Evaluating the Role of Chemotherapy in Addition to Radiotherapy for High-Risk Merkel Cell Carcinoma

Background: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with a high risk of recurrence. While adjuvant radiotherapy is standard following surgical resection in high-risk disease, the additional benefit of platinum–etoposide chemotherapy and the prognostic role of tumor anatomical location remain uncertain. Methods: We conducted a multicenter retrospective cohort study including patients with high-risk MCC (stage IIB–III) treated with surgery followed by adjuvant radiotherapy with or without platinum–etoposide chemotherapy. Tumor sites were classified according to sun-exposure status. Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier methods and compared using the log-rank test, with subgroup analyses by anatomical region and stage. Results: A total of 103 patients were included, of whom 77 (74.8%) received adjuvant chemoradiotherapy and 26 (25.2%) received radiotherapy alone. Patients with non-sun-exposed tumors demonstrated longer survival outcomes than those with sun-exposed tumors, with a median DFS of 57 months versus 42 months (p = 0.15), and a median OS of 179 months versus 109 months (p = 0.054), respectively. Among patients with sun-exposed tumors, chemoradiotherapy was associated with numerically improved DFS (42 vs. 34 months; p = 0.051) and OS (128 vs. 98 months; p = 0.08) compared with radiotherapy alone. In patients with non-sun-exposed tumors, chemoradiotherapy demonstrated a more pronounced improvement in OS (178 vs. 56 months; p = 0.054), while DFS also favored combined treatment (49 vs. 78 months; p = 0.078). Conclusions: In this multicenter cohort, adjuvant chemotherapy did not demonstrate a uniform survival benefit overall but was associated with improved outcomes in head and neck MCC, suggesting a potential site-specific effect. Similar outcomes across stage III subgroups suggest that chemotherapy may mitigate stage-related prognostic differences. These findings support a selective approach to adjuvant chemotherapy and highlight the need for prospective studies incorporating modern immunotherapy strategies.