Esophageal cancer

Section editors
	Neeta K. Venepalli, MD, MBA Chicago, IL		Travis Osterman, DO, MS Nashville, TN Twitter: TravisOsterman LinkedIn

Page editor
	Naina Singh, MD Chicago, IL

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.

56 regimens on this page 74 variants on this page

Guidelines

CAP/ASCP/ASCO

• 2017: HER2 testing and clinical decision making in gastroesophageal adenocarcinoma PubMed

ESMO

• 2016: Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers

Neoadjuvant induction therapy

Cisplatin & Docetaxel

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Regimen

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

Patients: 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

Treatment followed by neoadjuvant cisplatin, docetaxel, RT.

References

1. 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. link to original article contains verified protocol PubMed

Cisplatin & Etoposide

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Regimen

Study	Evidence	Comparator	Efficacy
Boonstra et al. 2011	Phase III	Surgery alone	Seems to have superior OS

Patients: 100% squamous cell histology

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 4 hours once on day 1
• Etoposide (Vepesid) 100 mg/m²/day IV over 2 hours once on days 1 & 2, then 200 mg/m²/day PO once per day on days 3 & 5

21-day cycle for 2 to 4 cycles, followed by surgery

References

1. Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, Siersema PD, Dinjens WN, van Lanschot JJ, Tilanus HW, van der Gaast A. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011 May 19;11:181. link to original article contains verified protocol link to PMC article PubMed

Cisplatin & Fluorouracil

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

Variant #1, 40/4200

Study	Evidence
Ajani et al. 2006 (RTOG 9904)	Phase II

Patients: 100% adenocarcinoma histology. The majority of patients had gastric adenocarcinoma. Although gastroesophageal junction was involved, percentages were not included.

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 & 5
• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion on days 1 to 21 (total dose per cycle: 4200 mg/m²)

28-day cycle for 2 cycles

Subsequent treatment

• Neoadjuvant fluorouracil, paclitaxel, RT, then surgery

Variant #2, 80/4000

Study	Evidence	Comparator	Efficacy
Alderson et al. 2017 (UK MRC OE05)	Phase III (C)	ECX	Seems not superior

Patients: 100% adenocarcinoma of the esophagus (including Siewert types 1 and 2 gastroesophageal junction tumors)

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion on days 1 to 4 (total dose per cycle: 4000 mg/m²)

21-day cycle for 2 cycles

Subsequent treatment

• Surgery

Variant #3, 100/4000

Study	Evidence	Comparator	Efficacy
Ychou et al. 2011	Phase III (E)	Surgery alone	Seems to have superior OS

This is the neoadjuvant portion of pre-planned perioperative chemotherapy.

Patients: 100% adenocarcinoma histology (65% esophagogastric junction, 10% lower esophageal, 25% gastric adenocarcinoma)

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion on days 1 to 5 (total dose per cycle: 4000 mg/m²)

28-day cycle for 2 or 3 cycles

Subsequent treatment

• Surgery, then adjuvant cisplatin & 5-FU

Variant #4, 100/5000

Study	Evidence	Comparator	Efficacy
Ancona et al. 2001	Phase III (E)	Surgery alone	Seems not superior

Note: it is not entirely clear from the paper whether this was a 96-hour or 120-hour infusion. This is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Patients: 100% squamous cell carcinoma histology

Chemotherapy

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

21-day cycle for 2 or 3 cycles

Subsequent treatment

• Surgery, performed 3 to 4 weeks after the last cycle of chemotherapy

References

1. RTOG 8911: Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. link to original article PubMed
   1. Update: Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG; Radiation Therapy Oncology Group; USA Intergroup. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007 Aug 20;25(24):3719-25. link to original article PubMed
2. Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, Bonavina L, Peracchia A. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001 Jun 1;91(11):2165-74. link to original article contains protocol PubMed
3. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33. link to original article PubMed
   1. Update: Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009 Oct 20;27(30):5062-7. Epub 2009 Sep 21. link to original article PubMed
4. RTOG 9904: 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. link to original article contains verified protocol PubMed
5. Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. link to original article contains verified protocol PubMed
6. UK MRC OE05: Alderson D, Cunningham D, Nankivell M, Blazeby JM, Griffin SM, Crellin A, Grabsch HI, Langer R, Pritchard S, Okines A, Krysztopik R, Coxon F, Thompson J, Falk S, Robb C, Stenning S, Langley RE. Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1249-1260. Epub 2017 Aug 4. link to original article link to PMC article contains verified protocol PubMed

Cisplatin & Irinotecan

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Regimen

Study	Evidence
Rivera et al. 2009	Phase II
Ilson et al. 2011	Phase II

Rivera et al. patients: 100% adenocarcinoma histology (43% gastroesophageal junction, 57% gastric adenocarcinoma)

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

Chemotherapy

• 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

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 (Atropen) 0.5 to 1 mg IV prn cholinergic symptoms

21-day cycle for 2 cycles

Treatment followed by neoadjuvant cisplatin, irinotecan, RT.

References

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

CX

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

Regimen

Study	Evidence
Lee et al. 2007	Retrospective

The study was for patients with stage IV disease.

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

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO BID on days 1 to 14
• Cisplatin (Platinol) 60 mg/m² IV over 60 minutes on day 1, given before the first dose of capecitabine

21-day cycles

For patients with M1a or M1b disease, treatment followed by capecitabine, cisplatin, RT.

References

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

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2006 (MAGIC)	Phase III	See link	See link
Al-Batran et al. 2017 (FLOT4-AIO)	Phase III	See link	See link

This is the neoadjuvant portion of pre-planned perioperative chemotherapy.

Cunningham et al. Patients: 100% adenocarcinoma histology. 75% gastric adenocarcinoma, 15% lower esophagus, 11% gastroesophageal junction.

Al-Batran et. al Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach.

Chemotherapy

• 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 (total dose per cycle: 4200mg/m² )

Supportive medications

• MAGIC: Warfarin (Coumadin) 1 mg PO once per day recommended for thrombosis prophylaxis

21-day cycle for 3 cycles

Surgery occurs 3 to 6 weeks after completing cycle 3. Adjuvant ECF is started 6 to 12 weeks after surgery.

References

1. MAGIC: Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. link to original article contains verified protocol PubMed
2. Abstract: Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 link to abstract

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2017 (UK MRC ST03)	Phase III (C)	ECX & Bevacizumab	Seems not superior
Al-Batran et al. 2017 (FLOT4-AIO)	Phase III	See link	See link

This is the neoadjuvant portion of pre-planned perioperative chemotherapy.

Cunningham et al. Patients: 100% adenocarcinoma histology (36% gastric, 14% lower esophageal, 50% gastroesophageal junction).

Al-Batran et al. Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV once on day 1
• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Capecitabine (Xeloda) 625 mg/m² PO BID on days 1 to 21

21-day cycle for 3 cycles

Treatment followed by surgery and adjuvant ECX.

References

1. Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, Griffin SM, Mansoor W, Coxon FY, Falk SJ, Darby S, Sumpter KA, Blazeby JM, Langley RE. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol. 2017 Mar;18(3):357-370. Epub 2017 Feb 3. link to original article contains protocol link to PMC article PubMed
2. Abstract: Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 link to abstract

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EOF: Epirubicin, Oxaliplatin, Fluorouracil

Regimen

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

Chemotherapy

• 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 on days 1 to 21 (total dose per cycle: 4200 mg/m²)

Supportive medications

• Dexamethasone (Decadron) 8 mg IV prior to day 1 chemotherapy and 4 mg PO TID x 2 days thereafter
• 5-HT3 antagonist prior to chemotherapy
• Metoclopramide (Reglan) 10 mg PO TID for 3 days after day 1 chemotherapy
• Warfarin (Coumadin) 1 mg PO once per day as thrombosis prophylaxis, started on day -1

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

EOX

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

Regimen

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

Chemotherapy

• 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 BID on days 1 to 21

Supportive medications

• Dexamethasone (Decadron) 8 mg IV prior to day 1 chemotherapy and 4 mg PO TID x 2 days thereafter
• 5-HT3 antagonist prior to chemotherapy
• Metoclopramide (Reglan) 10 mg PO TID for 3 days after day 1 chemotherapy

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

FLOT

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FLOT: Fluorouracil, Leucovorin, Oxaliplatin, Taxotere (Docetaxel)

Regimen

Study	Evidence	Comparator	Efficacy
Al-Batran et al. 2017 (FLOT4-AIO)	Phase III	See link	See link

This is the neoadjuvant portion of pre-planned perioperative chemotherapy.

Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach

Chemotherapy

• Fluorouracil (5-FU) 2600 mg/m² IV continuous 24-hour infusion on day 1
• Folinic acid (Leucovorin) 200 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
• Docetaxel (Taxotere) 50 mg/m² IV once on day 1

14-day cycle for 4 cycles

Treatment followed by surgery and adjuvant FLOT.

References

1. Abstract: Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 link to abstract

PLF

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PLF: Platinol (Cisplatin), Leucovorin, Fluorouracil

Variant #1, 12 weeks

Study	Evidence	Comparator	Efficacy
Stahl et al. 2009 (POET)	Phase III	See link	See link

Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV over 60 minutes once per day on days 1, 15, 29
• Folinic acid (Leucovorin) 500 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
• Fluorouracil (5-FU) 2000 mg/m² IV continuous 24-hour infusion on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000mg/m² )

42-day cycle for 2 cycles

Subsequent treatment

• Cisplatin, Etoposide, RT, then surgery

Variant #2, 15 weeks

Study	Evidence	Comparator	Efficacy
Stahl et al. 2009 (POET)	Phase III	PLF x 12 wk, then Cisplatin, Etoposide, RT	Might have inferior OS

Note: this regimen is given for 2.5 cycles, which is a highly unusual instruction; total duration of treatment is 15 weeks.

Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV over 60 minutes once per day on days 1, 15, 29
• Folinic acid (Leucovorin) 500 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
• Fluorouracil (5-FU) 2000 mg/m² IV continuous 24-hour infusion on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000mg/m² )

42-day cycle for 2.5 cycles

Subsequent treatment

• Surgery, in 3 to 4 weeks

References

1. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12. link to original article contains verified protocol PubMed
   1. Update: Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, Sandermann A, Bitzer M, Wilke H, Budach W. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. Eur J Cancer. 2017 Aug;81:183-190. PubMed

Neoadjuvant chemoradiotherapy

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

Capecitabine, Carboplatin, Paclitaxel, RT

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RT: Radiation Therapy

Regimen

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

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

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

Chemoradiotherapy

• 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 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

Subsequent treatment

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

References

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

Capecitabine, Cisplatin, RT

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RT: Radiation Therapy

Regimen

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

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

Preceding treatment

• Capecitabine & Cisplatin

Chemoradiotherapy

• Cisplatin (Platinol) 30 mg/m² IV over 60 minutes on day 1 and repeated weekly while radiation is being given; given before the first dose of capecitabine
• Capecitabine (Xeloda) 800 mg/m² PO BID, 5 days per week while radiation is being given
• Concurrent radiation therapy, total of 54 Gy given (dose per fraction and total duration of treatment was not specified)

1-week cycles until radiation therapy is complete

References

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

Capecitabine, Docetaxel, RT

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RT: Radiation Therapy

Regimen

Note: No primary reference could be found for this regimen; the reference below is for reference purposes only.

Chemoradiotherapy

• Docetaxel (Taxotere) 20 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Capecitabine (Xeloda) 625-825 mg/m² PO BID on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
• Concurrent radiation therapy not defined

5-week course

References

1. Phase I: 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 SD article link to PMC article PubMed

Capecitabine, Docetaxel, Oxaliplatin, RT

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RT: Radiation Therapy

Regimen

Study	Evidence
Spigel et al. 2010	Phase I/II

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

Chemoradiotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO BID 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
• 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.

Supportive medications

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

5-week course of therapy

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.

References

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

Capecitabine, Oxaliplatin, RT

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RT: Radiation Therapy

Regimen

Study	Evidence
Javle et al. 2009	Phase I

Chemoradiotherapy

• Capecitabine (Xeloda) 625 mg/m² PO BID 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
• Concurrent radiation therapy, total dose of 50.4 Gy

5-week course

References

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

Capecitabine, Paclitaxel, RT

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RT: Radiation Therapy

Regimen

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

Chemoradiotherapy

• 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
• Paclitaxel (Taxol) 45 to 50 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Concurrent radiation therapy not defined

5-week course

Carboplatin, Fluorouracil, RT

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RT: Radiation Therapy

Regimen

Study	Evidence
Zemanoa et al. 2009	Non-randomized

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

Chemoradiotherapy

• Carboplatin (Paraplatin) AUC 6 IV once per day on days 1 & 22
• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion on days 1 to 42 (total dose per cycle: 8400 mg/m²)
• 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 to 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

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

Carboplatin, Paclitaxel, RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
van Meerten et al. 2006	Phase II
van Hagen et al. 2012 (CROSS)	Phase III	Surgery alone	Superior OS

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

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

Chemoradiotherapy

• 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
• 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

Supportive medications

• Dexamethasone (Decadron) 10 mg IV 30 minutes prior to Paclitaxel (Taxol)
• Ranitidine (Zantac) 50 mg IV 30 minutes prior to Paclitaxel (Taxol)
• Clemastine (Tavist) 2 mg IV 30 minutes prior to Paclitaxel (Taxol)
• Between paclitaxel & carboplatin: 100 mL NS given over 30 minutes, then Ondansetron (Zofran) 8 mg in 100 mL NS given over 30 minutes

5-week course

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

References

1. van Meerten E, Muller K, Tilanus HW, Siersema PD, Eijkenboom WM, van Dekken H, Tran TC, van der Gaast A. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer. 2006 May 22;94(10):1389-94. link to PMC article contains verified protocol link to PMC article contains verified protocol PubMed
2. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. link to original article contains verified protocol link to appendix with details about administration PubMed
   1. Update: Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. Epub 2015 Aug 5. link to original article PubMed

Cisplatin, Docetaxel, RT

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RT: Radiation Therapy

Regimen

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

Patients: 55% adenocarcinoma, 45% squamous cell histology

Preceding treatment

• Cisplatin & Docetaxel x 2

Chemoradiotherapy

• 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

5-week course

Surgery planned to be done 3 to 8 weeks after finishing chemoradiation.

References

1. 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. link to original article contains verified protocol PubMed

Cisplatin, Etoposide, RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Stahl et al. 2009 (POET)	Phase III	See link	See link

Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.

Preceding treatment

• PLF x 12 wk

Chemoradiotherapy, to start 2 weeks after the last day of PLF

• Cisplatin (Platinol) 50 mg/m² IV over 60 minutes once per day on days 1 & 8
• Etoposide (Vepesid) 80 mg/m² IV over 60 minutes once per day on days 3 to 5
• Concurrent radiation therapy, 2.0 Gy fractions x 15 fractions, five days per week, for a target dose of 30 Gy

Subsequent treatment

• Surgery, in 3 to 4 weeks

References

1. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12. link to original article contains verified protocol PubMed
   1. Update: Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, Sandermann A, Bitzer M, Wilke H, Budach W. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. Eur J Cancer. 2017 Aug;81:183-190. PubMed

Cisplatin, Fluorouracil, RT

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RT: Radiation Therapy

Variant #1, 75/4000 x 2

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

Patients: 89% epidermoid, 11% glandular histology.

Chemoradiotherapy

• Cisplatin (Platinol) 15 mg/m² IV over 60 minutes once per day on days 1 to 5
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours on days 1 to 5 (total dose per cycle: 4000 mg/m²)
• Concurrent radiation therapy, 2 Gy fractions x 23 fractions given 5 days per week, for a total dose of 46 Gy
  • Earlier in the study, some patients instead received split-course radiation therapy, 3 Gy fractions x 5 fractions given on days 1 to 5. 15 Gy per cycle; total dose after 2 cycles is 30 Gy.

Supportive medications

• 1 liter NS IV over 2 hours before and after Cisplatin (Platinol)

21-day cycle for 2 cycles

Subsequent treatment

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

Variant #2, 80/3200

Study	Evidence	Comparator	Efficacy
Burmeister et al. 2005	Phase III (E)	Surgery alone	Seems not superior

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

Chemoradiotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 3200 mg/m²)
• Concurrent radiation therapy, 2.33 Gy fractions x 15 fractions for a total dose of 35 Gy

One course

Subsequent treatment

• Surgery

Variant #3, 100/8000 x 2

Study	Evidence	Comparator	Efficacy
Tepper et al. 2008 (CALGB 9781)	Phase III (E)	Surgery alone	Superior OS

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

Chemoradiotherapy

• 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 once per day on days 1 to 4, 29 to 32; given after cisplatin (total dose 8000 mg/m²)
• 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

5.5-week course

Subsequent treatment

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

References

1. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996 Aug 15;335(7):462-7. Erratum in: N Engl J Med 1999 Jul 29;341(5):384. link to original article PubMed
2. Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, Denham JW; Trans-Tasman Radiation Oncology Group; Australasian Gastro-Intestinal Trials Group. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005 Sep;6(9):659-68. link to original article contains protocol PubMed
3. FFCD 9102: Bedenne L, Michel P, Bouché O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007 Apr 1;25(10):1160-8. link to original article contains verified protocol PubMed
4. CALGB 9781: Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086-92. link to original article contains verified protocol link to PMC article PubMed

Cisplatin, Irinotecan, RT

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RT: Radiation Therapy

Variant #1

Study	Evidence
Yoon et al. 2011	Phase II

Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)

Chemoradiotherapy

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

In 'Yoon et al. 2011, surgery done at least 28 days after finishing chemoradiation, then begin adjuvant cisplatin & irinotecan at least 28 days after surgical resection.

Variant #2

Study	Evidence
Ilson et al. 2011	Phase II

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

Preceding treatment

• Cisplatin & Irinotecan induction x 2

Chemoradiotherapy

• 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

21-day cycle for 2 cycles

Surgery performed 4 to 8 weeks after chemoradiation.

Variant #3

Study	Evidence
Rivera et al. 2009	Phase II

Patients: 100% adenocarcinoma histology (43% gastroesophageal junction, 57% gastric adenocarcinoma)

Preceding treatment

• Cisplatin & Irinotecan induction x 2

Chemoradiotherapy

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

5-week course

Surgery done 5 to 8 weeks after finishing chemoradiation.

References

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

Cisplatin, Paclitaxel, RT

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RT: Radiation Therapy

Variant #1

Study	Evidence
Yoon et al. 2011	Phase II

Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)

Chemoradiotherapy

• Cisplatin (Platinol) 30 mg/m² IV once per day on days 1, 8, 15, 22, 29
• Paclitaxel (Taxol) 50 mg/m² IV over 60 minutes 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

Surgery done at least 28 days after finishing chemoradiation, then begin adjuvant cisplatin & paclitaxel at least 28 days after surgical resection.

