Esophageal squamous cell carcinoma

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Note: these are regimens tested in histology-specific populations, please see the main esophageal cancer page for other regimens that were tested in unselected populations.
Last updated on 2024-12-02:51 regimens on this page
69 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers.
=Perioperative therapy=
==Cisplatin & Paclitaxel (TP) & Camrelizumab==
TP & Camrelizumab: Taxol (Paclitaxel), Platinol (Cisplatin), Camrelizumab
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Qin et al. 2024 (ESCORT-NEO)	2021-04-28 to 2023-08-07	Phase 3 (E-esc)	1. TP 	Higher pCR rate (primary endpoint)
Qin et al. 2024 (ESCORT-NEO)	2021-04-28 to 2023-08-07	Phase 3 (E-esc)	2. nab-TP & Camrelizumab	Not reported
===Neoadjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
21-day cycle for 2 cycles
===Definitive===
====Local therapy====
*Surgery
===Adjuvant===
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
21-day cycle for up to 15 cycles
===References===
#ESCORT-NEO: Qin J, Xue L, Hao A, Guo X, Jiang T, Ni Y, Liu S, Chen Y, Jiang H, Zhang C, Kang M, Lin J, Li H, Li C, Tian H, Li L, Fu J, Zhang Y, Ma J, Wang X, Fu M, Yang H, Yang Z, Han Y, Chen L, Tan L, Dai T, Liao Y, Zhang W, Li B, Chen Q, Guo S, Qi Y, Wei L, Li Z, Tian Z, Kang X, Zhang R, Li Y, Wang Z, Chen X, Hou Z, Zheng R, Zhu W, He J, Li Y. Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial. Nat Med. 2024 Sep;30(9):2549-2557. Epub 2024 Jul 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR2000040034
==Cisplatin & Paclitaxel (TP) & Toripalimab==
TP & Toripalimab: Taxol (Paclitaxel), Platinol (Cisplatin), Toripalimab
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Zheng et al. 2024 (HCHTOG1909)	2020-05-15 to 2021-08-13	Phase 3 (E-esc)	Cisplatin & Paclitaxel	Seems to have longer EFS (primary endpoint)EFS12: 77.9% vs 64.3%(HR 0.62, 95% CI 0.39-1.00)Seems to have longer OS (secondary endpoint)OS12: 94.1% vs 83%(HR 0.48, 95% CI 0.24-0.97)
===Neoadjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Immunotherapy====
*Toripalimab (Loqtorzi) as follows:
**Cycle 1: 240 mg IV over 60 minutes once on day 1
**Cycle 2: 240 mg IV over 30 minutes once on day 1
21-day cycle for 2 cycles
===Definitive===
====Local therapy====
*Minimally invasive esophagectomy (MIE)
===Adjuvant===
====Immunotherapy====
*Toripalimab (Loqtorzi) 240 mg IV over 30 minutes once on day 1
21-day cycle for up to 8 cycles
===References===
#HCHTOG1909: Zheng Y, Liang G, Yuan D, Liu X, Ba Y, Qin Z, Shen S, Li Z, Sun H, Liu B, Gao Q, Li P, Wang Z, Liu S, Zhu J, Wang H, Ma H, Liu Z, Zhao F, Zhang J, Zhang H, Wu D, Qu J, Ma J, Zhang P, Ma W, Yan M, Yu Y, Li Q, Zhang J, Xing W. Perioperative toripalimab plus neoadjuvant chemotherapy might improve outcomes in resectable esophageal cancer: an interim analysis of a phase III randomized clinical trial. Cancer Commun (Lond). 2024 Oct;44(10):1214-1227. Epub 2024 Sep 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04280822
==Cisplatin & nab-Paclitaxel (nab-TP) & Camrelizumab==
nab-TP & Camrelizumab: nab-Taxol (Abraxane), Platinol (Cisplatin), Camrelizumab
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Qin et al. 2024 (ESCORT-NEO)	2021-04-28 to 2023-08-07	Phase 3 (E-esc)	1. TP 	Higher pCR rate (primary endpoint)
Qin et al. 2024 (ESCORT-NEO)	2021-04-28 to 2023-08-07	Phase 3 (E-esc)	2. TP & Camrelizumab	Not reported
===Neoadjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once per day on days 1 & 8
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
21-day cycle for 2 cycles
===Definitive===
====Local therapy====
*Surgery
===Adjuvant===
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
21-day cycle for up to 15 cycles
===References===
#ESCORT-NEO: Qin J, Xue L, Hao A, Guo X, Jiang T, Ni Y, Liu S, Chen Y, Jiang H, Zhang C, Kang M, Lin J, Li H, Li C, Tian H, Li L, Fu J, Zhang Y, Ma J, Wang X, Fu M, Yang H, Yang Z, Han Y, Chen L, Tan L, Dai T, Liao Y, Zhang W, Li B, Chen Q, Guo S, Qi Y, Wei L, Li Z, Tian Z, Kang X, Zhang R, Li Y, Wang Z, Chen X, Hou Z, Zheng R, Zhu W, He J, Li Y. Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial. Nat Med. 2024 Sep;30(9):2549-2557. Epub 2024 Jul 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR2000040034
=Neoadjuvant induction therapy=
==Carboplatin & Fluorouracil==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Noronha et al. 2024b	2014-08 to 2022-06 	Phase 3 (C)	1a. CP1b. TP	Non-inferior OS (primary endpoint)Median OS: 27.1 vs 27.5 mo(HR 1.12, 95% CI 0.92-1.39)
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgery
===References===
#Noronha V, Patil VM, Menon N, Joshi A, Shah MJ, Singh A, Goud S, Shah S, More S, Nawale K, Nakti D, Yadav A, Jogdhankar S, Kaushal RK, Tiwari VK, Niyogi D, Purandare N, Janu A, Chakrabarty N, Mahajan A, Tibdewal A, Agarwal J, Pawar A, Chowdhury OR, Sharma V, Kapu V, Trikha M, Kumar SV, Kolkur M, Bhagyavant P, Peelay Z, Khedkar R, Jain M, Badwe RA, Prabhash K. Phase III randomized trial comparing neoadjuvant paclitaxel plus platinum with 5-fluorouracil plus platinum in esophageal or gastroesophageal junction squamous cell carcinoma. J Natl Cancer Inst. 2025 Jan 1;117(1):58-75. Epub 2024 Sep 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2014/04/004516
==Carboplatin & Paclitaxel (CP)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Noronha et al. 2024b	2014-08 to 2022-06 	Phase 3 (E-switch-ic)	1a. Carboplatin & 5-FU1b. CF	Non-inferior OS (primary endpoint)Median OS: 27.5 vs 27.1 mo(HR 0.89, 95% CI 0.72-1.09)
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgery
===References===
#Noronha V, Patil VM, Menon N, Joshi A, Shah MJ, Singh A, Goud S, Shah S, More S, Nawale K, Nakti D, Yadav A, Jogdhankar S, Kaushal RK, Tiwari VK, Niyogi D, Purandare N, Janu A, Chakrabarty N, Mahajan A, Tibdewal A, Agarwal J, Pawar A, Chowdhury OR, Sharma V, Kapu V, Trikha M, Kumar SV, Kolkur M, Bhagyavant P, Peelay Z, Khedkar R, Jain M, Badwe RA, Prabhash K. Phase III randomized trial comparing neoadjuvant paclitaxel plus platinum with 5-fluorouracil plus platinum in esophageal or gastroesophageal junction squamous cell carcinoma. J Natl Cancer Inst. 2025 Jan 1;117(1):58-75. Epub 2024 Sep 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2014/04/004516
==Cisplatin & Etoposide (EP)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Boonstra et al. 2011	1989-1996 	Phase 3 (E-esc)	Surgery alone	Seems to have longer OS (primary endpoint)Median OS: 16 vs 12 mo(HR 0.71, 95% CI 0.51-0.98)
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV over 4 hours once on day 1
*Etoposide (Vepesid) 100 mg/m2 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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol (Cisplatin)
