Background: Head and neck squamous cell carcinoma (HNSCC) is among the top 10 most common cancer entities worldwide. For patients with locally advanced, non-metastatic HNSCC, the standard of care treatment often includes concomitant chemoradiotherapy with cisplatin. However, a considerable number of these patients are cisplatin-ineligible. To inform treatment selection for cisplatin-unfit patients undergoing radiotherapy (RT) for HNSCC, a network meta-analysis was performed. Method: In November 2023 a systematic search was conducted and updated in January 2026 searching four electronic databases (Medline, Web of Science, Cochrane Library, and Scopus) to identify randomized controlled trials (RCTs) analyzing overall survival (OS), progression-free survival (PFS), locoregional control (LC) and adverse events (AE) of RT combined with chemo-/immunotherapy with relevance to treatment selection in cisplatin-ineligible patients with HNSCC. Results: From all (15,551) search results, 52 publications concerning 28 RCTs reporting on approximately 7000 patients were included. The therapeutic concepts in the experimental group included all combinations of RT with concurrent systemic therapy, excluding cisplatin-based regimens, and were compared with any control treatment. All studies had sufficient quality for inclusion. None of the systemic agents showed a significant improvement in OS, PFS, or LC compared to cisplatin. Carboplatin + 5-FU and mitomycin C + 5-FU improved LC compared to hyperfractionated accelerated radiotherapy (HART). Compared to cisplatin, durvalumab and cetuximab were associated with less dysphagia, cetuximab with less renal impairment, and panitumumab and cetuximab with less weight loss. Conclusions: Carboplatin + 5-FU and Mitomycin C + 5-FU achieve superior LC compared to HART. Targeted therapy and immunotherapy were associated with less severe AEs.

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