Esophageal squamous cell carcinoma

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Neeta K. Venepalli, MD, MBA, FACP
University of North Carolina
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Note: these are regimens tested in histology-specific populations, please see the main esophageal cancer page for other regimens.

22 regimens on this page
27 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 3 (E-esc) Surgery alone Seems to have superior OS

Patients: 100% squamous cell histology

Chemotherapy

21-day cycle for 2 to 4 cycles

Subsequent treatment

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

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 2

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

Chemotherapy

Supportive medications

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.8 to 2 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 3 (C) Cisplatin, Paclitaxel, Erlotinib, ENI Seems to have inferior OS

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

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 3 (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

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

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 3 (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

Chemotherapy

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 (DC)

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

Regimen

Study Evidence
Kim et al. 2009 Phase 2

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

Chemotherapy

Supportive medications

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, 4-day infusion, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moehler et al. 2019 (POWER) 2012-2015 Phase 3 (C) CFP Did not meet primary endpoint of OS

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

Chemotherapy

28-day cycles

Regimen variant #2, 80/4000, 5-day infusion, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Doki et al. 2022 (CheckMate 648) 2017-2019 Phase 3 (C) 1. CF & Nivolumab
2. Ipilimumab & Nivolumab
Inferior OS1

1Reported efficacy is for the overall randomized population.

Chemotherapy

28-day cycles

Regimen variant #3, 100/5000 x 6

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lorenzen et al. 2009 2004-2006 Randomized Phase 2 (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

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
  3. CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains verified protocol PubMed NCT03143153

Cisplatin & Fluorouracil (CF) & 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 2 (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

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

Cisplatin & Fluorouracil (CF) & Nivolumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Doki et al. 2022 (CheckMate 648) 2017-2019 Phase 3 (E-esc) 1. CF Superior OS1
Median OS: 13.2 vs 10.7 mo
(HR 0.74, 99.1% CI 0.58-0.96)
2. Ipilimumab & Nivolumab Not reported

1Reported efficacy is for the overall randomized population.

Chemotherapy

Immunotherapy

28-day cycles

References

  1. CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains verified protocol PubMed NCT03143153

Cisplatin & Fluorouracil (CF) & Sintilimab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lu et al. 2022 (ORIENT-15) 2018-2021 Phase 3 (E-esc) 1. CF
2. Cisplatin & Paclitaxel
Superior OS1
Median OS: 17.2 vs 13.6 mo
(HR 0.64, 95% CI 0.48-0.85)

1Reported efficacy is for the primary efficacy population (CPS of 10 or more).

Chemotherapy

  • Cisplatin (Platinol) as follows:
    • Cycles 1 to 6: 75 mg/m2 IV once on day 1
  • Fluorouracil (5-FU) as follows:
    • Cycles 1 to 6: 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)

Immunotherapy

  • Sintilimab (Tyvyt) by the following weight-based criteria:
    • Weight less than 60 kg: 3 mg/kg IV once on day 1
    • Weight 60 kg or more: 200 mg IV once on day 1

28-day cycle for up to 26 cycles (2 years)

References

  1. ORIENT-15: Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L; ORIENT-15 study group. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022 Apr 19;377:e068714. link to original article contains verified protocol PubMed NCT03748134

Cisplatin & Paclitaxel

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Regimen variant #1, 6 cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Luo et al. 2021 (ESCORT-1st) 2018-2020 Phase 3 (C) Cisplatin, Paclitaxel, Camrelizumab Inferior OS
Wang et al. 2022 (JUPITER-06) 2019-2020 Phase 3 (C) Cisplatin, Paclitaxel, Toripalimab Inferior OS