Variant #2

Study	Evidence
Urba et al. 2003	Phase II

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

Chemoradiotherapy

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

Supportive medications

• Dexamethasone (Decadron) 20 mg PO given 12 and 6 hours before Paclitaxel (Taxol)
• Diphenhydramine (Benadryl) 50 mg IV 30 minutes prior to Paclitaxel (Taxol)
• Cimetidine (Tagamet) 300 mg IV 30 minutes prior to Paclitaxel (Taxol)
• 1 liter D5NS and mannitol 12.5 g bolus IV prior to Cisplatin (Platinol)
• Mannitol 25 g in 1 liter D5NS IV over 4 hours after Cisplatin (Platinol)
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 hours after the fourth dose of Paclitaxel (Taxol), continuing until ANC greater than 10,000/uL

4-week course of therapy

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

References

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

Docetaxel, Fluorouracil, RT

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RT: Radiation Therapy

Variant #1

Study	Evidence
Hihara et al. 2007	Phase II

Patients: 86% squamous cell, 14% carcinosarcoma histology

Chemoradiotherapy

• Docetaxel (Taxotere) 7.5 mg/m² IV over 60 minutes once per day on days 1, 8, 22, 29
• 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 (total dose: 8000 mg/m²)
• Concurrent radiation therapy, 2 Gy fractions x 30 to 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

Supportive medications

• Dexamethasone (Decadron) 8 mg IV 30 minutes prior to Docetaxel (Taxotere)

7-week course

Variant #2

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

Chemoradiotherapy

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

5-week course

References

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

Fluorouracil, Oxaliplatin, RT

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RT: Radiation Therapy

Variant #1, 45 Gy

Study	Evidence
Lorenzen et al. 2008	Phase I/II

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

Chemoradiotherapy

• Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion over days 1 to 33 (total dose: 7425 mg/m²)
• Oxaliplatin (Eloxatin) 45 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 given 5 days per week, for a total dose of 45 Gy

35-day course

Surgery 4 to 6 weeks after finishing chemoradiation.

Variant #2, 50.4 Gy, bi-weekly oxaliplatin

Study	Evidence
Khushalani et al. 2002	Phase II

58% patients were classified as stage IV disease

Chemoradiotherapy

• 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 days 8 to 42 (total dose per cycle: 6300mg/m²)
• Concurrent radiation therapy, 1.8 Gy fractions x 20 to 22 fractions, for an initial total dose of 36 to 39.6 Gy, started on day 8
  • Followed by off-cord conformal oblique fields, 5.4 to 9 Gy given to the clinical target volume (CTV). A second off-cord phase to the gross tumor volume (GTV) of 5.4 Gy was then given, for a total dose delivered of 50.4 Gy to the GTV.
• 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.

42-day cycle for 1 initial cycle (see above)

Variant #3, 50.4 Gy, weekly oxaliplatin

Study	Evidence
Ajani et al. 2013	Non-randomized portion of RCT

Preceding treatment

• Fluorouracil & Oxaliplatin induction versus no induction chemotherapy

Chemoradiotherapy

• Oxaliplatin (Eloxatin) 40 mg/m² IV once per week
• Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion 5 days per week (total dose: 6250mg/m²)
• Concurrent radiation therapy: 50.4 Gy of proton or photon (intensity modulated) radiation in 28 fractions

One 5-week course

Subsequent treatment

• Surgery

References

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

Fluorouracil, Paclitaxel, RT

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RT: Radiation Therapy

Regimen

Study	Evidence
Ajani et al. 2006 (RTOG 9904)	Phase II

Patients: 100% adenocarcinoma histology. The majority of patients had gastric adenocarcinoma. Although gastroesophageal junction was involved, percentages were not included.

Preceding treatment

• Cisplatin & 5-FU induction x 2

Chemoradiotherapy

• 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 (total dose per cycle: 7500 mg/m²)
• Paclitaxel (Taxol) 45 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, for a total dose of 45 Gy

5-week course, followed by surgery

References

1. 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. link to original article contains verified protocol PubMed

Definitive therapy

Capecitabine, Cisplatin, RT

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RT: Radiation Therapy

Variant #1

Study	Evidence	Comparator	Efficacy
Crosby et al. 2013 (SCOPE1)	Phase III	Capecitabine, Cisplatin, Cetuximab, RT	Seems not superior (*)

Note: efficacy is based on the 2017 update.

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

Chemoradiotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Capecitabine (Xeloda) 625 mg/m² PO BID on days 1 to 21
• Concurrent radiation therapy, total of 50 Gy given in 25 fractions with cycles 3 & 4

If patients were unable to swallow capecitabine, they could receive fluorouracil infusion dose 225 mg/m² per day on days 1 to 21 of each cycle (total dose: 4,725mg/m² per cycle)

21-day cycle for 4 cycles

Variant #2

Study	Evidence
Lee et al. 2007	Retrospective

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

The study was for patients with stage IV disease.

• Patients with M1b disease (visceral metastases) received the chemotherapy only part until progression of disease or unacceptable toxicity.
• Patients with M1a or M1b (non-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.

Preceding treatment

• XP x 2

Chemoradiotherapy

• Cisplatin (Platinol) 30 mg/m² IV over 60 minutes on day 1 and repeated weekly while radiation is being given; given before the first dose of capecitabine
• Capecitabine (Xeloda) 800 mg/m² PO BID, 5 days per week while radiation is being given
• 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.

1-week cycles until radiation therapy is complete

References

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

Cisplatin, Docetaxel, RT

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RT: Radiation Therapy

Variant #1

Study	Evidence
Li et al. 2009	Phase II

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

Chemoradiotherapy

• 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 to 2.0 Gy fractions, 5 days per week, to start within 24 hours of the day 1 of chemotherapy
  • Patients with stage I to III disease received a total dose of 60 to 64 Gy over 4 to 6 weeks
  • Patients with stage IV disease (lymph node only) received a total dose of 50 to 56 Gy

Note, dose reductions were permitted, see article for specifications

Supportive medications

• Dexamethasone (Decadron) 10 mg PO/IV the day before Docetaxel (Taxotere), 30 minutes prior to Docetaxel (Taxotere), and the day after Docetaxel (Taxotere)
• 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 to 2.0 liters fluids before Cisplatin (Platinol)

1 course

Variant #2

Study	Evidence
Day et al. 2010	Phase I

Patients: 46% squamous cell, 54% adenocarcinoma histology

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

Chemoradiotherapy

• 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
• 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.

Supportive medications

• "Steroid and anti-emetic pre-medication"

5-week course

References

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

Cisplatin, Fluorouracil, RT

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RT: Radiation Therapy

Variant #1

Study	Evidence	Comparator	Efficacy
Minsky et al. 2002 (RTOG 94-05)	Phase III	Cisplatin, 5-FU, high-dose RT	Seems not superior

Patients: study included both adenocarcinoma and squamous cell histology

Chemoradiotherapy

• 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 on days 1 to 4 (total dose per cycle: 4000mg/m²)
• 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 cycle for 2 cycles, followed by:

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 on days 1 to 4 (total dose per cycle: 4000mg/m²)

28-day cycle for 2 cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Herskovic et al. 1992 (RTOG 85-01)	Phase III	Radiation therapy	Superior OS

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

Chemoradiotherapy

• Cisplatin (Platinol) 75 mg/m² IV once per day on the first day of week 1, 5, 8, 11 (day 1, 29, 50, 71)
• 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 to 4, 29 to 32, 50 to 53, 71 to 74)
• Concurrent radiation therapy: starting on day 1, 2.0 Gy fractions x 15 fractions given 5 days per week for 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.

11-week course of therapy

References

1. Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992 Jun 11;326(24):1593-8. link to original article contains verified protocol PubMed
   1. Update: al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J, Byhardt R, Davis L, Emami B. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol. 1997 Jan;15(1):277-84. link to original article contains verified protocol PubMed
   2. Update: Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL. 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. link to original article contains verified protocol PubMed
2. Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002 Mar 1;20(5):1167-74. link to original article contains verified protocol PubMed
3. 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 PubMed
4. 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. link to PMC article contains verified protocol link to PMC article PubMed
5. Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article PubMed
   1. HRQoL analysis: Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. link to original article PubMed
6. Mariette C, Dahan L, Mornex F, Maillard E, Thomas PA, Meunier B, Boige V, Pezet D, Robb WB, Le Brun-Ly V, Bosset JF, Mabrut JY, Triboulet JP, Bedenne L, Seitz JF. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol. 2014 Aug 10;32(23):2416-22. Epub 2014 Jun 30. link to original article PubMed

Cisplatin, Paclitaxel, RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Suntharalingam et al. 2017 (RTOG 0436)	Phase III	Cisplatin, Paclitaxel, Cetuximab, RT	Seems not superior

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

Chemoradiotherapy

• Cisplatin (Platinol) 25 mg/m² IV once per week
• Paclitaxel (Taxol) 50 mg/m² IV once per week
• Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy

One course over 5 weeks

References

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

FOLFOX4 & RT

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

Regimen

Study	Evidence	Comparator	Efficacy
Conroy et al. 2010	Phase III	Cisplatin, 5-FU, RT	Not reported

Patients: 82% squamous cell, 18% adenocarcinoma histology. 7% Stage IVA and 2% ECOG PS of 2.

Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m².

Chemoradiotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus, then 600 mg/m²/day IV over 22 hours on days 1 & 2, given last (total dose per cycle: 1,600 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once 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 cycle for 3 cycles

Subsequent treatment

• FOLFOX x 3

References

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

Radiation therapy

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Regimen

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

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

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

Radiotherapy

• External beam radiotherapy total of 32 fractions in 6.4 weeks: 50 Gy of regional treatment and 14 Gy to the boost field, for total dose of 64 Gy

References

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

Surgery alone

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Regimen

Study	Evidence	Comparator	Efficacy
Ancona et al. 2001	Phase III (C)	CF, then surgery	Seems not superior
Macdonald et al. 2001	Phase III (C)	Adjuvant 5-FU & Leucovorin, then 5-FU, Leucovorin, RT, then 5-FU & Leucovorin	Inferior OS
Burmeister et al. 2005	Phase III (C)	Cisplatin, 5-FU, RT, then surgery	Seems not superior
Cunningham et al. 2006 (MAGIC)	Phase III (C)	Perioperative ECF	Inferior OS
Tepper et al. 2008 (CALGB 9781)	Phase III (C)	Neoadjuvant Cisplatin, Fluorouracil, RT	Inferior OS
van Hagen et al. 2012 (CROSS)	Phase III (C)	Neoadjuvant Carboplatin, Paclitaxel, RT	Inferior OS

Surgery as primary therapy; i.e., no induction chemotherapy or chemoradiotherapy, and no adjuvant therapy.

McDonald et al. patients: 100% adenocarcinoma histology, originating from the stomach or gastroesophageal junction. 

MAGIC patients: 100% adenocarcinoma of the stomach or lower third of the esophagus. 74% gastric, 15% lower esophagus, 11% gastroesophageal junction.

CALGB 9781 patients: 75% adenocarcinoma, 25% squamous cell histology. 5% with ECOG PS of 2.

CROSS patients: 75% adenocarcinoma, 23% squamous cell, 2% other. 24% gastroesophageal junction.

References

1. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996 Aug 15;335(7):462-7. Erratum in: N Engl J Med 1999 Jul 29;341(5):384. link to original article  contains verified protocol PubMed
2. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, Lozach P, Ollier JC, Pavy JJ, Mercier M, Sahmoud T. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997 Jul 17;337(3):161-7. link to original article PubMed
3. RTOG 8911: Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. link to original article PubMed
   1. Update: Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG; Radiation Therapy Oncology Group; USA Intergroup. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007 Aug 20;25(24):3719-25. link to original article PubMed
4. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001 Jan 15;19(2):305-13. link to original article PubMed
5. Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, Bonavina L, Peracchia A. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001 Jun 1;91(11):2165-74. link to original article contains protocol PubMed
6. 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. link to original article contains verified protocol PubMed
7. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33. link to original article PubMed
   1. Update: Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009 Oct 20;27(30):5062-7. Epub 2009 Sep 21. link to original article PubMed
8. Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, Denham JW; Trans-Tasman Radiation Oncology Group; Australasian Gastro-Intestinal Trials Group. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005 Sep;6(9):659-68. link to original article contains protocol PubMed
9. MAGIC: Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. link to original article contains verified protocol PubMed
10. CALGB 9781: Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086-92. link to original article contains verified protocol link to PMC article PubMed
11. Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. link to original article contains verified protocol PubMed
12. Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, Siersema PD, Dinjens WN, van Lanschot JJ, Tilanus HW, van der Gaast A. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011 May 19;11:181. link to original article contains verified protocol link to PMC article PubMed
13. CROSS: van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. link to original article contains verified protocol link to appendix with details about administration contains verified protocol PubMed
    1. Update: Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. Epub 2015 Aug 5. link to original article PubMed
14. 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

Adjuvant therapy

5-FU & Leucovorin, then 5-FU, Leucovorin, RT, then 5-FU & Leucovorin

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RT: Radiation Therapy

Variant #1

Study	Evidence	Comparator	Efficacy
Macdonald et al. 2001	Phase III	Surgery alone	Superior OS

Chemotherapy, part 1

• Fluorouracil (5-FU) 425 mg/m² IV bolus once per day on days 1 to 5 (total dose per cycle: 2125 mg/m²)
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1 to 5

28-day cycle, followed by:

Chemoradiotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy (total dose per cycle: 2800 mg/m²)
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy
• Concurrent radiation therapy starting cycle 2 day 1 with 1.8 Gy, 5 days per week; 25 fractions given over 5 weeks for a total of 45 Gy

35-day cycle, followed by:

Chemotherapy, part 2, to start one month after the completion of radiotherapy

• Fluorouracil (5-FU) 425 mg/m² IV bolus once per day on days 1 to 5 (total dose per cycle 2125 mg/m²)
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1 to 5

28-day cycle for 2 cycles

Variant #2

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

Chemotherapy

• 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 cycle for 3 total cycles (1 cycle given before radiation, and 2 cycles to be given after radiation)

References

1. 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. link to original article contains verified protocol PubMed

Cisplatin & Fluorouracil

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CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen

Study	Evidence	Comparator	Efficacy
Ychou et al. 2011	Phase III	Surgery alone	Seems to have superior OS

This is the adjuvant portion of pre-planned perioperative therapy.

Patients: 100% adenocarcinoma histology (65% gastroesophageal junction, 10% lower esophageal, 25% gastric adenocarcinoma)

Preceding treatment

• Neoadjuvant cisplatin & 5-FU and surgery

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion on days 1 to 5 (total dose per cycle: 4000 mg/m²)

28-day cycle for 3 to 4 cycles for a total of 6 cycles

References

1. Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. link to original article contains verified protocol PubMed

Cisplatin & Irinotecan

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Regimen

Study	Evidence
Yoon et al. 2011	Phase II

Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)

Preceding treatment

• Neoadjuvant cisplatin, irinotecan, RT and surgery

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 cycle for 3 cycles

References

1. 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. link to original article contains verified protocol link to PMC article PubMed

Cisplatin & Paclitaxel

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Regimen

Study	Evidence
Yoon et al. 2011	Phase II

Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)

Preceding treatment

• Neoadjuvant cisplatin, paclitaxel, RT and surgery

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 3 cycles

References

1. 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. link to original article contains verified protocol link to PMC article PubMed

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2006 (MAGIC)	Phase III	See link	See link
Al-Batran et al. 2017 (FLOT4-AIO)	Phase III	See link	See link

This is the adjuvant portion of pre-planned perioperative chemotherapy.

Cunningham et al. Patients: 100% adenocarcinoma histology (75% gastric adenocarcinoma, 15% lower esophagus, 11% gastroesophageal junction).

Al-Batran et. al Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach.

Preceding treatment

• Neoadjuvant ECF x 3, then surgery

Chemotherapy, to start 6 to 12 weeks after surgery

• 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 (total dose per cycle: 4200 mg/m²)

Supportive medications

• MAGIC: Warfarin (Coumadin) 1 mg PO once per day recommended for thrombosis prophylaxis

21-day cycle for 3 cycles

References

1. MAGIC: Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. link to original article contains verified protocol PubMed
2. Abstract: Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 link to abstract

ECF, then 5-FU & RT, then ECF

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ECF, then 5-FU & RT, then ECF: Epirubicin, Cisplatin, Fluorouracil, followed by 5-FluoroUracil & Radiation Therapy, followed by Epirubicin, Cisplatin, Fluorouracil

Regimen

Study	Evidence
Leong et al. 2010	Phase II

Note: In contrast to the primary reference, some guidelines list this regimen without ECF cycles 1, 3, 4.

Patients: 100% adenocarcinoma (6% gastroesophageal junction, 94% gastric origin). 

Chemotherapy, part 1, to start no later than 10 weeks after surgery

• 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 (total dose per cycle: 4200 mg/m²)

21-day cycle, followed 1-3 weeks later by:

Chemoradiotherapy

• Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion on days 1 to 35 (total dose per cycle: 7875 mg/m²)
• 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, followed 1 month later by:

Chemotherapy, part 2

• 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 (total dose per cycle: 4200 mg/m²)

21-day cycle for 2 cycles

References

1. 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. link to original article contains verified protocol PubMed

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2017 (UK MRC ST03)	Phase III (C)	ECX & Bevacizumab	Seems not superior
Al-Batran et al. 2017 (FLOT4-AIO)	Phase III	See link	See link

This is the adjuvant portion of pre-planned perioperative chemotherapy.

Cunningham et al. Patients: 100% adenocarcinoma histology (36% gastric, 14% lower esophageal, 50% gastroesophageal junction).

Al-Batran et al. Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.

Preceding treatment

• Neoadjuvant ECX x 3, then surgery

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV once on day 1
• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Capecitabine (Xeloda) 625 mg/m² PO BID on days 1 to 21

21-day cycle for 3 cycles

References

1. UK MRC ST03: Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, Griffin SM, Mansoor W, Coxon FY, Falk SJ, Darby S, Sumpter KA, Blazeby JM, Langley RE. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol. 2017 Mar;18(3):357-370. Epub 2017 Feb 3. link to original article contains protocol link to PMC article PubMed
2. Abstract: Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 link to abstract

FLOT

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FLOT: Fluorouracil, Leucovorin, Oxaliplatin, Taxotere (Docetaxel)

Regimen

Study	Evidence	Comparator	Efficacy
Al-Batran et al. 2017 (FLOT4-AIO)	Phase III	See link	See link

This is the adjuvant portion of pre-planned perioperative chemotherapy.

Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.

