 1 & 22
-*Concurrent radiation therapy, 1.8-2.0 Gy fractions, 5 days per week, to start within 24 hours of the day 1 of chemotherapy
-**Patients with stage I-III disease received a total dose of 60-64 Gy over 4-6 weeks
-**Patients with stage IV disease (lymph node only) received a total dose of 50-56 Gy
-'''1 cycle of chemoradiation'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 10 mg PO/IV the day before docetaxel, 30 minutes prior to docetaxel, and the day after docetaxel
-*Diphenhydramine (Benadryl) 40 mg IV prior to chemotherapy
-*Cimetidine (Tagamet) 40 mg IV prior to chemotherapy
-*Granisetron (Kytril) 2 mg IV prior to chemotherapy
-*1.5-2.0 liters fluids before cisplatin
-===Regimen #2, Day et al. 2011 {{#subobject:f4800d|Variant=1}}===
-''Note: The NCCN, Esophageal Cancer version 2.2011, suggests a wider dose range of 20-30 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.''
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV on days 1, 8, 15, 22, 29
-*[[Docetaxel (Taxotere)]] 30 mg/m2 IV on days 1, 8, 15, 22, 29
-*Concurrent radiation therapy, 2 Gy fractions x 25 fractions, 5 days per week, for a total dose of 50 Gy, to start within 4 hours after the first dose of chemotherapy.
 '''5-week course'''
+</div>
-Supportive medications:
+<div class="toccolours" style="background-color:#cbd5e7">
-*"Steroid and anti-emetic pre-medication"
+====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===
-# Li QQ, Liu MZ, Hu YH, Liu H, He ZY, Lin HX. Definitive concomitant chemoradiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus. 2010 Apr;23(3):253-9. Epub 2009 Aug 28. [http://onlinelibrary.wiley.com/doi/10.1111/j.1442-2050.2009.01003.x/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19732130 PubMed]
+#Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, Denham JW; Trans-Tasman Radiation Oncology Group; Australasian Gastro-Intestinal Trials Group. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005 Sep;6(9):659-68. [https://doi.org/10.1016/S1470-2045(05)70288-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16129366/ PubMed]
-# 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. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031899 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21157450 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]
-==Cisplatin, Fluorouracil, RT {{#subobject:2b3dbc|Regimen=1}}==
+==Cisplatin, Irinotecan, RT {{#subobject:4932b1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+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
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Herskovic et al. 1992 (RTOG 85-01); al-Sarraf et al. 1997 {{#subobject:ca1b71|Variant=1}}===
+''Note: Patients had 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated history; 33% gastroesophageal junction.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#cbd5e8">
-<span
+====Preceding treatment====
-style="background:#00CD00;
+*[[#Cisplatin_.26_Irinotecan_.28IC.29|IC]] induction x 2
-padding:3px 6px 3px 6px;
+</div>
-border-color:black;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-width:2px;
+====Chemotherapy====
-border-style:solid;">Phase III</span>
+*[[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'''
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV on the first day of week 1, 5, 8, 11 (day 1, 29, 50, 71)
+====Radiotherapy====
-*[[Fluorouracil (5-FU)]] 1000 mg/m2/day IV continuous infusion over 96 hours on the first 4 days of week 1, 5, 8, 11 (days 1-4, 29-32, 50-53, 71-74)
+*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)
-*Concurrent radiation therapy: starting on day 1, 2.0 Gy fractions x 15 fractions given 5 days per week x 3 weeks; then 2.0 Gy fractions x 10 fractions x 2 weeks to the initial tumor length plus a 5 cm margin, for a total dose of 50.0 Gy.
+'''5.5-week course'''
+</div>
-'''11-week course of therapy'''
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-===Regimen #2, Minsky et al. 2002 (RTOG 94-05) {{#subobject:3272d5|Variant=1}}===
+*[[Surgery#Esophagectomy|Surgery]], performed 4 to 8 weeks after chemoradiation
-Level of Evidence:
+</div></div>
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 30 minutes on day 1
-*[[Fluorouracil (5-FU)]] 1000 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4
-*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, starting on day 1, for a total dose of 50.4 Gy.
-'''28-day cycles x 2 cycles, THEN'''
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 30 minutes on day 1
-*[[Fluorouracil (5-FU)]] 1000 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4
-'''28-day cycles x 2 cycles'''
 ===References===
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJM199206113262403 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1584260 PubMed]
+#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]
-## '''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. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA. 1999 May 5;281(17):1623-7. [http://jama.jamanetwork.com/article.aspx?articleid=189737 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10235156 PubMed]
-# 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. [http://jco.ascopubs.org/content/15/1/277.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/8996153 PubMed]
-# 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. [http://jco.ascopubs.org/content/20/5/1167.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11870157 PubMed]
-# 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. [http://jco.ascopubs.org/content/25/10/1160.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17401004 PubMed]
-# Conroy T, Yataghène Y, Etienne PL, Michel P, Senellart H, Raoul JL, Mineur L, Rives M, Mirabel X, Lamezec B, Rio E, Le Prisé E, Peiffert D, Adenis A. Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer. Br J Cancer. 2010 Oct 26;103(9):1349-55. Epub 2010 Oct 12. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990616 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20940718 PubMed]
-==Cisplatin, Irinotecan, RT {{#subobject:c0c088|Regimen=1}}==
+==Cisplatin, Paclitaxel, RT {{#subobject:3d8eaa|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+Cisplatin, Paclitaxel, RT: Cisplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===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
 |-
-|[[#toc|back to top]]
 |}
-See [[#Cisplatin_.28Platinol.29_.26_Irinotecan_.28Camptosar.29|Cisplatin (Platinol) & Irinotecan (Camptosar) Regimen #1, Ilson et al. 2011 & Regimen #2, Sharma et al. 2009]].
+''Note: Patients had 83% adenocarcinoma, 14% squamous cell, 3% undifferentiated histology''
+<div class="toccolours" style="background-color:#b3e2cd">
-==Cisplatin, Paclitaxel, RT {{#subobject:3ab15|Regimen=1}}==
+====Chemotherapy====
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Paclitaxel (Taxol)]] 60 mg/m<sup>2</sup> 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 [[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]]
+|-
+|[http://ar.iiarjournals.org/content/27/4C/2597.long Hihara et al. 2007]
+|2004-04-21 to 2005-04-07
+| style="background-color:#ffffbe" |Phase 1
 |-
-|[[#toc|back to top]]
 |}
-See [[#Cisplatin_.28Platinol.29_.26_Paclitaxel_.28Taxol.29|Cisplatin (Platinol) & Paclitaxel (Taxol)]], except patients did not undergo surgery.
+''Note: Patients had 86% squamous cell, 14% carcinosarcoma histology''
+<div class="toccolours" style="background-color:#b3e2cd">
-==Docetaxel, Fluorouracil, RT {{#subobject:e37962|Regimen=1}}==
+====Chemotherapy====
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[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
+*[[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>)
+====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===
+#'''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]
+==Fluorouracil, Oxaliplatin, RT {{#subobject:94b79a|Regimen=1}}==
+Fluorouracil, Oxaliplatin, RT: Fluorouracil, Oxaliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 5040 cGy, bi-weekly oxaliplatin {{#subobject:ae22de|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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1200/jco.2002.12.032 Khushalani et al. 2002]
-|}
+|2000-02 to 2001-05
-See [[#Docetaxel_.28Taxotere.29_.26_Fluorouracil_.285-FU.29|Docetaxel (Taxotere) & Fluorouracil (5-FU) Regimen #1, Hihara et al. 2007 & Regimen #2]].
+| style="background-color:#91cf61" |Phase 2
-==Fluorouracil, Oxaliplatin, RT {{#subobject:ab0124|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-See [[#Oxaliplatin_.28Eloxatin.29_.26_Fluorouracil_.285-FU.29|Oxaliplatin (Eloxatin) & Fluorouracil (5-FU) Regimen #1, Lorenzen et al. 2008]].  ''Note: Regimen #1 was a neoadjuvant regimen, but is also listed under definitive chemoradiation by the NCCN, Esophageal Cancer version 2.2011.''  See [[#Oxaliplatin_.28Eloxatin.29_.26_Fluorouracil_.285-FU.29|Oxaliplatin (Eloxatin) & Fluorouracil (5-FU) Regimen #2, Khushalani et al. 2002]].
+''Note: 58% of patients had stage IV disease''
+<div class="toccolours" style="background-color:#b3e2cd">
-==FOLFOX 4 & RT -> FOLFOX 4 {{#subobject:1f91c5|Regimen=1}}==
+====Chemotherapy====
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[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]], 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]]
 |-
-|[[#toc|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937600/ Ajani et al. 2013 (MDACC 2004-0703)]
-|}
+|2005-2011
-FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
+| style="background-color:#91cf61" |Non-randomized part of phase 2 RCT
-===Regimen {{#subobject:e2fc30|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II, >20 per arm</span>
-''Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011, lists the dosage of leucovorin as 400 mg/m2.''
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus, then 600 mg/m2/day IV over 22 hours on days 1 & 2; given after Oxaliplatin (Eloxatin) and Folinic acid (Leucovorin)
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 2 hours on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV over 2 hours on day 1
-*Concurrent radiation therapy, 2 Gy fractions x 25 fractions given 5 days per week, for a total dose of 50 Gy
-'''14-day cycles x 3 cycles, THEN'''
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus, then 600 mg/m2/day IV over 22 hours on days 1 & 2; given after Oxaliplatin (Eloxatin) and Folinic acid (Leucovorin)
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 2 hours on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV over 2 hours on day 1
-'''14-day cycles x 3 cycles'''
-===References===
-# Conroy T, Yataghène Y, Etienne PL, Michel P, Senellart H, Raoul JL, Mineur L, Rives M, Mirabel X, Lamezec B, Rio E, Le Prisé E, Peiffert D, Adenis A. Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer. Br J Cancer. 2010 Oct 26;103(9):1349-55. Epub 2010 Oct 12. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990616 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20940718 PubMed]
-==Radiation therapy {{#subobject:345c2d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
+''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.''
-===Regimen {{#subobject:1be630|Variant=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
-Level of Evidence:
+====Preceding treatment====
-<span
+*[[#FUOX_999|FUOX]] versus [[Esophageal_cancer_-_null_regimens#No_neoadjuvant_therapy|no induction chemotherapy]]
-style="background:#00CD00;
+</div>
-padding:3px 6px 3px 6px;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-color:black;
+====Chemotherapy====
-border-width:2px;
+*[[Oxaliplatin (Eloxatin)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-border-style:solid;">Phase III</span>
+*[[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>)
+====Radiotherapy====
-''Radiation as primary therapy; used as a comparator arm and here for reference purposes only.''
+*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 5040 cGy of proton or photon (intensity modulated) radiation in 28 fractions
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Esophagectomy|Surgery]]
+</div></div>
 ===References===
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJM199206113262403 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1584260 PubMed]
+#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]
-# 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. [http://jco.ascopubs.org/content/15/1/277.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/8996153 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=
-==Surgery alone {{#subobject:20ca6e|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">
+===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%"|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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1016/S1470-2045(13)70136-0 Crosby et al. 2013 (SCOPE-1)]
-|}
+|2008-2012
+| style="background-color:#1a9851" |Phase 3 (C)
-===Regimen {{#subobject:ad67e8|Variant=1}}===
+|[[Stub#Capecitabine.2C_Cisplatin.2C_Cetuximab.2C_RT|Capecitabine, Cisplatin, Cetuximab, RT]]
-Level of Evidence:
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-''Surgery as primary therapy; used as a comparator arm and here for reference purposes only.''
