ORIGINAL ARTICLE MERKEL CELL CARCINOMA: IMPROVED OUTCOME WITH ADJUVANT RADIOTHERAPY

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1 ANZ J. Surg. 2005; 75: ORIGINAL ARTICLE ORIGINAL ARTICLE MERKEL CELL CARCINOMA: IMPROVED OUTCOME WITH ADJUVANT RADIOTHERAPY MICHAEL J. VENESS,* LAKMALIE PERERA,* JUNIE MCCOURT,* JENNIFER SHANNON,* T. MICHAEL HUGHES, GARY J. MORGAN* AND VAL GEBSKI* *Head and Neck Cancer Service, Westmead Hospital and Surgical Oncology Service, Westmead Hospital, Sydney, Australia Background: Merkel cell carcinoma is an aggressive primary cutaneous neuroendocrine carcinoma. Patients remain at high risk of locoregional and distant relapse despite treatment. Most studies support the incorporation of locoregional adjuvant radiotherapy in reducing the risk of relapse. Methods: Between 1980 and 2002, 86 patients diagnosed with Merkel cell carcinoma were treated with curative intent at Westmead Hospital, Sydney. Multivariate analysis was performed using Cox regression analysis. Disease-free survival and overall survival was calculated using Kaplan Meier survival curves. Results: Median age at diagnosis was 75 years (range years) in 49 men and 37 women. Median duration of follow up was 31 months (range months). Fifty-one (59%) patients presented with a primary lesion, 19 (22%) with a primary lesion and clinical nodal disease and 16 (19%) with lymph node metastases from an unknown primary. A total of 47 of 86 (55%) relapsed with regional nodal relapse, the commonest site of first relapse. Local relapse was similar for patients undergoing surgery (5/37; 14%) compared with surgery and adjuvant radiotherapy (3/25; 12%). Nodal relapse occurred in 14 of 36 (37%) treated with surgery compared with 7 of 38 (18%) patients treated with surgery and adjuvant radiotherapy. Patients treated with surgery and adjuvant radiotherapy experienced a better median disease free survival compared to those undergoing surgery alone (10.5 months vs 4 months; P < 0.01). The 5-year overall and disease-free survival rate for the entire study population was 47% and 25%, respectively. Twenty-six patients (30%) died as a result of Merkel cell carcinoma. Conclusion: Merkel cell carcinoma is an aggressive skin cancer. The addition of adjuvant radiotherapy markedly improves regional control rates and should be considered best practice. Keywords: Merkel cell carcinoma, neuroendocrine, radiotherapy, skin cancer, small cell carcinoma. Abbreviations: DFS, disease-free survival; MCC, Merkel cell carcinoma; NMSC, non-melanoma skin cancer; OS, overall survival; SEER, Surveillance, Epidemiology, and End-Results; SNB, sentinel node biopsy. INTRODUCTION Australia has the highest annual incidence of non-melanoma skin cancer (NMSC) in the world (approximately 1000/ population and rising). 1 Most lesions (80 90%) arise in the sunexposed head and neck in older patients, with basal cell carcinoma occurring more often than squamous cell carcinoma. 2 Merkel cell carcinoma (MCC) is a rare and aggressive primary neuroendocrine NMSC arising from the basal epidermis and first reported in While the majority of patients with a NMSC are adequately treated and cured by local treatment those diagnosed with MCC have a poor outcome characterized by local and/ or regional and distant relapse. 4 6 Despite a paucity of evidence from controlled trials in MCC there are numerous descriptive studies addressing the issue of treatment and outcome of patients diagnosed with MCC. While many studies have been small case series, 7 9 some centres have reported M. J. Veness MMed (Clin Epi), FRANZCR; L. Perera MB BS, BSc; J. McCourt BA (Psych) Hons; J. Shannon PhD, FRACP; T. M. Hughes FRACS; G. J. Morgan FRACDS, FRACS; V. Gebski BA, Mstat. Correspondence: Dr Michael J. Veness, Radiation Oncologist, Staff Specialist, Department of Radiation Oncology, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia. michael@radonc.wsahs.nsw.gov.au Accepted for publication 3 September larger series that often includes multivariate analysis This later group includes the experience of some Australian centres There is mounting evidence that combined treatment, incorporating adjuvant radiotherapy, confers a better outcome than surgery alone in the majority of patients with MCC. 6,10,12,14,16,17 Despite this, some clinicians still consider surgery alone as adequate treatment, at least in early stage disease. 8,11,18 20 Currently the routine use of adjuvant chemotherapy remains unresolved despite the high risk of distant metastases. 4,5,21 This is a large single institution series of patients with MCC treated with curative intent within the context of a tertiary referral multidisciplinary clinic. The aim of this study is to report on the patterns of relapse following initial treatment, outcome and any predictors for survival. METHODS Between 1980 and 2002 patients diagnosed with MCC were identified from a computer database. Patients with distant metastatic disease at presentation were excluded. All patients were treated with curative intent and assessed in multidisciplinary clinics at Westmead Hospital, Sydney. Patients had to have histological findings consistent with a diagnosis of MCC. We identified 86 patients that fulfilled these criteria. Data on patient demographics, clinical details, tumour details, pathology and treatment were extracted from a prospective database, radiation oncology files, medical records and referring clinicians.