===Regimen variant #1, 75/4000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Noronha et al. 2024b	2014-08 to 2022-06 	Phase 3 (C)	1a. CP1b. TP	Non-inferior OS (primary endpoint)Median OS: 27.1 vs 27.5 mo(HR 1.12, 95% CI 0.92-1.39)
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgery
===Regimen variant #2, 80/4000===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Ando et al. 2011 (JCOG 9907) 	2000-2006 	Phase 3 (E-switch-ic)	Adjuvant CF	Seems to have longer OS (secondary endpoint)OS60: 55% vs 43%(HR 0.73, 95% CI 0.54-0.99)Did not meet primary endpoint of PFSPFS60: 44% vs 39%(HR 0.84, 95% CI 0.63-1.11)
Kato et al. 2024 (JCOG 1109 NExT)	2012-12-05 to 2018-07-20	Phase 3 (C) 	1. DCF 	Shorter OS
Kato et al. 2024 (JCOG 1109 NExT)	2012-12-05 to 2018-07-20	Phase 3 (C) 	2. CF & RT 	Did not meet primary endpoint of OSOS36: 62.6% vs 68.3%(HR 1.19, 95% CI 0.89-1.59)
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
21-day cycle for 2 cycles
====Subsequent treatment====
*Surgery
===Regimen variant #3, 100/5000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ancona et al. 2001 (CNR-012809)	1992-1997 	Phase 3 (E-esc)	Surgery alone	Did not meet primary endpoint of OS
Note: it is not entirely clear from Ancona et al. 2001 whether this was a 96-hour or 120-hour infusion; there was option to proceed after the 2nd cycle. This is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: see note)
28-day cycle for 3 cycles
====Subsequent treatment====
*Surgery, performed 3 to 4 weeks after the last cycle of chemotherapy
===References===
#CNR-012809: 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 partial protocol EuroPMC NCT00002897
#JCOG 9907: Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00190554
#JCOG 1109 NExT: Kato K, Machida R, Ito Y, Daiko H, Ozawa S, Ogata T, Hara H, Kojima T, Abe T, Bamba T, Watanabe M, Kawakubo H, Shibuya Y, Tsubosa Y, Takegawa N, Kajiwara T, Baba H, Ueno M, Takeuchi H, Nakamura K, Kitagawa Y; JCOG1109 investigators. Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial. Lancet. 2024 Jul 6;404(10447):55-66. Epub 2024 Jun 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC jRCTs031180202
==Cisplatin & Paclitaxel (TP)==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Noronha et al. 2024b 	2014-08 to 2022-06 	Phase 3 (E-switch-ic)	1a. Carboplatin & 5-FU1b. CF 	Non-inferior OS (primary endpoint)Median OS: 27.5 vs 27.1 mo(HR 0.89, 95% CI 0.72-1.09)
Tang et al. 2023 (CMISG1701) 	2017-01-01 to 2019-12-31	Randomized (C) 	TP & RT 	Did not meet primary endpoint of OS36OS36: 54.9% vs 64.1%(HR 1.22, 95% CI 0.85-1.72)
Zheng et al. 2024 (HCHTOG1909)	2020-05-15 to 2021-08-13	Phase 3 (C) 	Perioperative TP & Toripalimab 	Seems to have shorter EFS (primary endpoint)EFS12: 64.3% vs 77.9%(HR 1.61, 95% CI 1.00-2.56)Seems to have shorter OS (secondary endpoint)OS12: 83% vs 94.1%(HR 2.08, 95% CI 1.03-4.17)
Qin et al. 2024 (ESCORT-NEO) 	2021-04-28 to 2023-08-07	Phase 3 (C) 	1. TP & Camrelizumab2. nab-TP & Camrelizumab	Lower pCR rate
Note: the CT.gov record for CMISG1701 reports a paclitaxel dose of 135 mg/m2, whereas the manuscript reports 175 mg/m2. The authors have been contacted to resolve this discrepancy but have not replied.
====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 varying durations: 2 cycles (CMISG1701, ESCORT-NEO, HCHTOG1909); 3 cycles (Noronha et al. 2024b)
====Subsequent treatment====
*Surgery
===References===
#CMISG1701: Tang H, Wang H, Fang Y, Zhu JY, Yin J, Shen YX, Zeng ZC, Jiang DX, Li WF, Hou YY, Du M, Lian CH, Zhao Q, Jiang HJ, Gong L, Li ZG, Liu J, Xie DY, Chen C, Zheng B, Chen KN, Dai L, Liao YD, Li K, Li HC, Zhao NQ, Tan LJ. Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy for locally advanced esophageal squamous cell carcinoma: a prospective multicenter randomized clinical trial. Ann Oncol. 2023 Feb;34(2):163-172. Epub 2022 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03001596
#ESCORT-NEO: Qin J, Xue L, Hao A, Guo X, Jiang T, Ni Y, Liu S, Chen Y, Jiang H, Zhang C, Kang M, Lin J, Li H, Li C, Tian H, Li L, Fu J, Zhang Y, Ma J, Wang X, Fu M, Yang H, Yang Z, Han Y, Chen L, Tan L, Dai T, Liao Y, Zhang W, Li B, Chen Q, Guo S, Qi Y, Wei L, Li Z, Tian Z, Kang X, Zhang R, Li Y, Wang Z, Chen X, Hou Z, Zheng R, Zhu W, He J, Li Y. Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial. Nat Med. 2024 Sep;30(9):2549-2557. Epub 2024 Jul 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR2000040034
#HCHTOG1909: Zheng Y, Liang G, Yuan D, Liu X, Ba Y, Qin Z, Shen S, Li Z, Sun H, Liu B, Gao Q, Li P, Wang Z, Liu S, Zhu J, Wang H, Ma H, Liu Z, Zhao F, Zhang J, Zhang H, Wu D, Qu J, Ma J, Zhang P, Ma W, Yan M, Yu Y, Li Q, Zhang J, Xing W. Perioperative toripalimab plus neoadjuvant chemotherapy might improve outcomes in resectable esophageal cancer: an interim analysis of a phase III randomized clinical trial. Cancer Commun (Lond). 2024 Oct;44(10):1214-1227. Epub 2024 Sep 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04280822
#Noronha V, Patil VM, Menon N, Joshi A, Shah MJ, Singh A, Goud S, Shah S, More S, Nawale K, Nakti D, Yadav A, Jogdhankar S, Kaushal RK, Tiwari VK, Niyogi D, Purandare N, Janu A, Chakrabarty N, Mahajan A, Tibdewal A, Agarwal J, Pawar A, Chowdhury OR, Sharma V, Kapu V, Trikha M, Kumar SV, Kolkur M, Bhagyavant P, Peelay Z, Khedkar R, Jain M, Badwe RA, Prabhash K. Phase III randomized trial comparing neoadjuvant paclitaxel plus platinum with 5-fluorouracil plus platinum in esophageal or gastroesophageal junction squamous cell carcinoma. J Natl Cancer Inst. 2025 Jan 1;117(1):58-75. Epub 2024 Sep 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2014/04/004516
==DCF==
DCF: Docetaxel, Cisplatin, Fluorouracil
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Kato et al. 2024 (JCOG 1109 NExT)	2012-12-05 to 2018-07-20	Phase 3 (E-esc)	1. CF x 2 	Longer OS (primary endpoint)OS36: 72.1% vs 62.6%(HR 0.68, 95% CI 0.50-0.92)
Kato et al. 2024 (JCOG 1109 NExT)	2012-12-05 to 2018-07-20	Phase 3 (E-esc)	2. CF & RT	Not reported
====Chemotherapy====
*Docetaxel (Taxotere) 70 mg/m2 IV once on day 1
*Cisplatin (Platinol) 70 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m2)
21-day cycle for 3 cycles 
====Subsequent treatment====
*Surgery
===References===
#JCOG 1109 NExT: Kato K, Machida R, Ito Y, Daiko H, Ozawa S, Ogata T, Hara H, Kojima T, Abe T, Bamba T, Watanabe M, Kawakubo H, Shibuya Y, Tsubosa Y, Takegawa N, Kajiwara T, Baba H, Ueno M, Takeuchi H, Nakamura K, Kitagawa Y; JCOG1109 investigators. Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial. Lancet. 2024 Jul 6;404(10447):55-66. Epub 2024 Jun 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC jRCTs031180202
=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.