Preceding treatment

• Neoadjuvant FLOT x 4, then surgery

Chemotherapy

• Fluorouracil (5-FU) 2600 mg/m² IV continuous 24-hour infusion on day 1
• Folinic acid (Leucovorin) 200 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
• Docetaxel (Taxotere) 50 mg/m² IV once on day 1

14-day cycle for 4 cycles

References

1. Abstract: Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 link to abstract

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin 4

Regimen

Study	Evidence	Comparator	Efficacy
Conroy et al. 2010	Phase III	Cisplatin, 5-FU, RT	Not reported

Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m².

Patients: 82% squamous cell, 18% adenocarcinoma histology. 7% Stage IVA and 2% ECOG PS of 2.

Preceding treatment

• FOLFOX4 & RT

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus, then 600 mg/m²/day IV over 22 hours on days 1 & 2, given last (total dose per cycle: 1600 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

14-day cycle for 3 cycles

References

1. 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. link to PMC article contains verified protocol link to PMC article PubMed
2. Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article PubMed
   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

Metastatic or locally advanced disease (non-radiation/surgery candidate)

CapeOx

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CapeOx: Capecitabine and Oxaliplatin

Regimen

Study	Evidence	Comparator	Efficacy
Hecht et al. 2015 (LOGiC)	Phase III	CapeOx & Lapatinib	Seems not superior

100% adenocarcinoma histology (4% esophagus, 9% gastroesophageal junction, 87% gastric origin). 9% with ECOG PS of 2. 

Chemotherapy

• Capecitabine (Xeloda) 850 mg/m² PO BID on days 1 to 14
• Oxaliplatin (Eloxatin) 130 mg/m2 IV on day 1

21-day cycle for up to 8 cycles

References

1. Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, Jeziorski K, Shparyk Y, Hoff PM, Sobrero A, Salman P, Li J, Protsenko SA, Wainberg ZA, Buyse M, Afenjar K, Houé V, Garcia A, Kaneko T, Huang Y, Khan-Wasti S, Santillana S, Press MF, Slamon D. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC--a randomized phase III trial. J Clin Oncol. 2016 Feb 10;34(5):443-51. Epub 2015 Nov 30. link to original article PubMed

CAPIRI

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

Regimen

Study	Evidence	Comparator	Efficacy
Leary et al. 2008	Phase II
Moehler et al. 2009	Randomized Phase II	XP	Seems not superior

Patients: 45% esophageal, 38% gastroesophageal junction, 17% gastric origin. 93% adenocarcinoma, 7% squamous cell histology. 86% metastatic disease. 14% ECOG PS of 2. 

Chemotherapy

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

Supportive medications

• Atropine (Atropen) 0.25 mg SC before Irinotecan (Camptosar) 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

21-day cycles

Leary et al. 2008 treated for up to 8 cycles; Moehler et al. 2009 treated indefinitely.

References

1. Leary A, Assersohn L, Cunningham D, Norman AR, Chong G, Brown G, Ross PJ, Costello C, Higgins L, Oates J. A phase II trial evaluating capecitabine and irinotecan as second line treatment in patients with oesophago-gastric cancer who have progressed on, or within 3 months of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2009 Aug;64(3):455-62. Epub 2008 Dec 23. link to original article contains verified protocol PubMed
2. Moehler M, Kanzler S, Geissler M, Raedle J, Ebert MP, Daum S, Flieger D, Seufferlein T, Galle PR, Hoehler T; Arbeitsgemeinschaft Internistische Onkologie. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2010 Jan;21(1):71-7. Epub 2009 Jul 15. link to original article PubMed

Carboplatin & Paclitaxel

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Regimen

Study	Evidence
Philip et al. 1997	Phase II

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

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

Chemotherapy

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

21-day cycles

References

1. Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. contains protocol PubMed

Carboplatin, Docetaxel, Fluorouracil

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Regimen

Study	Evidence
Elkerm et al. 2008	Phase II

Note: this study does not appear to have been published as a manuscript, and the abstract link no longer works.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 2
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1200 mg/m²/day IV continuous infusion on days 1 to 3

Supportive medications

• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 9

21-day cycles

References

1. Abstract: 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. link to abstract

Cetuximab monotherapy

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Regimen

Study	Evidence
Gold et al. 2010 (SWOG S0415)	Phase II

Patients: 100% metastatic esophageal adenocarcinoma who failed one prior chemotherapy regimen. 10% had ECOG PS of 2. 

Chemotherapy

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

Supportive medications

• Diphenhydramine (Benadryl) 50 mg PO/IV 30 to 60 minutes prior to cetuximab

28-day cycles

References

1. 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. link to PMC article contains verified protocol link to PMC articlePubMed

Cisplatin & Docetaxel

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

Variant #1

Study	Evidence	Comparator	Efficacy
Ajani et al. 2005	Randomized Phase II	DCF	Seems to have inferior ORR

Patients: 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70. 

Chemotherapy

• Docetaxel (Taxotere) 85 mg/m² IV over 60 minutes once on day 1
• Cisplatin (Platinol) 75 mg/m² IV over 1 to 3 hours once on day 1

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 (Platinol) and 8 hours after Cisplatin (Platinol)
• Ondansetron (Zofran) 8 mg IV before Cisplatin (Platinol), 4 hours after Cisplatin (Platinol), and 8 hours after Cisplatin (Platinol)
• "Hydration was administered in a standard manner"

21-day cycles

Variant #2

Study	Evidence
Kim et al. 2009	Phase II

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

Chemotherapy

• Docetaxel (Taxotere) 70 mg/m² IV over 60 minutes once on day 1, given 3 hours before cisplatin
• Cisplatin (Platinol) 70 mg/m² IV over 60 minutes once on day 1

Supportive medications

• Dexamethasone (Decadron) 8 mg PO BID x 1 day, starting 1 day before Docetaxel (Taxotere) administration
• At least 3 liters hydration (with mannitol, magnesium, and potassium chloride)
• "Antiemetic treatment"

21-day cycle for up to 6 cycles, progression of disease, or unacceptable toxicity

References

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

Cisplatin & Fluorouracil

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CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Variant #1

Study	Evidence	Comparator	Efficacy
Van Cutsem et al. 2006 (V325 Study Group)	Phase III	DCF	Seems to have inferior OS
Dank et al. 2008	Phase III	IF	Seems not superior

Van Cutsem et al Patients: 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70.

Dank et al Patients: 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric origin). 96% with metastatic disease. 1% with Karnofsky PS of 70. 

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 1 to 3 hours once on day 1, given before Fluorouracil (5-FU)
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion on days 1 to 5, started after cisplatin (total dose per cycle: 5000 mg/m² )

Supportive medications

• As described in Dank et al. 2008:
• "Hyperhydration" for 2 to 3 days with each infusion
• Ondansetron (Zofran) IV for antiemetic prophylaxis
• Dexamethasone (Decadron) IV for antiemetic prophylaxis, then PO for 2 to 3 days
• Metoclopramide (Reglan) for antiemetic prophylaxis
• Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/uL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection
• Atropine (Atropen) prn cholinergic symptoms
• Loperamide (Imodium) prn delayed diarrhea

28-day cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Lorenzen et al. 2009	Randomized Phase II	CF & Cetuximab	Seems not superior

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

Chemotherapy

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

Supportive medications

• "Standard antiemetic prophylaxis and pre- and post- Cisplatin (Platinol) hydration"

29-day cycles until disease progression or unacceptable toxicity for up to 6 cycles

Variant #3

Study	Evidence	Comparator	Efficacy
Bang et al. 2010 (ToGA)	Phase III	CF & Trastuzumab	Inferior OS

Patients in ToGA had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.

ToGA Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2. 

Chemotherapy

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

Supportive medications

• "Hyperhydration" for Cisplatin (Platinol)

21-day cycles, up to 6 cycles in ToGA

References

1. V325 Study Group: 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. link to original article contains verified protocol PubMed
2. 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. link to original article contains verified protocol PubMed
3. Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article contains verified protocol PubMed
4. ToGA: 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. link to original article contains verified protocol PubMed

Cisplatin, Fluorouracil, Cetuximab

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CF-C: Cisplatin, Fluorouracil, Cetuximab

Regimen

Study	Evidence	Comparator	Efficacy
Lorenzen et al. 2009	Randomized Phase II	CF	Seems not superior

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

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 60 minutes once on day 1, given before fluorouracil
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion on days 1 to 5, given after cisplatin (total dose per cycle: 5000 mg/m² )
• Cetuximab (Erbitux) as follows:
  • Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once per day on days 8, 15, 22
  • Cycles 2 to 6: 250 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

• "Standard antiemetic prophylaxis and pre- and post- Cisplatin (Platinol) hydration"

29-day cycle for up to 6 cycles

References

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

CF & Trastuzumab

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CF: Cisplatin, Fluorouracil

Regimen

Study	Evidence	Comparator	Efficacy
Bang et al. 2010 (ToGA)	Phase III	CF	Superior OS

Patients had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.

Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2. 

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion on days 1 to 5 (total dose per cycle: 4000 mg/m²)
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Subsequent cycles: 6 mg/kg IV once on day 1

21-day cycles

References

1. 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. link to original article contains verified protocol PubMed

Cisplatin, Doxorubicin liposomal, Fluorouracil

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Regimen

Study	Evidence	Comparator	Efficacy
Cascinu et al. 2010	Randomized Phase II	MCF	Seems to have superior OS

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

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Pegylated liposomal doxorubicin (Doxil) 20 mg/m² IV once on day 1
• Fluorouracil (5-FU) 400 mg/m² IV bolus, then 600 mg/m²/day IV continuous infusion on days 1 to 2 (total dose per cycle: 1600 mg/m² )

14-day cycles

References

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

Cisplatin & Irinotecan

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CI: Cisplatin & Irinotecan

Variant #1

Study	Evidence
Ilson et al. 2004	Phase II

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

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

Chemotherapy

• 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

Variant #2

Study	Evidence
Ilson et al. 1999	Phase II

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

Chemotherapy

• 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 medications

• Dexamethasone (Decadron) 20 mg IV prior to chemotherapy
• Granisetron (Kytril) 2 mg PO prior to chemotherapy
• At least 500 mL D5NS IV over 30 to 60 minutes before Cisplatin (Platinol)
• Atropine (Atropen) used as pretreatment medication if there was diarrhea or abdominal cramps within 1 hour of Irinotecan (Camptosar)

42-day cycle for 1 to 3 cycles, or until disease progression or unacceptable toxicity.