2 276 VENESS ET AL. Statistical analysis Multivariate analysis was performed using Cox regression analysis. 22 The following variables were analysed as potential predictors of survival: age, gender, modality, presence of metastatic nodes, primary location and primary size. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan Meier survival curves. 23 RESULTS Median age at diagnosis was 75 years (range years) in 49 men and 37 women. Median duration of follow up was 31 months (range months). One patient was immunosuppressed (renal transplant). Extent of disease at presentation Fifty-one (59%) patients presented with a primary. Nineteen patients (22%) presented with a primary and clinically involved nodes with the remaining 16 (19%) presenting with lymph node metastases from an unknown primary (Table 1). The most frequently reported primary site was the head and neck (55%), followed by the lower limb (20%), the upper limb (14%) and the trunk (11%). The median tumour size was 12 mm (range 3 44 mm). The most frequent site of nodal metastases were to the parotid or upper neck (14/35), the groin (11/35) and the axilla (6/35). Unknown primary Sixteen patients presented with nodal metastases without an identifiable primary lesion. In these cases the commonest nodal site of metastases were the head and neck (cervical and/or parotid nodes) (10/16) followed by the groin (5/16) and axilla (1/16). In all patients thoracic imaging was performed to exclude metastatic small cell lung cancer as a cause of metastatic spread. Treatment Forty-two (49%) patients were treated with a single modality: 36 (42%) underwent surgery and 6 (7%) received definitive radiotherapy (Table 2). The remaining 44 received combined treatment: 38 (44%) patients underwent surgery followed by adjuvant radiotherapy and five (6%) received chemotherapy in conjunction with surgery and radiotherapy, one patient receiving chemotherapy did not have radiotherapy (Table 3). surgery and chemotherapy. Twenty-seven patients had local excision without treatment to regional lymph nodes. No patient underwent Moh s micrographic surgery. Fifty-six patients had a documented excision margin with 21/56 (38%) reported as clear and 35/56 (62%) reported as either close ( 2 mm) or positive. Twenty-three patients underwent re-excision and all subsequently achieved negative margins. Radiotherapy Six patients received radiotherapy as definitive treatment usually in the setting of advanced disease and/or with medical co-morbidity that precluded surgery. One patient underwent irradiation to the primary, two to the primary and nodes and three to nodes only. Five subsequently relapsed with all but one being a distant relapse. Another 43 received radiotherapy in combination with surgery (38), chemotherapy (1) or both (5). The median radiotherapy dose delivered was 50 Gy (range Gy) in 2 Gy daily fractions. Most patients were treated with either multifield megavoltage photons (42%) (parallel opposed or wedged pair) or a single field technique utilizing moderate energy (9 12 MeV) electrons (46%) with the addition of tissue equivalent (1 1.5 cm) bolus. The remainder received either superficial/orthovoltage photons or a combination of beams. Locoregional radiotherapy fields usually extended 3 5 cm beyond the primary excision site or clinical disease and, where feasible, included first echelon lymph nodes and in-transit lymphatic tissue. Patients with lesions located on the lower limb were occasionally treated with separate fields to the primary site and groin nodes. Table 2. Single modality treatment Modality n (%) Surgery Local excision 27 (31) Local excision + therapeutic nodal dissection 4 (5) Local excision + elective nodal dissection 2 (2) Nodal dissection 3 (4) Radiotherapy Primary 1 (1) Primary + nodes 2 (2) Nodes (unknown primary) 3 (3) Total 42/86 (49) Surgery In total, 80 patients had an operation, either alone (36/80), or in combination with adjuvant locoregional radiotherapy (+/ chemotherapy) (43/80), excluding one patient undergoing Table 1. Extent of disease at presentation Disease site n (%) Primary 51 (59) Primary + nodes 19 (22) Involved nodes with unknown primary 16 (19) Total 86 (100) Table 3. Multimodality treatment Modality n (%) Local Sx + local RTx 5 (6) Local Sx + local and nodal RTx 13 (15) Local Sx + nodal RTx 3 (3) Local and nodal Sx + local and nodal RTx 8 (9) Nodal Sx + nodal RTx 9 (11) Sx + RTx + CTx 5 (6) Sx + CTx 1 (1) Total 44/86 (51) CTx, chemotherapy; RTx, radiotherapy; Sx, surgery.