==Cisplatin & Vinorelbine (CVb) & RT==
CVb & RT: Cisplatin, Vinorelbine, Radiation Therapy
===Regimen variant #1, standard cisplatin===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yang et al. 2018 (NEOCRTEC5010)	2007-2014 	Phase 3 (E-esc)	No neoadjuvant therapy	Seems to have longer OS1 (primary endpoint)OS60: 59.9% vs 49.1%(HR 0.74, 95% CI 0.57-0.97)
1Reported efficacy is based on the 2021 update.
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 3 hours once per day on days 1 & 22
*Vinorelbine (Navelbine) 25 mg/m2 IV bolus once per day on days 1, 8, 22, 29
====Radiotherapy====
*Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26 (20 fractions, for a total dose of 4000 cGy)
6-week course
====Subsequent treatment====
*Surgery
===Regimen variant #2, split-dose cisplatin===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yang et al. 2018 (NEOCRTEC5010)	2007-2014 	Phase 3 (E-esc)	No neoadjuvant therapy	Seems to have longer OS1 (primary endpoint)OS60: 59.9% vs 49.1%(HR 0.74, 95% CI 0.57-0.97)
1Reported efficacy is based on the 2021 update.
====Chemotherapy====
*Cisplatin (Platinol) 25 mg/m2 IV over 2 hours once per day on days 1 to 4, 22 to 26
*Vinorelbine (Navelbine) 25 mg/m2 IV bolus once per day on days 1, 8, 22, 29
====Radiotherapy====
*Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26 (20 fractions, for a total dose of 4000 cGy)
6-week course
====Subsequent treatment====
*Surgery
===References===
#NEOCRTEC5010: Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Lordick F, D'Journo XB, Cerfolio RJ, Korst RJ, Novoa NM, Swanson SJ, Brunelli A, Ismail M, Fernando HC, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J; AME Thoracic Surgery Collaborative Group. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial. J Clin Oncol. 2018 Sep 20;36(27):2796-2803. Epub 2018 Aug 8. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01216527
##Update: Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J. Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial. JAMA Surg. 2021 Aug 1;156(8):721-729. link to original article link to PMC article EuroPMC
==Fluorouracil, Oxaliplatin, RT==
Fluorouracil, Oxaliplatin, RT: Fluorouracil, Oxaliplatin, Radiation Therapy
===Regimen variant #1, 4500 cGy===
Study 	Dates of enrollment	Evidence
Lorenzen et al. 2008	2003-2005 	Phase 1/2
Note: Patients had 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: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)
5-week course
====Subsequent treatment====
*Surgery, 4 to 6 weeks after finishing chemoradiation
===References===
#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 original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
=Adjuvant therapy=
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ando et al. 2003 (JCOG 9204)	1992-1997 	Phase 3 (E-esc)	Observation 	Might have longer DFS (primary endpoint)DFS60: 55% vs 45%(HR 0.73, 95% CI 0.51-1.03)
Ando et al. 2011 (JCOG 9907)	2000-2006 	Phase 3 (C) 	Neoadjuvant CF	Seems to have shorter OS (secondary endpoint)OS60: 43% vs 55%(HR 1.37, 95% CI 1.01-1.85)Did not meet primary endpoint of PFSPFS60: 39% vs 44%(HR 1.19, 95% CI 0.90-1.59)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
21-day cycle for 2 cycles
===References===
#JCOG 9204: Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, Takiyama W, Watanabe H, Isono K, Aoyama N, Makuuchi H, Tanaka O, Yamana H, Ikeuchi S, Kabuto T, Nagai K, Shimada Y, Kinjo Y, Fukuda H; JCOG. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. J Clin Oncol. 2003 Dec 15;21(24):4592-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#JCOG 9907: Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00190554
=Definitive therapy=
==Capecitabine & Cisplatin (CX) & RT==
CX & RT: Cisplatin, Xeloda (Capecitabine), Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (KUNLUN)	2020-2025 	Phase 3 (C)	1a. CX, Durvalumab, RT1b. CF, Durvalumab, RT	To be determined
====Chemotherapy====
*Capecitabine (Xeloda)
*Cisplatin (Platinol)
====Radiotherapy====
*Concurrent radiation therapy
===References===
#KUNLUN: NCT04550260
==Cisplatin & Docetaxel (DC) & RT==
DC & RT: Docetaxel, Cisplatin, Radiation Therapy
===Regimen variant #1, 80/60 x 2===
Study 	Dates of enrollment	Evidence
Li et al. 2009	2004-2007 	Phase 2
Note: Patients had 5% gastroesophageal junction site. 44% of patients had stage IV disease.
====Chemotherapy====
*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
====Supportive therapy====
*Dexamethasone (Decadron) 10 mg IV or PO once per day on days -1 & 21, then once per day on days 1 & 22; 30 minutes prior to docetaxel, then once per day on days 2 & 23
*Diphenhydramine (Benadryl) 40 mg IV once per day on days 1 & 22, prior to chemotherapy
*Cimetidine (Tagamet) 40 mg IV once per day on days 1 & 22, prior to chemotherapy
*Granisetron 2 mg IV once per day on days 1 & 22, prior to chemotherapy
*1.5 to 2 liters fluids prior to cisplatin
====Radiotherapy====
*Concurrent radiation therapy 180 to 200 cGy fractions, to start within 24 hours of the start of chemotherapy
**Patients with stage I to III disease received a total dose of 6000 to 6400 cGy over 4 to 6 weeks
**Patients with stage IV disease (lymph node only) received a total dose of 5000 to 5600 cGy
Note, dose reductions were permitted, see article for specifications 
One course
===References===
#Li QQ, Liu MZ, Hu YH, Liu H, He ZY, Lin HX. Definitive concomitant chemoradiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus. 2010 Apr;23(3):253-9. Epub 2009 Aug 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Fluorouracil (CF) & RT==
CF & RT: Cisplatin, Fluorouracil, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Jia et al. 2024 (CRTCOESC) 	2014-10 to 2020-04 	Phase 3 (C)	1. Capecitabine & RT 	Did not meet co-primary endpoint of OS	Higher incidence of grade 3 to 5 AEs (co-primary endpoint): 45.7% vs 28.8%
Jia et al. 2024 (CRTCOESC) 	2014-10 to 2020-04 	Phase 3 (C)	2. CapeOx & RT 	Did not meet co-primary endpoint of OS	Similar incidence of grade 3 to 5 AEs (co-primary endpoint): 45.7% vs 36.5%
Awaiting publication (KUNLUN)	2020-2025 	Phase 3 (C)	1a. CX, Durvalumab, RT1b. CF, Durvalumab, RT	To be determined 	
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once per day on days 1 & 29
*Fluorouracil (5-FU) 750 mg/m2 IV once per day on days 1 to 4, 29 to 32
====Radiotherapy====
*Concurrent radiation therapy 50 Gy in 25 fractions
8-week course
===References===
#CRTCOESC: Jia R, Shan T, Zheng A, Zhang Y, Lu P, Zhang G, Wang F, Xu Z, Zheng G, Tang D, Zhang W, Li W, Li R, Guo Y, Liu L, Luo X, Zheng Y, Chang Z, Wang Q, Wang X, Yuan X, Kong G, Li S, Yang R, Zhou D, Ren J, Yin W, Li J, Zhang J, Wang Z, Sheng M, Xu B, Li L, Liu X, Lu Z, Wan L, Zhou F, Gao S. Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial. J Clin Oncol. 2024 Jul 10;42(20):2436-2445. Epub 2024 May 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02025036
#KUNLUN: NCT04550260
==Cisplatin & Paclitaxel (TP) & RT==
TP & RT: Taxol (Paclitaxel), Platinol (Cisplatin), Radiation Therapy
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wu et al. 2018 (Shixiu - 1)	2007-2015 	Phase 3 (C)	1. TP, Erlotinib, ENI2. #Cisplatin_&_Paclitaxel_(TP)_&_RT; ENI3. TP, Erlotinib, CFI	Seems to have shorter OS
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 3, 29 to 31
*Paclitaxel (Taxol) 135 mg/m2 IV once per day on days 1 & 29
====Radiotherapy====
*Concurrent radiation therapy 6000 cGy in 30 fractions over 6 weeks
8-week course
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (RATIONALE 311)	2019-ongoing 	Phase 3 (C)	TP, Tislelizumab, RT	To be determined
====Chemotherapy====
*Cisplatin (Platinol) 25 mg/m2 IV once per day on days 1 to 3, 22 to 24
*Paclitaxel (Taxol) 135 mg/m2 IV once per day on days 1 & 22
====Radiotherapy====
*Concurrent radiation therapy 5040 cGy in 28 fractions
6-week course
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00686114
## 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 EuroPMC
#KEYSTONE-002: NCT04807673
#RATIONALE 311: dosing details on CT.gov have been reviewed by our editors NCT03957590
#SHR-1210-III-323: NCT04426955
==Fluorouracil, Mitomycin, RT==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Smith et al. (ECOG E1282)	1982-07 to 1988-07 	Randomized (E-esc)	RT 	Seems to have longer OS (primary endpoint)Median OS: 14.8 vs 9.2 mo(HR not reported, p=0.03)
====Chemotherapy====
*Fluorouracil (5-FU) 1000 mg/m2/day (maximum dose of 1800 mg/day) IV continuous infusion over 96 hours, started on days 2 & 28 (total dose: 8000 mg/m2)
*Mitomycin (Mutamycin) 10 mg/m2 (maximum dose of 18 mg) IV bolus once on day 2
====Radiotherapy====
*Concurrent radiation therapy
One course
===References===
#ECOG E1282: Smith TJ, Ryan LM, Douglass HO Jr, Haller DG, Dayal Y, Kirkwood J, Tormey DC, Schutt AJ, Hinson J, Sischy B. Combined chemoradiotherapy vs radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):269-76. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Fluorouracil, Paclitaxel, RT==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Chen et al. 2019 (ESO-Shanghai1)	2012-2015 	Phase 3 (E-switch-ic)	CF & RT 	Did not meet primary endpoint of OS36
Note: 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.