-===References===
-# Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [http://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11547741 PubMed]
-# Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [http://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]
-# 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. [http://jco.ascopubs.org/content/26/7/1086.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18309943 PubMed]
-# 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. doi: 10.1056/NEJMoa1112088. [http://www.nejm.org/doi/full/10.1056/NEJMoa1112088 link to original article] '''contains verified protocol''' [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1112088/suppl_file/nejmoa1112088_appendix.pdf link to appendix with details about administration] [http://www.ncbi.nlm.nih.gov/pubmed/22646630 PubMed]
-=Chemotherapy for metastatic or locally advanced disease (non-radiation/surgery candidate)=
-==Best supportive care {{#subobject:15ddd8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
+''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br>
-===Regimen {{#subobject:5a09b7|Variant=1}}===
+''Note: Patients had 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology''
-{| border="1" style="text-align:center;" !align="left"
+<div class="toccolours" style="background-color:#b3e2cd">
-|'''Study'''
+====Chemotherapy====
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+*[[Capecitabine (Xeloda)]] as follows:
-|'''Comparator'''
+**Cycles 1 & 2: 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
+**Cycle 3 (chemoradiation): 625 mg/m<sup>2</sup> PO twice per day on days 1 to 42
+*[[Cisplatin (Platinol)]] as follows:
+**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:
+**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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 1600/30/54 {{#subobject:f7a6c1|Variant=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 50%" |Study
+! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.ejcancer.info/article/S0959-8049%2811%2900396-0/fulltext Thuss-Patience et al. 2011]
+|[http://jjco.oxfordjournals.org/content/37/11/829.long Lee et al. 2007<sub>esoph</sub>]
-|<span
+| style="background-color:#ffffbe" |Retrospective
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Irinotecan_.28Camptosar.29|Irinotecan]]
 |-
 |}
+''Note: Patients had 97% adenocarcinoma, 3% squamous cell histology; 3% with ECOG PS of 2.''
-''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''
+<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)]] 30 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
+'''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 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===
-# Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. [http://www.ejcancer.info/article/S0959-8049%2811%2900396-0/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21742485 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 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]
-==Capecitabine (Xeloda) {{#subobject:a9eb0b|Regimen=1}}==
+==Cisplatin, Docetaxel, RT {{#subobject:21719f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+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 variant #1 {{#subobject:f4800d|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]
+|2001-05 to 2007-01
+| style="background-color:#ffffbe" |Phase 1
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:b6ba4c|Variant=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.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-padding:3px 6px 3px 6px;
+*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-border-color:black;
+====Supportive therapy====
-border-width:2px;
+*"Steroid and anti-emetic pre-medication"
-border-style:solid;">Phase II</span>
+====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.
-''Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011, lists the dosage of capecitabine as 1000 mg/m2.''
+'''5-week course'''
-*[[Capecitabine (Xeloda)]] 1250 mg/m2 PO BID on days 1 to 14
+</div></div>
-'''21-day cycles x up to 6 cycles'''
 ===References===
-# Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep;15(9):1344-7. [http://annonc.oxfordjournals.org/content/15/9/1344.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15319239 PubMed]
+#'''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}}==
-==Carboplatin & Paclitaxel {{#subobject:4df570|Regimen=1}}==
+CF & RT: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br>
-{| class="wikitable" style="float:right; margin-left: 5px;"
+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%"|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(13)70136-0 Crosby et al. 2013 (SCOPE-1)]
+|2008-2012
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Stub#Capecitabine.2C_Cisplatin.2C_Cetuximab.2C_RT|Capecitabine, Cisplatin, Cetuximab, RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:9725d8|Variant=1}}===
+''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br>
-{| border="1" style="text-align:center;" !align="left"
+''Note: This regimen was an alternative for patients who could not swallow pills. Patients had 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology''
-|'''Study'''
+<div class="toccolours" style="background-color:#b3e2cd">
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+====Chemotherapy====
+*[[Cisplatin (Platinol)]] as follows:
+**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
+*[[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:
+**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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 75/4000 x 2 (5040 cGy) {{#subobject:3272d5|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://www.ncbi.nlm.nih.gov/pubmed/9427274 Philip et al. 1997]
+|[https://doi.org/10.1200/jco.2002.20.5.1167 Minsky et al. 2002 (RTOG 94-05)]
-|<span
+|1995-1999
-style="background:#EEEE00;
+| style="background-color:#1a9851" |Phase 3 (C)
-padding:3px 6px 3px 6px;
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]; high-dose RT
-border-color:black;
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS24
-border-width:2px;
-border-style:solid;">Phase II</span>
 |-
-!colspan="4" align="center"|
+|[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]]
 |-
-|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract Gadgeel et al. 2003]
+|}
-|<span
+''Note: Patients had RTOG 94-05 included both adenocarcinoma and squamous cell histology''
-style="background:#EEEE00;
+<div class="toccolours" style="background-color:#b3e2cd">
-padding:3px 6px 3px 6px;
+====Chemotherapy====
-border-color:black;
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 29
-border-width:2px;
+*[[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>)
-border-style:solid;">Phase II</span>
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Cisplatin_.26_Fluorouracil_.28CF.29_2|CF]] consolidation
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 75/4000 x 3 (6600 cGy) {{#subobject:0d8520|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.2005.04.7118 Bedenne et al. 2007 (FFCD 9102)]
+|1993-2000
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|[[Surgery#Esophageal_cancer_surgery|Surgery]]
+| style="background-color:#eeee01" |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.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Induction [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]] 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">
-''Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011, lists the dosage of carboplatin as AUC 6.''
+===Regimen variant #4, 75/4000 x 4 (5000 cGy) {{#subobject:ca1b71|Variant=1}}===
-*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1, '''given second'''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*[[Paclitaxel (Taxol)]] 200 mg/m2 IV over 3 hours once on day 1, '''given first'''
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-'''21-day cycles'''
+!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 (E-esc)
+|[[#Radiation_therapy|Radiation therapy]]
+| style="background-color:#1a9850" |Superior OS
+|-
+|}
+''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:
+**Cycle 1 (chemoradiation): 75 mg/m<sup>2</sup> IV once per day on days 1 & 29
+**Cycles 2 & 3: 75 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] as follows:
+**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>)
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|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'''
+</div></div>
 ===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 protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9427274 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://doi.org/10.1056/NEJM199206113262403 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1584260/ PubMed]
-# Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, Philip PA. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003 Feb;26(1):37-41. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12576922 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]
-==Cetuximab (Erbitux) {{#subobject:5aca6d|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
+##'''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]
+##'''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]
+==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%"|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/pmc5710193/ Suntharalingam et al. 2017 (RTOG 0436)]
+|2008-2013
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cisplatin.2C_Paclitaxel.2C_Cetuximab.2C_RT_999|Cisplatin, Paclitaxel, Cetuximab, RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:b11ea0|Variant=1}}===
+''Note: patients had 62% adenocarcinoma, 38% squamous cell histology. 14% with M1a disease. 6% with Zubrod PS score 2.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-padding:3px 6px 3px 6px;
+*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-border-color:black;
+====Radiotherapy====
-border-width:2px;
+*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)
-border-style:solid;">Phase II</span>
+'''6-week course'''
+</div></div>
-*[[Cetuximab (Erbitux)]] 400 mg/m2 IV over 120 minutes on cycle 1 day 1, then 250 mg/m2 IV over 60 minutes on days on cycle 1 days 8, 15, 22; then in cycles 2 and on, [[Cetuximab (Erbitux)]] is 250 mg/m2 IV on days 1, 8, 15, 22
-'''28-day cycles, given until progression of disease or unacceptable toxicity'''
-Supportive medications:
-*Diphenhydramine (Benadryl) 50 mg PO/IV 30-60 minutes prior to cetuximab
 ===References===
-# Gold PJ, Goldman B, Iqbal S, Leichman LP, Zhang W, Lenz HJ, Blanke CD. Cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma: a phase II Southwest Oncology Group Study (S0415). J Thorac Oncol. 2010 Sep;5(9):1472-6. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928397 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20631636 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 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]
-==DC, TC {{#subobject:724868|Regimen=1}}==
+==FOLFOX4 & RT {{#subobject:1f91c5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+FOLFOX4 & RT: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e2fc30|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(14)70028-2 Conroy et al. 2014 (PRODIGE5/ACCORD17)]
+|2004-2011
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
+| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
 |-
-|[[#toc|back to top]]
 |}
-DC: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin
+''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.''
-<br>TC: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-===Regimen #1 {{#subobject:cd0910|Variant=1}}===
+*[[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>)
-{| border="1" style="text-align:center;" !align="left"
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29
-|'''Study'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+====Radiotherapy====
-|'''Comparator'''
+*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)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#FOLFOX4|FOLFOX4]] consolidation x 3
+</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]
+##'''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]
+==Radiation therapy {{#subobject:16tea6|Regimen=1}}==
+<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]]
 |-
-|[http://jco.ascopubs.org/content/25/22/3217.long Roth et al. 2007]
+|[https://doi.org/10.1056/NEJM199206113262403 Herskovic et al. 1992 (RTOG 85-01)]
-|<span
+|1986-1990
-style="background:#00CD00;
+| style="background-color:#1a9851" |Phase 3 (C)
-padding:3px 6px 3px 6px;
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT]]
-border-color:black;
+| style="background-color:#d73027" |Inferior OS
-border-width:2px;
-border-style:solid;">Randomized Phase II</span>
-|[[#ECF_2|ECF]]<br> [[#DCF.2C_TCF|TCF]]
 |-
 |}
+''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.''
