Esophageal squamous cell carcinoma

Page editor		Section editor
	Ryan Nguyen, DO University of Illinois at Chicago Chicago, IL LinkedIn		Neeta K. Venepalli, MD, MBA University of Illinois at Chicago Chicago, IL

Note: these are regimens tested in histology-specific populations, please see the main esophageal cancer page for other regimens.

45 regimens on this page 66 variants on this page

Neoadjuvant induction therapy

Cisplatin & Etoposide (EP)

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Regimen

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

Patients: 100% squamous cell histology

Chemotherapy

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

21-day cycle for 2 to 4 cycles

Subsequent treatment

• 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

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.

Fluorouracil, Oxaliplatin, RT

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

Regimen variant #1, 45 Gy

Study	Evidence
Lorenzen et al. 2008	Phase I/II

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

Chemotherapy

• Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion over 33 days, started on day 1 (total dose: 7425 mg/m²)
• Oxaliplatin (Eloxatin) 45 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29

Radiotherapy

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

35-day course

Subsequent treatment

• Surgery, 4 to 6 weeks after finishing chemoradiation

References

1. 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

Definitive therapy

Cisplatin, Docetaxel, RT

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DC & RT: Docetaxel, Cisplatin, Radiation Therapy

Regimen variant #1, 80/60 x 2

Study	Evidence
Li et al. 2009	Phase II

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

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

Supportive medications

• Dexamethasone (Decadron) 10 mg IV or PO once on day -1, then once on day 1; 30 minutes prior to Docetaxel (Taxotere), then once on day 2
• Diphenhydramine (Benadryl) 40 mg IV once on day 1, prior to chemotherapy
• Cimetidine (Tagamet) 40 mg IV once on day 1, prior to chemotherapy
• Granisetron 2 mg IV once on day 1, prior to chemotherapy
• 1.5 to 2.0 liters fluids before Cisplatin (Platinol)

21-day cycle for 2 cycles

Radiotherapy

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

Note, dose reductions were permitted, see article for specifications

One course

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

Cisplatin, Paclitaxel, RT

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2018 (Shixiu - 1)	2007-2015	Phase III (C)	Cisplatin, Paclitaxel, Erlotinib, ENI	Seems to have inferior OS

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 3
• Paclitaxel (Taxol) 135 mg/m² IV once on day 1

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy

References

1. Shixiu - 1: Wu SX, Wang LH, Luo HL, Xie CY, Zhang XB, Hu W, Zheng AP, Li DJ, Zhang HY, Xie CH, Lian XL, Du DX, Chen M, Bian XH, Tan BX, Jiang H, Zhang HB, Wang JH, Jing Z, Xia B, Zhang N, Zhang P, Li WF, Zhao FJ, Tian ZF, Liu H, Huang KW, Hu J, Xie RF, Du L, Li G. Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer. Eur J Cancer. 2018 Apr;93:99-107. Epub 2018 Mar 20. link to original article contains protocol PubMed NCT00686114
   1. Update: Xie C, Jing Z, Luo H, Jiang W, Ma L, Hu W, Zheng A, Li D, Ding L, Zhang H, Xie C, Lian X, Du D, Chen M, Bian X, Tan B, Xia B, Xie R, Liu Q, Wang L, Wu S. Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial. Br J Cancer. 2020 Nov;123(11):1616-1624. Epub 2020 Sep 22. link to original article link to PMC article PubMed

Fluorouracil, Paclitaxel, RT

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Regimen

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

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

Chemotherapy

• Fluorouracil (5-FU) 75 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 300 mg/m²)
• Paclitaxel (Taxol) 50 mg/m² IV once on day 1

7-day cycle for 5 cycles

Radiotherapy

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

7-week course

Subsequent treatment

• Fluorouracil & Paclitaxel consolidation

References

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

Consolidation after definitive therapy

Fluorouracil & Paclitaxel

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Regimen

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

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

Preceding treatment

• 5-FU, Paclitaxel, RT

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m²)
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

28-day cycle for 2 cycles

References

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

Metastatic or locally advanced disease, first-line

Cisplatin & Docetaxel

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

Regimen

Study	Evidence
Kim et al. 2009	Phase II

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

Chemotherapy

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

Supportive medications

• Dexamethasone (Decadron) 8 mg PO twice per day 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

References

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

Cisplatin & Fluorouracil (CF)

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CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen variant #1, 80/4000, indefinite

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

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

Chemotherapy

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

28-day cycles

Regimen variant #2, 100/5000 x 6

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

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

Chemotherapy

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

Supportive medications

• "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
2. POWER: Moehler M, Maderer A, Thuss-Patience PC, Brenner B, Meiler J, Ettrich TJ, Hofheinz RD, Al-Batran SE, Vogel A, Mueller L, Lutz MP, Lordick F, Alsina M, Borchert K, Greil R, Eisterer W, Schad A, Slotta-Huspenina J, Van Cutsem E, Lorenzen S. Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER). Ann Oncol. 2020 Feb;31(2):228-235. Epub 2019 Dec 16. link to original article contains verified protocol PubMed NCT01627379

Cisplatin, Fluorouracil, Cetuximab

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CF-C: Cisplatin, Fluorouracil, Cetuximab

Regimen

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

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

Chemotherapy

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

Targeted therapy

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

Supportive medications

• "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

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

Metastatic or locally advanced disease, subsequent lines of therapy

Camrelizumab monotherapy

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Regimen

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

Immunotherapy

• Camrelizumab (AiRuiKa) 200 mg IV once on day 1

14-day cycles

References

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

Nivolumab monotherapy

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Regimen

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

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

Immunotherapy

• Nivolumab (Opdivo) 240 mg IV once on day 1

14-day cycles

References

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

Pembrolizumab monotherapy

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Regimen

FDA-recommended dose

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

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

Biomarker eligibility criteria

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

Immunotherapy

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

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

References

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