Introduction: Metastatic or unresectable locally advanced oesophageal cancer remains a disease with high mortality. More recently, pembrolizumab plus chemotherapy has been indicated as the first-line treatment for those patients, but the predictive factors for treatment efficacy remain controversial. This study investigated the clinical utility of early tumour shrinkage (ETS) and depth of response (DpR) in metastatic or unresectable oesophageal cancer treated with pembrolizumab plus CF therapy. Methods: ETS and DpR, defined as the percent decreases at the second evaluation and the percentage of the maximal tumour shrinkage during treatment, were measured in 53 eligible patients. The ETS and DpR cut-off values were 20% and 30%, respectively, based on survival outcomes. Results: Twenty-seven patients (51%) were treatment naïve, while 26 (49%) had received any treatment before initiating pembrolizumab plus CF therapy. The median progression-free survival (PFS) and overall survival for ETS ≥20% and <20% were 12.7 and 5.5 months and 14.4 and 8.2 months and 12.7 and 4.9 months and 14.4 and 8.0 months for DpR ≥30% and <30%, respectively. ETS <20% showed early tumour growth, whereas ETS ≥20% had a good response rate with sufficient longer response duration. In addition, an ETS cut-off of 20% predicted the best overall response and was not associated with prior treatment. In multivariable analysis, ETS ≥20% and DpR ≥30% were independent factors of longer PFS. Conclusion: Our findings suggest that an ETS is a promising on-treatment marker for early prediction of further sensitivity to pembrolizumab plus CF therapy.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12(7):681–92.
van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–84.
Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. 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;19(1):68–74.
Kato K, Ito Y, Daiko H, Ozawa S, Ogata T, Hara H, et al. A randomized controlled phase III trial comparing two chemotherapy regimen and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced esophageal cancer, JCOG1109 NExT study. J Clin Oncol. 2022;40(4_Suppl):238.
Sugase T, Sugimura K, Kanemura T, Takeoka T, Yamamoto M, Shinno N, et al. Recurrence pattern comparing preoperative chemoradiotherapy and preoperative chemotherapy with docetaxel plus 5-fluorouracil and cisplatin for advanced esophageal cancer. Oncology. 2022;100(12):655–65.
Sugimura K, Miyata H, Tanaka K, Makino T, Takeno A, Shiraishi O, et al. Multicenter randomized phase 2 trial comparing chemoradiotherapy and docetaxel plus 5-fluorouracil and cisplatin chemotherapy as initial induction therapy for subsequent conversion surgery in patients with clinical T4b esophageal cancer: short-term results. Ann Surg. 2021;274(6):e465–72.
Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759–71.
Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449–62.
Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191–203.
National Comprehensive Cancer Network. NCCN Guidelines in Esophageal and Esophagogastric Junction Cancers. Version 3. 2021.
Muro K, Lordick F, Tsushima T, Pentheroudakis G, Baba E, Lu Z, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann Oncol. 2019;30(1):34–43.
Moehler M, Maderer A, Thuss-Patience PC, Brenner B, Meiler J, Ettrich TJ, et al. 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;31(2):228–35.
DeVita VT, Lawrence TS, Rosenberg SA. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 8th ed.2008. p. 1032–56.
Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, et al. 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;20(11):1506–17.
Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, et al. 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;5(4):546–50.
Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, et al. Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol. 2020;38(35):4138–48.
Kitagawa Y, Ishihara R, Ishikawa H, Ito Y, Oyama T, Oyama T, et al. Esophageal cancer practice guidelines 2022 edited by the Japan Esophageal Society: part 2. Esophagus. 2023;20(3):373–89.
Giessen C, Laubender RP, Fischer von Weikersthal L, Schalhorn A, Modest DP, Stintzing S, et al. Early tumor shrinkage in metastatic colorectal cancer: retrospective analysis from an irinotecan-based randomized first-line trial. Cancer Sci. 2013;104(6):718–24.
Modest DP, Laubender RP, Stintzing S, Giessen C, Schulz C, Haas M, et al. Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: an analysis of the German AIO KRK 0104 trial. Acta Oncol. 2013;52(5):956–62.
Piessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2013;31(30):3764–75.
Modest DP, Stintzing S, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser UCremolini C, et al. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. 2015;26(6):1188–94.
Cremolini C, Loupakis F, Antoniotti C, Lonardi S, Masi G, Salvatore L, et al. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. 2015;26(6):1188–94.
Tsuji A, Sunakawa Y, Ichikawa W, Nakamura M, Kochi M, Denda T, et al. Early tumor shrinkage and depth of response as predictors of favorable treatment outcomes in patients with metastatic colorectal cancer treated with FOLFOX plus cetuximab (JACCRO CC-05). Target Oncol. 2016;11(6):799–806.
Ichante J, Adenis A, Malka D, Francois E, Boucher E, Chauffert B, et al. Impact of early tumor shrinkage on long-term outcome in metastatic colorectal cancer (mCRC) treated with 5FU plus irinotecan plus leucovorin (FOLFIRI) or capecitabine plus irinotecan XELIRI plus bevacizumab. J Clin Oncol. 2011;29(15 Suppl):e14041.
Mansmann UR, Sartorius U, Laubender RP, Giessen CA, Esser R, Heinemann V. Quantitative analysis of the impact of deepness of response on post-progression survival time following first-line treatment in patients with mCRC. J Clin Oncol. 2013;31(15 Suppl):3630.
Heinemann V, Modest DP, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U, et al. Independent radiological evaluation of objective response early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306). Ann Oncol. 2014;25:117.
Ura T, Hironaka S, Tsubosa Y, Mizusawa J, Kato K, Tsushima T, et al. Early tumor shrinkage and depth of response in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil: an exploratory analysis of the JCOG0807. Esophagus. 2023;20(2):272–80.
Claret L, Jin JY, Ferté C, Winter H, Girish S, Stroh M, et al. A model of overall survival predicts treatment outcomes with atezolizumab versus chemotherapy in non-small cell lung cancer based on early tumor kinetics. Clin Cancer Res. 2018;24(14):3292–8.
Wang M, Chen C, Jemielita T, Anderson J, Li XN, Hu C, et al. Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma?J Immunother Cancer. 2019;7(1):39.
Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ. Early tumor shrinkage identifies long-term disease control and survival in patients with lung cancer treated with atezolizumab. J Immunother Cancer. 2020;8(1):e000500.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.
Sugase T, Kanemura T, Takeoka T, Sugimura K, Yamamoto M, Shinno N, et al. Clinicopathological characteristics and survival outcomes in patients with advanced esophageal squamous cell carcinoma who were intraoperatively diagnosed non-curative. Oncology. 2023:1–11. in press.
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