====Eligibility criteria====
*Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated.
====Chemotherapy====
*Fluorouracil (5-FU) 75 mg/m2/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22, 29 (total dose: 1800 mg/m2)
*Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1, 8, 15, 22, 29
====Radiotherapy====
*Concurrent radiation therapy, 180 cGy fractions x 34 fractions, for a total dose of 6120 cGy
7-week course
====Subsequent treatment====
*Fluorouracil & Paclitaxel consolidation
===References===
#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 link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01591135
==Radiation therapy==
RT: Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Smith et al. (ECOG E1282) 	1982-07 to 1988-07 	Randomized (C)	5-FU, Mitomycin, RT	Seems to have shorter OS (primary endpoint)Median OS: 9.2 vs 14.8 mo(HR not reported, p=0.03)
Wang et al. 2023 (3JECROG-P01)	2017-03 to 2020-04 	Phase 3 (C) 	S-1 & RT 	Seems to have shorter OS (primary endpoint)OS24: 33.9% vs 46.2%(HR 1.37, 95% CI 1.04-1.79)
====Eligibility criteria====
*3JECROG-P01: 70 years old or older
====Radiotherapy====
*External beam radiotherapy
One course
===References===
#ECOG E1282: Smith TJ, Ryan LM, Douglass HO Jr, Haller DG, Dayal Y, Kirkwood J, Tormey DC, Schutt AJ, Hinson J, Sischy B. Combined chemoradiotherapy vs radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):269-76. link to original article EuroPMC
#3JECROG-P01: Wang X, Han W, Zhang W, Wang X, Ge X, Lin Y, Zhou H, Hu M, Wang W, Liu K, Lu J, Qie S, Zhang J, Deng W, Wang L, Han C, Li M, Zhang K, Li L, Wang Q, Shi H, Yu Z, Zhao Y, Sun X, Shi Y, Pang Q, Zhou Z, Liang J, Chen D, Feng Q, Bi N, Zhang T, Deng L, Wang W, Liu W, Wang J, Zhai Y, Wang J, Chen W, Chen J, Xiao Z; Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group (3JECROG). Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2312625. link to original article link to PMC article contains partial dosing details in manuscript EuroPMC NCT02979691
==S-1 & RT==
S-1 & RT: S-1 & Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wang et al. 2023 (3JECROG-P01)	2017-03 to 2020-04 	Phase 3 (E-esc)	RT x 6000 cGy	Seems to have longer OS (primary endpoint)OS24: 46.2% vs 33.9%(HR 0.73, 95% CI 0.56-0.96)
====Eligibility criteria====
*70 years old or older
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38
====Radiotherapy====
*External beam radiotherapy SIB 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38 (28 fractions for a total dose of 5040 cGy)
6-week course
====Subsequent treatment====
*S-1 consolidation
===References===
#3JECROG-P01: Wang X, Han W, Zhang W, Wang X, Ge X, Lin Y, Zhou H, Hu M, Wang W, Liu K, Lu J, Qie S, Zhang J, Deng W, Wang L, Han C, Li M, Zhang K, Li L, Wang Q, Shi H, Yu Z, Zhao Y, Sun X, Shi Y, Pang Q, Zhou Z, Liang J, Chen D, Feng Q, Bi N, Zhang T, Deng L, Wang W, Liu W, Wang J, Zhai Y, Wang J, Chen W, Chen J, Xiao Z; Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group (3JECROG). Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2312625. link to original article link to PMC article contains partial dosing details in manuscript EuroPMC NCT02979691
=Consolidation after definitive therapy=
==Fluorouracil & Paclitaxel==
===Regimen===
Study 	Dates 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
====Eligibility criteria====
*Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated
====Preceding treatment====
*Definitive 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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01591135
=Metastatic or locally advanced disease, first-line=
==Capecitabine & Cisplatin (CX)==
CX: Cisplatin & Xeloda (Capecitabine)
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. 
====Chemotherapy====
*Cisplatin (Platinol) 60 to 80 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==Capecitabine & Cisplatin (CX) & Tislelizumab==
CX & Tislelizumab: Cisplatin, Xeloda (Capecitabine), Tislelizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (E-esc)	1a. CF1b. CX1c. Cisplatin & Paclitaxel1d. FUOX1e. CapeOx1f. Oxaliplatin & Paclitaxel	Longer OS (primary endpoint)Median OS: 17.2 vs 10.6 mo(sHR 0.66, 95% CI 0.54-0.80)
====Chemotherapy====
*Cisplatin (Platinol) 60 to 80 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==CapeOx==
CapeOx: Capecitabine & Oxaliplatin
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==Capecitabine & Oxaliplatin (CapeOx) & Tislelizumab==
CapeOx & Tislelizumab: Capecitabine, Oxaliplatin, Tislelizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (E-esc)	1a. CF1b. CX1c. Cisplatin & Paclitaxel1d. FUOX1e. CapeOx1f. Oxaliplatin & Paclitaxel	Longer OS (primary endpoint)Median OS: 17.2 vs 10.6 mo(sHR 0.66, 95% CI 0.54-0.80)
====Chemotherapy====
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==Cisplatin & Docetaxel (DC)==
DC: Docetaxel, Cisplatin
TC: Taxotere (Docetaxel), Cisplatin
===Regimen===
Study 	Dates of enrollment	Evidence
Kim et al. 2009	2004-2007 	Phase 2
Note: 5% of patients had 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 therapy====
*Dexamethasone (Decadron) 8 mg PO twice per day x 1 day, starting 1 day prior to docetaxel administration
*At least 3 liters hydration (with mannitol, magnesium, and potassium chloride)
*"Antiemetic treatment"
21-day cycle for up to 6 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol
===Regimen variant #1, 50/2400===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Song et al. 2023 (ATRUM-007)	2019-06-19 to 2021-12-17	Phase 3 (C)	CF & Serplulimab	Shorter OS (co-primary endpoint)Median OS: 11.8 vs 15.3 mo(HR 1.47, 95% CI 1.15-1.89)Shorter PFS (co-primary endpoint)Median PFS: 5.3 vs 5.8 mo(HR 1.67, 95% CI 1.33-2.08)
====Biomarker eligibility criteria====
*PD-L1 combined positive score of at least 1
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 8: 50 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1200 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 2400 mg/m2)
14-day cycle for 12 cycles
===Regimen variant #2, 60/3750===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the lower bound of cisplatin AND 5-FU. 
