Approach Considerations
MCC is an aggressive malignant tumor with a high propensity for local recurrence, regional nodal involvement, and distant metastases. Treatment depends on the clinical stage at presentation and may involve surgery, radiation therapy, and/or chemotherapy. Multimodal therapy for MCC is often challenging because many patients are elderly and cannot tolerate aggressive treatments. [27] Problems with healing, as well as surgical-site morbidity, must be taken into account to create an effective, individualized therapeutic regimen.
Surgical Treatment
The treatment of choice for the primary lesion in MCC is surgical excision. Because of the high propensity for local recurrence, wide local excision including 2-3 cm of normal-appearing skin is the standard recommendation for reducing the incidence of recurrence. However, this margin is not always possible in the head and neck region.
In addition, in a study of patients with MCC, 35.4% of whom had primary head and neck lesions, Perez et al found that, in comparing resection margins of 1 cm, 1.1-1.9 cm, and 2 cm or more, the 1 cm margins were not associated with a greater rate of local recurrence or significantly different rates of disease-specific and overall survival. [28]
In practice, a disease-free margin appears to be most important factor in the evaluation of patient outcomes.
For the reasons just discussed, Mohs micrographic surgery followed by radiation therapy has proven to be an equally effective option for small primary facial MCCs. This surgical approach has the advantage of sparing as much normal adjacent tissue as possible, an important consideration when the primary lesion occurs on cosmetically important areas of the head and neck. Studies have demonstrated equivalent rates of local disease control with Mohs surgery and radiation therapy, as compared with standard surgical excision.
Treatment of first- and second-echelon nodal basins for the clinically negative neck (stage I) is controversial. Some suggest that prophylactic lymphadenectomy should not be performed routinely. On the other hand, based on a retrospective case series and literature review, Papadiochos et al recommended that in patients with head and neck MCC, elective regional lymph node management rather than observation be employed even when there is no identifiable lymph node disease. [29]
However, although prophylactic lymphadenectomy substantially decreases the local recurrence rate, it does not appear to affect disease survival. Some surgeons recommend prophylactic neck dissection for aggressive tumors, that is, those >2 cm, those with >10 mitotic figures per high-power field, and/or those with histologic evidence of lymphatic involvement.
Most surgeons are now performing intraoperative lymphoscintigraphy in most cases, reserving neck dissection for cases involving nodal positivity. Lymphoscintigraphy may spare patients from unnecessary lymphadenectomy, and it theoretically improves accuracy in staging clinically localized MCC. This treatment has been described in only a few centers, and its role in the routine management of MCC remains undefined.
Radiation Therapy
MCC is a radiosensitive tumor. Doses of 45-60 Gy are administered in standard fractions to the surgical site and to the regional lymphatic bed.
A study by Bishop et al indicated that treatment for MCC of the head and neck that includes radiation therapy provides effective local and regional control of the disease. The study, which included 106 patients with the condition who underwent radiation treatment, found that the 5-year actuarial rates for local and regional control of MCC were both 96%. [30, 31]
As the sole treatment for localized (stage I) lesions, radiation therapy has been used with some success. In the Bishop study, no regional recurrences were found among 22 patients with gross nodal disease who received radiation therapy but no neck dissection. [30] However, some studies have demonstrated high rates of local-regional recurrence in patients treated with radiation alone. [32]
Radiation therapy is not recommended as treatment for primary disease in patients able to undergo surgery. It is used as a primary treatment when patients are unable to tolerate surgery or when wide resection is required to remove the disease with a negative margin.
Radiation therapy is most often used an adjunctive therapy after surgical resection of the primary lesion and/or affected nodal basins. In one study, postoperative radiation therapy appeared to reduce local recurrence rates from 44% to 12%. A meta-analysis of 333 reports in the literature concluded that surgery plus radiation therapy decreases the rates of local and regional recurrence as compared to surgery alone. [33]
Radiation therapy may also be used in the palliative setting to reduce symptoms of pain, bleeding, ulceration, and secondary infection.
Chemotherapy
Chemotherapy has primarily been used for the palliation of advanced-stage MCC. Although most cases of advanced disease have some response to chemotherapy, the effect is not long term. Complete cure is extremely rare in patients with locally advanced disease or metastasis.
