{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:17:47Z","timestamp":1788455867097,"version":"build-2803163510"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Bleomycin, etoposide, and cisplatin (BEP) remains the cornerstone of curative first-line treatment for metastatic germ cell tumors (GCTs) across all prognostic risk groups. Although etoposide-cisplatin (EP) and etoposide-ifosfamide-cisplatin (VIP) are validated alternatives in selected clinical scenarios, oncologic efficacy among standard first-line cisplatin-based regimens is largely comparable within their respective indications. Consequently, treatment selection is increasingly driven by differences in toxicity profiles rather than antitumor effectiveness. Bleomycin exposure distinguishes BEP from other cisplatin-based regimens and underlies its distinct spectrum of adverse effects. Among these, pulmonary toxicity is the most clinically consequential and potentially irreversible complication. Bleomycin-induced pulmonary toxicity is characterized by marked interindividual variability, clinically significant toxicity occurring even at relatively low cumulative exposure despite cumulative dose remaining an important risk factor, and clinically meaningful morbidity and mortality in a predominantly young and otherwise curable population. Accumulating evidence indicates that bleomycin lung injury represents an immune-mediated process driven by dysregulated alveolar-immune crosstalk, innate immune activation, and profibrotic signaling. This review provides a toxicity-focused comparison of standard first-line cisplatin-based regimens used in the curative treatment of metastatic GCTs, particularly BEP, EP, and VIP regimens within the framework of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification and repositions bleomycin pulmonary toxicity as a model of immune-mediated chemotherapy toxicity. We integrate clinical and experimental data on immunopathogenesis and discuss emerging biomarkers of alveolar injury and immune activation, as promising investigational tools that require prospective validation before routine implementation in first-line treatment selection or pulmonary toxicity monitoring.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1861834","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:27:44Z","timestamp":1785756464000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Toxicity of BEP chemotherapy in germ cell tumors: focus on immune-mediated bleomycin pulmonary toxicity in comparison with EP and VIP regimens"],"prefix":"10.3389","volume":"17","author":[{"given":"Patrik","family":"Olah","sequence":"first","affiliation":[{"name":"2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute","place":["Bratislava, Slovakia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Celec","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biomedicine, Comenius University","place":["Bratislava, Slovakia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Vlkova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biomedicine, Comenius University","place":["Bratislava, Slovakia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Rejlekova","sequence":"additional","affiliation":[{"name":"2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute","place":["Bratislava, Slovakia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/b978-1-4377-1604-7.00206-2","article-title":"Testicular cancer as a model for a curable neoplasm: The Richard and Hinda Rosenthal Foundation Award Lecture","volume":"41","author":"Einhorn","year":"1981","journal-title":"Cancer Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1200\/JCO.1997.15.2.594","article-title":"International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers","volume":"15","year":"1997","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.04.008","article-title":"Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors","volume":"22","author":"Fizazi","year":"2004","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1997.15.5.1837","article-title":"Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group","volume":"15","author":"de Wit","year":"1997","journal-title":"J Clin Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.0171","article-title":"Randomized phase III study comparing paclitaxel\u2013bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer: intergroup study EORTC 30983","volume":"30","author":"de Wit","year":"2012","journal-title":"J Clin Oncol"},{"key":"B6","article-title":"Testicular cancer. 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