-*[[Docetaxel (Taxotere)]] 75 mg/m2 IV over 1 hour once on day 1; the protocol was amended to change the original dose of 85 mg/m2 to 75 mg/m2 based on high incidence of febrile neutropenia
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 4 hours once on day 1
+====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
-'''21-day cycle x up to 8 cycles'''
+'''6.4-week course'''
+</div></div><br>
-Supportive medications:
+<div class="toccolours" style="background-color:#eeeeee">
-*3 liters per day "hyperhydration"
+===Regimen variant #2, 6000 cGy {{#subobject:adu60d|Variant=1}}===
-*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours before docetaxel, then 8 mg PO BID x 4 days after docetaxel
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*5-HT3 antagonist for emesis prophylaxis
+!style="width: 20%"|Study
-*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-===Regimen #2 {{#subobject:f1913d|Variant=1}}===
+!style="width: 20%"|Comparator
-{| border="1" style="text-align:center;" !align="left"
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/23/24/5660.long Ajani et al. 2005]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343504/ Ji et al. 2021 (ZJCH-E-E)]
-|<span
+|2016-06-01 to 2018-08-31
-style="background:#00CD00;
+| style="background-color:#1a9851" |Phase 3 (C)
-padding:3px 6px 3px 6px;
+|[[#S-1_.26_RT|S-1 & RT]]
-border-color:black;
+| style="background-color:#d73027" |Inferior OS24
-border-width:2px;
-border-style:solid;">Randomized Phase II</span>
-|[[#DCF.2C_TCF|DCF]]
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Docetaxel (Taxotere)]] 85 mg/m2 IV over 1 hour once on day 1
+====Radiotherapy====
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 1 to 3 hours once on day 1
+*[[External beam radiotherapy]] 200 cGy per day, 5 days per week, for 30 fractions (total dose of 6000 cGy)
+'''One course'''
-'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+</div></div>
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 8 mg PO the night before chemotherapy, the morning of day 1, 1 hour before chemotherapy, the night of day 1, the morning of day 2, and the evening of day 2 (6 total doses)
-*[[Dexamethasone (Decadron)]] 20 mg IV before cisplatin and 8 hours after cisplatin
-*[[Ondansetron (Zofran)]] 8 mg IV before cisplatin, 4 hours cisplatin, and 8 hours after cisplatin
-*"Hydration [was] administered in a standard manner"
-===Regimen #3, Kim et al. 2010 {{#subobject:6adc30|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Docetaxel (Taxotere)]] 70 mg/m2 IV over 1 hour once on day 1, '''given 3 hours before cisplatin'''
-*[[Cisplatin (Platinol)]] 70 mg/m2 IV over 1 hour once on day 1
-'''21-day cycle x up to 6 cycles, progression of disease, or unacceptable toxicity'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 8 mg PO BID x 1 day, starting 1 day before docetaxel administration
-*At least 3 liters hydration (with mannitol, magnesium, and potassium chloride)
-*"Antiemetic treatment"
 ===References===
-# Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [http://jco.ascopubs.org/content/23/24/5660.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16110025 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://doi.org/10.1056/NEJM199206113262403 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1584260/ PubMed]
-# Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17664469 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]
-# Kim JY, Do YR, Park KU, Kim MK, Lee KH, Bae SH, Ryoo HM, Baek JH, Song HS. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010 May;66(1):31-6. Epub 2009 Sep 18. [http://www.springerlink.com/content/e131402311p276x0/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19763571 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]
-==CF, FP {{#subobject:4d9936|Regimen=1}}==
+==S-1 & RT {{#subobject:cff3w6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+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)
 |-
-|[[#toc|back to top]]
 |}
-CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+<div class="toccolours" style="background-color:#b3e2cd">
-<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol
+====Chemotherapy====
-===Regimen #1, Van Cutsem et al. 2006 & Dank et al. 2008 {{#subobject:10f0c6|Variant=1}}===
+*[[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)
-Level of Evidence:
+====Radiotherapy====
-<span
+*[[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)
-style="background:#00CD00;
+'''6-week course'''
-padding:3px 6px 3px 6px;
+</div></div>
-border-color:black;
+===References===
-border-width:2px;
+#'''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]
-border-style:solid;">Phase III</span>
-*[[Cisplatin (Platinol)]] 100 mg/m2 IV over 1-3 hours on day 1, given before Fluorouracil (5-FU)
+=Consolidation after definitive therapy=
-*[[Fluorouracil (5-FU)]] 1000 mg/m2/day IV continuous infusion on days 1 to 5, given after cisplatin
+==Cisplatin & Fluorouracil (CF) {{#subobject:cf23a6|Regimen=1}}==
+CF: '''<u>C</u>'''isplatin & '''<u>F</u>'''luorouracil
-'''28-day cycles, given until progression of disease or unacceptable toxicity'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:ade242|Variant=1}}===
-Supportive medications, as described in Dank et al. 2008:
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*"Hyperhydration" for 2-3 days with each infusion
+!style="width: 20%"|Study
-*Ondansetron IV for antiemetic prophylaxis
+!style="width: 20%"|Dates of enrollment
-*Dexamethasone IV for antiemetic prophylaxis, then PO for 2-3 days
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-*Metoclopramide for antiemetic prophylaxis
+!style="width: 20%"|Comparator
-*[[Filgrastim (Neupogen)]] daily SC, starting on day 4, to be continued until ANC > 1 x 10^9/L for grade 3-4 neutropenia, febrile neutropenia, or neutropenic infection
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-*Atropine prn cholinergic symptoms
+|-
-*Loperamide prn delayed diarrhea
+|[https://doi.org/10.1200/jco.2002.20.5.1167 Minsky et al. 2002 (RTOG 94-05)]
+|1995-1999
-===Regimen #2, Lorenzen et al. 2009 {{#subobject:fe6c13|Variant=1}}===
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-Level of Evidence:
+| style="background-color:#d3d3d3" |
-<span
+| style="background-color:#d3d3d3" |
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II, >20 per arm</span>
-*[[Cisplatin (Platinol)]] 100 mg/m2 IV over 60 minutes on day 1, given before Fluorouracil (5-FU)
-*[[Fluorouracil (5-FU)]] 1000 mg/m2/day IV continuous infusion on days 1 to 5, given after cisplatin
-'''29-day cycles x up to 6 cycles'''
-===Regimen #3, Kang et al. 2009 {{#subobject:782e95|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Cisplatin (Platinol)]] 80 mg/m2 IV over 2 hours on day 1
-*[[Fluorouracil (5-FU)]] 800 mg/m2/day IV continuous infusion on days 1 to 5
-'''21-day cycles, given until progression of disease or unacceptable toxicity'''
-Supportive medications:
-*"Hyperhydration" for cisplatin
-===Regimen #4 {{#subobject:16f18e|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG9205)]
+|[https://doi.org/10.1016/S1470-2045(14)70028-2 Conroy et al. 2014 (PRODIGE5/ACCORD17)]
-|<span
+|2004-2011
-style="background:#00CD00;
+| style="background-color:#1a9851" |Phase 3 (C)
-padding:3px 6px 3px 6px;
+|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
-border-color:black;
+| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Fluorouracil_.285-FU.29|Fluorouracil]]<br> [[#UFTM|UFTM]]
 |-
 |}
+''Note: study included both adenocarcinoma and squamous cell histology''
-*[[Cisplatin (Platinol)]] 20 mg/m2 IV over 30 minutes once per day on days 1 to 5
+<div class="toccolours" style="background-color:#cbd5e8">
-*[[Fluorouracil (5-FU)]] 800 mg/m2/day IV continuous infusion on days 1 to 5
+====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
-'''28-day cycle x up to 6 cycles'''
+*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
+*[[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>)
+'''28-day cycle for 2 cycles'''
+</div></div>
 ===References===
-# Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12506170 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. [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]
-# Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [http://jco.ascopubs.org/content/24/31/4991.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17075117 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]
-# Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. [http://annonc.oxfordjournals.org/content/19/8/1450.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18558665 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]
-# Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [http://annonc.oxfordjournals.org/content/20/4/666.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19153121 PubMed]
+==FOLFOX4 {{#subobject:a8048e|Regimen=1}}==
-# Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. [http://annonc.oxfordjournals.org/content/20/10/1667.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19549707 PubMed]
+FOLFOX4: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin 4
-# Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:f200f1|Variant=1}}===
-==CF & Cetuximab {{#subobject:717dc4|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]]
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70028-2 Conroy et al. 2014 (PRODIGE5/ACCORD17)]
+|2004-2011
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
+| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]
 |-
-|[[#toc|back to top]]
 |}
+''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">
+====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>)
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours 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'''
+</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]
+##'''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=
+==Cisplatin & Fluorouracil (CF) {{#subobject:e35a6c|Regimen=1}}==
 CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-===Regimen {{#subobject:54b7fe|Variant=1}}===
+<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol
-{| border="1" style="text-align:center;" !align="left"
+<div class="toccolours" style="background-color:#eeeeee">
-|'''Study'''
+===Regimen {{#subobject:fc3c70|Variant=1}}===
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+{| class="wikitable" style="width: 60%; text-align:center;"
-|'''Comparator'''
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://annonc.oxfordjournals.org/content/20/10/1667.long Lorenzen et al. 2009]
+|[https://doi.org/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]
-|<span
+|1990-1995
-style="background:#00CD00;
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II</span>
-|[[#CF.2C_FP|CF]]
 |-
 |}
+''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.''
-*[[Cisplatin (Platinol)]] 100 mg/m2 IV over 60 minutes once on day 1, '''given before fluorouracil'''
+<div class="toccolours" style="background-color:#cbd5e8">
-*[[Fluorouracil (5-FU)]] 1000 mg/m2/day IV continuous infusion on days 1 to 5, '''given after cisplatin'''
+====Preceding treatment====
-*[[Cetuximab (Erbitux)]] as follows:
+*Neoadjuvant [[#Cisplatin_.26_Fluorouracil_.28CF.29|CF]], then [[Surgery#Esophageal_cancer_surgery|surgery]]
-**Cycle 1: 400 mg/m2 IV over 120 minutes once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8, 15, 22
+</div>
-**Cycles 2 to 6: 250 mg/m2 IV once per day on days 1, 8, 15, 22
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-'''29-day cycle x up to 6 cycles'''
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: see note)
-Supportive medications:
+'''28-day cycle for 3 cycles'''
-*"Standard antiemetic prophylaxis and pre- and post- cisplatin hydration"
+</div></div>
 ===References===
-# Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. [http://annonc.oxfordjournals.org/content/20/10/1667.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19549707 PubMed]
+#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://doi.org/10.1056/NEJM199812313392704 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9869669/ PubMed]
-==CF & Trastuzumab {{#subobject:ca9cd1|Regimen=1}}==
+==Nivolumab monotherapy {{#subobject:e3u15c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e4f654|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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1056/nejmoa2032125 Kelly et al. 2021 (CheckMate 577)]
-|}
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-279-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-===Regimen {{#subobject:b2731|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]
+|} -->
-|<span
+|2016-2019
-style="background:#00CD00;
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-padding:3px 6px 3px 6px;
+|[[Esophageal_cancer_-_null_regimens#Placebo_2|Placebo]]
-border-color:black;
+| 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)
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#CF.2C_FP|CF]]
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
-*[[Cisplatin (Platinol)]] 80 mg/m2 IV once on day 1
+====Preceding treatment====
-*[[Fluorouracil (5-FU)]] 800 mg/m2/day IV continuous infusion on days 1 to 5
+*Neoadjuvant [[Regimen_classes#Chemoradiotherapy-based_regimen|chemoradiotherapy (not specified)]], then [[Surgery#Esophageal_cancer_surgery|surgery]], with residual pathologic disease
-*[[Trastuzumab (Herceptin)]] as follows:
+</div>
-**Cycle 1: 8 mg/kg IV once on day 1
+<div class="toccolours" style="background-color:#b3e2cd">
-**Subsequent cycles: 6 mg/kg IV once on day 1
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] as follows:
-'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+**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===
-# Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]
+#'''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]
-==Cisplatin (Platinol), Fluorouracil (5-FU), Doxorubicin liposomal (Doxil) {{#subobject:f31fcc|Regimen=1}}==
+=Metastatic or locally advanced disease, first-line=
-{| class="wikitable" style="float:right; margin-left: 5px;"
+==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]]
 |-
-|[[#toc|back to top]]
+|[https://pubmed.ncbi.nlm.nih.gov/9427274 Philip et al. 1997]
-|}
+|NR in abstract
-===Regimen {{#subobject:1b58a0|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II, >20 per arm</span>
-*[[Cisplatin (Platinol)]] 50 mg/m2 IV on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion on days 1 to 2
-*[[Doxorubicin liposomal (Doxil)]] 20 mg/m2 IV on day 1
-'''14-day cycles, given until progression of disease or unacceptable toxicity'''
-===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. [http://www.springerlink.com/content/n8477v3g21081103/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20821330 PubMed]
-==Cisplatin (Platinol) & Irinotecan (Camptosar) (CI) {{#subobject:ec60da|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-CI: '''<u>C</u>'''isplatin, '''<u>I</u>'''rinotecan
+''Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6.''
-===Regimen #1, Ilson et al. 1999 {{#subobject:219a1|Variant=1}}===
+<div class="toccolours" style="background-color:#fdcdac">
-Level of Evidence:
+====Eligibility criteria====
-<span
+*Locally advanced metastatic or recurrent esophageal or gastric cancer
-style="background:#EEEE00;
+</div>
-padding:3px 6px 3px 6px;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-color:black;
+====Chemotherapy====
-border-width:2px;
+*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1, '''given second'''
-border-style:solid;">Phase II</span>
+*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV bolus on days 1, 8, 15, 22
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV over 30 minutes on  days 1, 8, 15, 22
-'''6-week cycles x 1-3 cycles, or until disease progression or unacceptable toxicity.'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 20 mg IV prior to chemotherapy
-*Granisetron 2 mg PO prior to chemotherapy
-*At least 500 mL D5NS IV over 30-60 minutes before cisplatin
-*Atropine used as pretreatment medication if there was diarrhea or abdominal cramps within 1 hour of irinotecan
-===Regimen #2, Ilson et al. 2004 {{#subobject:8f624d|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-''Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011 lists cisplatin 25 mg/m2 as an alternate dosage.''
