The Evolving Treatment Landscape of Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) has a high risk of recurrence and requires unique treatment relative to other skin cancers. The patient population is generally older, with comorbidities. Multidisciplinary and personalized care is therefore paramount, based on patient preferences regarding risks and benefits. Positron emission tomography and computed tomography (PET-CT) is the most sensitive staging modality and reveals clinically occult disease in ~ 16% of patients. Discovery of occult disease spread markedly alters management. Newly diagnosed, localized disease is often managed with sentinel lymph node biopsy (SLNB), local excision, primary wound closure, and post-operative radiation therapy (PORT). In contrast, metastatic disease is usually treated systemically with an immune checkpoint inhibitor (ICI). However, one or more of these approaches may not be indicated. Criteria for such exceptions and alternative approaches will be discussed. Because MCC recurs in 40% of patients and early detection/treatment of advanced disease is advantageous, close surveillance is recommended. Given that over 90% of initial recurrences arise within 3 years, surveillance frequency can be rapidly decreased after this high-risk period. Patient-specific assessment of risk is important because recurrence risk varies widely (15 to > 80%: Merkelcell.org/recur) depending on baseline patient characteristics and time since treatment. Blood-based surveillance tests are now available (Merkel cell polyomavirus (MCPyV) antibodies and circulating tumor DNA (ctDNA)) with excellent sensitivity that can spare patients from contrast dye, radioactivity, and travel to a cancer imaging facility. If recurrent disease is locoregional, management with surgery and/or RT is typically indicated. ICIs are now the first line for systemic/advanced MCC, with objective response rates (ORRs) exceeding 50%. Cytotoxic chemotherapy is sometimes used for debulking disease or in patients who cannot tolerate ICI. ICI-refractory disease is the major problem faced by this field. Fortunately, numerous promising therapies are on the horizon to address this clinical need.

Keywords: Cutaneous neuroendocrine carcinoma; Immunotherapy; Merkel cell carcinoma; Merkel cell polyomavirus; Multidisciplinary care.

Fig. 1

Flow chart for Merkel cell carcinoma evaluation and treatment management. a Consider baseline Merkel cell polyomavirus serology test for prognostic significance and surveillance (for seropo-*/ + -*itive patients). b Whole body FDG-PET/CT (preferred at baseline) or CT of chest, abdomen, pelvis with/without neck with contrast; brain MRI if symptomatic. c No enlarged/concerning nodes on physical examination and by imaging study. d Enlarged/concerning nodes on physical examination or by imaging study. e SLNB may not be indicated if a patient would not benefit from the prognostic information, if it would not alter management of the regional nodes, or if a patient is not a good candidate for surgery/anesthesia. f Consider excisional biopsy primarily or after negative needle/core biopsy to exclude false-negative biopsy result. g Adjuvant RT is often indicated unless the following low-risk features are present: primary lesion ≤ 1 cm, primary site not on head/neck, no lymphovascular invasion, widely negative pathologic margins, negative SLNB, and patient not immunosuppressed. h Consider RT to the nodal basin in high-risk patients (e.g., profound chronic immune suppression). Adapted, with permission, from Park et al., Future Oncol 2021 [7] and Akaike et al., Journal of Dermatological Science 2022 [8].

Fig. 2

Clinical images of primary Merkel cell carcinoma tumors. The marking pen ink indicates the palpable edge of the tumors, which often extends well beyond the elevated portion of the lesion.

Fig. 3

Before and after photos of MCC tumor treated with definitive hypo-fractionated radiation therapy (24 Gy in 3 fractions).

Fig. 4

Schema for surveillance blood testing (AMERK and/or ctDNA) in MCC. X-axis represents time, with each blood vial corresponding with an approximately a 3-month testing interval. Blue dots indicate no detectable disease. The 1st red dot represents baseline lab values, reflecting the presence of disease prior to treatment. The 2nd red dot indicates early detection of a recurrence. Laboratory detection of recurrence may warrant imaging (PET/CT is significantly more sensitive than CT for detecting early recurrence) to localize the site of disease. Blood test results should decrease following successful treatment of recurrence.