Adjuvant Radiation Therapy Is Associated With Improved Survival in Merkel Cell Carcinoma of the Skin

Pablo Mojica, David Smith, Joshua D.I. Ellenhorn

Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1043-1047
Purpose: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy. Because of the absence of randomized studies, the real benefit of adjuvant radiation therapy in MCC is unclear. The aim of this study was to better define the role of adjuvant radiation therapy in the management of MCC.

Methods: The Surveillance, Epidemiology, and End Results (SEER) survey from the National Cancer Institute was queried from 1973 through 2002. Retrospective analysis was performed. The end point of the study was overall survival.

Results: There were 1,665 cases of MCC in the SEER registry. Presentation by stage were 55% stage I, 31% stage II, and 6% stage III. Eight percent of the cases could not be staged because of incomplete data. Surgical intervention was a component of therapy in 89% of the cases (n = 1,487). The median survival for the entire cohort was 49 months, and median follow-up was 40 months. Adjuvant radiation was a component of therapy in 40% of the surgical cases. The median survival for those patients receiving adjuvant radiation therapy was 63 months compared with 45 months for those treated without adjuvant radiation. The use of radiation was associated with an improved survival for patients with all sizes of tumors, but the improvement with radiation use was particularly prominent when analyzing those patients with primary lesions larger than 2 cm.

MCC is a relatively rare, but aggressive, cutaneous malignant tumor. The incidence of MCC appears to be increasing from a rate of 0.15 cases per 100,000 in 1986 to 0.44 cases per 100,000 in 2001. It is associated with a high rate of local failure, regional recurrence, and distant metastases. The overall recurrence rate ranges from 50% to 79%, most often manifesting as local or locoregional recurrence. In addition, MCC is a highly radiosensitive tumor, and small retrospective studies have suggested an association between the use of adjuvant radiotherapy and reduced recurrence risk. Unfortunately, there have been no prospective randomized clinical trials of adjuvant therapy, and the management of MCC remains controversial. The mainstay of therapy is surgical resection, but optimal resection margins are also controversial, with some investigators suggesting that wide resection margins of 3 cm or more are needed to improve local control.The high local and regional recurrence rate, along with its radiosensitive nature, provide a rationale for the use of adjuvant radiation therapy as a component of the multimodality therapy for MCC.

Morrison  investigated the role of adjuvant radiation therapy after surgery in 45 patients. They reported a decrease in locoregional recurrence rate from 89% with surgery alone to 41% with the use of adjuvant radiation therapy (50 to 55 Gy). In addition, Meeuwissen  analyzed the use of radiation therapy in the adjuvant setting. They reported, in a cohort of 38 patients, an absolute decrease of 70% in locoregional recurrence rate with the use of radiation therapy after surgery. More recently,  reported their experience in 31 patients with MCC. Locoregional control improved, and recurrence rate dropped from 36% for surgery alone to a 6% recurrence rate with the addition of adjuvant radiation therapy. In addition, Eng reported on a cohort of 88 patients demonstrating a reduction in locoregional recurrence from 52.7% in the surgery-alone group to 32.5% in the surgery plus adjuvant radiation group. Most of the patients who received radiation in these studies underwent radiation therapy to both the primary site and regional lymph node basins, and all of these studies support the use of adjuvant radiation therapy to address both the primary site and the regional nodal basin. However, the use of adjuvant radiation therapy for MCC has been challenged by others. Allen reported their experience in MCC in a cohort of 251 patients. The use of adjuvant radiation therapy was not associated with an improved local control (P = .76). Unfortunately, in that study, only 17% of the patients received adjuvant radiation therapy, and this small number of patients may reflect an underpowered study. It is important to point out that, in an institution with a high number of cases, surgeons may have more experience treating this disease, which may influence the treatment outcome. The effect of adjuvant radiation therapy on survival has not been adequately analyzed in prior reports.

The present study demonstrated a positive association between adjuvant radiation therapy and overall survival. This association remained statistically significant on multivariate analysis. The overall median survival for the entire surgical cohort in the SEER data set was 49 months, with an improvement in the overall median survival from 45 months to 63 months associated with the use of adjuvant radiation therapy. Subgroup analysis demonstrated that the larger the tumor, the greater the improvement in overall survival associated with the use of adjuvant radiation therapy. The association of adjuvant radiation therapy and improved overall median survival for tumor size less than 1 cm is marginally significant, so the use of radiation in this patient population should be individualized, taking into consideration tumor characteristics, staging, and patient factors.

There are several limitations to the present study. The SEER database does not report on completeness of resection, and the margin status of resections is unknown. In addition, the number of cases in which lymph node dissection was performed is small, precluding meaningful conclusions as to the necessity of elective lymph node treatment. The number of patients who completed their adjuvant therapy is unknown, and there are no details as to treatment fields or dosages. The SEER database provides no information as to whether chemotherapy was administered, and we cannot make conclusions regarding the impact of chemotherapy in MCC. One of the greatest limitations of the database is the lack of information regarding recurrence. In addition, the average age of the patients who received adjuvant radiation therapy was younger that that of the patients who did not receive radiation. This raises the possibility of bias toward better postoperative performance status in those patients treated with adjuvant radiation therapy. Despite theses limitations, the data support the continued development of adjuvant radiation therapy for MCC, particularly because of the high local and regional recurrence rate after surgery alone.

In conclusion, MCC is a rare skin cancer with a high rate of local failure, regional recurrence, distant metastases, and death. The use of adjuvant radiation therapy after cancer-directed surgery is associated with improved survival, particularly in larger tumors.