====Chemotherapy====
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m2)
21-day cycles
===Regimen variant #3, 80/3200===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Li et al. 2024 (GEMSTONE-304)	2019-12-19 to 2021-12-23	Phase 3 (C)	CF & Sugemalimab	Shorter OS (co-primary endpoint)Median OS: 11.5 vs 15.3 mo(HR 1.43, 95% CI 1.11-1.82)Shorter PFS (co-primary endpoint)Median PFS: 5.4 vs 6.2 mo(HR 1.49, 95% CI 1.22-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. 
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3200 mg/m2)
21-day cycle for up to 6 cycles
===Regimen variant #4, 80/4000, 4-day infusion, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Moehler et al. 2019 (POWER)	2012-2015 	Phase 3 (C)	CFP 	Did not meet primary endpoint of OSMedian OS: 10.2 vs 9.4 mo(HR 0.85, 95% CI 0.57-1.27)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. 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 #5, 80/4000, 5-day infusion, indefinite===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Doki et al. 2022 (CheckMate 648)	2017-2019 	Phase 3 (C)	1. CF & Nivolumab2. Ipilimumab & Nivolumab 	Shorter OS1
Xu et al. 2023 (RATIONALE-306) 	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
1Reported efficacy for CheckMate 648 is for the overall randomized population.
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the upper bound of cisplatin AND 5-FU in RATIONALE-306. 
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
28-day cycles
===Regimen variant #6, 100/5000===
Study 	Dates 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
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. 87% of patients had 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 therapy====
*Standard antiemetic prophylaxis
*Pre- and post-cisplatin hydration
29-day cycle for up to 6 cycles
===References===
#Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01627379
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03143153
##Update: Kato K, Doki Y, Chau I, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Makino T, Blum Murphy M, Amaya-Chanaga C, Patel A, Hu N, Matsumura Y, Kitagawa Y, Ajani J. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. 2024 May;13(9):e7235. link to original article link to PMC article EuroPMC
#ASTRUM-007: Song Y, Zhang B, Xin D, Kou X, Tan Z, Zhang S, Sun M, Zhou J, Fan M, Zhang M, Song Y, Li S, Yuan Y, Zhuang W, Zhang J, Zhang L, Jiang H, Gu K, Ye H, Ke Y, Li J, Wang Q, Zhu J, Huang J; ASTRUM-007 investigators. First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. Nat Med. 2023 Feb;29(2):473-482. Epub 2023 Feb 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03958890
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
#GEMSTONE-304: Li J, Chen Z, Bai Y, Liu B, Li Q, Zhang J, Zhou J, Deng T, Zhou F, Gao S, Yang S, Ye F, Chen L, Bai W, Yin X, Cang S, Liu L, Pan Y, Luo H, Ji Y, Zhang Z, Wang J, Yang Q, Li N, Huang R, Qu C, Ni J, Wang B, Xu Y, Hu J, Shi Q, Yang J. First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study. Nat Med. 2024 Mar;30(3):740-748. Epub 2024 Feb 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04187352
==Cisplatin & Fluorouracil (CF) & Cetuximab==
CF-C: Cisplatin, Fluorouracil, Cetuximab
===Regimen===
Study 	Dates 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
Note: 87% patients had 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 therapy====
*Standard antiemetic prophylaxis
*Pre- and post-cisplatin hydration
29-day cycle for up to 6 cycles
===References===
#Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Fluorouracil (CF) & Nivolumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Doki et al. 2022 (CheckMate 648)	2017-2019 	Phase 3 (E-RT-esc)	1. CF 	Longer OS1 (co-primary endpoint)Median OS: 13.2 vs 10.7 mo(HR 0.74, 99.1% CI 0.58-0.96)
Doki et al. 2022 (CheckMate 648)	2017-2019 	Phase 3 (E-RT-esc)	2. Ipilimumab & Nivolumab	Not reported
1Reported efficacy is for the overall randomized population.
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Immunotherapy====
*Nivolumab (Opdivo) as follows:
**Cycle 1 up to 26: 240 mg IV once per day on days 1 & 15
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03143153
##Update: Kato K, Doki Y, Chau I, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Makino T, Blum Murphy M, Amaya-Chanaga C, Patel A, Hu N, Matsumura Y, Kitagawa Y, Ajani J. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. 2024 May;13(9):e7235. link to original article link to PMC article EuroPMC
==Cisplatin & Fluorouracil (CF) & Pembrolizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (LEAP-014)	2021-ongoing 	Phase 3 (C)	1a. FP, Lenvatinib, Pembrolizumab1b. TP, Lenvatinib, Pembrolizumab1c. mFOLFOX6, Lenvatinib, Pembrolizumab	TBD if different co-primary endpoints of PFS/OS
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. There is no doubt that the 5-FU is given as a continuous infusion, but these details are not provided on CT.gov.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 up to 3: 80 mg/m2 IV once per day on days 1 & 22
*Fluorouracil (5-FU) 4000 mg/m2 IV once per day on days 1 & 22
====Immunotherapy====
*Pembrolizumab (Keytruda) 400 mg IV once on day 1
42-day cycle for up to 18 cycles (2 years)
===References===
#LEAP-014: dosing details on CT.gov have been reviewed by our editors NCT04949256
==Cisplatin & Fluorouracil (CF) & Serplulimab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Song et al. 2023 (ATRUM-007)	2019-06-19 to 2021-12-17	Phase 3 (E-RT-esc)	CF 	Longer OS (co-primary endpoint)Median OS: 15.3 vs 11.8 mo(HR 0.68, 95% CI 0.53-0.87)Longer PFS (co-primary endpoint)Median PFS: 5.8 vs 5.3 mo(HR 0.60, 95% CI 0.48-0.75)
====Biomarker eligibility criteria====
*PD-L1 combined positive score of at least 1
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 8: 50 mg/m2 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 12: 1200 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 2400 mg/m2)
====Immunotherapy====
*Serplulimab (Hansizhuang) 3 mg/kg IV once on day 1
14-day cycle for up to 52 cycles (2 years)
===References===
#ASTRUM-007: Song Y, Zhang B, Xin D, Kou X, Tan Z, Zhang S, Sun M, Zhou J, Fan M, Zhang M, Song Y, Li S, Yuan Y, Zhuang W, Zhang J, Zhang L, Jiang H, Gu K, Ye H, Ke Y, Li J, Wang Q, Zhu J, Huang J; ASTRUM-007 investigators. First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. Nat Med. 2023 Feb;29(2):473-482. Epub 2023 Feb 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03958890
==Cisplatin & Fluorouracil (CF) & Sintilimab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lu et al. 2022 (ORIENT-15)	2018-2021 	Phase 3 (E-esc)	1a. CF1b. Cisplatin & Paclitaxel	Longer OS1 (co-primary endpoint)Median OS: 17.2 vs 13.6 mo(HR 0.64, 95% CI 0.48-0.85)
1Reported efficacy is for the population with tumors having 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:
**Less than 60 kg: 3 mg/kg IV once on day 1
**60 kg or more: 200 mg IV once on day 1
28-day cycle for up to 26 cycles (2 years)
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03748134
##HRQoL analysis: Lu Z, Kong L, Wang B, Wang J, Liu L, Shu Y, Yang L, Sun G, Cao G, Ji Y, Cui T, Liu H, Qiu W, Li N, Li G, Luo H, Hou X, Zhang Y, Yue W, Xue L, Liu Z, Pan Y, Gao S, Wang X, Pan Z, Zhang S, Lin G, Xie Y, Gu K, Ren T, Li W, Li T, Wang S, He W, Fan Y, Liang J, Xia B, Zhao L, Wang S, Shen L. Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study. EClinicalMedicine. 2024 May 17;72:102623. link to original article link to PMC article EuroPMC
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==Cisplatin & Fluorouracil (CF) & Sugemalimab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Li et al. 2024 (GEMSTONE-304)	2019-12-19 to 2021-12-23	Phase 3 (E-esc)	CF 	Longer OS (co-primary endpoint)Median OS: 15.3 vs 11.5 mo(HR 0.70, 95% CI 0.55-0.90)Longer PFS (co-primary endpoint)Median PFS: 6.2 vs 5.4 mo(HR 0.67, 95% CI 0.54-0.82)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 6: 800 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3200 mg/m2)
====Immunotherapy====
*Sugemalimab (Cejemly) 1200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
#GEMSTONE-304: Li J, Chen Z, Bai Y, Liu B, Li Q, Zhang J, Zhou J, Deng T, Zhou F, Gao S, Yang S, Ye F, Chen L, Bai W, Yin X, Cang S, Liu L, Pan Y, Luo H, Ji Y, Zhang Z, Wang J, Yang Q, Li N, Huang R, Qu C, Ni J, Wang B, Xu Y, Hu J, Shi Q, Yang J. First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study. Nat Med. 2024 Mar;30(3):740-748. Epub 2024 Feb 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04187352
==Cisplatin & Fluorouracil (CF) & Tislelizumab==
CF & Tislelizumab: Cisplatin, Fluorouracil, Tislelizumab
===Regimen variant #1, 3750===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (E-esc)	1a. CF1b. CX1c. Cisplatin & Paclitaxel1d. FUOX1e. CapeOx1f. Oxaliplatin & Paclitaxel	Longer OS (primary endpoint)Median OS: 17.2 vs 10.6 mo(sHR 0.66, 95% CI 0.54-0.80)
Note: this was the lower bound of 5-FU dosing. 