Chemotherapy

21-day cycle for up to 6 cycles

Regimen variant #2, indefinite

Study Evidence
Zhang et al. 2008 Phase 2

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

Chemotherapy

21-day cycles

References

  1. Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 2008 Feb;31(1):29 to 33. link to original article contains protocol PubMed
  2. ESCORT-1st: Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):916-925. link to original article contains protocol link to PMC article PubMed NCT03691090
  3. JUPITER-06: Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, Shen L, Shu Y, Wang C, Dai T, Mao T, Chen L, Guo Z, Liu B, Pan H, Cang S, Jiang Y, Wang J, Ye M, Chen Z, Jiang D, Lin Q, Ren W, Wang J, Wu L, Xu Y, Miao Z, Sun M, Xie C, Liu Y, Wang Q, Zhao L, Li Q, Huang C, Jiang K, Yang K, Li D, Liu Y, Zhu Z, Chen R, Jia L, Li W, Liao W, Liu HX, Ma D, Ma J, Qin Y, Shi Z, Wei Q, Xiao K, Zhang Y, Zhang Y, Chen X, Dai G, He J, Li J, Li G, Liu Y, Liu Z, Yuan X, Zhang J, Fu Z, He Y, Ju F, Liu Z, Tang P, Wang T, Wang W, Zhang J, Luo X, Tang X, May R, Feng H, Yao S, Keegan P, Xu RH, Wang F. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. 2022 Mar 14;40(3):277-288.e3. Epub 2022 Mar 3. link to original article contains verified protocol PubMed NCT03829969

Cisplatin, Paclitaxel, Camrelizumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Luo et al. 2021 (ESCORT-1st) 2018-2020 Phase 3 (E-esc) Cisplatin & Paclitaxel Superior OS
Median OS: 15.3 vs 12 mo
(HR 0.70, 95% CI 0.56-0.88)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. ESCORT-1st: Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):916-925. link to original article contains protocol link to PMC article PubMed NCT03691090

Cisplatin, Paclitaxel, Sintilimab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lu et al. 2022 (ORIENT-15) 2018-2021 Phase 3 (E-esc) 1. CF
2. Cisplatin & Paclitaxel
Superior OS1
Median OS: 17.2 vs 13.6 mo
(HR 0.64, 95% CI 0.48-0.85)

1Reported efficacy is for the primary efficacy population (CPS of 10 or more).

Chemotherapy

  • Cisplatin (Platinol) as follows:
    • Cycles 1 to 6: 75 mg/m2 IV once on day 1
  • Paclitaxel (Taxol) as follows:
    • Cycle 1: 87.5 mg/m2 IV once per day on days 1 & 8
    • Cycles 2 to 6: 175 mg/m2/day IV once on day 1

Immunotherapy

  • Sintilimab (Tyvyt) by the following weight-based criteria:
    • Weight less than 60 kg: 3 mg/kg IV once on day 1
    • Weight 60 kg or more: 200 mg IV once on day 1

28-day cycle for up to 26 cycles (2 years)

References

  1. ORIENT-15: Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L; ORIENT-15 study group. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022 Apr 19;377:e068714. link to original article contains verified protocol PubMed NCT03748134

Cisplatin, Paclitaxel, Toripalimab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2022 (JUPITER-06) 2019-2020 Phase 3 (E-esc) Cisplatin & Paclitaxel Superior OS
Median OS: 17 vs 11 mo
(HR 0.58, 95% CI 0.43-0.78)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. JUPITER-06: Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, Shen L, Shu Y, Wang C, Dai T, Mao T, Chen L, Guo Z, Liu B, Pan H, Cang S, Jiang Y, Wang J, Ye M, Chen Z, Jiang D, Lin Q, Ren W, Wang J, Wu L, Xu Y, Miao Z, Sun M, Xie C, Liu Y, Wang Q, Zhao L, Li Q, Huang C, Jiang K, Yang K, Li D, Liu Y, Zhu Z, Chen R, Jia L, Li W, Liao W, Liu HX, Ma D, Ma J, Qin Y, Shi Z, Wei Q, Xiao K, Zhang Y, Zhang Y, Chen X, Dai G, He J, Li J, Li G, Liu Y, Liu Z, Yuan X, Zhang J, Fu Z, He Y, Ju F, Liu Z, Tang P, Wang T, Wang W, Zhang J, Luo X, Tang X, May R, Feng H, Yao S, Keegan P, Xu RH, Wang F. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. 2022 Mar 14;40(3):277-288.e3. Epub 2022 Mar 3. link to original article contains verified protocol PubMed NCT03829969

