Abstract: Although cytotoxic chemotherapy has been used often in the management of Merkel cell carcinoma (MCC), its benefit remains uncertain. Despite being considered a chemosensitive disease, the duration of response is generally short, and the survival benefit is unclear. With the recent FDA approval of the anti-programmed cell death ligand 1 (PD-L1) antibody avelumab for patients with advanced MCC and the limited and controversial data on chemotherapy, it is important to put in perspective whether conventional chemotherapy should remain an option for these patients. Here, we review the evidence and controversies around chemotherapy in MCC as well as two recent studies on immunotherapy that changed the treatment paradigm for this disease.
Keywords: Merkel cell carcinoma, chemotherapy, immunotherapy, review, future

INTRODUCTION

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy managed primarily with surgery and radiation therapy, despite its high metastatic potential.1

Approximately half of the patients who present with locally advanced disease die of recurrence or metastasis.2 The highest risk of recurrence is within the first 2 years following treatment, with most recurrences happening outside the radiation treatment fields, causing some to consider MCC a systemic disease regardless of its stage at presentation.1,3 MCC is known to be a chemosensitive disease, with reported response rates as high as 60%–75%.4 Commonly used agents include platinum, etoposide, cyclophosphamide, vincristine, doxorubicin, and topotecan, alone or in combination.4,5 Chemotherapy is generally used for the treatment of local and/or regional recurrence4 or distant disease,5 although it is often given in the adjuvant setting – despite unclear survival benefit.3,6 A single-institution, retrospective study of 62 patients with metastatic MCC who received first- and second-line chemotherapy reported a response rate of 55% and 23% and a median progression-free survival of 94 and 61 days among patients, respectively, and a median overall survival of only 9.5 months.5 The relatively short duration of response seen in the metastatic setting, significant treatment-related toxicities, and concerns regarding immunosuppression cause many to consider chemotherapy as the “last resort” for these patients and underlines the urgent need for enhanced treatment options for this disease.4,5

Main evidence and controversies of chemotherapy in the adjuvant treatment of MCC

Interpretation of studies on the use of adjuvant chemotherapy in MCC is challenging due to the lack of prospective randomized trials, limited experience, different chemotherapy regimens used, heterogeneous patient population, small sample size, and short follow-up.

To date, only two prospective trials have evaluated the role of chemotherapy in the adjuvant setting. The first study was a Phase II trial of synchronous chemoradiation therapy in high-risk MCC patients (TROG 96:07) that was conducted by the Trans-Tasman Radiation Oncology Group.7 High risk was defined as primary tumors >1 cm in size, recurrence following initial surgery, gross residual disease after surgery, or occult primary with nodal involvement. Wide surgical clearance of the primary site was not required nor recommended, and it was not a prerequisite to have nodal disease resected or positive margins re-excised. Radiotherapy was given for 5 weeks, with combination chemotherapy consisting of carboplatin and etoposide administered during weeks 1 and 4 of radiotherapy and at weeks 7 and 10. Fifty-three patients were enrolled: 12 (23%) patients presented with recurrence after prior therapy; 13 (25%) had unknown primary disease; and 33 (62%) had nodal disease. Fifteen (28%) patients received chemoradiotherapy as definitive therapy. Forty-six (87%) patients received all four doses of chemotherapy. Grade 3–4 skin reactions and febrile neutropenia occurred in 64% and 35% of patients, respectively. No treatment-related deaths occurred. The 3-year overall survival was 76% (83% for occult primary and 74% for known primary disease); relapse-free survival was 65%; locoregional control was 75% (91% for occult primary and 70% for known primary disease); and distant control was 76% (91% for occult primary and 56% for known primary disease). Locoregional failure at the primary site, in-transit areas, or draining nodes occurred in 9 (17%) of the 53 patients; 7 in the absence of distant disease. Patients with occult primary disease were considered high-risk patients and eligible for this trial, and had a better prognosis in comparison with those with known primary disease. The excellent outcome seen in the unknown primary MCC group could be attributed, at least in part, to the chemotherapy, but the lower distant control seen in the known primary disease group argues against a chemotherapy effect. Moreover, other studies have demonstrated a better outcome for patients with unknown primary MCC, regardless of whether chemotherapy was administered.8,9

In an attempt to better clarify the effect of chemotherapy in the adjuvant setting, Poulsen et al retrospectively compared the data of patients with known primary MCC from the TROG 96:07 study with the results of patients with known primary MCC from the Queensland Radium Institute database who would have been otherwise eligible to participate in the TROG 96:07 study, but were treated without chemotherapy. The patients selected from the database had no evidence of disease beyond regional nodes and had high risk of recurrence (primary size >1 cm, involved nodes, recurrence after initial surgery, or gross residual disease after surgery).10 Of a total of 102 patients, 40 were treated with chemotherapy as part of the TROG 96:07, and 62 were treated without chemotherapy in the historic control group. Although cancer-related and cancer-unrelated deaths – as well as recurrences in locoregional and distant sites – were lower in the chemotherapy group, no statistically significant difference was detected in disease-specific survival, local and distant control, and overall survival (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.34–1.2; p=0.16) in multivariate analysis between the groups. The authors suggested the small number of patients, in addition to the large imbalance in measured and possibly unmeasured covariates, as possible explanations for this lack of difference between the groups.

A second prospective study was initiated in order to decrease the risk of neutropenic fever seen in the TROG 96:07 trial. This Australian study was launched utilizing weekly carboplatin concurrently with radiotherapy, followed by three cycles of adjuvant carboplatin and etoposide combination for local or locally advanced, high-risk MCC.11 High risk was defined as previously described. Eighteen patients (14 with known primary) were enrolled. No patient developed a relapse in the primary site, but in-transit recurrences developed in one patient, nodal metastasis in four (only one within the radiation field), and distant relapse in three patients. No treatment-related deaths occurred. Grade 3 skin and neutrophil toxicities occurred in 23% and 25% of patients, respectively, in contrast to the 65% and 57% seen in the TROG 96:07, respectively. In addition, weekly carboplatin did not appear to have a detrimental effect on tumor control, suggesting it may be a better regimen if concurrent chemoradiation therapy is planned.