Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma

Merkel Cell Carcinoma (MCC) is an aggressive cutaneous neoplasm with malignant neuroendocrine differentiation[1]. It was first reported by Toker in 1972. It is a rare tumour that predominantly afflicts the elderly white population with a male predominance[2‐9]. MCC has early local invasion, nodal involvement, distant metastases and a high rate of recurrence[10‐13]. There is controversy internationally in the relative roles of surgery and RT in treatment[14]. There have been no completed randomised controlled trials reported in this disease as yet. Treatment regimes are variable. As MCC has been shown to have high radiosensitivity, adjuvant RT (adj RT) is supported by a number of studies[7, 15‐17]. Surgery followed by adj RT to the primary site as well as the lymphatic basin is recommended by some previous studies[8, 18‐22]. Few studies examined the effect of immune status on of MCC[1, 2, 5, 6, 23]. This study is a single institutional retrospective study of consecutive patients with MCC at St Vincent’s and Mater hospitals, both tertiary referral hospitals in Sydney. The aim of this study was to investigate the influence of RT on the local and regional control of MCC lesions and survival of patients with MCC.

Research was carried out in compliance with the Helsinki Declaration and this project was approved by the St Vincent’s Hospital Human Research Ethics Committee. Patients with a histologically proven diagnosis of MCC who presented between January 1996 and June 2007 to the St. Vincent’s and Mater Hospitals, Sydney, Australia were identified by the International Code of Diseases index from medical records database in anatomical pathology, RT and surgical departments.

Patient tumour and treatment characteristics were collected and analysed. Patient factors include age, sex and any history of immunosuppression. Immunosuppressed patients were either six transplant patients [heart (3), lung (2) and kidney (1)] or eight patients that had been on long term steroids. They included seven patients with connective tissue diseases [Ulcerative colitis, Pyoderma gangredorsum, Scleroderma, Myasthenia gravis, Psoriatic arthritis, Rheumatoid arthritis and multiple myeloma] and one patient with long term kidney cancer. Some of these patients also had diabetes mellitus. There were no patients who had diabetes alone without either being a transplant patient or had not been on long term steroids. Tumour factors recorded included tumour site, size, and involvement of regional lymph nodes, distant metastatic disease and overall staging. Treatment characteristics recorded included whether wide local excision (WLE) is used or not, regional dissection, RT to the primary and regional sites and the use of chemotherapy both in the adjuvant and definitive settings.

RT as an important part of the treatment paradigm of MCC is supported by our study. Local recurrence free survival and regional recurrence free survival were significantly increased with the addition of RT to the primary site and regional lymph nodes respectively. The addition of these fields was associated with increased DFS for the whole cohort. However, the addition of RT was not found to influence overall or MCCSS. This may be due to small numbers, but may also be because this group of older patients have significant competing risks of death, and have a disease that metastasises early to distant sites out of the treatment volumes of loco-regional RT.

The relative roles of surgery and RT in MCC are controversial. There are proponents of a predominantly surgical approach while others favour minimal surgery followed by adj RT[3, 8, 25‐27]. Postoperative RT has been strongly recommended by other studies due to its aggressiveness and high risk of recurrence[4, 8, 28, 29] and MCC is known to be highly radiosensitive (Figure7)[30]. In a review done by Medina-Franco et al. which had 1,024 patients, the mean relapse rate with RT was 10% and 53% without (p=.000001)[5]. The average disease-free period for local recurrence was 7.4 months (range, 4–10 months)[5]. Other studies have found adj RT and adjuvant chemotherapy to be associated with better survival rates[13, 31]. Due to the high metastatic potential of MCC, others have suggested systemic therapy and RT rather than radical surgery only[8, 15, 32]. In patients from the Queensland Radium Institute who were treated with surgery only, all of them had loco-regional relapse and disease-free survival rate at 36 months was 0%[18]. A French trial has recently published that RT to lymph node basin showed a low probability for regional recurrence compared with the observation group who had no regional RT[33]. This study was unfortunately terminated early due to inadequate accrual.

Immune status at diagnosis was associated with increased MCCSS and OS on multivariate analysis in our study. This is understandable in a disease that is associated with distant spread in the immune-compromised. Immunosuppression appears to be an important risk factor for MCC[1, 2, 5, 6, 23]. Immunosuppression enhances the development of MCC in patients with human immunodeficiency virus. They have a relative risk of 13.4 for MCC compared to the general population[22, 34]. Studies have shown high risk of developing MCC at a younger age in organ transplantation at presentation[22, 35]. Long-term immunosuppressive therapies such as chemotherapy and steroids are associated with aggressive forms of non-melanoma skin cancers[6, 23].

Our study does add to the field as it represents a collection of patients treated in a uniform fashion with real conclusions being able to be drawn. However it has significant limitations. It is a retrospective single institutional study, with treatments done in an era where newer advances such as PET and SLNBx have not been incorporated, and so the data could be regarded as obsolete. Polyomavirus was not known in the treatment era of this study. The role of polyomavirus in MCC is one of recent findings that may lead to better therapeutics for MCC[15, 36, 37]. Our study suggests that local and regional RT are worthwhile treatments for MCC and stratification for immunosuppression should be factored into any future trial design. The limitations of this study include a small sample size and lack of inclusion of new technologies such as PET, SLNBx, and the knowledge of polyomavirus. Randomised studies are needed to guide management and should include RT as treatment and should stratify for immune status at diagnosis.

This retrospective single institution study of 67 consecutive patients with MCC supports the use of RT to local and regional sites to enhance loco-regional control and hence DFS. RT was not found to increase MCC-specific or overall survival in this disease of older patients that metastasises early to distant sites out of the field of RT. Patients immunocompromised at diagnosis do poorly.