What is the treatment approach for Merkel cell carcinoma?

Treatment of Merkel Cell Carcinoma

The treatment of Merkel cell carcinoma requires a stage-based algorithmic approach: localized disease is managed with wide local excision (1-2 cm margins to fascia), sentinel lymph node biopsy, and expeditious adjuvant radiation therapy (50-56 Gy for negative margins), while metastatic disease should be treated first-line with immune checkpoint inhibitors (avelumab or pembrolizumab). 1, 2

Initial Diagnostic Approach

• Perform excisional biopsy with narrow margins initially to obtain accurate diagnostic and microstaging information, rather than attempting wide excision at first presentation 1
• Coordinate sentinel lymph node biopsy (SLNB) before or concurrent with definitive wide local excision to maximize staging accuracy—performing SLNB after wide excision compromises the accuracy of lymphatic mapping 3, 1
• Obtain baseline whole body imaging (PET-CT preferred) to rule out regional and distant metastasis, as this reveals clinically occult disease in approximately 16% of patients and markedly alters management 4, 5

Localized Disease Management

Surgical Approach

• Achieve 1-2 cm lateral margins extending to investing fascia of muscle or pericranium when clinically feasible 3, 1
• Do not pursue extensive surgery to achieve clear margins if it will significantly delay adjuvant radiation therapy—pre-radiation margin status has no impact on locoregional failure in patients receiving adjuvant RT 2
• Delay extensive reconstruction involving undermining or flaps until negative surgical margins are confirmed histologically, and minimize tissue movement that could delay adjuvant radiation 3, 1
• Consider Mohs technique or complete circumferential and peripheral deep margin assessment (CCPDMA) as alternative surgical approaches 3

Sentinel Lymph Node Biopsy Strategy

• SLNB is an important staging tool that dictates the need for regional irradiation 3
• If SLNB is negative, radiation therapy is given to the primary site only and regional nodal basins can be observed 3, 1
• If SLNB is positive (microscopic disease), administer 50 Gy to the nodal basin (axilla/groin) or 50-56 Gy (head and neck) 3, 1
• If SLNB is not performed or unsuccessful, consider irradiating nodal beds for subclinical disease 3

Adjuvant Radiation Therapy

Expeditious initiation of adjuvant radiation therapy after surgery is critical, as delay has been associated with worse outcomes 3, 2

Primary Site Dosing (Standard 2 Gy/fraction):

• 50-56 Gy for negative resection margins 1, 2
• 56-60 Gy for microscopic positive margins 2
• 60-66 Gy for gross positive or unresectable disease 2

Regional Nodal Basin Dosing:

• 50 Gy for axilla or groin after positive SLNB 3, 1
• 50-56 Gy for head and neck after positive SLNB 3, 1
• 50-54 Gy for axilla/groin after lymph node dissection 3, 2
• 50-60 Gy for head and neck after lymph node dissection 3, 2

Technical Considerations:

• Use bolus to achieve adequate skin dose and wide margins (5 cm) around the primary site when possible 3, 2
• If using electron beam, select energy and isodose line (e.g., 90%) that delivers adequate lateral and deep margins 3, 2

Head and Neck Specific Considerations

The risk of false-negative SLNB is higher in head and neck MCC due to aberrant lymph node drainage and frequent presence of multiple sentinel node basins 3, 2

Treatment options for clinically node-negative head and neck MCC include:

• Perform SLNB and wide local excision; if SLNB is negative, irradiate the primary site ± nodal beds and in-transit lymphatics, or observe 3
• OR perform wide local excision without SLNB and irradiate the primary tumor site, in-transit lymphatics, and regional nodal sites 3

The radiation field treating the primary site often overlies draining lymph node beds in head and neck cases 3, 2

Regional Disease (Clinically Evident Lymph Nodes)

• Confirm diagnosis with fine-needle aspiration or core biopsy with appropriate immunopanel 1
• Obtain imaging (CT, MRI, or PET/CT) to exclude distant metastasis 1
• Lymph node dissection is the recommended initial therapy for clinically evident adenopathy in the axilla or groin, followed by postoperative radiation if indicated 3
• After lymph node dissection for macroscopic nodal involvement, the standard of care is complete lymph node dissection potentially followed by post-operative RT 4
• Postoperative radiation is indicated for multiple involved nodes and/or presence of more than focal extracapsular extension 3

Metastatic/Advanced Disease

Immune checkpoint inhibitors (avelumab or pembrolizumab) are recommended as first-line therapy for advanced/metastatic Merkel cell carcinoma, with objective response rates exceeding 50% 1, 6, 7, 5

First-Line Immunotherapy:

• Avelumab is FDA-approved for adults and pediatric patients 12 years and older with metastatic MCC 6
• Pembrolizumab is FDA-approved for adult and pediatric patients with recurrent locally advanced or metastatic MCC 7

Chemotherapy (Second-Line or Special Circumstances):

• For patients requiring debulking or unable to tolerate immunotherapy, use cisplatin or carboplatin with or without etoposide 1
• Chemotherapy can be used when patients fail to respond or are intolerant to anti-PD-(L)1 immunotherapy 4
• Responses to chemotherapy are mostly of short duration, and the associated clinical benefit on overall survival is unclear 8

Alternative chemotherapy regimens include:

• Cyclophosphamide, doxorubicin (or epirubicin), and vincristine 3
• Topotecan 3

Adjuvant Chemotherapy:

• Adjuvant chemotherapy is not recommended for local disease unless clinical judgment dictates otherwise 3
• Adjuvant chemotherapy is not routinely recommended for regional disease because adequate trials to evaluate usefulness have not been performed 3

Palliative Radiation

• For palliative intent, use a less protracted fractionation schedule such as 30 Gy in 10 fractions 3, 2

Surveillance After Treatment

• Perform complete skin and regional lymph node examination every 3-6 months for the first 2 years, then every 6-12 months thereafter 1
• 90% of recurrences occur within 24 months, with a median time to recurrence of 8 months 1
• Blood-based surveillance tests are now available (Merkel cell polyomavirus antibodies and circulating tumor DNA) with excellent sensitivity 5
• Surveillance frequency can be rapidly decreased after the high-risk 3-year period, as over 90% of initial recurrences arise within this timeframe 5

Critical Pitfalls to Avoid

• Never delay adjuvant radiation therapy to pursue wider surgical margins—this worsens outcomes 3, 2
• Do not perform wide local excision before SLNB, as this compromises lymphatic mapping accuracy 3, 1
• Do not use extensive tissue movement during reconstruction that could obscure the radiation target area 2
• Recognize that systemic disease is nearly uniformly preceded by nodal metastases and is uniformly fatal regardless of subsequent therapy, suggesting an orderly "cascade" pattern of spread 9
• ICI-refractory disease is the major problem faced in advanced MCC management 5