-*[[Cisplatin (Platinol)]] 30 mg/m2 IV on days 1 & 8
-*[[Irinotecan (Camptosar)]] 65 mg/m2 IV on days 1 & 8
 '''21-day cycles'''
+</div></div>
 ===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. [http://jco.ascopubs.org/content/17/10/3270.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10506629 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 dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9427274/ 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. '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15685830 PubMed]
+==Cisplatin & Fluorouracil (CF) {{#subobject:cjuc2x|Regimen=1}}==
+CF: '''<u>C</u>'''isplatin & '''<u>F</u>'''luorouracil
-==CLF, FLP {{#subobject:b913d6|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:cf5acj2|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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1016/s0140-6736(21)01234-4 Sun et al. 2021 (KEYNOTE-590)]
-|}
+|2017-2019
-CLF: '''<u>C</u>'''isplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil
+| style="background-color:#1a9851" |Phase 3 (C)
-<br>FLP: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>P</u>'''latinol
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_Pembrolizumab|CF & Pembrolizumab]]
-===Regimen #1, Al-Batran et al. 2008 {{#subobject:beef19|Variant=1}}===
+| style="background-color:#d73027" |Inferior OS (co-primary endpoint)
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-''Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011, lists [[Fluorouracil (5-FU)]] as being given every 2 weeks rather than the schedule below.''
-*[[Cisplatin (Platinol)]] 50 mg/m2 IV over 2 hours on days 1, 15, 29, 43
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 2 hours on days 1, 15, 29, 43
-*[[Fluorouracil (5-FU)]] 2000 mg/m2 IV continuous 24-hour infusion on days 1, 8, 15, 22, 29, 36
-'''8-week cycles, given until progression of disease or unacceptable toxicity'''
-Supportive medications:
-*Up to 3 liters normal saline as hydration with cisplatin
-*Antiemetic medications per "local protocols"
-===Regimen #2, Bouche et al. 2004 (FFCD 9803) {{#subobject:34890|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II, >20 per arm</span>
-*[[Cisplatin (Platinol)]] 50 mg/m2 IV over 1 hour on either day 1 or 2
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 2 hours on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours on days 1 to 2
-'''14-day cycles x at least 4 cycles or until progression of disease or unacceptable toxicity''' (primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used)
-Supportive medications:
-*1 liter hydration over 3 hours before and after cisplatin
-*5-HT3 antagonist IV before cisplatin
-*Methylprednisolone (Solu-Medrol) 120 mg IV 10 minutes before cisplatin
-*Oral antiemetics and corticosteroids from days 2-5
-===References===
-# Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [http://jco.ascopubs.org/content/22/21/4319.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15514373 PubMed]
-# Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. [http://jco.ascopubs.org/content/26/9/1435.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18349393 PubMed]
-==Cisplatin (Platinol) & Paclitaxel (Taxol) {{#subobject:5d50ee|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Ilson et al. 2000 {{#subobject:ffaa05|Variant=1}}===
+''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.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
-padding:3px 6px 3px 6px;
+*[[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>)
-border-color:black;
+'''21-day cycle for up to 35 cycles (2 years)'''
-border-width:2px;
+</div></div>
-border-style:solid;">Phase II</span>
-''Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011, lists the paclitaxel dose as 135 mg/m2.  No primary reference could be found for the 135 mg/m2 dosage.''
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV on day 2, given after paclitaxel
-*[[Paclitaxel (Taxol)]] 200 mg/m2 IV over 24 hours on day 1; the protocol was amended to change the original dose of 250 mg/m2 to 200 mg/m2 based on toxicity and treatment-related deaths
-'''21-day cycles'''
-Supportive medications:
-*"Granulocyte colony stimulating factor support"
-===Regimen #2, Zhang et al. 2008 {{#subobject:c401a9|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 2 hours on day 1
-*[[Paclitaxel (Taxol)]] 175 mg/m2 IV on day 1
-'''21-day cycles'''
-===Regimen #3, Petrasch et al. 1998 {{#subobject:a5b523|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Cisplatin (Platinol)]] 50 mg/m2 IV over 60 minutes on day 1, given second
-*[[Paclitaxel (Taxol)]] 90 mg/m2 IV over 3 hours on day 1, given first
-'''14-day cycles'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 20 mg IV 30 minutes prior to paclitaxel
-*Cimetidine (Tagamet) 300 mg IV 30 minutes prior to paclitaxel
-*Clemastine 2 mg IV 30 minutes prior to paclitaxel
-*Ondansetron 8 mg IV 30 minutes prior to paclitaxel
-*"Adequate pre- and posthydration" for cisplatin
 ===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. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063082 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9716036 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]
-# 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''' [http://www.ncbi.nlm.nih.gov/pubmed/11079171 PubMed]
+==Cisplatin & Fluorouracil (CF) & Pembrolizumab {{#subobject:c798a3|Regimen=1}}==
-# Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 2008 Feb;31(1):29-33. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2008&issue=02000&article=00005&type=abstract link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18376224 PubMed]
+CF & Pembrolizumab: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, Pembrolizumab
+<div class="toccolours" style="background-color:#eeeeee">
-==CX, XP {{#subobject:c58325|Regimen=1}}==
+===Regimen {{#subobject:d18acj2|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
 |-
-|[[#toc|back to top]]
 |}
-CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-===Regimen,  &  {{#subobject:130681|Variant=1}}===
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-{| border="1" style="text-align:center;" !align="left"
+!style="width: 20%"|Comparator
-|'''Study'''
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://annonc.oxfordjournals.org/content/20/4/666.long Kang et al. 2009]
+|[https://doi.org/10.1016/s0140-6736(21)01234-4 Sun et al. 2021 (KEYNOTE-590)]
-|<span
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-style="background:#00CD00;
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-308-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[Esophageal_cancer#CF.2C_FP|CF]]
 |-
-!colspan="4" align="center"|
+|} -->
-|-
+|2017-2019
-|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|<span
+|[[#Cisplatin_.26_Fluorouracil_.28CF.29_4|CF]]
-style="background:#00CD00;
+| 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)
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#CX_.26_Trastuzumab|CX & Trastuzumab]]
-|-
-!colspan="4" align="center"|
-|-
-|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70102-5/abstract Lordick et al. 2013 (EXPAND)]
-|<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#CX_.26_Cetuximab|CX & Cetuximab]]
 |-
 |}
+''Note: 73% of patients had squamous histology. MCBS score is for all patients, regardless of CPS status.''
-*[[Cisplatin (Platinol)]] 80 mg/m2 IV over 2 hours once on day 1
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID on days 1 to 14
+====Immunotherapy====
-**Lordick et al. 2013 gave [[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID from the evening of day 1 to the morning of day 15 (28 doses per cycle)
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+====Chemotherapy====
-Supportive medications per Kang et al. 2009:
+*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*"Hyperhydration" for [[Cisplatin (Platinol)]]
+*[[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)'''
-'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+</div></div>
 ===References===
-# Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [http://annonc.oxfordjournals.org/content/20/4/666.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19153121 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]
-# Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]
-# Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie (AIO) and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. doi: 10.1016/S1470-2045(13)70102-5. Epub 2013 Apr 15. [http://www.sciencedirect.com/science/article/pii/S1470204513701025 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23594786 PubMed]
-==CX & Cetuximab {{#subobject:318959|Regimen=1}}==
+==Cisplatin & Irinotecan (IC) {{#subobject:ec60da|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+IC: '''<u>I</u>'''rinotecan & '''<u>C</u>'''isplatin
+<br>CI: '''<u>C</u>'''isplatin & '''<u>I</u>'''rinotecan
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:8f624d|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.cancernetwork.com/view/phase-ii-trial-weekly-irinotecancisplatin-advanced-esophageal-cancer Ilson 2004]
+|NR
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#toc|back to top]]
 |}
-CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
-===Regimen {{#subobject:afe6a1|Variant=1}}===
+====Chemotherapy====
-{| border="1" style="text-align:center;" !align="left"
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
-|'''Study'''
+*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV once per day on days 1 & 8
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+'''21-day cycles'''
-|'''Comparator'''
+</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]]
 |-
-|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70102-5/abstract Lordick et al. 2013 (EXPAND)]
+|[https://doi.org/10.1200/jco.1999.17.10.3270 Ilson et al. 1999]
-|<span
+|1997-07 to 1998-09
-style="background:#00CD00;
+| style="background-color:#91cf61" |Phase 2
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[Esophageal_cancer#CX.2C_XP|CX]]
 |-
 |}
+''Note: Patients had 66% adenocarcinoma, 34% squamous cell histology. Did not receive any prior chemotherapy. 97% with metastatic disease.''
-*[[Cisplatin (Platinol)]] 80 mg/m2 IV over 2 hours once on day 1
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID from the evening of day 1 to the morning of day 15 (28 doses per cycle)
+====Chemotherapy====
-*[[Cetuximab (Erbitux)]] as follows:
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
-**Cycle 1 day 1: 400 mg/m2 IV once
+*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22
-**Subsequently: 250 mg/m2 IV once per week
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] 20 mg IV once per day on days 1, 8, 15, 22, prior to chemotherapy
-'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+*[[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'''
+</div></div>
 ===References===
-# Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie (AIO) and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70102-5/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23594786 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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10506629/ 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. [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]
-==CX & Trastuzumab {{#subobject:7cbb79|Regimen=1}}==
+==Cisplatin & Paclitaxel {{#subobject:5d50ee|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:ffaa05|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://pubmed.ncbi.nlm.nih.gov/11079171 Ilson et al. 2000]
+|NR in abstract
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#toc|back to top]]
 |}
-CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
-===Regimen {{#subobject:27adc6|Variant=1}}===
+====Chemotherapy====
-{| border="1" style="text-align:center;" !align="left"
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 2, '''given second'''
-|'''Study'''
+*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+====Supportive therapy====
-|'''Comparator'''
+*"Granulocyte colony stimulating factor support"
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:a5b523|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]]
 |-
-|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063082 Petrasch et al. 1998]
-|<span
+|NR
-style="background:#00CD00;
+| style="background-color:#91cf61" |Phase 2
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[Esophageal_cancer#CX.2C_XP|CX]]
 |-
 |}
+''Note: Patients had 25% adenocarcinoma, 75% squamous cell histology. Consisting of unresectable stage III disease, recurrent or metastatic tumors of esophageal origin.''
-*[[Cisplatin (Platinol)]] 80 mg/m2 IV once on day 1
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID on days 1 to 14
+====Chemotherapy====
-*[[Trastuzumab (Herceptin)]] as follows:
+*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
-**Cycle 1: 8 mg/kg IV once on day 1
+*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-**Subsequent cycles: 6 mg/kg IV once on day 1
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] 20 mg IV once on day 1; 30 minutes prior to paclitaxel
-'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+*[[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- [[:Category:Hydration|hydration]]" for cisplatin
+'''14-day cycles'''
+</div></div>
 ===References===
-# Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20728210 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://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]
+#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]
-==Docetaxel (Taxotere) {{#subobject:421f5e|Regimen=1}}==
+==Docetaxel & Irinotecan {{#subobject:96e013|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:38cdd0|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/PMC2699385/ Burtness et al. 2009]
+|2001-12 to 2004-10
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:b279a5|Variant=1}}===
+''Note: Patients had 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''
-padding:3px 6px 3px 6px;
+*[[Irinotecan (Camptosar)]] 50 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
-border-color:black;
+====Supportive therapy====
-border-width:2px;
+*[[Dexamethasone (Decadron)]] as follows:
-border-style:solid;">Phase II</span>
+**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
-Note: In addition to the original reference, the NCCN, Esophageal Cancer version 2.2011, also lists docetaxel 75 mg/m2 as an alternate dosage.
