Prognostic value of liver metastasis in patients with esophageal squamous cell carcinoma treated with nivolumab

Morita,Ryuichi; Ishikawa,Takeshi; Doi,Toshifumi; Itani,Junichiro; Sone,Daiki; Iwai,Naoto; Inoue,Ken; Konishi,Hirotaka; Dohi,Osamu; Yoshida,Naohisa; Shiozaki,Atsushi; Uchiyama,Kazuhiko; Takagi,Tomohisa; Fujiwara,Hitoshi; Konishi,Hideyuki; Itoh,Yoshito

doi:10.3892/ol.2025.14891

Prognostic value of liver metastasis in patients with esophageal squamous cell carcinoma treated with nivolumab

Authors:
- Ryuichi Morita
- Takeshi Ishikawa
- Toshifumi Doi
- Junichiro Itani
- Daiki Sone
- Naoto Iwai
- Ken Inoue
- Hirotaka Konishi
- Osamu Dohi
- Naohisa Yoshida
- Atsushi Shiozaki
- Kazuhiko Uchiyama
- Tomohisa Takagi
- Hitoshi Fujiwara
- Hideyuki Konishi
- Yoshito Itoh
View Affiliations

Affiliations: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602‑8566, Japan, Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602‑8566, Japan
Published online on: January 17, 2025 https://doi.org/10.3892/ol.2025.14891
Article Number: 145

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Nivolumab has been approved for unresectable recurrent advanced esophageal cancer. The present study aimed to provide real‑world data on diverse patient profiles, including the elderly and those with poor performance status, while exploring therapeutic efficacy biomarkers. This retrospective study included 42 patients with esophageal cancer who received nivolumab after second‑ or later‑line treatment at Kyoto Prefectural University of Medicine (Kyoto, Japan) from February 2020 to December 2021. The study evaluated real‑world patient data for the outcomes, safety and clinical characteristics impacting efficacy. The median patient age was 70 years (range, 52‑80), and 36 patients (85%) were male. A total of 22 patients (52%) were ≥70 years of age, and three (7%) had an Eastern Clinical Oncology Group Performance Status of 2, which was not included in the clinical trial. The response and disease control rates were 26 and 78%, respectively. With a median follow‑up period of 7.9 months, the median progression‑free survival and overall survival were 3.5 (95% CI, 2.0‑6.0) and 19 (95% CI, 6.4‑not reached) months, respectively. Patients with liver metastases had significantly worse progression‑free survival and overall survival, while lung and lymph node metastases did not clearly impact nivolumab efficacy. Multivariate analysis revealed that liver metastases may predict both worse progression‑free survival [hazard ratio (HR) 2.37; 95% CI, 1.07‑5.24; P=0.03) and overall survival (HR, 2.75; 95% CI, 1.00‑7.53; P=0.04). This study provided real‑world evidence of nivolumab's favorable efficacy across diverse profiles, including the elderly and those with impaired performance status. No serious immune‑related adverse events occurred and liver metastasis emerged as a predictive biomarker for nivolumab efficacy in esophageal squamous cell cancer.