Etoposide monotherapy

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Regimen

Study Evidence
Harstrick et al. 1992 Phase 2

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

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

Ipilimumab & Nivolumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Doki et al. 2022 (CheckMate 648) 2017-2019 Phase 3 (E-switch-ooc) 1. CF Superior OS
Median OS: 12.7 vs 10.7 mo
(HR 0.78, 98.2% CI 0.62-0.98)
2. CF & Nivolumab Not compared

Immunotherapy

42-day cycle for up to 17 cycles (2 years)

References

  1. CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains verified protocol PubMed NCT03143153

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 3 (E-switch-ooc) 1. Docetaxel
2. Irinotecan
Superior OS
Median OS: 8 mo vs 6 mo
(HR 0.71, 95% CI 0.57-0.87)

Immunotherapy

14-day cycles

References

  1. ESCORT: Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, Chen J, Zhang H, Niu Z, Fan Q, Lin L, Gu K, Liu Y, Ba Y, Miao Z, Jiang X, Zeng M, Chen J, Fu Z, Gan L, Wang J, Zhan X, Liu T, Li Z, Shen L, Shu Y, Zhang T, Yang Q, Zou J; ESCORT Study Group. 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

Docetaxel monotherapy

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Regimen variant #1, 75 mg/m2, indefinite

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

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.

Chemotherapy

21-day cycles

Regimen variant #2, 100 mg/m2

Study Evidence
Albertsson et al. 2007 Phase 2

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

Chemotherapy

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. 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
  3. RATIONALE 302: NCT03430843

Irinotecan monotherapy

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Regimen variant #1, 14-day cycles

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

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.

Chemotherapy

14-day cycles

Regimen variant #2, 4 out of 6 weeks

Study Evidence
Mühr-Wilkenshoff et al. 2003 Phase 2, <20 patients

Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m2 IV once per day on days 1 & 8, with 21-day cycles.

Patients: Ten with esophageal squamous cell carcinoma, three with esophageal adenocarcinoma

Chemotherapy

42-day cycles

References

  1. Mühr-Wilkenshoff F, Hinkelbein W, Ohnesorge I, Wolf KJ, Riecken EO, Zeitz M, Scherübl H. A pilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or metastatic esophageal carcinoma. Int J Colorectal Dis. 2003 Jul;18(4):330-4. Epub 2003 Feb 1. link to original article PubMed
  2. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains verified protocol PubMed NCT02564263
  3. RATIONALE 302: NCT03430843

Nivolumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kato et al. 2019 (ATTRACTION-3) 2016-2017 Phase 3 (E-RT-switch-ooc) 1. Docetaxel
2. Paclitaxel
Seems to have superior OS
Median OS: 11 mo vs 8 mo
(HR 0.77, 95% CI 0.62-0.96)

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

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

Paclitaxel monotherapy

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Regimen variant #1, weekly

Study Evidence
Ilson et al. 2007 Phase 2

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

Chemotherapy

Supportive medications

28-day cycles

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

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

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.
This is the lower bound of dosing specified in KEYNOTE-181.

Chemotherapy

28-day cycles

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

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

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.
This is the upper bound of dosing specified in the protocol.

Chemotherapy

28-day cycles

References

  1. Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-902. Epub 2007 Mar 9. link to original article contains verified protocol 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
  3. RATIONALE 302: NCT03430843

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 3 (E-RT-switch-ooc) Investigator's choice of:
1. Docetaxel
2. Irinotecan
3. Paclitaxel
Superior OS1
Shah et al. 2019 (KEYNOTE-180) 2016-2017 Phase 2 (RT)

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the 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

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