+**8 mg PO once per day on days 1 & 8; 12 hour afters chemotherapy
-*[[Docetaxel (Taxotere)]] 100 mg/m2 IV over 1 hour on day 1
+*[[: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'''
+</div></div>
 ===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. '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17917090 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 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]
+==ECF {{#subobject:6325cb|Regimen=1}}==
-==DCF, TCF {{#subobject:efbdc5|Regimen=1}}==
+ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen {{#subobject:e5ede0|Variant=1}}===
-|[[#toc|back to top]]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|}
+!style="width: 20%"|Study
-DCF: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+!style="width: 20%"|Dates of enrollment
-<br>TCF: '''<u>T</u>'''axotere, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-===Regimen #1 {{#subobject:5aba07|Variant=1}}===
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/23/24/5660.long Ajani et al. 2005]
+|[https://doi.org/10.1200/jco.2002.08.105 Ross et al. 2002]
-|<span
+|1995-1998
-style="background:#00CD00;
+| style="background-color:#1a9851" |Phase 3 (C)
-padding:3px 6px 3px 6px;
+|[[#MCF|MCF]]
-border-color:black;
+| style="background-color:#eeee01" |Seems to have non-inferior OS
-border-width:2px;
-border-style:solid;">Randomized Phase II</span>
-|[[#DC.2C_TC|DC]]
 |-
-|[http://jco.ascopubs.org/content/24/31/4991.long Van Cutsem et al. 2006 (V325 Study Group)]
+| rowspan="3" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
-|<span
+|rowspan=3|2000-2005
-style="background:#00CD00;
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (C)
-padding:3px 6px 3px 6px;
+|1. [[#ECX_2|ECX]]
-border-color:black;
+| style="background-color:#eeee01" |Non-inferior OS
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#CF.2C_FP|CF]]
 |-
-|}
+|2. [[#EOF_2|EOF]]
+| style="background-color:#eeee01" |Non-inferior OS
-''Note: In contrast to the original references, the NCCN, Esophageal Cancer version 2.2011, lists each cycle as lasting 28 days.''
-*[[Docetaxel (Taxotere)]] 75 mg/m2 IV over 1 hour once on day 1
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 1 to 3 hours once on day 1
-*[[Fluorouracil (5-FU)]] 750 mg/m2/day IV continuous infusion on days 1 to 5
-'''21-day cycles, given until progression of disease or unacceptable toxicity'''
-Supportive medications (varied depending on reference):
-*[[Dexamethasone (Decadron)]] 8 mg PO the night before chemotherapy, the morning of day 1, 1 hour before chemotherapy, the night of day 1, the morning of day 2, and the evening of day 2 (6 total doses)
-*[[Dexamethasone (Decadron)]] 20 mg IV before cisplatin and 8 hours after cisplatin
-*[[Ondansetron (Zofran)]] 8 mg IV before cisplatin, 4 hours cisplatin, and 8 hours after cisplatin
-*"Hydration [was] administered in a standard manner"
-===Regimen #2 {{#subobject:baa015|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/25/22/3217.long Roth et al. 2007]
+|3. [[#EOX_2|EOX]]
-|<span
+| style="background-color:#fc8d59" |Seems to have inferior OS
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II</span>
-|[[#ECF_2|ECF]]<br> [[#DC.2C_TC|TC]]
 |-
 |}
-*[[Docetaxel (Taxotere)]] 75 mg/m2 IV over 1 hour once on day 1; the protocol was amended to change the original dose of 85 mg/m2 to 75 mg/m2 based on high incidence of febrile neutropenia
+''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.''
-*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 4 hours once on day 1
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Fluorouracil (5-FU)]] 300 mg/m2/day IV continuous infusion on days 1 to 14
+====Chemotherapy====
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-'''21-day cycle x up to 8 cycles'''
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 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:
+====Supportive therapy====
+*(varied depending on reference):
 *3 liters per day "hyperhydration"
-*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours before docetaxel, then 8 mg PO BID x 4 days after docetaxel
+*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis
-*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'''
+</div></div>
 ===References===
-# Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [http://jco.ascopubs.org/content/23/24/5660.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16110025 PubMed]
+#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]
-# Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [http://jco.ascopubs.org/content/24/31/4991.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17075117 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://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
-# Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17664469 PubMed]
+==ECX {{#subobject:bb95b5|Regimen=1}}==
+ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)
-==mDCF {{#subobject:70e20f|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:e965c5|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]]
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+|rowspan=2|2000-2005
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|1. [[#ECF_2|ECF]]
+| 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)
 |-
-|[[#toc|back to top]]
 |}
-mDCF: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+''Note: REAL-2 patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric primary site. 11% ECOG PS of 2.''
-===Regimen #1, Ozal et al. 2010 {{#subobject:323b13|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Docetaxel (Taxotere)]] 60 mg/m2 IV on day 1
+====Chemotherapy====
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV on day 1
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Fluorouracil (5-FU)]] 750 mg/m2/day IV continuous infusion on days 1 to 4
+*[[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 cycles'''
+'''21-day cycle for up to 8 cycles'''
+</div></div>
-===Regimen #2, Shah et al. 2011 {{#subobject:372f9c|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-''Note: In contrast to the primary reference, the NCCN, Esophageal Cancer version 2.2011 listed this regimen without bevacizumab.  Please see below for the original mDCF regimen that included bevacizumab.''
-*[[Docetaxel (Taxotere)]] 40 mg/m2 IV over 1 hour on days 1, 15, 29
-*[[Cisplatin (Platinol)]] 40 mg/m2 IV over 1-3 hours on days 3, 17, 31
-*[[Folinic acid (Leucovorin)]] 400 mg/m2 IV on days 1, 15, 29
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus on days 1, 15, 29, then 1000 mg/m2/day IV continuous infusion on days 1 to 2, 15-16, 29-30
-'''42-day cycles, given until progression of disease or unacceptable toxicity'''
-Supportive medications:
-*"Standard premedication and delayed emesis regimens"
 ===References===
-# G. Ozal, M. Dogan, H. Akbulut, B. Yalcin, G. Utkan, Y. Urun, F. Icli. The safety and efficacy of modified-dose docetaxel, cisplatin, and 5-fluorouracil (mDCF) combination in the front-line treatment of advanced gastric cancer. 2010 Gastrointestinal Cancers Symposium abstract 113. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=72&abstractID=1882 link to abstract]
+#'''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
-# Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [http://jco.ascopubs.org/content/29/7/868.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21189380 PubMed]
+==EOF {{#subobject:a6390c|Regimen=1}}==
+EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
-==mDCF & Bevacizumab (Avastin) {{#subobject:30ea9e|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:abf19f|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]]
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]
+|rowspan=2|2000-2005
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|1. [[#ECF_2|ECF]]<br>2. [[#ECX_2|ECX]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
+|-
+|3. [[#EOX_2|EOX]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
 |-
-|[[#toc|back to top]]
 |}
-mDCF: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+''Note: Patients had 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''
-===Regimen {{#subobject:5485f9|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-Level of Evidence:
+====Chemotherapy====
-<span
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1
-style="background:#EEEE00;
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-padding:3px 6px 3px 6px;
+*[[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>)
-border-color:black;
+====Supportive therapy====
-border-width:2px;
+*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
-border-style:solid;">Phase II</span>
+'''21-day cycle for up to 8 cycles'''
+</div></div>
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV on days 1, 15, 29
-*[[Docetaxel (Taxotere)]] 40 mg/m2 IV over 1 hour on days 1, 15, 29
-*[[Cisplatin (Platinol)]] 40 mg/m2 IV over 1-3 hours on days 3, 17, 31
-*[[Folinic acid (Leucovorin)]] 400 mg/m2 IV on days 1, 15, 29
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus on days 1, 15, 29, then 1000 mg/m2/day IV continuous infusion on days 1 to 2, 15-16, 29-30
-'''42-day cycles, given until progression of disease or unacceptable toxicity'''
-Supportive medications:
-*"Standard premedication and delayed emesis regimens"
 ===References===
-# Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [http://jco.ascopubs.org/content/29/7/868.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21189380 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://doi.org/10.1056/NEJMoa073149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172173/ PubMed] ISRCTN51678883
+==EOX {{#subobject:438182|Regimen=1}}==
-==Docetaxel (Taxotere), Carboplatin (Paraplatin), Fluorouracil (5-FU) {{#subobject:f4e05b|Regimen=1}}==
+EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:339609|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]]
+|-
+| 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 (E-RT-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 (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
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:e0e534|Variant=1}}===
+''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.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
-padding:3px 6px 3px 6px;
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-border-color:black;
+*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21
-border-width:2px;
+'''21-day cycle for up to 8 cycles'''
-border-style:solid;">Phase II</span>
+</div></div>
-*[[Docetaxel (Taxotere)]] 75 mg/m2 IV on day 1
-*[[Carboplatin (Paraplatin)]] AUC 6 IV on day 2
-*[[Fluorouracil (5-FU)]] 1200 mg/m2/day IV continuous infusion on days 1 to 3
-'''21-day cycles'''
-Supportive medications:
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC on days 4-9
 ===References===
-# Y. M. Elkerm, A. Elsaid, S. AL-Batran, C. Pauligk. Final results of a phase II trial of docetaxel-carboplatin-FU in locally advanced gastric carcinoma. 2008 Gastrointestinal Cancers Symposium abstract 38. [http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=53&abstractID=10199 link to abstract]
+#'''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
+#'''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]
-==Docetaxel (Taxotere) & Irinotecan (Camptosar) {{#subobject:96e013|Regimen=1}}==
+==mFOLFOX6 & Cetuximab {{#subobject:e51095|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
+<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">
+===Regimen {{#subobject:2a9d10|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]]
 |-
-|[[#toc|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019745/ Enziger et al. 2016 (CALGB 80403/ECOG E1206)]
-|}
+|2006-2009
-===Regimen {{#subobject:38cdd0|Variant=1}}===
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
-Level of Evidence:
+|1. [[#ECF_.26_Cetuximab_888|ECF-C]]<br>2. [[#Cisplatin_.26_Irinotecan_.28IC.29_.26_Cetuximab_888|IC-C]]
-<span
+| style="background-color:#d3d3d3" |Not powered to draw conclusions
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Docetaxel (Taxotere)]] 35 mg/m2 IV over 1 hour on days 1 & 8, given first
-*[[Irinotecan (Camptosar)]] 50 mg/m2 IV over 30 minutes on days 1 & 8, given second
-'''21-day cycles'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours before docetaxel, then 10 mg IV within 1 hour before chemotherapy
-===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. [http://annonc.oxfordjournals.org/content/20/7/1242.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19429872 PubMed]
-==DOF {{#subobject:6e7c57|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-DOF: '''<u>D</u>'''ocetaxel, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
+''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.''
-===Regimen {{#subobject:2e0f55|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-Level of Evidence:
+====Chemotherapy====
-<span
+*[[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>)
-style="background:#EEEE00;
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with oxaliplatin'''
-padding:3px 6px 3px 6px;
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with leucovorin'''
-border-color:black;
+====Targeted therapy====
-border-width:2px;
+*[[Cetuximab (Erbitux)]] as follows, '''given first''':
-border-style:solid;">Phase II</span>
+**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
-*[[Docetaxel (Taxotere)]] 50 mg/m2 IV on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV on day 1
-*[[Fluorouracil (5-FU)]] 1200 mg/m2/day IV continuous infusion over 46 hours (2400 mg/m2 total dose) on days 1 to 2
 '''14-day cycles'''
+</div></div>
 ===References===
-# V. Shankaran, M. F. Mulcahy, H. S. Hochster, T. Ryan, H. Choi, A. B. Benson. Docetaxel, oxaliplatin, and 5-fluorouracil for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinomas: Preliminary results of a phase II study. 2009 Gastrointestinal Cancers Symposium abstract 47. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=63&abstractID=10246 link to abstract]
+<!--
+# 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] -->
-==ECF {{#subobject:6325cb|Regimen=1}}==
+#'''CALGB 80403/ECOG E1206:''' Enzinger PC, Burtness BA, Niedzwiecki D, Ye X, Douglas K, Ilson DH, Villaflor VM, Cohen SJ, Mayer RJ, Venook A, Benson AB 3rd, Goldberg RM. CALGB 80403 (Alliance)/E1206: a randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers. J Clin Oncol. 2016 Aug 10;34(23):2736-42. Epub 2016 Jul 5. [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]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+==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/10.1159/000087815 Morgan-Meadows et al. 2005]
+|1998-06 to 2001-11
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#toc|back to top]]
 |}
-ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+''Note: Patients had 100% esophageal cancer (both squamous and adenocarcinoma histology). Patients received no prior therapy.''
