Optimal Duration of Adjuvant Platinum-Etoposide in High-Risk Merkel Cell Carcinoma

Background and Objectives: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin malignancy associated with high rates of recurrence and disease-specific mortality. Although adjuvant platinum-etoposide chemotherapy is used in high-risk disease, the optimal number of treatment cycles has not been established. Materials and Methods: This multicenter retrospective cohort study included 104 patients with resected high-risk MCC (pathological stage IIB-III) treated at Israeli medical centers between September 1985 and February 2021. Patients were assigned to one of three treatment groups: radiotherapy alone, four cycles of platinum-etoposide plus radiotherapy, or six cycles of platinum-etoposide plus radiotherapy. The chemotherapy regimen consisted of cisplatin or carboplatin combined with etoposide in 21-day cycles, with the first two cycles administered concurrently with radiotherapy. Primary endpoints were disease-free survival (DFS) and overall survival (OS), analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards regression. Results: Four cycles of adjuvant platinum-etoposide combined with radiotherapy were associated with the most favorable survival outcomes at all follow-up time points. Five-year DFS and OS in the four-cycle group were 65% (95% CI: 58-72%) and 75% (95% CI: 68-82%), respectively, compared with 55% and 60% in the six-cycle group, and 40% and 45% in the radiotherapy-only group (p < 0.001). The survival advantage of four cycles over radiotherapy alone was sustained at 10- and 20-year follow-up (p < 0.0001). In patients with stage III disease and nodal involvement, the four-cycle group achieved a median DFS of 93 months and a median OS of approximately 110 months, significantly exceeding outcomes in both the six-cycle and radiotherapy-alone groups. No statistically significant survival benefit from chemotherapy was identified in the small subgroup of patients with stage IIB/T4N0 disease. Conclusions: In patients with high-risk resected MCC, the addition of adjuvant platinum-etoposide chemotherapy to radiotherapy significantly improves DFS and OS, with the greatest benefit observed in patients with stage III disease and lymph node involvement. Four cycles represent an optimal treatment duration, delivering durable long-term survival benefit without the need for more prolonged chemotherapy exposure. These findings support a risk-adapted multimodality approach and provide real-world evidence to guide adjuvant therapy decisions in this rare and aggressive malignancy.