View Figures

View References

1	Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A and Bray F: Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 144:1941–1953. 2019. View Article : Google Scholar : PubMed/NCBI
2	Lin Y, Totsuka Y, He Y, Kikuchi S, Qiao Y, Ueda J, Wei W, Inoue M and Tanaka H: Epidemiology of esophageal cancer in Japan and China. J Epidemiol. 23:233–242. 2013. View Article : Google Scholar : PubMed/NCBI
3	Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, 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. 20:1506–1517. 2019. View Article : Google Scholar : PubMed/NCBI
4	Kim JH, Ahn B, Hong SM, Jung HY, Kim DH, Choi KD, Ahn JY, Lee JH, Na HK, Kim JH, et al: Real-world efficacy data and predictive clinical parameters for treatment outcomes in advanced esophageal squamous cell carcinoma treated with immune checkpoint inhibitors. Cancer Res Treat. 54:505–516. 2022. View Article : Google Scholar : PubMed/NCBI
5	Farhood B, Najafi M and Mortezaee K: CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. J Cell Physiol. 234:8509–8521. 2019. View Article : Google Scholar : PubMed/NCBI
6	Ikoma T, Shimokawa M, Matsumoto T, Boku S, Yasuda T, Shibata N, Kurioka Y, Takatani M, Nobuhisa T, Namikawa T, et al: Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab. Cancer Immunol Immunother. 72:427–435. 2023. View Article : Google Scholar : PubMed/NCBI
7	Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, Rizvi SM, Qin A, Waninger JJ and Lang X: Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 27:152–164. 2021. View Article : Google Scholar : PubMed/NCBI
8	Sasaki A, Nakamura Y, Mishima S, Kawazoe A, Kuboki Y, Bando H, Kojima T, Doi T, Ohtsu A, Yoshino T, et al: Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer. Gastric Cancer. 22:793–802. 2019. View Article : Google Scholar : PubMed/NCBI
9	Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Sosman JA, Atkins MB and Leming PD: Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab. JAMA Oncol. 5:1411–1420. 2019. View Article : Google Scholar : PubMed/NCBI
10	Lee JC, Mehdizadeh S, Smith J, Young A, Mufazalov IA, Mowery CT, Daud A and Bluestone JA: Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis. Sci Immunol. 5:eaba07592020. View Article : Google Scholar : PubMed/NCBI
11	Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, et al: Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 40:201–218.e9. 2022. View Article : Google Scholar : PubMed/NCBI
12	Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, Leibowitz-Amit R, Sonpavde G, Knox JJ, Tran B, et al: Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: A systematic review and meta-analysis. J Natl Cancer Inst. 106:dju1242014. View Article : Google Scholar : PubMed/NCBI
13	Zhang L, Ma W, Qiu Z, Kuang T, Wang K, Hu B and Wang W: Prognostic nutritional index as a prognostic biomarker for gastrointestinal cancer patients treated with immune checkpoint inhibitors. Front Immunol. 14:12199292023. View Article : Google Scholar : PubMed/NCBI
14	Nakahama K, Izumi M, Yoshimoto N, Fukui M, Sugimoto A, Nagamine H, Ogawa K, Sawa K, Tani Y, Kaneda H, et al: Influence of smoking history on the effectiveness of immune-checkpoint inhibitor therapy for non-small cell lung cancer: Analysis of real-world data. Anticancer Res. 43:2185–2197. 2023. View Article : Google Scholar : PubMed/NCBI
15	Sun Y, Yang Q, Shen J, Wei T, Shen W, Zhang N, Luo P and Zhang J: The effect of smoking on the immune microenvironment and immunogenicity and its relationship with the prognosis of immune checkpoint inhibitors in non-small cell lung cancer. Front Cell Dev Biol. 9:7458592021. View Article : Google Scholar : PubMed/NCBI
16	Wang X, Ricciuti B, Alessi JV, Nguyen T, Awad MM, Lin X, Johnson BE and Christiani DC: Smoking history as a potential predictor of immune checkpoint inhibitor efficacy in metastatic non-small cell lung cancer. J Natl Cancer Inst. 113:1761–1769. 2021. View Article : Google Scholar : PubMed/NCBI
17	Giustini N and Bazhenova L: Recognizing prognostic and predictive biomarkers in the treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs). Lung Cancer (Auckl). 12:21–34. 2021.PubMed/NCBI
18	Sacdalan DB, Lucero JA and Sacdalan DL: Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: A review and meta-analysis. Onco Targets Ther. 11:955–965. 2018. View Article : Google Scholar : PubMed/NCBI
19	Xie X, Liu J, Yang H, Chen H, Zhou S, Lin H, Liao Z, Ding Y, Ling L and Wang X: Prognostic value of baseline neutrophil-to-lymphocyte ratio in outcome of immune checkpoint inhibitors. Cancer Invest. 37:265–274. 2019. View Article : Google Scholar : PubMed/NCBI
20	Muhammed A, Fulgenzi CAM, Dharmapuri S, Pinter M, Balcar L, Scheiner B, Marron TU, Jun T, Saeed A, Hildebrand H, et al: The systemic inflammatory response identifies patients with adverse clinical outcome from immunotherapy in hepatocellular carcinoma. Cancers (Basel). 14:1862021. View Article : Google Scholar : PubMed/NCBI
21	Chau I, Ajani JA, Doki Y, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu C, Adenis A, et al: Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648. J Clin Oncol. 40 (Suppl 16):S4035. 2022. View Article : Google Scholar