Adjuvant Radiation in Resectable Node-Positive Merkel Cell Carcinoma in the Immunotherapy Era: Implications for Future and Ongoing Trials

Merkel cell carcinoma (MCC) is a rare, aggressive type of skin cancer that has been found to respond well to immunotherapy in the metastatic setting; ongoing large trials are exploring the addition of this therapy to earlier stage disease to prevent recurrence after surgery, particularly distant metastatic recurrence. However, newer clinical data suggest that non-metastatic MCC may have a better prognosis than what was previously observed, in part because of new technologies that have improved the detection of MCC spread to regional lymph nodes or other organs (i.e., distant metastases). Thus, preventing MCC from recurring in the area of the original surgery may be more important in achieving a cure for these patients without distant metastatic disease. Radiation therapy is an effective treatment for preventing these local recurrences, but there is significant variability in how ongoing immunotherapy trials allow for its use. This review describes the evidence supporting the ongoing use of adjuvant radiation therapy, how variability in radiation therapy use may have led to negative results in a large trial of immunotherapy in non-metastatic MCC, and the risk this poses for two large ongoing studies in this domain. Merkel cell carcinoma (MCC) is a cutaneous malignancy often treated with surgical resection followed by adjuvant radiation therapy (RT). In the node-positive setting, adjuvant RT reduces the risk of locoregional recurrence, but historical data suggest that distant failure is a persistent issue and often fatal. This has prompted new efforts to intensify treatment in these patients with the addition of neoadjuvant or adjuvant immune checkpoint inhibitor therapy. However, newer diagnostic techniques have led to stage migration in patients with previously subclinical metastatic disease; consequently, preventing locoregional recurrence may be a higher priority in node-positive MCC patients than was previously believed. Recent trials in node-positive MCC, such as ADMEC-O, have had lower rates of adjuvant RT utilization in treatment versus control arms, which may have attenuated the observed effect of adjuvant immunotherapy. The low utilization of adjuvant RT may have also resulted in a higher recurrence rate in patients who did not have a complete response to neoadjuvant immunotherapy in the CHECKMATE 358 trial. Altogether, these are important considerations for ongoing and future immunotherapy trials in MCC and may affect the interpretation of their results. Ongoing clinical trials may determine which patients are at low risk of recurrence when treated with immunotherapy and whether adjuvant RT could be omitted in select patients.