References

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

CLF

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CLF: Cisplatin, Leucovorin, Fluorouracil
FLP: Fluorouracil, Leucovorin, Platinol (Cisplatin)

Variant #1

Study	Evidence	Comparator	Efficacy
Al-Batran et al. 2008	Phase III	FLO	Might have inferior PFS

Note: In contrast to the original reference, some guidelines list 5-FU as being given every 2 weeks rather than the schedule below.

Patients: 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric).

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV over 2 hours once per day on days 1, 15, 29, 43
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once per day 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 (total dose per cycle: 12,000 mg/m²)

Supportive medications

• Up to 3 liters normal saline as hydration with Cisplatin (Platinol)
• Antiemetic medications per "local protocols"

8-week cycles

Variant #2

Study	Evidence	Comparator
Bouché et al. 2004 (FFCD 9803)	Randomized Phase II	LV5FU2 LV5FU2 & Irinotecan

Note: the 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.

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV over 60 minutes once on either day 1 or 2
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once 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 (total dose per cycle: 1600 mg/m²)

Supportive medications

• 1 liter hydration over 3 hours before and after Cisplatin (Platinol)
• 5-HT3 antagonist IV before Cisplatin (Platinol)
• Methylprednisolone (Solumedrol) 120 mg IV 10 minutes before Cisplatin (Platinol)
• Oral antiemetics and corticosteroids from days 2 to 5

14-day cycle for at least 4 cycles or until progression of disease or unacceptable toxicity

References

1. 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. link to original article contains verified protocol PubMed
2. 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. link to original article contains verified protocol PubMed

Cisplatin & Paclitaxel

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Variant #1

Study	Evidence
Zhang et al. 2008	Phase II

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 2 hours once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycles

Variant #2

Study	Evidence
Ilson et al. 2000	Phase II

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

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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 2, given after paclitaxel
• Paclitaxel (Taxol) 200 mg/m² IV over 24 hours once on day 1

Supportive medications

• "Granulocyte colony stimulating factor support"

21-day cycles

Variant #3

Study	Evidence
Petrasch et al. 1998	Phase II

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

Chemotherapy

• 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 medications

• Dexamethasone (Decadron) 20 mg IV 30 minutes prior to Paclitaxel (Taxol)
• Cimetidine (Tagamet) 300 mg IV 30 minutes prior to Paclitaxel (Taxol)
• Clemastine (Tavist) 2 mg IV 30 minutes prior to Paclitaxel (Taxol)
• Ondansetron (Zofran) 8 mg IV 30 minutes prior to Paclitaxel (Taxol)
• "Adequate pre- and posthydration" for Cisplatin (Platinol)

14-day cycles

References

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

CX

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

Regimen

Study	Evidence	Comparator	Efficacy
Moehler et al. 2009	Randomized Phase II	XI	Seems not superior
Bang et al. 2010 (ToGA)	Phase III (C)	CX & Trastuzumab	Inferior OS
Lordick et al. 2013 (EXPAND)	Phase III (C)	CX & Cetuximab	Seems not superior

Patients in ToGA had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Patients:100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2. 

Lordick Patients: 100% adenocarcinoma (stomach or gastroesophageal junction) locally advanced unresectable (M0) or metastatic (M1).

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 2 hours once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO BID on days 1 to 14
  • 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)

Supportive medications

• per Kang et al. 2009:
• "Hyperhydration" for Cisplatin (Platinol)

21-day cycles

References

1. Moehler M, Kanzler S, Geissler M, Raedle J, Ebert MP, Daum S, Flieger D, Seufferlein T, Galle PR, Hoehler T; Arbeitsgemeinschaft Internistische Onkologie. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2010 Jan;21(1):71-7. Epub 2009 Jul 15. link to original article PubMed
2. ToGA: 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. link to original article contains verified protocol PubMed
3. EXPAND: 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. link to original article contains verified protocol PubMed

CX-C

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CX-C: Cisplatin, Xeloda (Capecitabine), Cetuximab

Regimen

Study	Evidence	Comparator	Efficacy
Lordick et al. 2013 (EXPAND)	Phase III	CX	Seems not superior

Lordick Patients: 100% adenocarcinoma (stomach or gastroesophageal junction) locally advanced unresectable (M0) or metastatic (M1).

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 2 hours once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO BID from the evening of day 1 to the morning of day 15 (28 doses per cycle)
• Cetuximab (Erbitux) as follows:
  • Cycle 1: 400 mg/m² IV once on day 1
  • Subsequently: 250 mg/m² IV once per week

21-day cycles

References

1. 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. link to original article contains verified protocol PubMed

CX & Trastuzumab

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CX: Cisplatin, Xeloda (Capecitabine)

Variant #1

Study	Evidence	Comparator	Efficacy
Shah et al. 2017 (HELOISE)	Phase IIIb	CX & HD-Trastuzumab	Seems not superior

Patients had overexpression of HER2 protein by immunohistochemistry AND gene amplification by in-situ hybridisation. Patients: 100% metastatic adenocarcinoma (gastroesophageal junction or gastric)

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Capecitabine (Xeloda) 800 mg/m² PO BID on days 1 to 14
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Subsequent cycles: 6 mg/kg IV once on day 1

21-day cycle for up to 6 cycles; trastuzumab alone continued until progression of disease or unacceptable toxicity

Variant #2

Study	Evidence	Comparator	Efficacy
Bang et al. 2010 (ToGA)	Phase III	CX	Superior OS

Patients had overexpression of HER2 protein by immunohistochemistry OR gene amplification by fluorescence in-situ hybridisation. Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO BID on days 1 to 14
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Subsequent cycles: 6 mg/kg IV once on day 1

21-day cycles

References

1. 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. link to original article contains verified protocol PubMed
2. Shah MA, Xu RH, Bang YJ, Hoff PM, Liu T, Herráez-Baranda LA, Xia F, Garg A, Shing M, Tabernero J. HELOISE: Phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2017 Aug 1;35(22):2558-2567. Epub 2017 Jun 2.link to original article contains verified protocol PubMed

Docetaxel monotherapy

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Variant #1

Study	Evidence	Comparator	Efficacy
Ford et al. 2013 (COUGAR-2)	Phase III	Active symptom control	Superior OS

Patients: 100% adenocarcinoma histology  (20% esophageal, 35% gastroesophageal junction, 45% stomach) that progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. 15% ECOG PS of 2. 12% locally advanced, 88% metastatic disease. 

Chemotherapy

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

21-day cycle for up to 6 cycles

Variant #2

Study	Evidence
Albertsson et al. 2007	Phase II

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

Chemotherapy

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

21-day cycles

References

1. Albertsson M, Johansson B, Friesland S, Kadar L, Letocha H, Frykholm G, Wagenius G. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol. 2007;24(4):407-12. link to original article contains protocol PubMed
2. 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. link to original article PubMed
3. Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. link to original article contains verified protocol PubMed

DCF

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DCF: Docetaxel, Cisplatin, Fluorouracil
TCF: Taxotere (Docetaxel), Cisplatin, Fluorouracil

Variant #1

Study	Evidence	Comparator	Efficacy
Ajani et al. 2005	Randomized Phase II	DC	Seems to have superior ORR
Van Cutsem et al. 2006 (V325 Study Group)	Phase III	CF	Seems to have superior OS

Note: In contrast to the original references, some guidelines list each cycle as lasting 28 days.

Anjani et al. Patients: 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70. 

Van Cutsem et al Patients: 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS score of 70.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes 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 (total dose per cycle: 3750 mg/m²)

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 (Platinol) and 8 hours after Cisplatin (Platinol)
• Ondansetron (Zofran) 8 mg IV before Cisplatin (Platinol), 4 hours after Cisplatin (Platinol), and 8 hours after Cisplatin (Platinol)
• "Hydration [was] administered in a standard manner"

21-day cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Roth et al. 2007	Randomized Phase II	ECF	Not reported
		TC	Might have superior ORR

Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m² to 75 mg/m² based on high incidence of febrile neutropenia.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1
• Cisplatin (Platinol) 75 mg/m² IV over 4 hours once on day 1
• Fluorouracil (5-FU) 300 mg/m²/day IV continuous infusion on days 1 to 14 (total dose per cycle: 4200 mg/m²)

Supportive medications

• 3 liters per day "hyperhydration"
• Dexamethasone (Decadron) 8 mg PO given 12 hours & 6 hours before Docetaxel (Taxotere), then 8 mg PO BID for 4 days after Docetaxel (Taxotere)
• 5-HT3 antagonist for emesis prophylaxis
• Growth factor support allowed, such as with Filgrastim (Neupogen)

21-day cycle for up to 8 cycles

References

1. 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. link to original article contains verified protocol PubMed
2. 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. link to original article contains verified protocol PubMed
3. 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. link to original article contains verified protocol PubMed

mDCF

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mDCF: modified Docetaxel, Cisplatin, Fluorouracil

Variant #1

Study	Evidence
Ozal et al. 2010	Phase II

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1
• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion on days 1 to 4

21-day cycles

Variant #2

Study	Evidence
Shah et al. 2010	Phase II

Note: In contrast to the primary reference, some guidelines list this regimen without bevacizumab. Please see below for the original mDCF regimen that included bevacizumab.