3 MERKEL CELL CARCINOMA AND ADJUVANT RADIOTHERAPY 277 Chemotherapy Six patients received chemotherapy in combination with either surgery or surgery and radiotherapy. All six received combination chemotherapy with five receiving platinum based combination. In three the chemotherapy was sandwiched following surgery and prior to commencing radiotherapy. Only one received both concurrent and adjuvant chemotherapy. Relapse A majority (47/86; 55%) of patients experienced a relapse. Local, nodal, local + nodal and distant relapse occurred as first sites of relapse in 9 of 86 (10%), 21 of 86 (24%), 1 of 86 (1%) and 16 of 86 (19%), respectively. In the 47 patients experiencing a relapse, median time to local, regional and distant relapse was 3, 6, and 7 months, respectively. Seventeen patients (36%) out of the 47 that relapsed had at least one other documented relapse, most often a distant relapse after nodal failure. Included in the 16 patients developing distant relapse were five patients with in-transit metastases. Local (primary site) relapse was similar for patients undergoing surgery alone to the primary (+/ nodal surgery) (5/37; 14%) compared with local surgery and adjuvant radiotherapy that encompassed the excision site (3/25; 12%) (Table 4). Thirty-four patients had no regional treatment (surgery and/or radiotherapy) and subsequently 11 of 34 (35%) experienced a regional nodal relapse (Table 5). Nodal relapse occurred in 14 of 36 (37%) undergoing surgery alone (includes nine also undergoing nodal dissection) compared with seven of 38 (18%) patients undergoing surgery and adjuvant radiotherapy (all patients received nodal irradiation). Of note, four of seven regional relapses postirradiation occurred just outside a radiotherapy field and usually in the inferior neck beyond the first echelon nodes. Of the 27 patients undergoing local excision, 10 (37%) subsequently developed nodal relapse. In patients with tumours between 5 and 10 mm, 33% developed nodal relapse compared with 50% of patients with tumours >10 mm (Table 6). Univariate On univariate analysis the following variables were associated with OS: gender (M vs F) (P = 0.02), age ( 60 vs >60) (P = 0.13), nodal disease (node negative vs node positive) (P = 0.91), size of lesion ( 10 mm vs >10 mm) (P = 0.16), location of primary lesion (head/neck vs rest) (P = 0.37) and treatment (surgery vs surgery/adjuvant radiotherapy) (P = 0.88). The following variables were associated with DFS: gender (M vs F) (P = 0.06), age ( 60 vs >60) (P = 0.37), disease extent at presentation (node negative vs node positive) (P = 0.2), lesion size ( 10 mm vs >10 mm) (P = 0.98), location of primary (head/ neck vs rest) (P = 0.67) and treatment (surgery vs surgery/ adjuvant radiotherapy) (P = 0.002). Cox regression analysis On multivariate analysis no variables were associated with OS at P < A better DFS was associated with the patients receiving adjuvant radiotherapy (P = 0.08). No other variable predicted for DFS. Survival The 5-year OS and DFS rates for the entire study population were 47% and 25%, respectively (Figs 1,2). Patients treated with surgery and adjuvant radiotherapy (n = 38) experienced a better median DFS compared with those undergoing surgery alone (n = 36) (10.5 months vs 4 months; P < 0.01) (Fig. 3). Twentysix patients (30%) died as a result of MCC. Table 4. Local relapse based on treatment Primary treatment n Local relapse (%) Surgery only 37 5/37 (14%) Surgery + radiotherapy + chemotherapy 5 0/5 Surgery + radiotherapy 25 3/25 (12%) Radiotherapy only 3 1/3 (33%) Unknown primary 16 0/16 Total 86 9/86 (12%) Table 5. Nodal relapse based on treatment Nodal treatment n Nodal relapse (%) No nodal treatment 34 11/34 (35%) Elective nodal dissection 2 0/2 Therapeutic nodal dissection 7 3/7 (43%) Therapeutic nodal dissection + adjuvant 22 3/22 (14%) radiotherapy Elective nodal radiotherapy 16 3/16 (19%) Therapeutic nodal radiotherapy 5 1/5 (20%) Total 86 21/86 (26%) Table 6. Relapse details for patients undergoing local excision (n = 27) Pathological size Nil Local Nodal Local + nodal Distant Total <5 mm mm >10 mm Unknown size Total