====Chemotherapy====
*Cisplatin (Platinol) 60 to 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m2)
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===Regimen variant #2, 4000===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (E-esc)	1a. CF1b. CX1c. Cisplatin & Paclitaxel1d. FUOX1e. CapeOx1f. Oxaliplatin & Paclitaxel	Longer OS (primary endpoint)Median OS: 17.2 vs 10.6 mo(sHR 0.66, 95% CI 0.54-0.80)
Note: this was the upper bound of 5-FU dosing. 
====Chemotherapy====
*Cisplatin (Platinol) 60 to 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==Cisplatin & Paclitaxel (TP)==
===Regimen variant #1, 60/175===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the lower bound of cisplatin dosing.
====Chemotherapy====
*Cisplatin (Platinol) 60 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 75/175===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Zhang et al. 2008 	2001-07 to 2006-04 	Phase 2 	 	
Luo et al. 2021 (ESCORT-1st) 	2018-2020 	Phase 3 (C)	TP & Camrelizumab	Shorter OS1 (co-primary endpoint)Median OS: 12.6 vs 15.6 mo(HR 1.43, 95% CI 1.19-1.72)Shorter PFS (co-primary endpoint)Median PFS: 5.6 vs 6.9 mo(HR 1.79, 95% CI 1.47-2.17)
Wang et al. 2022 (JUPITER-06)	2019-01-28 to 2020-11-30	Phase 3 (C)	TP & Toripalimab 	Shorter OSMedian OS: 11 vs 17 mo(HR 1.72, 95% CI 1.28-2.33)
1Reported efficacy for ESCORT-1st is based on the 2024 update.
Note: Patients in Zhang et al. 2008 had 100% squamous cell carcinoma with advanced or metastatic disease. 18% ECOG PS of 2.
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 60 minutes once on day 1, given second
*Paclitaxel (Taxol) 175 mg/m2 IV over 2 hours once on day 1, given first
21-day cycle for varying durations: 6 cycles (ESCORT-1st, JUPITER-06); indefinitely (Zhang et al. 2008)
===Regimen variant #3, 80/175===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the upper bound of cisplatin dosing.
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
===References===
#Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 2008 Feb;31(1):29-33. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03691090
##Update: He M, Wang Z, 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, Sheng Z, Zeng W, Song L, Xu RH, Luo H. Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial. Med. 2024 Sep 13;5(9):1137-1149.e3. Epub 2024 Jun 12. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03829969
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
#SKYSCRAPER-08: NCT04540211
==Cisplatin & Paclitaxel (TP) & Camrelizumab==
TP & Camrelizumab: Taxol (Paclitaxel), Platinol (Cisplatin), Camrelizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Luo et al. 2021 (ESCORT-1st)	2018-2020 	Phase 3 (E-esc)	Cisplatin & Paclitaxel	Longer OS1 (co-primary endpoint)Median OS: 15.6 vs 12.6 mo(HR 0.70, 95% CI 0.58-0.84)Longer PFS (co-primary endpoint)Median PFS: 6.9 vs 5.6 mo(HR 0.56, 95% CI 0.46-0.68)
1Reported efficacy is based on the 2024 update.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 up to 6: 75 mg/m2 IV once on day 1
*Paclitaxel (Taxol) as follows:
**Cycles 1 up to 6: 175 mg/m2 IV once on day 1
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03691090
##Update: He M, Wang Z, 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, Sheng Z, Zeng W, Song L, Xu RH, Luo H. Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial. Med. 2024 Sep 13;5(9):1137-1149.e3. Epub 2024 Jun 12. link to original article EuroPMC
==Cisplatin & Paclitaxel (TP) & Pembrolizumab==
TP & Pembrolizumab: Taxol (Paclitaxel), Platinol (Cisplatin), Pembrolizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (LEAP-014)	2021-ongoing 	Phase 3 (C)	1a. FP, Lenvatinib, Pembrolizumab1b. TP, Lenvatinib, Pembrolizumab1c. mFOLFOX6, Lenvatinib, Pembrolizumab	TBD if different co-primary endpoints of PFS/OS
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 up to 3: 75 mg/m2 IV once per day on days 1 & 22
*Paclitaxel (Taxol) as follows:
**Cycles 1 up to 3: 175 mg/m2 IV once per day on days 1 & 22
====Immunotherapy====
*Pembrolizumab (Keytruda) 400 mg IV once on day 1
42-day cycle for up to 18 cycles (2 years)
===References===
#LEAP-014: dosing details on CT.gov have been reviewed by our editors NCT04949256
==Cisplatin & Paclitaxel (TP) & Sintilimab==
TP & Sintilimab: Taxol (Paclitaxel), Platinol (Cisplatin), Sintilimab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lu et al. 2022 (ORIENT-15)	2018-2021 	Phase 3 (E-esc)	1a. CF1b. Cisplatin & Paclitaxel	Longer OS1 (co-primary endpoint)Median OS: 17.2 vs 13.6 mo(HR 0.64, 95% CI 0.48-0.85)
1Reported efficacy is for the population having tumors with 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 IV once on day 1
====Immunotherapy====
*Sintilimab (Tyvyt) by the following weight-based criteria:
**Less than 60 kg: 3 mg/kg IV once on day 1
**60 kg or more: 200 mg IV once on day 1
28-day cycle for up to 26 cycles (2 years)
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03748134
##HRQoL analysis: Lu Z, Kong L, Wang B, Wang J, Liu L, Shu Y, Yang L, Sun G, Cao G, Ji Y, Cui T, Liu H, Qiu W, Li N, Li G, Luo H, Hou X, Zhang Y, Yue W, Xue L, Liu Z, Pan Y, Gao S, Wang X, Pan Z, Zhang S, Lin G, Xie Y, Gu K, Ren T, Li W, Li T, Wang S, He W, Fan Y, Liang J, Xia B, Zhao L, Wang S, Shen L. Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study. EClinicalMedicine. 2024 May 17;72:102623. link to original article link to PMC article EuroPMC
==Cisplatin & Paclitaxel (TP) & Tislelizumab==
TP & Tislelizumab: Taxol (Paclitaxel), Platinol (Cisplatin), Tislelizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (E-esc)	1a. CF1b. CX1c. Cisplatin & Paclitaxel1d. FUOX1e. CapeOx1f. Oxaliplatin & Paclitaxel	Longer OS (primary endpoint)Median OS: 17.2 vs 10.6 mo(sHR 0.66, 95% CI 0.54-0.80)
====Chemotherapy====
*Cisplatin (Platinol) 60 to 80 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==Cisplatin & Paclitaxel (TP) & Toripalimab==
TP & Toripalimab: Taxol (Paclitaxel), Platinol (Cisplatin), Toripalimab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wang et al. 2022 (JUPITER-06)	2019-01-28 to 2020-11-30	Phase 3 (E-esc)	Cisplatin & Paclitaxel	Longer OS (co-primary endpoint)Median OS: 17 vs 11 mo(HR 0.58, 95% CI 0.43-0.78)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 up to 6: 75 mg/m2 IV once on day 1
*Paclitaxel (Taxol) as follows:
**Cycle 1 up to 6: 175 mg/m2 IV once on day 1
====Immunotherapy====
*Toripalimab (Loqtorzi) 240 mg IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03829969
==Etoposide monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Harstrick et al. 1992	1989-02 to not reported	Phase 2
Note: this is higher than the dose usually employed in modern settings. Patients had metastatic 100% squamous cell carcinoma of the esophagus, with ECOG PS range 1-2.