Patients: 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy. 

Chemotherapy

• Docetaxel (Taxotere) 40 mg/m² IV over 60 minutes on days 1, 15, 29
• Cisplatin (Platinol) 40 mg/m² IV over 1 to 3 hours once per day on days 3, 17, 31
• Folinic acid (Leucovorin) 400 mg/m² IV once per day on days 1, 15, 29
• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1, 15, 29, then 1000 mg/m²/day IV continuous infusion on days 1 & 2, 15 & 16, 29 & 30 (total dose per cycle: 7200 mg/m²)

Supportive medications

• "Standard premedication and delayed emesis regimens"

42-day cycles

References

1. Abstract: 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. link to abstract
2. 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. link to original article contains verified protocol link to PMC article PubMed

mDCF & Bevacizumab

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mDCF: modified Docetaxel, Cisplatin, Fluorouracil

Regimen

Study	Evidence
Shah et al. 2010	Phase II

Patients: 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.

Chemotherapy

• Docetaxel (Taxotere) 40 mg/m² IV over 60 minutes on days 1, 15, 29
• Cisplatin (Platinol) 40 mg/m² IV over 1 to 3 hours once per day on days 3, 17, 31
• Folinic acid (Leucovorin) 400 mg/m² IV once per day on days 1, 15, 29
• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1, 15, 29, then 1000 mg/m²/day IV continuous infusion on days 1 to 2, 15 to 16, 29 to 30 (total dose per cycle: 7200 mg/m²)
• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1, 15, 29

Supportive medications

• "Standard premedication and delayed emesis regimens"

42-day cycles

References

1. 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. link to original article contains verified protocol link to PMC article PubMed

Docetaxel & Irinotecan

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Regimen

Study	Evidence
Burtness et al. 2009	Phase II

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

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV over 60 minutes 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 medications

• Dexamethasone (Decadron) 8 mg PO given 12 hours before Docetaxel (Taxotere), then 10 mg IV within 1 hour before chemotherapy. Then 8 mg PO given 12 hour afters chemotherapy.
• 5-HT3 antagonist antiemetic IV given within 1 hour before chemotherapy 
• "Oral antiemetic therapy prescribed"
• Loperamide as needed

21-day cycles

References

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

DOF

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DOF: Docetaxel, Oxaliplatin, Fluorouracil

Regimen

Study	Evidence
Shankaran et al. 2009	Phase II

Chemotherapy

• Docetaxel (Taxotere) 50 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1200 mg/m²/day IV continuous infusion over 46 hours on days 1 to 2 (total dose: 2400 mg/m²)

14-day cycles

References

1. Abstract: 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. link to abstract

ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study	Evidence	Comparator	Efficacy
Findlay et al. 1994	Phase II
Ross et al. 2002	Phase III	MCF	Seems to have noninferior OS
Roth et al. 2007	Randomized Phase II	TC TCF	Not reported
Cunningham et al. 2008 (REAL-2)	Phase III	ECX	Non-inferior OS
		EOF	Non-inferior OS
		EOX	Seems to have inferior OS

Findlay et al. Patients: all metastatic gastric cancer

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

Roth et al. Patients: all metastatic gastric cancer

Cunningham et al Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 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 (total dose 4200 mg/m²)

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 once per day for catheter thrombosis prophylaxis

21-day cycle for up to 8 cycles

References

1. Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson V, Nash A, Sacks N, Ford H, Carter R, Hill A. A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol. 1994 Sep;5(7):609-16. link to original article contains verified protocol PubMed
2. Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. link to original article contains verified protocol PubMed
3. 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. link to original article contains verified protocol PubMed
4. REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article contains verified protocol PubMed

ECX

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ECX: Epirubicin, Cisplatin, Xeloda (Capecitabine)

Regimen

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2008 (REAL-2)	Phase III	ECF	Non-inferior OS
		EOF EOX	Non-inferior OS

Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 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 BID on days 1 to 21

21-day cycle for up to 8 cycles

References

1. REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article contains verified protocol PubMed
2. Iveson T, Donehower RC, Davidenko I, Tjulandin S, Deptala A, Harrison M, Nirni S, Lakshmaiah K, Thomas A, Jiang Y, Zhu M, Tang R, Anderson A, Dubey S, Oliner KS, Loh E. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 2014 Aug;15(9):1007-18. Epub 2014 Jun 22. link to original article PubMed
3. Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, André T, Gornet JM, Aparicio T, Nguyen S, Azzedine A, Etienne PL, Boucher E, Rebischung C, Hammel P, Rougier P, Bedenne L, Bouché O. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol. 2014 Nov 1;32(31):3520-6. Epub 2014 Oct 6. Erratum in: J Clin Oncol. 2015 Apr 20;33(12):1416. link to original article PubMed

EOF

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EOF: Epirubicin, Oxaliplatin, Fluorouracil

Regimen

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2008 (REAL-2)	Phase III	ECF ECX	Non-inferior OS
		EOX	Non-inferior OS

Patients: 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 on days 1 to 21 (total dose per cycle: 4200 mg/m²)

Supportive medications

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

21-day cycle for up to 8 cycles

References

1. REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article contains verified protocol PubMed

EOX

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

Variant #1

Study	Evidence	Comparator	Efficacy
Waddell et al. 2013 (REAL3)	Phase III	mEOC+P	Seems to have superior OS

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

Chemotherapy

• 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 cycle for up to 8 cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2008 (REAL-2)	Phase III	ECF	Seems to have superior OS
		ECX	Non-inferior OS
		EOF	Non-inferior OS

Patients: 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
• Capecitabine (Xeloda) 625 mg/m² PO BID on days 1 to 21

21-day cycle for up to 8 cycles

References

1. REAL-2: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. link to original article contains verified protocol PubMed content property of HemOnc.org
2. REAL3: 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. Epub 2013 Apr 15. contains verified protocol link to PMC articlePubMed

Erlotinib monotherapy

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Regimen

Study	Evidence
Dragovich et al. 2006 (SWOG 0127)	Phase II
Ilson et al. 2010	Phase II

Dragovich et al. Patients: 100% adenocarcinoma (63% gastroesophageal junction, 37% gastric origin). All with ECOG PS of 0 or 1.

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

Chemotherapy

• 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

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

Etoposide monotherapy

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Regimen

Study	Evidence
Harstrick et al. 1992	Phase II

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

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

Chemotherapy

• Etoposide (Vepesid) 200 mg/m² (route not specified) once per day on days 1 to 3

21-day cycles

References

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

Fluorouracil & Folinic acid (LV5FU2)

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Regimen

Study	Evidence	Comparator
Bouché et al. 2004 (FFCD 9803)	Randomized Phase II	LV5FU2 & Cisplatin LV5FU2 & Irinotecan

Note: the 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 typical schedule was used.

Chemotherapy

• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once 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 cycle for at least 4 cycles or until progression of disease or unacceptable toxicity

References

1. 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. link to original article contains verified protocol PubMed

Fluorouracil, Folinic acid, Gemcitabine

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Regimen

Study	Evidence
Morgan-Meadows et al. 2005	Phase II

Chemotherapy

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

28-day cycles

References

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

FLOT

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FLOT: Fluorouracil, Leucovorin, Oxaliplatin, Taxotere (Docetaxel)

Regimen

Study	Evidence
Al-Batran et al. 2008	Phase II

Chemotherapy

• Fluorouracil (5-FU) 2600 mg/m² IV continuous 24-hour infusion on day 1, given last
• Folinic acid (Leucovorin) 200 mg/m² IV over 1 to 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 1 to 2 hours once on day 1
• Docetaxel (Taxotere) 50 mg/m² IV over 1 to 2 hours once on day 1

Supportive medications

• Dexamethasone (Decadron) 8 mg PO once per day on days 0 to 3 of every cycle

14-day cycle for up to 8 (or more) cycles

References

1. 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. link to original article contains verified protocol PubMed

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan
IF: Irinotecan & 5-Fluorouracil

Variant #1, "IF"

Study	Evidence	Comparator	Efficacy
Dank et al. 2008	Phase III	CF	Seems not superior

Chemotherapy

• Fluorouracil (5-FU) 2000 mg/m²/day IV continuous 22-hour infusion on days 1, 8, 15, 22, 29, 36; given last
• Folinic acid (Leucovorin) 500 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36; given second
• Irinotecan (Camptosar) 80 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36; given first

Supportive medications

• Ondansetron (Zofran) for antiemetic prophylaxis
• Dexamethasone (Decadron) for antiemetic prophylaxis
• Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/uL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection
• Atropine (Atropen) prn cholinergic symptoms
• Loperamide (Imodium) prn delayed diarrhea

7-week cycles

Variant #2, LV5FU2 & Irinotecan

Study	Evidence	Comparator
Bouché et al. 2004 (FFCD 9803)	Randomized Phase II	LV5FU2 LV5FU2 & Cisplatin

Chemotherapy

• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once 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 once on day 1

14-day cycle for 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 typical schedule was used)

