Emerging and mechanism-based therapies for recurrent or metastatic Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with a disease-specific mortality of approximately 40 %. The association of MCC with a recently discovered polyomavirus, combined with the increased incidence and mortality of MCC among immunocompromised patients, highlight the importance of the immune system in controlling this cancer. Initial management of MCC is summarized within the NCCN guidelines and in recently published reviews. The high rate of recurrent and metastatic disease progression in MCC, however, presents a major challenge in a cancer that lacks mechanism-based, disease-specific therapies. Traditional treatment approaches have focused on cytotoxic chemotherapy that, despite frequent initial efficacy, rarely provides durable responses and has high morbidity among the elderly. In addition, the immunosuppressive nature of chemotherapy is of concern when treating a virus-associated cancer for which survival is unusually tightly linked to immune function. With a median survival of 9.6 months after development of an initial metastasis (n = 179, described herein), and no FDA-approved agents for this cancer, there is an urgent need for more effective treatments. We review diverse management options for patients with advanced MCC, with a focus on emerging and mechanism-based therapies, some of which specifically target persistently expressed viral antigens. These treatments include single-dose radiation and novel immunotherapies, some of which are in clinical trials. Due to their encouraging efficacy, low toxicity, and lack of immune suppression, these therapies may offer viable alternatives to traditional cytotoxic chemotherapy.

Figure 1

Disease-specific survival in patients who developed metastatic Merkel cell carcinoma. Survival data are shown from 179 patients with metastatic MCC who were followed through the University of Washington/Fred Hutchinson Cancer Research Center. Median survival was 289 days from initial diagnosis of metastatic disease. When measured starting at the time of developing metastatic disease, there were no significant differences in survival based on the initial stage at presentation (data not shown). However, stage greatly influenced the likelihood of and median time to developing metastatic disease [11]. Among patients who developed metastatic disease, the interval between initial diagnosis and metastasis was longer for patients presenting with less advanced stage. Overall survival is very similar to the MCC-specific survival curve shown above.