What is the treatment for Merkel cell carcinoma?

Treatment of Merkel Cell Carcinoma

Surgery followed by adjuvant radiation therapy is the cornerstone of treatment for localized Merkel cell carcinoma, with sentinel lymph node biopsy performed concurrently to guide regional management, while immune checkpoint inhibitors (avelumab or pembrolizumab) are first-line therapy for metastatic disease. 1, 2

Localized Disease (Clinical Node-Negative)

Initial Surgical Management

• Perform excisional biopsy with narrow margins initially to obtain accurate diagnostic and microstaging information 1
• Coordinate sentinel lymph node biopsy (SLNB) before or concurrent with definitive wide local excision to maximize staging accuracy 1, 3
• Achieve 1-2 cm lateral margins extending to investing fascia or pericranium when clinically feasible 1, 3
• For facial or cosmetically sensitive areas, Mohs micrographic surgery or complete circumferential peripheral and deep-margin assessment (CCPDMA) may be used for tissue conservation 3
• Delay extensive reconstruction until negative margins are confirmed histologically, and minimize tissue movement that could delay adjuvant radiation 1, 3

Adjuvant Radiation Therapy

Expeditious initiation of radiation therapy after surgery is critical, as delay worsens outcomes 1

Primary Site Dosing:

• Negative margins: 50-56 Gy 1
• Microscopic positive margins: 56-60 Gy 1
• Gross positive or unresectable: 60-66 Gy 1

Regional Nodal Management Based on SLNB Results:

For extremity/torso lesions:

• Negative SLNB: Radiation to primary site only; observe regional nodes 1
• Positive SLNB (microscopic): 50 Gy to nodal basin 1
• No SLNB performed: Consider 46-50 Gy to at-risk nodal beds 1

For head and neck lesions (higher false-negative SLNB risk):

• Negative SLNB: Consider 46-50 Gy to nodal beds if at risk for false-negative 1
• Positive SLNB (microscopic): 50-56 Gy to nodal basin 1
• Alternative: Wide local excision without SLNB, then irradiate primary site, in-transit lymphatics, and regional nodes 1

Observation Without Radiation

Observation may be considered only for small primary lesions that are widely excised with no adverse risk factors (no lymphovascular invasion, no immunosuppression) 1

Management of Positive Sentinel Lymph Node

• Multidisciplinary tumor board consultation is preferred 1
• Clinical trial participation is encouraged when available 1
• Most patients undergo completion lymph node dissection and/or radiation therapy 1
• After lymph node dissection: 50-54 Gy (axilla/groin) or 50-60 Gy (head/neck) 1

Regional Disease (Clinical Node-Positive)

• Confirm diagnosis with fine-needle aspiration or core biopsy with appropriate immunopanel 1
• Obtain imaging (CT, MRI, or PET/CT) if not already performed to exclude distant metastasis 1
• If no distant metastasis: lymph node dissection with or without radiation therapy 1
• Clinically evident lymphadenopathy: 60-66 Gy after lymph node dissection 1
• Adjuvant chemotherapy may be considered in select cases, though no survival benefit has been reported 1

Metastatic Disease

Immune checkpoint inhibitors are first-line therapy for advanced/metastatic Merkel cell carcinoma, with objective response rates exceeding 50% 2, 4

Systemic Treatment Options:

First-line:

• Avelumab or pembrolizumab (immune checkpoint inhibitors with durable antitumor activity) 2, 4

For patients requiring debulking or unable to tolerate immunotherapy:

• Cisplatin or carboplatin with or without etoposide 1
• Topotecan (particularly for older patients) 1
• Cyclophosphamide, doxorubicin, and vincristine (CAV) - associated with significant toxicity 1

Multimodal Approach:

• Multidisciplinary tumor board consultation to consider combination of chemotherapy, radiation, and surgery 1
• Full imaging workup recommended for all patients with clinically proven regional or metastatic disease 1
• Surgery may be beneficial for select patients with oligometastatic disease 1
• All patients should receive best supportive care 1
• Clinical trial enrollment is strongly encouraged 1

Important Caveats

• Retrospective data do not suggest prolonged survival benefit for adjuvant chemotherapy in local or regional disease 1
• Chemotherapy responses in metastatic disease are mostly short-duration (approximately 3 months) 5, 4
• ICI-refractory disease remains the major unmet clinical need, with multiple novel therapies under investigation including tyrosine kinase inhibitors, peptide receptor radionuclide therapy, therapeutic vaccines, and adoptive cellular immunotherapies 4
• Standard fractionation is 2 Gy/day with bolus to achieve adequate skin dose and 5 cm margins around primary site when possible 1
• For palliative radiation, less protracted schedules may be used (e.g., 30 Gy in 10 fractions) 1

Surveillance After Treatment

• Complete skin and regional lymph node examination every 3-6 months for first 2 years, then every 6-12 months thereafter 1
• 90% of recurrences occur within 24 months (median time to recurrence: 8 months) 1
• PET/CT useful for identifying and quantifying metastases, especially bone involvement 1
• Blood-based surveillance tests (MCPyV antibodies and circulating tumor DNA) now available with excellent sensitivity 2