Chemotherapy with radiation therapy is being used to treat locally advanced or recurrent disease. A study by Chen et al of 4815 patients with MCC of the head and neck indicated that postoperative adjuvant therapy with chemoradiotherapy offers greater improvement in the overall survival rate than does postoperative radiation therapy alone in patients with male sex, tumor size of at least 3 cm, and positive margins. [34]
Chemotherapy for MCC is based on previous experience with small-cell lung carcinoma, which is pathologically similar to MCC. Common regimens include cyclophosphamide, doxorubicin, vincristine or etoposide, and cisplatin. Partial response rates approach 75%, and complete response rates are observed in 40% of patients with locally recurrent or advanced disease. Chemotherapy appears to be more effective for patients with locally advanced disease (response rate, 69%) than for those with metastatic disease (response rate, 57%).
Avelumab (Bavencio), an anti–programmed death ligand-1 (anti-PD-L1) immunoglobulin G1(IgG1) monoclonal antibody, was approved by the US Food and Drug Administration (FDA) in March 2017 for metastatic MCC in adults and pediatric patients aged 12 years or older.
Approval of avelumab was based on the JAVELIN Merkel 200 open-label, single-arm, multicenter study in 88 patientsin whommetastatic MCC had been histologically confirmed and in whomthe disease had progressed on or after administration of chemotherapy for distant metastatic disease.The overall response ratereached 33% (29 patients), partial response was 22%, and complete response was 11%. Eight-sixpercentof tumor responses lasted at least 6 months (25 patients), and 45% lasted at least 12 months (13 patients). Response duration lastedfrom 2.8 to over 23.3 months. [35]
Pembrolizumab(Keytruda), another PD-L1 inhibitor, was approved by the FDA in December 2018 for adults and children with metastatic or recurrent, locally advanced Merkel cell carcinoma. The drug’s pediatric efficacy was extrapolated from adult study data. Results from a multicenter, nonrandomized, open-label trial by Nghiem et al formed the basis for pembrolizumab’s approval. In patients who received pembrolizumab monotherapy who had not previously undergone systemic treatment, the overall, complete, and partial response rates were 56%, 24%, and 32%, respectively. Among responding patients, the DOR for 6 months or longer and 12 months or longer was 96% and 54%, respectively, with median DOR not reached in the study. [36]
In March 2023, the FDA approved retifanlimab (Zynyz) for adults with metastatic or recurrent, locally advanced Merkel cell carcinoma.
Approval was based on data from the phase 2 POD1UM-201 trial, an open-label, multiregional, single-arm study that evaluated retifanlimab in adults with metastatic or recurrent, locally advanced MCC in whom the advanced disease had not previously been addressed with systemic therapy. There was a 52% overall response rate among chemotherapy-naive patients for retifanlimab monotherapy, with 35% of responding patients achieving a complete response. In 62% of the responding patients, the duration of response was at least 12 months. [37]
Future treatments
Upcoming medical treatment of MCC may involve the Merkel cell polyomavirus. In tumor cells positive for Merkel cell polyomavirus, type I interferon has been shown to increase their apoptotic cell death in vivo through interference of the large T antigen of MCV. [38] Other proteins are the target of experimental vaccines. [39] Further exploration of virus-specific therapy will provide exciting new modes of treatment of this malignant cancer.
Treatments by Stage
Stage I
Therapeutic options for stage I disease include surgical excision and radiation therapy. Adjuvant chemotherapy is generally used postoperatively, especially when wide surgical margins are unattainable or when the surgical margins were involved with tumor.
Stage II
Patients with clinical stage II disease present with clinically positive regional nodes. Fine-needle aspiration can be used to confirm regional metastatic spread. Most authorities recommend complete lymphadenectomy and postoperative radiation therapy given to the regional site.
Biopsy of any suggestive lesion at the primary site is performed to confirm local recurrence. If recurrence is present, treatment involves repeat excision with a 2-cm margin or with Mohs micrographic surgery. Administer additional radiation therapy if possible.
Biopsy of suggestive nodes is also done to confirm regional recurrence. If present, treatment includes repeat dissection of the lymph node basin and further radiation therapy, if possible. Adjuvant chemotherapy is used to manage regional recurrence.
Stage III
Distant metastatic disease (stage III) most often occurs in the lungs, liver, bone, or brain. The prognosis for patients with stage III disease is poor, with a mean survival time of 8 months.
MCC is a chemosensitive tumor. Because MCC is histochemically similar to small cell carcinoma of the lung, the chemotherapeutic regimens to treat them are similar. Carboplatin and etoposide havedisplayed promising results with comparatively less toxicity. In the setting of advanced disease, chemotherapy has produced good response rates, including complete remission; however, such favorable responses are usually short-lived. Nevertheless, occasional cases of long-term remission justify the use of systemic therapy in patients who can tolerate the toxicities of the chemotherapeutic agents. In March 2017, the PD-1/PD-L1 inhibitor avelumabbecame the first drug approved by the US Food and Drug Administrationfor metastatic MCC. [35]