-===Regimen {{#subobject:e5ede0|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-Level of Evidence:
+====Chemotherapy====
-<span
+*[[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>)
-style="background:#00CD00;
+*[[Leucovorin (Folinic acid)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-padding:3px 6px 3px 6px;
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-border-color:black;
+'''28-day cycles'''
-border-width:2px;
+</div></div>
-border-style:solid;">Phase III</span>
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV bolus on day 1
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV over 4 hours on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m2/day IV continuous infusion on days 1 to 21
-'''21-day cycles x up to 8 cycles'''
-Supportive medications (varied depending on reference):
-*3 liters per day "hyperhydration"
-*5-HT3 antagonist for emesis prophylaxis
-*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]
-*Ross et al. 2002 & Cunningham et al. 2008 used [[Warfarin (Coumadin)]] 1 mg PO daily for catheter thrombosis prophylaxis
 ===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. [http://jco.ascopubs.org/content/20/8/1996.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11956258 PubMed]
+<!-- # 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] -->
-# Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17664469 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]
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed]
+==LdCF {{#subobject:f31fcc|Regimen=1}}==
+LdCF: '''<u>L</u>'''iposomal '''<u>d</u>'''oxorubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-==ECX {{#subobject:bb95b5|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:1b58a0|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/10.1007/s00280-010-1424-8 Cascinu et al. 2010]
+|2002-2005
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
+|[[#MCF|MCF]]
+| style="background-color:#91cf60" |Seems to have superior OS
 |-
-|[[#toc|back to top]]
 |}
-ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda
+''Note: Patients had 11% gastroesophageal junction, 89% gastric origin. 90% metastatic. 6% with ECOG PS of 2.''
-===Regimen {{#subobject:e965c5|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-Level of Evidence:
+====Chemotherapy====
-<span
+*[[Pegylated liposomal doxorubicin (Doxil)]] 20 mg/m<sup>2</sup> IV once on day 1
-style="background:#00CD00;
+*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once on day 1
-padding:3px 6px 3px 6px;
+*[[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>)
-border-color:black;
+'''14-day cycles'''
-border-width:2px;
+</div></div>
-border-style:solid;">Phase III</span>
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV bolus on day 1
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV over 4 hours on day 1
-*[[Capecitabine (Xeloda)]] 625 mg/m2 PO BID on days 1 to 21
-'''21-day cycles x up to 8 cycles'''
-Supportive medications:
-*[[Warfarin (Coumadin)]] 1 mg PO daily for catheter thrombosis prophylaxis
 ===References===
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18172173 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]
+==MCF {{#subobject:d3775b|Regimen=1}}==
-==EOF {{#subobject:a6390c|Regimen=1}}==
+MCF: '''<u>M</u>'''itomycin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:47b99f|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.2002.08.105 Ross et al. 2002]
+|1995-1998
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#ECF_2|ECF]]
+| style="background-color:#eeee01" |Seems to have non-inferior OS (primary endpoint)
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1007/s00280-010-1424-8 Cascinu et al. 2010]
-|}
+|2002-2005
-EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-===Regimen {{#subobject:abf19f|Variant=1}}===
+|[[#LdCF|LdCF]]
-Level of Evidence:
+| style="background-color:#fc8d59" |Seems to have inferior OS
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV bolus on day 1
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m2 IV over 2 hours on day 1
-*[[Fluorouracil (5-FU)]] 200 mg/m2/day IV continuous infusion on days 1 to 21
-'''21-day cycles x up to 8 cycles'''
-Supportive medications:
-*[[Warfarin (Coumadin)]] 1 mg PO daily for catheter thrombosis prophylaxis
-===References===
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed]
-==EOX, EOC {{#subobject:438182|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda
+''Note: Cascinu et al. patients had 11% gastroesophageal junction, 89% gastric primary site. 90% metastatic. 6% with ECOG PS of 2.''
-<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-===Regimen #1, Cunningham et al. 2008 (REAL-2) {{#subobject:3e4f2b|Variant=1}}===
+*[[Mitomycin (Mutamycin)]] 7 mg/m<sup>2</sup> (maximum dose of 14 mg) IV once on day 1
-Level of Evidence:
+*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 22
-<span
+*[[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>)
-style="background:#00CD00;
+====Supportive therapy====
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[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)]] 625 mg/m2 PO BID on days 1 to 21
-'''21-day cycles x up to 8 cycles'''
-Supportive medications:
 *[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis
+'''42-day cycle for up to 5 cycles (6 months)'''
-===Regimen #2, Waddell et al. 2013 (REAL3) {{#subobject:339609|Variant=1}}===
+</div></div>
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Epirubicin (Ellence)]] 50 mg/m2 IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m2 IV once on day 1
-*[[Capecitabine (Xeloda)]] 1250 mg/m2/day PO (it is assumed this daily dose was divided into two doses per day) on days 1 to 21
-'''21-day cycles x up to 8 cycles'''
 ===References===
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed] content property of [http://hemonc.org HemOnc.org]
+#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]
-# Waddell T, Chau I, Cunningham D, Gonzalez D, Frances A, 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. doi: 10.1016/S1470-2045(13)70096-2. Epub 2013 Apr 15. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669518/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23594787 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]
-==Erlotinib (Tarceva) {{#subobject:5efb4d|Regimen=1}}==
+==Paclitaxel monotherapy {{#subobject:ed008a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, weekly {{#subobject:dd30a4|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]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1093/annonc/mdm004 Ilson et al. 2007]
-|}
+|1998-01 to 2000-04
-===Regimen {{#subobject:eaf7de|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day on days 1 to 28, at least 1 hour before a meal, or 2 hours after a meal
-'''28-day cycles'''
-===References===
-# Dragovich T, McCoy S, Fenoglio-Preiser CM, Wang J, Benedetti JK, Baker AF, Hackett CB, Urba SG, Zaner KS, Blanke CD, Abbruzzese JL. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006 Oct 20;24(30):4922-7. [http://jco.ascopubs.org/content/24/30/4922.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17050876 PubMed]
-# 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. doi: 10.1002/cncr.25602. Epub 2010 Nov 8. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.25602/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21425140 PubMed]
-==Etoposide (Vepesid) {{#subobject:344c29|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:bdcf31|Variant=1}}===
+''Note: Patients had 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.''
-''Note: The references cited by the NCCN, Esophageal Cancer version 2.2011, did not contain this regimen.  Etoposide 120 mg/m2 was used as part of ELF (Etoposide (Vepesid), Folinic acid (Leucovorin), Fluorouracil (5-FU)) regimens in [http://jco.ascopubs.org/content/18/14/2648.long Vanhoefer U et al. 2000] ([http://www.ncbi.nlm.nih.gov/pubmed/10894863 PubMed]) and [http://annonc.oxfordjournals.org/content/5/1/90.long Taal BG et al. 1994] ([http://www.ncbi.nlm.nih.gov/pubmed/8172800 PubMed]).  No primary reference could be found for this monotherapy regimen.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Etoposide (Vepesid)]] 90 to 120 mg/m2 IV once per day on days 1 to 3
+====Chemotherapy====
+*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> 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'''
+</div></div><br>
-==Fluorouracil (5-FU) {{#subobject:588907|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen variant #2, CI {{#subobject:1d24a4|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]]
 |-
-|[[#toc|back to top]]
+|[http://jnci.oxfordjournals.org/content/86/14/1086.long Ajani et al. 1994]
-|}
+|1992-08 to 1993-12
-===Regimen {{#subobject:3289d8|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
-|-
-|[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG9205)]
-|<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#CF.2C_FP|FP]]<br> [[#UFTM|UFTM]]
 |-
 |}
+''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">
-*[[Fluorouracil (5-FU)]] 800 mg/m2/day IV continuous infusion on days 1 to 5
+====Dose and schedule modifications====
+*[[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>
-'''28-day cycles'''
+</div></div>
 ===References===
-# Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12506170 PubMed]
+#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]
-==Fluorouracil (5-FU) & Folinic acid (Leucovorin) {{#subobject:5aad1e|Regimen=1}}==
+=Metastatic or locally advanced disease, subsequent lines of therapy=
-{| class="wikitable" style="float:right; margin-left: 5px;"
+==CAPIRI {{#subobject:c699c3|Regimen=1}}==
+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
+<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]]
+|-
+|[https://doi.org/10.1007/s00280-008-0893-5 Leary et al. 2008]
+|2003-10 to 2005-09
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:2d601|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-Level of Evidence:
+====Chemotherapy====
-<span
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-style="background:#00CD00;
+*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1
-padding:3px 6px 3px 6px;
+====Supportive therapy====
-border-color:black;
+*[[Atropine (Atropen)]] 0.25 mg SC once on day 1, given prior to irinotecan
-border-width:2px;
+*[[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
-border-style:solid;">Randomized Phase II, >20 per arm</span>
+*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day prn diarrhea lasting longer than 24 hours despite loperamide
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 2 hours on day 1
+'''21-day cycle for up to 8 cycles'''
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours on days 1 to 2
+</div></div>
-'''14-day cycles x at least 4 cycles or until progression of disease or unacceptable toxicity''' (primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used)
 ===References===
-# Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [http://jco.ascopubs.org/content/22/21/4319.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15514373 PubMed]
+#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}}==
-==Fluorouracil (5-FU), Folinic acid (Leucovorin), Mitomycin (Mutamycin) {{#subobject:a4ca9d|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===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>
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:672a28|Variant=1}}===
+''<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.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-padding:3px 6px 3px 6px;
+'''21-day cycles'''
-border-color:black;
+</div></div><br>
-border-width:2px;
+<div class="toccolours" style="background-color:#eeeeee">
-border-style:solid;">Phase II</span>
+===Regimen variant #2, 100 mg/m<sup>2</sup> {{#subobject:b279a5|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-*[[Folinic acid (Leucovorin)]] 500 mg/m2 IV over 2 hours on days 1, 8, 15, 22, 29, 36; given before Fluorouracil (5-FU)
+!style="width: 33%"|Study
-*[[Fluorouracil (5-FU)]] 2600 mg/m2 IV continuous infusion over 24 hours on days 1, 8, 15, 22, 29, 36; given after Folinic acid (Leucovorin)
+!style="width: 33%"|Dates of enrollment
-*[[Mitomycin (Mutamycin)]] 10 mg/m2 IV on days 1 & 22
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-'''56-day cycles x 2 cycles'''
-===References===
-# Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. Onkologie. 2002 Jun;25(3):255-60. '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12119460 PubMed]
-==FLOT {{#subobject:b427b1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1007/s12032-007-0028-6 Albertsson et al. 2007]
-|}
+|1997-2003
-FLOT: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin, '''<u>T</u>'''axotere
+| style="background-color:#91cf61" |Phase 2
-===Regimen {{#subobject:bb5eb6|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Fluorouracil (5-FU)]] 2600 mg/m2 IV continuous 24-hour infusion on day 1, given after leucovorin, oxaliplatin, and docetaxel
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 1-2 hours on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV over 1-2 hours on day 1
-*[[Docetaxel (Taxotere)]] 50 mg/m2 IV over 1-2 hours on day 1
-'''14-day cycles x up to 8 (or more) cycles'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 8 mg PO daily on days 0-3 of every cycle
-===References===
-# Al-Batran SE, Hartmann JT, Hofheinz R, Homann N, Rethwisch V, Probst S, Stoehlmacher J, Clemens MR, Mahlberg R, Fritz M, Seipelt G, Sievert M, Pauligk C, Atmaca A, Jäger E. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2008 Nov;19(11):1882-7. Epub 2008 Jul 31. [http://annonc.oxfordjournals.org/content/19/11/1882.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18669868 PubMed]
-==FOLFIRI {{#subobject:ba35aa|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
+''Note: Patients had squamous cell or adenocarcinoma histology of the esophagus or gastric cardia.''