Variant #3

Study	Evidence
Samalin et al. 2010	Retrospective

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given second
• Fluorouracil (5-FU) 400 mg/m² IV bolus, then 1200 mg/m²/day IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2400 mg/m²)
• Irinotecan (Camptosar) 180 mg/m² IV over 90 minutes once on day 1, given first

14-day cycles

References

1. 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. link to original article contains verified protocol PubMed
2. 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. link to original article contains verified protocol PubMed
3. 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. link to original article contains protocol PubMed
4. Retrospective: 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. 2011 Jan;35(1):48-54. Epub 2010 Oct 28. link to original article contains verified protocol PubMed
5. Retrospective: 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 PubMed
6. Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, André T, Gornet JM, Aparicio T, Nguyen S, Azzedine A, Etienne PL, Boucher E, Rebischung C, Hammel P, Rougier P, Bedenne L, Bouché O. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol. 2014 Nov 1;32(31):3520-6. Epub 2014 Oct 6. Erratum in: J Clin Oncol. 2015 Apr 20;33(12):1416. link to original article PubMed

FOLFOX-C

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FOLFOX-C: FOLinic acid, Fluorouracil, OXaliplatin, Cetuximab

Regimen

Study	Evidence	Comparator
Enziger et al. 2016 (CALGB 80403/ECOG E1206)	Randomized Phase II	ECF-C IC-C

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus, then 2400 mg/m² IV continuous infusion over 46 to 48 hours, given after oxaliplatin and folinic acid (total dose per cycle: 2800 mg/m²)
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1
• Cetuximab (Erbitux) 400 mg/m² IV over 2 hours once on day 1 of the first cycle and then 250 mg/m² IV over 60 minutes once per week

14-day cycles

References

1. Enzinger PC, Burtness BA, Niedzwiecki D, Ye X, Douglas K, Ilson DH, Villaflor VM, Cohen SJ, Mayer RJ, Venook A, Benson AB 3rd, Goldberg RM. CALGB 80403 (Alliance)/E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancers. J Clin Oncol. 2016 Aug 10;34(23):2736-42. Epub 2016 Jul 5. link to original article contains verified protocol link to PMC article PubMed

Irinotecan monotherapy

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Regimen

Study	Evidence
Mühr-Wilkenshoff et al. 2003	Phase II, <20 patients
Enzinger et al. 2005	Phase II

Note: In contrast to the primary references, some guidelines list a dosing schedule of 125 mg/m² IV once per day 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."

Chemotherapy

• 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

42-day cycles

References

1. Mühr-Wilkenshoff F, Hinkelbein W, Ohnesorge I, Wolf KJ, Riecken EO, Zeitz M, Scherübl H. A pilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or metastatic esophageal carcinoma. Int J Colorectal Dis. 2003 Jul;18(4):330-4. Epub 2003 Feb 1. link to original article PubMed
2. 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. link to original article PubMed

Irinotecan & Mitomycin

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Variant #1

Study	Evidence	Comparator
Lustberg et al. 2010	Randomized Phase II	Irinotecan & Mitomycin

Chemotherapy

• Irinotecan (Camptosar) 125 mg/m² IV once per day on days 2 & 9
• Mitomycin (Mutamycin) 6 mg/m² IV once on day 1

Supportive medications

• Ondansetron (Zofran) or Granisetron (Kytril) and Dexamethasone (Decadron) premedication
• Loperamide (Imodium) started with first episode of diarrhea
• Erythropoietin for hemoglobin less than 10 g/dL permitted

28-day cycle for up to 6 cycles

Variant #2

Study	Evidence
Giuliani et al. 2005	Phase II

Chemotherapy

• Irinotecan (Camptosar) 150 mg/m² IV once per day on days 1 & 15
• Mitomycin (Mutamycin) 8 mg/m² IV once on day 1

28-day cycles

Variant #3

Study	Evidence
Bamias et al. 2003	Phase II

Chemotherapy

• Irinotecan (Camptosar) 125 mg/m² IV once on day 1
• Mitomycin (Mutamycin) 5 mg/m² IV once on day 1

14-day cycles

References

1. Bamias A, Papamichael D, Syrigos K, Pavlidis N. Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother. 2003 Jun;15(3):275-81. link to original article contains protocol PubMed
2. Giuliani F, Molica S, Maiello E, Battaglia C, Gebbia V, Di Bisceglie M, Vinciarelli G, Gebbia N, Colucci G; Gruppo Oncologico dell' Italia Meridionale. 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. link to original article contains protocol PubMed
3. 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. link to original article contains verified protocol link to PMC article PubMed

MCF

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MCF: Mitomycin, Cisplatin, Fluorouracil

Regimen

Study	Evidence	Comparator	Efficacy
Ross et al. 2002	Phase III	ECF	Seems to have noninferior OS
Cascinu et al. 2010	Randomized Phase II	Cisplatin, Doxorubicin liposomal, Fluorouracil	Seems to have inferior OS

Chemotherapy

• Mitomycin (Mutamycin) 7 mg/m² (maximum dose of 14 mg per cycle) 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 on days 1 to 42

Supportive medications

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

42-day cycle for up to 6 months

References

1. Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. link to original article contains verified protocol PubMed
2. Cascinu S, Galizia E, Labianca R, Ferraù F, Pucci F, Silva RR, Luppi G, Beretta GD, Berardi R, Scartozzi M. Pegylated liposomal doxorubicin, 5-fluorouracil and cisplatin versus mitomycin-C, 5-fluorouracil and cisplatin for advanced gastric cancer: a randomized phase II trial. Cancer Chemother Pharmacol. 2011 Jul;68(1):37-43. Epub 2010 Sep 7. link to original article contains verified protocol PubMed

OLF

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OLF: Oxaliplatin, Leucovorin, Fluorouracil
FLO: Fluorouracil, Leucovorin, Oxaliplatin

Regimen

Study	Evidence	Comparator	Efficacy
Al-Batran et al. 2008	Phase III	FLP	Might have superior PFS

Chemotherapy

• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once per day on days 1, 15, 29, 43
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once per day on days 1, 15, 29, 43
• Fluorouracil (5-FU) 2600 mg/m² IV continuous 24-hour infusion on days 1, 15, 29, 43

Supportive medications

• Antiemetic medications per "local protocols"

8-week cycles

References

1. 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. link to original article contains verified protocol PubMed

Paclitaxel monotherapy

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Variant #1, weekly

Study	Evidence
Ilson et al. 2007	Phase II

Chemotherapy

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

Supportive medications

• Dexamethasone (Decadron) 20 mg IV 30 to 60 minutes before paclitaxel
• Cimetidine (Tagamet) 300 mg IV 30 to 60 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV 30 to 60 minutes prior to paclitaxel

28-day cycles

Variant #2, CI

Study	Evidence
Ajani et al. 1994	Phase II

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

Chemotherapy

• 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

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 once per day, starting 24 hours after the paclitaxel infusion finishes

21-day cycles

References

1. Ajani JA, Ilson DH, Daugherty K, Pazdur R, Lynch PM, Kelsen DP. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst. 1994 Jul 20;86(14):1086-91. link to original article contains verified protocol PubMed
2. Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-902. Epub 2007 Mar 9. link to original article contains verified protocol PubMed
3. RAINBOW: Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. link to original article PubMed

Paclitaxel & Ramucirumab

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Regimen

Study	Evidence	ORR	Comparator	Comparator ORR	Efficacy	Pt Population
Wilke et al. 2014 (RAINBOW)	Phase III	28% (95% CI 23-33%)	Paclitaxel	16% (95% CI 13-20%)	Seems to have superior OS	Chemo exposed

Eligibility criteria for patients in RAINBOW included: "documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline."

Chemotherapy

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

28-day cycles

References

1. RAINBOW: Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. link to original article contains verified protocol PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Fuchs et al. 2013 (REGARD)	Phase III (C)	Ramucirumab	Seems to have inferior OS
Ford et al. 2013 (COUGAR-02)	Phase III (C)	Docetaxel	Inferior OS
Dutton et al. 2014 (COG)	Phase III (C)	Gefitinib	Seems not superior
Li et al. 2016	Phase III (C)	Apatinib	Seems to have inferior OS

Patients in REGARD previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."

No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.

References

1. REGARD: Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3. link to original article contains verified protocol PubMed
2. COUGAR-02: Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. link to original article contains verified protocol PubMed
3. COG: Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W, Thompson J, Harrison M, Chatterjee A, Falk S, Garcia-Alonso A, Fyfe DW, Hubner RA, Gamble T, Peachey L, Davoudianfar M, Pearson SR, Julier P, Jankowski J, Kerr R, Petty RD. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 2014 Jul;15(8):894-904. Epub 2014 Jun 17. link to original article PubMed
4. Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R, Wang Z, Wang Q, Ouyang X, Yang Y, Ba Y, Liang J, Lin X, Luo D, Zheng R, Wang X, Sun G, Wang L, Zheng L, Guo H, Wu J, Xu N, Yang J, Zhang H, Cheng Y, Wang N, Chen L, Fan Z, Sun P, Yu H. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016 May 1;34(13):1448-54. Epub 2016 Feb 16. link to original article PubMed

Ramucirumab monotherapy

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Regimen

Study	Evidence	ORR	Comparator	Comparator ORR	Efficacy	Pt Population
Fuchs et al. 2013 (REGARD)	Phase III	3%	Placebo	3%	Seems to have superior OS	Chemo exposed

Patients in REGARD previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."

Chemotherapy

• Ramucirumab (Cyramza) 8 mg/kg IV once every 2 weeks

Given until progression of disease, unacceptable toxicity, or death

References

1. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3. link to original article contains verified protocol PubMed