Skin Cancer - Merkel Cell Carcinoma Treatment & Management

The aforementioned 2015 European guidelines on the diagnosis and management of Merkel cell carcinoma included the following regarding treatment ^[4] :

• The primary tumor should be excised with 1-2 cm margins

• In patients with regional lymph node involvement, radical lymphadenectomy is recommended

• Adjuvant radiation therapy may be considered in patients with multiple affected lymph nodes of extracapsular extension

• In unresectable metastatic Merkel cell carcinoma, monochemotherapy or polychemotherapy achieve high remission rates; however, responses are usually short-lived

• Treatment within clinical trials is regarded as a standard of care in disseminated Merkel cell carcinoma

A study by Bishop et al indicated that treatment for Merkel cell carcinoma 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 Merkel cell carcinoma were both 96%. In addition, no regional recurrences were found among 22 patients with gross nodal disease who received radiation therapy but no neck dissection. ^[18]

A study by Chen et al of 4815 patients with Merkel cell carcinoma of the head and neck indicated that postoperative adjuvant therapy with chemoradiotherapy offers greater improvement in the overall survival rate than does postoperative radiotherapy alone in patients with male sex, tumor size of at least 3 cm, and positive margins. ^[19]

Avoidance

As with other skin cancers, the risk of developing Merkel cell carcinoma (MCC) can likely be decreased via protection from ultraviolet (UV) light. This can be accomplished through the following ^{[6, 5]} :

• Reduction of sun exposure during peak daylight hours
• Application and reapplication of sunscreen
• Use of protective clothing during sun exposure
• Avoidance of tanning beds and sunlamps

Individuals can also regularly check themselves for skin changes, contacting a doctor if any occur. ^[6] Nonetheless, it remains unproven whether Merkel cell carcinoma (MCC) is associated with sun exposure, ^[5] and the disease has been reported in areas not exposed to the sun, such as the nasal cavity, buccal mucosa, gingiva, hard palate, and postauricular skin.

PD-1/PD-L1 inhibitors

Avelumab

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 Merkel cell carcinoma 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 patients in whom metastatic Merkel cell carcinoma had been histologically confirmed and in whom the disease had progressed on or after administration of chemotherapy for distant metastatic disease. The overall response rate (ORR) reached 33% (29 patients), partial response rate (PRR) was 22%, and complete response rate (CRR) was 11%. Eight-six percent of tumor responses lasted at least 6 months (25 patients), and 45% lasted at least 12 months (13 patients). The duration of response (DOR) lasted from 2.8 to over 23.3 months. ^[20]

Pembrolizumab

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. ^[21]  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 ORR, CRR, 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. ^[22]

Retifanlimab 

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% ORR 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. ^[23]

For patients with operable disease, most agree that surgery is the treatment of choice. As with most tumors, treatment is based on the stage. The Yiengpruksawan system is used here. ^[17]

Stage I

Aggressive wide local excision is the treatment of choice for the primary tumor. A 2- to 3-cm margin is recommended because it is thought to decrease the risk of recurrence. (However, in a study of patients with Merkel cell carcinoma, 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. ^[24] ) All margins should be confirmed with frozen sections.

The role of elective neck dissection in the absence of clinically positive nodes is controversial. ^[25] Because of the low incidence of Merkel cell carcinoma (MCC), most reports are based on retrospective or anecdotal studies. Lymph node metastases develop in approximately 55% of patients; therefore, some authors recommend prophylactic neck dissection in all patients. Others recommend neck dissection after the tumor reaches 2 cm in diameter.

Silva et al (1984) recommend neck dissection for tumors with 10 or more mitoses per high-power field, for cases of lymphatic invasion, or for tumors composed of small cells. ^[26] Cotlar et al (1986) recommend lymphadenectomy for tumors present longer than 6 weeks. ^[27] Tumors in the midline present the problem of bilateral drainage. Goepfert et al (1984) and Hitchcock et al (1988) recommend that patients with such lesions undergo a bilateral neck dissection. ^{[28, 29]}

Recent studies have been conducted to investigate the efficacy of sentinel node biopsy to determine whether neck dissection is necessary. These studies have been small, but their results indicate that a negative sentinel node may obviate the need for neck dissection.

When one contemplates neck dissection, realize that no indications are universally accepted and that the effect of regional lymphadenopathy on overall survival is uncertain.

Merkel cell carcinoma (MCC) is a radiosensitive tumor, and radiotherapy is currently used as an adjuvant. Most clinical studies demonstrate better local control rates with adjuvant radiotherapy after surgery. Numerous authors have recommended postexcision irradiation of the primary site and primary areas of lymph node drainage. Adjuvant radiotherapy is routinely given by some practitioners, whereas other practitioners only give it to patients considered to be high risk, which is inconsistently defined as demonstrating any of the following: (1) primary tumor >1.5 cm; (2) positive margins; (3) margins < 2 mm; (4) evidence of lymphatic, vascular, or perineural invasion; or (5) regional lymph node involvement.

The recommended dosing schedule is 45-50 Gy for 5 weeks; this is increased to 56-65 Gy for tumors with positive margins. These doses are similar to those used to treat squamous cell carcinoma. Therapy for recurrent localized disease or extensive unresectable stage I disease is similar to that given for stage II disease because lymphadenopathy is more likely to occur in this situation than in primary disease.

Stage II

A widely accepted practice is for patients with regional node metastases or local or regional recurrence to undergo excision of the primary lesion and lymph node dissection. Adjuvant radiation therapy to the primary site and regional nodes is generally recommended in addition to neck dissection.

Chemotherapy is generally not currently advocated for stage II disease.