-===Regimen #1, Dank et al. 2008 {{#subobject:cec083|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-Level of Evidence:
+====Chemotherapy====
-<span
+*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-style="background:#00CD00;
+'''21-day cycles'''
-padding:3px 6px 3px 6px;
+</div></div>
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Fluorouracil (5-FU)]] 2000 mg/m2/day IV continuous 22-hour infusion on days 1, 8, 15, 22, 29, 36; given after Irinotecan (Camptosar) and Folinic acid (Leucovorin)
-*[[Folinic acid (Leucovorin)]] 500 mg/m2 IV over 2 hours on days 1, 8, 15, 22, 29, 36; given second
-*[[Irinotecan (Camptosar)]] 80 mg/m2 IV over 30 minutes on days 1, 8, 15, 22, 29, 36; given first
-'''7-week cycles'''
-Supportive medications:
-*Ondansetron for antiemetic prophylaxis
-*Dexamethasone for antiemetic prophylaxis
-*[[Filgrastim (Neupogen)]] daily SC, starting on day 4, to be continued until ANC > 1 x 10^9/L for grade 3-4 neutropenia, febrile neutropenia, or neutropenic infection
-*Atropine prn cholinergic symptoms
-*Loperamide prn delayed diarrhea
-===Regimen #2, Bouché et al. 2004 (FFCD 9803) {{#subobject:56018a|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II, >20 per arm</span>
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 2 hours on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours on days 1 to 2
-*[[Irinotecan (Camptosar)]] 180 mg/m2 IV over 90 minutes on day 1
-'''14-day cycles x at least 4 cycles or until progression of disease or unacceptable toxicity''' (primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used)
-===Regimen #3, Samalin et al. 2010 & Samalin et al. 2011 {{#subobject:6526d0|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Non-randomized</span>
-*[[Folinic acid (Leucovorin)]] 400 mg/m2 IV over 2 hours on day 1, given second
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus, then 1200 mg/m2/day (2400 mg/m2 total dose) IV continuous infusion over 46 hours on days 1 to 2
-*[[Irinotecan (Camptosar)]] 180 mg/m2 IV over 90 minutes on day 1, given first
-'''14-day cycles'''
 ===References===
-# Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [http://jco.ascopubs.org/content/22/21/4319.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15514373 PubMed]
+#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]
-# Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. [http://annonc.oxfordjournals.org/content/19/8/1450.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18558665 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] -->
-# Wolff K, Wein A, Reulbach U, Männlein G, Brückl V, Meier C, Ostermeier N, Schwab SA, Horbach T, Hohenberger W, Hahn EG, Boxberger F. Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial. Anticancer Drugs. 2009 Mar;20(3):165-73. [http://journals.lww.com/anti-cancerdrugs/pages/articleviewer.aspx?year=2009&issue=03000&article=00002&type=abstract link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19125117 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]
-# Samalin E, Afchain P, Thézenas S, Abbas F, Romano O, Guimbaud R, Bécouarn Y, Desseigne F, Edeline J, Mitry E, Bouché O, Adenis A, Aparicio T, Dorval E, Kramar A, Ychou M. Efficacy of irinotecan in combination with 5-fluorouracil (FOLFIRI) for metastatic gastric or gastroesophageal junction adenocarcinomas (MGA) treatment. Gastroenterol Clin Biol. 2010 Oct 28. [Epub ahead of print] [http://www.em-consulte.com/article/280010/alertePM link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21035972 PubMed]
+#'''INTEGRATE IIb:''' [https://clinicaltrials.gov/study/NCT04879368 NCT04879368]
-# Samalin E, Afchain P, Thézenas S, Abbas F, Romano O, Guimbaud R, Bécouarn Y, Desseigne F, Edeline J, Mitry E, Bouché O, Adenis A, Aparicio T, Dorval E, Kramar A, Ychou M. Efficacy of irinotecan in combination with 5-fluorouracil (FOLFIRI) for metastatic gastric or gastroesophageal junction adenocarcinomas (MGA) treatment. Clin Res Hepatol Gastroenterol. 2011 Jan;35(1):48-54. '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21634054 PubMed]
+==Docetaxel & Irinotecan {{#subobject:96f053|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==FOLFOX-C (Cetuximab (Erbitux)) {{#subobject:e51095|Regimen=1}}==
+===Regimen {{#subobject:38cff0|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]]
 |-
-|[[#toc|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ Burtness et al. 2009]
-|}
+|2001-12 to 2004-10
-FOLFOX-C: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>C</u>'''etuximab
+| style="background-color:#ffffbe" |Phase 2, fewer than 20 pts in this subgroup
-===Regimen {{#subobject:2a9d10|Variant=1}}===
-''Note: This regimen included Cetuximab (Erbitux), but the dosage was not listed in the abstract nor clinicaltrials.gov listing.  The NCCN, Esophageal Cancer version 2.2011, listed this regimen without cetuximab.''
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV bolus, then 1200 mg/m2/day IV continuous infusion on days 1 & 2; given after Oxaliplatin (Eloxatin) and Folinic acid (Leucovorin)
-*[[Folinic acid (Leucovorin)]] 500 mg/m2 IV over 2 hours on day 1, given second
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV over 2 hours on day 1, given first
-*Cetuximab (Erbitux) dosage not described (but based on other applications may be 400 mg/m2 for the first dose, then 250 mg/m2 on subsequent doses) IV over 1-2 hours on days 1 & 8
-'''14-day cycles'''
-===References===
-# [http://clinicaltrials.gov/ct2/show/NCT00381706 Combination Chemotherapy and Cetuximab in Treating Patients With Metastatic Esophageal Cancer or Gastroesophageal Junction Cancer] (ClinicalTrials.gov)
-# 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]
-==Gemcitabine (Gemzar), Fluorouracil (5-FU), Folinic acid (Leucovorin) {{#subobject:876cd7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:173a91|Variant=1}}===
+''Note: Patients had 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''
-padding:3px 6px 3px 6px;
+*[[Irinotecan (Camptosar)]] 50 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
-border-color:black;
+====Supportive therapy====
-border-width:2px;
+*[[Dexamethasone (Decadron)]] as follows:
-border-style:solid;">Phase II</span>
+**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
-*[[Gemcitabine (Gemzar)]] 1000 mg/m2 IV on days 1, 8, 15
+**8 mg PO once per day on days 1 & 8; 12 hour afters chemotherapy
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1, 8, 15
+*[[:Category:Serotonin 5-HT3 antagonists|Serotonin 5-HT3 antagonist]] IV once per day on days 1 & 8, within 1 hour before chemotherapy
-*[[Folinic acid (Leucovorin)]] 20 mg/m2 IV on days 1, 8, 15
+*"Oral antiemetic therapy prescribed"
+*[[Loperamide (Imodium)]] as needed
-'''28-day cycles x up to 8 cycles'''
+'''21-day 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]
+#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]
+==Erlotinib monotherapy {{#subobject:5efb4d|Regimen=1}}==
-==Irinotecan (Camptosar) {{#subobject:6df2c0|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:eaf7de|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]]
 |-
-|[[#toc|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116987/ Ilson et al. 2010]
-|}
+|2002-07 to 2005-09
-===Regimen #1, q3wk dosing {{#subobject:160f2f|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
-|-
-|[http://www.ejcancer.info/article/S0959-8049%2811%2900396-0/fulltext Thuss-Patience et al. 2011]
-|<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Best_supportive_care|Best supportive care]]
 |-
 |}
+''Note: Patients had 57% adenocarcinoma, 43% squamous cell histology. 6% proximal esophagus, 35% distal esophagus, 59% gastroesophageal junction.''
+<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 (Camptosar)]] as follows:
+==Irinotecan monotherapy {{#subobject:6df2c0|Regimen=1}}==
-**Cycle 1: 250 mg/m2 (capped at BSA = 2 m2) IV over 30 minutes once on day 1
+<div class="toccolours" style="background-color:#eeeeee">
-**Cycles 2 to 10 (depending on toxicity): 350 mg/m2 IV over 30 minutes once on day 1
+===Regimen variant #1, 14-day cycles {{#subobject:9b9303|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-'''21-day cycle x up to 10 cycles'''
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-Supportive medications:
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-*Atropine 0.25 mg SC before irinotecan as prophylaxis against cholinergic symptoms
+!style="width: 20%"|Comparator
-*"5-HT3 antagonists and dexamethasone"
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-===Regimen #2, 4 weeks on, 2 weeks off dosing {{#subobject:9fb427|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://link.springer.de/link/service/journals/00384/contents/02/00464/ Mühr-Wilkenshoff et al. 2003]
+|[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
-|<span
+|2015-2017
-style="background:#ff0000;
+| style="background-color:#1a9851" |Phase 3 (C)
-padding:3px 6px 3px 6px;
+|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-border-color:black;
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
-border-width:2px;
-border-style:solid;">Phase II, <20 patients</span>
-|-
-|[http://link.springer.com/article/10.1007%2Fs10620-005-3038-2 Enzinger et al. 2005]
-|<span
-style="background:#eeee00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
 |-
 |}
-''Note: In contrast to the primary references, the NCCN, Esophageal Cancer version 2.2011, lists a dosing schedule of [[Irinotecan (Camptosar)]] 125 mg/m2 IV on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when [irinotecan is] used as a single-agent, a tri-weekly schedule may be preferable."''
+''<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.''