====Chemotherapy====
*Etoposide (Vepesid) 200 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3
21-day cycle for up to 6 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==FUOX==
FUOX: 5-FU & OXaliplatin
===Regimen variant #1===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the lower bound of 5-FU dosing. 
====Chemotherapy====
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m2)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the upper bound of 5-FU dosing. 
====Chemotherapy====
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==Fluorouracil & Oxaliplatin (FUOX) & Tislelizumab==
FUOX & Tislelizumab: 5-FU, OXaliplatin, Tislelizumab
===Regimen variant #1===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (E-esc)	1a. CF1b. CX1c. Cisplatin & Paclitaxel1d. FUOX1e. CapeOx1f. Oxaliplatin & Paclitaxel	Longer OS (primary endpoint)Median OS: 17.2 vs 10.6 mo(sHR 0.66, 95% CI 0.54-0.80)
Note: this was the lower bound of 5-FU dosing. 
====Chemotherapy====
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m2)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===Regimen variant #2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (E-esc)	1a. CF1b. CX1c. Cisplatin & Paclitaxel1d. FUOX1e. CapeOx1f. Oxaliplatin & Paclitaxel	Longer OS (primary endpoint)Median OS: 17.2 vs 10.6 mo(sHR 0.66, 95% CI 0.54-0.80)
Note: this was the upper bound of 5-FU dosing. 
====Chemotherapy====
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==mFOLFOX6 & Pembrolizumab==
mFOLFOX6 & Pembrolizumab: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Pembrolizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (LEAP-014)	2021-ongoing 	Phase 3 (C)	1a. FP, Lenvatinib, Pembrolizumab1b. TP, Lenvatinib, Pembrolizumab1c. mFOLFOX6, Lenvatinib, Pembrolizumab	TBD if different co-primary endpoints of PFS/OS
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Fluorouracil (5-FU) as follows: 
**Cycles 1 up to 2: 400 mg/m2 IV bolus once per day on days 1, 15, 29, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours (total dose per cycle: 8400 mg/m2)
*Leucovorin (Folinic acid) as follows: 
**Cycles 1 up to 2: 400 mg/m2 IV once per day on days 1, 15, 29
*Oxaliplatin (Eloxatin) as follows: 
**Cycles 1 up to 2: 85 mg/m2 IV once per day on days 1, 15, 29
====Immunotherapy====
*Pembrolizumab (Keytruda) 400 mg IV once on day 1
42-day cycle for up to 18 cycles (2 years)
===References===
#LEAP-014: dosing details on CT.gov have been reviewed by our editors NCT04949256
==Ipilimumab & Nivolumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Doki et al. 2022 (CheckMate 648)	2017-2019 	Phase 3 (E-RT-switch-ooc)	1. CF 	Longer OS (co-primary endpoint)Median OS: 12.7 vs 10.7 mo(HR 0.78, 98.2% CI 0.62-0.98)
Doki et al. 2022 (CheckMate 648)	2017-2019 	Phase 3 (E-RT-switch-ooc)	2. CF & Nivolumab	Not compared
====Immunotherapy====
*Ipilimumab (Yervoy) 1 mg/kg IV once on day 1
*Nivolumab (Opdivo) 3 mg/kg IV once per day on days 1, 15, 29
42-day cycle for up to 17 cycles (2 years)
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03143153
##Update: Kato K, Doki Y, Chau I, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Makino T, Blum Murphy M, Amaya-Chanaga C, Patel A, Hu N, Matsumura Y, Kitagawa Y, Ajani J. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. 2024 May;13(9):e7235. link to original article link to PMC article EuroPMC
==Oxaliplatin & Paclitaxel==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (C)	1a. CF & Tislelizumab1b. CX & Tislelizumab1c. TP & Tislelizumab1d. FUOX & Tislelizumab1e. CapeOx & Tislelizumab1f. Oxaliplatin, Paclitaxel, Tislelizumab	Shorter OSMedian OS: 10.6 vs 17.2 mo(sHR 1.52, 95% CI 1.25-1.85)
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
==Oxaliplatin, Paclitaxel, Tislelizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2023 (RATIONALE-306)	2018-12-12 to 2020-11-24	Phase 3 (E-esc)	1a. CF1b. CX1c. Cisplatin & Paclitaxel1d. FUOX1e. CapeOx1f. Oxaliplatin & Paclitaxel	Longer OS (primary endpoint)Median OS: 17.2 vs 10.6 mo(sHR 0.66, 95% CI 0.54-0.80)
====Chemotherapy====
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
#RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT0378442
=Metastatic or locally advanced disease, subsequent lines of therapy=
==Camrelizumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Huang et al. 2020 (ESCORT)	2017-05-10 to 2018-07-24	Phase 3 (E-switch-ooc)	Investigator's choice of:1a. Docetaxel1b. Irinotecan	Longer OS (primary endpoint)Median OS: 8 vs 6 mo (HR 0.71, 95% CI 0.57-0.87)
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV over 30 minutes once on day 1
14-day cycles
===References===
# 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 Jun;21(6):832-842. Epub 2020 May 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03099382
==Docetaxel monotherapy==
===Regimen variant #1, 70 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shen et al. 2022 (RATIONALE 302)	2018-2020 	Phase 3 (C)	Tislelizumab	Shorter OSMedian OS: 6.3 vs 8.6 mo(HR 1.43, 95% CI 1.18-1.75)
Note: this is Japanese dosing.
====Prior treatment criteria====
*RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy
====Chemotherapy====
*Docetaxel (Taxotere) 70 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===Regimen variant #2, 75 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017 	Phase 3 (C)	Pembrolizumab	Shorter OS1 (co-primary endpoint)Median OS: 6.7 vs 9.3 mo(HR 1.45, 95% CI 1.08-1.92)
Kato et al. 2019 (ATTRACTION-3) 	2016-01-07 to 2017-05-25	Phase 3 (C)	Nivolumab 	Seems to have shorter OSMedian OS: 8 vs 11 mo(HR 1.30, 95% CI 1.04-1.61)
Huang et al. 2020 (ESCORT) 	2017-05-10 to 2018-07-24	Phase 3 (C)	Camrelizumab 	Shorter OSMedian OS: 6 vs 8 mo(HR 1.41, 95% CI 1.15-1.75)
Shen et al. 2022 (RATIONALE 302)	2018-2020 	Phase 3 (C)	Tislelizumab 	Shorter OSMedian OS: 6.3 vs 8.6 mo(HR 1.43, 95% CI 1.18-1.75)
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 shorter OS.