Stage III

The development of distant metastases portends a poor prognosis, with a mean life expectancy of 5 months. Many types of chemotherapeutic agents have been used with brief success in treating stage III disease, with no increase in the survival rate. Because of the morphologic and immunohistochemical similarities of Merkel cell carcinoma (MCC) to small cell lung cancer, these regimens have been used as treatment models.

Pharmacologic agents most commonly used are doxorubicin and cyclophosphamide. Other agents are cisplatin, vincristine, etoposide, methotrexate, bleomycin, and 5-fluorouracil. However, reports of these treatments to date have consisted of small studies and anecdotal evidence. Merkel cell carcinomas (MCCs) often respond to chemotherapy; however, as with small cell carcinoma, remission is brief. No chemotherapeutic protocol has notably increased survival rates.

The role of radiation therapy in disseminated disease is to achieve palliation.

After treatment, monitor patients closely. Recommended follow-up is every month for 6 months, every 3 months for the next 2 years, and every 6 months thereafter.

Merkel cell carcinoma (MCC) is a deadly disease with a poor outlook for survival. Local recurrence occurs in 44% of patients; multiple local recurrences occur in 15%. These recurrences usually happen within 5 months after the primary lesion is treated. About 15% of patients have palpable nodes at the time of diagnosis. Lymph node metastases eventually develop in 55% of patients, and distant metastases develop in 34%. Most metastases occur before the eighth month after diagnosis.

The areas where metastases are most likely to occur are the liver, bone, brain, and lung. The presence of distant metastases is the only factor that is consistently predictive of the outcome. The mean time to death after the discovery of distant metastases is 5 months. Mortality rates for patients with distant metastases are 75-100%. In patients without distant metastases, mortality rates are 4%.

The aforementioned study by Uitentuis et al found that in the Netherlands, out of a cohort of 1977 patients, the relative 5-year survival rate for individuals with Merkel cell carcinoma (MCC) was 63.0%, with greater mortality seen in males (hazard ratio [HR] 1.24), in patients of higher age (HR 1.07), in individuals with nodal invasion (HR 1.26), and in patients with distant disease spread (HR 2.44). ^[9]

A review of a prospective database of 500 patients with Merkel cell carcinoma (MCC) treated at a single institution reported a median age at diagnosis of 71 years and 5-year overall survival and disease-specific death (DSD) rates of 56% and 30%, respectively. (The staging system for this study was based up on the American Joint Committee on Cancer [AJCC], 7th edition, 2010.) Pathologic stage and lymphovascular invasion were independent predictors of DSD. Patients with metastatic disease (stage 4) or clinically positive lymph nodes (stage 3b) demonstrated increased DSD compared with patients with lower-staged disease. Of note, no difference was noted in DSD demonstrated for stage 3a or 2 compared with stage 1. Also of note, only 1 of 132 patients without lymphovascular invasion died of MCC. The authors note that overall survival is a poor measure of the influence of MCC on life expectancy. ^[30]

Future directions for the treatment of Merkel cell carcinoma (MCC) that are still under investigation include Mohs surgery for excision of the primary lesion, lymphoscintigraphy, intraoperative mapping of lymph nodes, biopsy of sentinel lymph nodes to treat and stage occult neck disease, as well as to further define the role of chemotherapy.

O'Connor et al (1997) compared the efficacy of Mohs surgery to that of wide local excision. ^[31] Following up 86 patients, they determined that Mohs surgery fared well compared with the standard treatment of wide local excision.

When weighing the choice between wide local excision and Mohs surgery, one must consider the advantage of Mohs surgery because it allows for histologic control of margins of the tumor, minimizing the extent of excision. In the head and neck, conservation of tissue is imperative to preserve vital structures. Considering this information, many authors now advocate Mohs excision in lieu of wide local excision.

In Merkel cell carcinoma (MCC), the prognosis and the treatment of the disease is largely based on the presence or absence of metastases. To facilitate appropriate treatment and staging, the clinician must determine the state of the regional lymphatics in the clinically negative neck. At present, prophylactic neck dissection is advocated, but the procedure entails morbidity. In addition, because drainage patterns in the head and neck are notoriously ambiguous and difficult to predict, which lymph node basins should be dissected is often unclear.

For the treatment of melanomas of the head and neck, preoperative lymphoscintigraphy and intraoperative lymphatic mapping have been used to successfully identify draining lymph node basins and localize the sentinel lymph node for biopsy. Preliminary studies have demonstrated that, in Merkel cell carcinoma (MCC), the status of the sentinel node is predictive of the status of the remaining lymph node basin.

Recent work in this area by Schmalbach et al (2005) supports these preliminary findings. ^[32] Regional failure in the setting of negative findings on sentinel lymph node biopsy was observed in 1 (13%) of 8 patients. This rate of regional recurrence compares favorably with mean rates of regional recurrence reported in the literature. If data from large studies confirm these findings, sentinel lymph node biopsy may provide an accurate and less morbid alternative to neck dissection for the treatment and staging of regional occult neck disease in Merkel cell carcinoma (MCC).

However, elective lymph node dissection may still be warranted in Merkel cell carcinoma (MCC) patients with head and neck primaries because of the complex and unpredictable nature of lymphatic drainage patterns in these areas. The best conclusion at this point is that sentinal node biopsy may allow for more selective lymphadenectomy and may help determine the need for elective radiotherapy to the proper nodal basins.

The role of adjuvant chemotherapy remains unresolved. Palliative chemotherapy is often used for unresectable or recurrent disease. No prospective randomized, case-controlled phase III studies exist to clearly define the role of chemotherapy in the treatment of Merkel cell carcinoma (MCC). Recently, the National Institutes of Health approved a phase II trial of imatinib mesylate (Gleevac) in treating metastatic or unresectable Merkel cell carcinoma (MCC).