-*[[Irinotecan (Camptosar)]] 125 mg/m2 IV over 60 minutes (Mühr-Wilkenshoff et al. 2003) or 90 minutes (Enzinger et al. 2005) once per day on days 1, 8, 15, 22
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-'''6-week cycles'''
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
+'''14-day cycles'''
-===Regimen #3, alternate q3wk dosing {{#subobject:c410d|Variant=1}}===
+</div></div><br>
-{| border="1" style="text-align:center;" !align="left"
+<div class="toccolours" style="background-color:#eeeeee">
-|'''Study'''
+===Regimen variant #2, 4 out of 6 weeks {{#subobject:9fb427|Variant=1}}===
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-|'''Comparator'''
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://annonc.oxfordjournals.org/content/24/6/1567.long Roy et al. 2013]
+|[https://doi.org/10.1007/s00384-002-0464-x Mühr-Wilkenshoff et al. 2003]
-|<span
+|1999-2000
-style="background:#00CD00;
+| style="background-color:#ffffbe" |Phase 2, fewer than 20 patients
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II</span>
-|[[#Docetaxel_.28Taxotere.29|Docetaxel]]<br> Irinotecan liposome
 |-
 |}
-*[[Irinotecan (Camptosar)]] 300 mg/m2 IV over 90 minutes once on day 1
+''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''
+<div class="toccolours" style="background-color:#b3e2cd">
+====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]
-'''21-day cycles'''
+==IRIS {{#subobject:252c51|Regimen=1}}==
+IRIS: '''<u>IRI</u>'''notecan & '''<u>S</u>'''-1
-===Regimen #4, q2wk dosing {{#subobject:fa1ef9|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| border="1" style="text-align:center;" !align="left"
+===Regimen {{#subobject:cdcc15|Variant=1}}===
-|'''Study'''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+!style="width: 20%"|Study
-|'''Comparator'''
+!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://jco.ascopubs.org/content/30/13/1513.full Kang et al. 2012]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ Huang et al. 2019 (ESWN 01)]
-|<span
+|2014-2016
-style="background:#00CD00;
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-padding:3px 6px 3px 6px;
+|[[#S-1_monotherapy|S-1]]
-border-color:black;
+| 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)
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Best_supportive_care|Best supportive care]]
 |-
 |}
-''Note: This regimen was listed by the NCCN, Esophageal Cancer version 2.2011 as 180 mg/m2 dosing, but no primary reference could be found for esophageal cancer at this dose level. This regimen is a gastric cancer regimen.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Irinotecan (Camptosar)]] 150 mg/m2 IV on day 1
+====Chemotherapy====
+*[[Irinotecan (Camptosar)]] 160 mg/m<sup>2</sup> IV once on day 1, '''given first'''
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+**Less than 1.25 m<sup>2</sup>: 40 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
+**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===
-# 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. [http://link.springer.de/link/service/journals/00384/contents/02/00464/ link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12774248 PubMed]
+#'''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]
-# Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [http://link.springer.com/article/10.1007%2Fs10620-005-3038-2 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16416165 PubMed]
+==Paclitaxel monotherapy {{#subobject:ec998a|Regimen=1}}==
-# Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. [http://www.ejcancer.info/article/S0959-8049%2811%2900396-0/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21742485 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-# Kang JH, Lee SI, Lim do H, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [http://jco.ascopubs.org/content/30/13/1513.full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22412140 PubMed]
+===Regimen variant #1, weekly {{#subobject:aa30a4|Variant=1}}===
-# Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [http://annonc.oxfordjournals.org/content/24/6/1567.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/23406728 PubMed]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
-==Irinotecan (Camptosar) & Capecitabine (Xeloda) {{#subobject:c699c3|Regimen=1}}==
+!style="width: 33%"|Dates of enrollment
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1093/annonc/mdm004 Ilson et al. 2007]
-|}
+|1998-01 to 2000-04
-===Regimen {{#subobject:d233c0|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Irinotecan (Camptosar)]] 250 mg/m2 IV over 30-90 minutes on day 1
-*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID on days 1 to 14
-'''21-day cycles x up to 8 cycles'''
-Supportive medications:
-*Atropine 0.25 mg SC before irinotecan as prophylaxis against cholinergic symptoms
-*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 BID prn diarrhea lasting longer than 24 hours despite Loperamide (Imodium)
-===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. [http://www.springerlink.com/content/8051q1q431p22662/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19104814 PubMed]
-==Irinotecan (Camptosar) & Mitomycin (Mutamycin) {{#subobject:dfc95f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Giuliani et al. 2005 {{#subobject:4a905|Variant=1}}===
+''Note: Patients had 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22
-padding:3px 6px 3px 6px;
+====Supportive therapy====
-border-color:black;
+*[[Dexamethasone (Decadron)]] 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel
-border-width:2px;
+*[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel
-border-style:solid;">Phase II</span>
+*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to paclitaxel
-*[[Irinotecan (Camptosar)]] 150 mg/m2 IV on days 1 & 15
-*[[Mitomycin (Mutamycin)]] 8 mg/m2 IV on day 1
 '''28-day cycles'''
+</div></div><br>
-===Regimen #2, Bamias et al. 2003 {{#subobject:3213a7|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-Level of Evidence:
+===Regimen variant #2, 80 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:cc40a4|Variant=1}}===
-<span
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-style="background:#EEEE00;
+!style="width: 20%"|Study
-padding:3px 6px 3px 6px;
+!style="width: 20%"|Dates of enrollment
-border-color:black;
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-border-width:2px;
+!style="width: 20%"|Comparator
-border-style:solid;">Phase II</span>
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
-*[[Irinotecan (Camptosar)]] 125 mg/m2 IV on day 1
+|[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
-*[[Mitomycin (Mutamycin)]] 5 mg/m2 IV on day 1
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (C)
-'''14-day cycles, given until progression of disease or unacceptable toxicity'''
+|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
-===Regimen #3, Lustberg et al. 2010 {{#subobject:87100a|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Irinotecan (Camptosar)]] 125 mg/m2 IV on days 2 & 9
-*[[Mitomycin (Mutamycin)]] 6 mg/m2 IV on day 1
-'''28-day cycles x up to 6 cycles'''
-Supportive medications:
-*"Ondansetron or granisetron and dexamethasone premedication"
-*Loperamide started with first episode of diarrhea
-*Erythropoietin for hemoglobin <10 g/dL permitted
-===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''' [http://www.ncbi.nlm.nih.gov/pubmed/12868555 PubMed]
-# Giuliani F, Molica S, Maiello E, Battaglia C, Gebbia V, Di Bisceglie M, Vinciarelli G, Gebbia N, Colucci G; Gruppo Oncologico dell' Italia Meridionale (prot. 2106). Irinotecan (CPT-11) and mitomycin-C (MMC) as second-line therapy in advanced gastric cancer: a phase II study of the Gruppo Oncologico dell' Italia Meridionale (prot. 2106). Am J Clin Oncol. 2005 Dec;28(6):581-5. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2005&issue=12000&article=00009&type=abstract link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16317268 PubMed]
-# Lustberg MB, Bekaii-Saab T, Young D, Otterson G, Burak W, Abbas A, McCracken-Bussa B, Lustberg ME, Villalona-Calero MA. Phase II randomized study of two regimens of sequentially administered mitomycin C and irinotecan in patients with unresectable esophageal and gastroesophageal adenocarcinoma. J Thorac Oncol. 2010 May;5(5):713-8. [http://journals.lww.com/jto/Fulltext/2010/05000/Phase_II_Randomized_Study_of_Two_Regimens_of.20.aspx link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20354452 PubMed]
-==MCF {{#subobject:d3775b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-MCF: '''<u>M</u>'''itomycin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+''<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>
-===Regimen {{#subobject:47b99f|Variant=1}}===
+''Note: This is the lower bound of dosing specified in KEYNOTE-181.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#b3e2cd">
-<span
+====Chemotherapy====
-style="background:#00CD00;
+*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-padding:3px 6px 3px 6px;
+'''28-day cycles'''
-border-color:black;
+</div></div><br>
-border-width:2px;
+<div class="toccolours" style="background-color:#eeeeee">
-border-style:solid;">Phase III</span>
+===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;"
-*[[Mitomycin (Mutamycin)]] 7 mg/m2 (maximum dose of 14 mg per cycle) IV day 1
+!style="width: 20%"|Study
-*[[Cisplatin (Platinol)]] 60 mg/m2 IV on days 1 & 22
+!style="width: 20%"|Dates of enrollment
-*[[Fluorouracil (5-FU)]] 300 mg/m2/day IV continuous infusion on days 1 to 42
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-'''42-day cycles x up to 6 months'''
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-Supportive medications:
-*[[Warfarin (Coumadin)]] 1 mg PO daily for catheter thrombosis prophylaxis
-===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. [http://jco.ascopubs.org/content/20/8/1996.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/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. [http://www.springerlink.com/content/n8477v3g21081103/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20821330 PubMed]
-==OLF, FLO {{#subobject:98b4fa|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
+|[https://doi.org/10.1200/jco.20.01888 Kojima et al. 2020 (KEYNOTE-181)]
-|}
+|2015-2017
-OLF: '''<u>O</u>'''xaliplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil
+| style="background-color:#1a9851" |Phase 3 (C)
-<br>FLO: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin
+|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-===Regimen {{#subobject:3d7273|Variant=1}}===
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV over 2 hours on days 1, 15, 29, 43
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 2 hours on days 1, 15, 29, 43
-*[[Fluorouracil (5-FU)]] 2600 mg/m2 IV continuous 24-hour infusion on days 1, 15, 29, 43
-'''8-week cycles, given until progression of disease or unacceptable toxicity'''
-Supportive medications:
-*Antiemetic medications per "local protocols"
-===References===
-# Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. [http://jco.ascopubs.org/content/26/9/1435.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18349393 PubMed]
-==Paclitaxel (Taxol) {{#subobject:ed008a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Ajani et al. 1994 {{#subobject:1d24a4|Variant=1}}===
+''<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>
-Level of Evidence:
+''Note: This is the upper bound of dosing specified in the protocol.''
-<span
+<div class="toccolours" style="background-color:#b3e2cd">
-style="background:#EEEE00;
+====Chemotherapy====
-padding:3px 6px 3px 6px;
+*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-Note: In contrast to the original reference, the NCCN, Esophageal Cancer version 2.2011, lists the dosage of paclitaxel as 135-175 mg/m2.
-*[[Paclitaxel (Taxol)]] 250 mg/m2 IV over 24 hours on day 1; dosage adjusted based on toxicity down to 150 or 200 mg/m2, or up to 280 mg/m2
-'''21-day cycles'''
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 20 mg PO 14 hours and 7 hours before paclitaxel
-*Cimetidine (Tagamet) 300 mg IV 60 minutes prior to paclitaxel
-*Diphenhydramine (Benadryl) 50 mg IV 60 minutes prior to paclitaxel
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC daily, starting 24 hours after the paclitaxel infusion finishes
-===Regimen #2, Ilson et al. 2007 {{#subobject:dd30a4|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Paclitaxel (Taxol)]] 80 mg/m2 IV over 1 hour on days 1, 8, 15, 22
 '''28-day cycles'''
+</div></div>
-Supportive medications:
-*[[Dexamethasone (Decadron)]] 20 mg IV 30-60 minutes before paclitaxel
-*Cimetidine (Tagamet) 300 mg IV 30-60 minutes prior to paclitaxel
-*Diphenhydramine (Benadryl) 50 mg IV 30-60 minutes prior to paclitaxel
 ===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''' [http://www.ncbi.nlm.nih.gov/pubmed/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, 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. [http://annonc.oxfordjournals.org/content/18/5/898.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33026938/ PubMed] [https://clinicaltrials.gov/study/NCT02564263 NCT02564263]
-==UFTM {{#subobject:96e8bf|Regimen=1}}==
+#'''INTEGRATE IIb:''' [https://clinicaltrials.gov/study/NCT04879368 NCT04879368]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+==S-1 monotherapy {{#subobject:387c51|Regimen=1}}==
-|-
+<div class="toccolours" style="background-color:#eeeeee">
-|[[#toc|back to top]]
+===Regimen {{#subobject:cdff15|Variant=1}}===
-|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-UFTM: '''<u>UFT</u>''' (Tegafur-uracil), '''<u>M</u>'''itomycin
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-===Regimen {{#subobject:3a603b|Variant=1}}===
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-{| border="1" style="text-align:center;" !align="left"
+!style="width: 20%"|Comparator
-|'''Study'''
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG9205)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ Huang et al. 2019 (ESWN 01)]
-|<span
+|2014-2016
-style="background:#00CD00;
+| style="background-color:#1a9851" |Phase 3 (C)
-padding:3px 6px 3px 6px;
+|[[#IRIS|IRIS]]
-border-color:black;
+| style="background-color:#d73027" |Inferior PFS
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Fluorouracil_.285-FU.29|Fluorouracil]]<br> [[#CF.2C_FP|FP]]
 |-
 |}
+''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.''
-*[[Tegafur-uracil (UFT)]] 375 mg/m2/day PO divided into two doses given BID
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Mitomycin (Mutamycin)]] 5 mg/m2 IV once per week
+====Chemotherapy====
-**"Mitomycin was interrupted for 1 month after patients received a total dose of 60 mg."
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
+**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
+**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===
-# Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12506170 PubMed]
+#'''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]
+[[Category:Esophageal cancer regimens]]
-[[Category:Chemotherapy regimens]]
+[[Category:Disease-specific pages]]
-[[Category:Solid oncology regimens]]
+[[Category:Gastroesophageal cancers]]
-[[Category:Gastrointestinal (GI) oncology regimens]]

Difference between revisions of "Esophageal cancer"

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