====Prior treatment criteria====
*KEYNOTE-181: One prior line of standard therapy
*RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over at least 60 minutes once on day 1
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02569242
# 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 Jun;21(6):832-842. Epub 2020 May 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03099382
 
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02564263
##HRQoL analysis: Adenis A, Kulkarni AS, Girotto GC, de la Fouchardiere C, Senellart H, van Laarhoven HWM, Mansoor W, Al-Rajabi R, Norquist J, Amonkar M, Suryawanshi S, Bhagia P, Metges JP. Impact of Pembrolizumab Versus Chemotherapy as Second-Line Therapy for Advanced Esophageal Cancer on Health-Related Quality of Life in KEYNOTE-181. J Clin Oncol. 2022 Feb;40(4):382-391. link to original article link to EuroPMC
# RATIONALE 302: Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. Epub 2022 Apr 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03430843
==Irinotecan monotherapy==
===Regimen variant #1, 14-day cycles===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017 	Phase 3 (C)	Pembrolizumab	Shorter OS1 (co-primary endpoint)Median OS: 6.7 vs 9.3 mo(HR 1.45, 95% CI 1.08-1.92)
Huang et al. 2020 (ESCORT) 	2017-05-10 to 2018-07-24	Phase 3 (C)	Camrelizumab 	Shorter OSMedian OS: 6 vs 8 mo(HR 1.41, 95% CI 1.15-1.75)
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 shorter OS.
====Prior treatment criteria====
*One prior line of standard therapy
====Chemotherapy====
*Irinotecan (Camptosar) 180 mg/m2 IV over 60 minutes once on day 1
14-day cycles
===Regimen variant #2, 21-day cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shen et al. 2022 (RATIONALE 302)	2018-2020 	Phase 3 (C)	Tislelizumab	Shorter OSMedian OS: 6.3 vs 8.6 mo(HR 1.43, 95% CI 1.18-1.75)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Prior treatment criteria====
*RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 1 & 8
21-day cycles
===References===
# 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 Jun;21(6):832-842. Epub 2020 May 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03099382
 
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02564263
##HRQoL analysis: Adenis A, Kulkarni AS, Girotto GC, de la Fouchardiere C, Senellart H, van Laarhoven HWM, Mansoor W, Al-Rajabi R, Norquist J, Amonkar M, Suryawanshi S, Bhagia P, Metges JP. Impact of Pembrolizumab Versus Chemotherapy as Second-Line Therapy for Advanced Esophageal Cancer on Health-Related Quality of Life in KEYNOTE-181. J Clin Oncol. 2022 Feb;40(4):382-391. link to original article link to EuroPMC
# RATIONALE 302: Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. Epub 2022 Apr 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03430843
==Nivolumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kato et al. 2019 (ATTRACTION-3)	2016-01-07 to 2017-05-25	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. Docetaxel1b. Paclitaxel	Seems to have longer OS (primary endpoint)Median OS: 11 vs 8 mo (HR 0.77, 95% CI 0.62-0.96)
 
====Eligibility 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 over 30 minutes once on day 1
14-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02569242
==Paclitaxel monotherapy==
===Regimen variant #1, 80 mg/m2, 3 out of 4 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017 	Phase 3 (C)	Pembrolizumab	Shorter OS1 (co-primary endpoint)Median OS: 6.7 vs 9.3 mo(HR 1.45, 95% CI 1.08-1.92)
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 shorter OS.
Note: This was the lower bound of dosing specified in KEYNOTE-181.
====Prior treatment criteria====
*One prior line of standard therapy
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===Regimen variant #2, 100 mg/m2, 3 out of 4 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017 	Phase 3 (C)	Pembrolizumab	Shorter OS1 (co-primary endpoint)Median OS: 6.7 vs 9.3 mo(HR 1.45, 95% CI 1.08-1.92)
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 shorter OS.
Note: This was the upper bound of dosing specified in the protocol.
====Prior treatment criteria====
*One prior line of standard therapy
====Chemotherapy====
*Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===Regimen variant #3, 100 mg/m2, 6 out of 7 weeks===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kato et al. 2019 (ATTRACTION-3) 	2016-01-07 to 2017-05-25	Phase 3 (C)	Nivolumab 	Seems to have shorter OSMedian OS: 8 vs 11 mo(HR 1.30, 95% CI 1.04-1.61)
Shen et al. 2022 (RATIONALE 302)	2018-2020 	Phase 3 (C)	Tislelizumab	Shorter OSMedian OS: 6.3 vs 8.6 mo(HR 1.43, 95% CI 1.18-1.75)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Prior treatment criteria====
*RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy
====Chemotherapy====
*Paclitaxel (Taxol) 100 mg/m2 IV over at least 60 minutes once per day on days 1, 8, 15, 22, 29, 36
49-day cycles
===Regimen variant #4, 135 mg/m2, 21-day cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shen et al. 2022 (RATIONALE 302)	2018-2020 	Phase 3 (C)	Tislelizumab	Shorter OSMedian OS: 6.3 vs 8.6 mo(HR 1.43, 95% CI 1.18-1.75)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This is the lower bound of q3wk dosing in the protocol.
====Prior treatment criteria====
*RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy
====Chemotherapy====
*Paclitaxel (Taxol) 135 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #5, 175 mg/m2, 21-day cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shen et al. 2022 (RATIONALE 302)	2018-2020 	Phase 3 (C)	Tislelizumab	Shorter OSMedian OS: 6.3 vs 8.6 mo(HR 1.43, 95% CI 1.18-1.75)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This is the upper bound of q3wk dosing in the protocol.
====Prior treatment criteria====
*RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02569242
 
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02564263
##HRQoL analysis: Adenis A, Kulkarni AS, Girotto GC, de la Fouchardiere C, Senellart H, van Laarhoven HWM, Mansoor W, Al-Rajabi R, Norquist J, Amonkar M, Suryawanshi S, Bhagia P, Metges JP. Impact of Pembrolizumab Versus Chemotherapy as Second-Line Therapy for Advanced Esophageal Cancer on Health-Related Quality of Life in KEYNOTE-181. J Clin Oncol. 2022 Feb;40(4):382-391. link to original article link to EuroPMC
# RATIONALE 302: Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. Epub 2022 Apr 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03430843
==Pembrolizumab monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017 	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. Docetaxel1b. Irinotecan1c. Paclitaxel	Longer OS1 (co-primary endpoint)Median OS: 9.3 vs 6.7 mo(HR 0.69, 95% CI 0.52-0.93)
Shah et al. 2019 (KEYNOTE-180) 	2016-2017 	Phase 2 (RT) 	 	
1Reported efficacy in KEYNOTE-181 is for patients with PD-L1 combined positive score of at least 10; in all patients the experimental arm might have longer OS.
Patients in KEYNOTE-180 had 100% squamous histology.
====Prior treatment criteria====
*KEYNOTE-181: One prior line of standard therapy
*KEYNOTE-180: 2 or more lines of therapy
====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===
#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 link to PMC article EuroPMC NCT02559687
 
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02564263
##HRQoL analysis: Adenis A, Kulkarni AS, Girotto GC, de la Fouchardiere C, Senellart H, van Laarhoven HWM, Mansoor W, Al-Rajabi R, Norquist J, Amonkar M, Suryawanshi S, Bhagia P, Metges JP. Impact of Pembrolizumab Versus Chemotherapy as Second-Line Therapy for Advanced Esophageal Cancer on Health-Related Quality of Life in KEYNOTE-181. J Clin Oncol. 2022 Feb;40(4):382-391. link to original article link to EuroPMC
==Tislelizumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shen et al. 2022 (RATIONALE 302)	2018-2020 	Phase 3 (E-switch-ooc)	Investigator's choice of:1a. Docetaxel1b. Irinotecan1c. Paclitaxel	Longer OS (primary endpoint)Median OS: 8.6 vs 6.3 mo(HR 0.70, 95% CI 0.57-0.85)
====Prior treatment criteria====
*RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
# RATIONALE 302: Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. Epub 2022 Apr 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03430843
Category:Esophageal cancer regimens
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Category:Gastroesophageal cancers