4 278 VENESS ET AL. DISCUSSION Fig. 1. Fig. 2. Overall survival curve for all 86 patients. Disease free survival curve for all 86 patients. Fig. 3. Disease free survival in patients treated with surgery and adjuvant radiotherapy (n = 38) compared with those undergoing surgery alone (n = 36) (P < 0.01). MCC is a rare and aggressive skin cancer. Based on the SEER (Surveillance, Epidemiology, and End-Results) database the annual incidence of MCC for whites in the USA is 0.23/ Similar epidemiological data for the Australian setting is lacking but an even higher incidence is possible. In a comprehensive review of the literature published in 2002 in the Journal of Clinical Oncology, Goessling et al. suggested approximately 2000 cases of MCC have been reported. 4 As with other NMSC, sun exposure is a likely causative agent with most lesions arising on the sun-exposed head and neck or extremities. Many institutions, both in Australia and elsewhere, have accumulated data on the presentation, treatment and outcome of patients with MCC. The aggressiveness of MCC is typified by high rates of early (<12 months) local and/or regional relapse (20 80%) and distant failure (10 60%) Cancer specific death occurs in 25 50% 4,5 of patients and those presenting with local disease have the best chance of cure. 7,11,18 Many patients experiencing a local or regional relapse will subsequently die and those with distant metastases, either at presentation or subsequent to initial treatment, are incurable. In our series MCC occurred slightly more in men (58%) with the head and neck the primary site in just over half of all patients (55%). While these findings are in keeping with other series the proportion of patients diagnosed with advanced disease is higher than reported by others. Nodal metastases were present in 40% of our patients at diagnosis. In contrast, Gillenwater et al. reported 11% of patients with nodal metastases at presentation. 6 Similarly, Morrison et al. 17 and Allen et al. 11 documented 17% and 22% of patients, respectively, node positive at presentation. At the time of diagnosis 19% of our patients had metastatic nodes from an unknown primary. This is similar to another Australian study of 80 patients that reported a 16% rate of nodal metastases from an unknown primary. 12 In this latter study from Queensland, 33% presented with nodal involvement, not dissimilar to our 40%. Many studies have reported on prognostic variables in MCC. While studies report patient factors such as age 16,25 and gender 12,25,26 as predictive of outcome, others fail to support this. Many identify tumour (site, size, stage) and treatment (addition of adjuvant therapy) factors as predictive. Pitale et al. analysed 306 cases from the literature and could identify only male gender as an independent predictor of survival. In this study tumour factors, in particular the presence of local or regional recurrence, did not predict survival. 26 The presence of nodal metastases at diagnosis is considered a strong predictor of poor outcome. 11,16,21,25,27 In patients without nodal metastases lesion size has also been shown to predict outcome by some, 11,28 but not by others. 10,19,21 Similarly, the site of MCC (head and neck vs elsewhere) while predictive in some studies, 11,16,25,27 has not been supported by others. 12,19,21 However, the addition of adjuvant radiotherapy has consistently been proven to confer a benefit in reducing both local and regional relapse. 6,8,10,12,14,16,17 Several studies even suggest a survival benefit to the addition of adjuvant radiotherapy 12,16 although others fail to confirm this benefit. 6,8 We report a significant benefit in median DFS to the addition of adjuvant radiotherapy (10.5 months vs 4 months; P < 0.01), although there remained no benefit in OS in this older population who often succumb to co-morbid disease. Despite the aggressive natural history of MCC, and evidence supporting the benefits of adjuvant radiotherapy, there are proponents of local excision as appropriate treatment for patients

5 MERKEL CELL CARCINOMA AND ADJUVANT RADIOTHERAPY 279 without nodal involvement. 8,11,19 Furthermore, some clinicians propose Moh s micrographic surgery 19 as the preferred surgical approach while others take the view that a conventional surgical approach is recommended. 8,11 The definition of an adequate surgical margin in MCC is unclear but margins of 2 3 cm are often recommended. 16,25 However, the location of many lesions, particularly in the head and neck, makes the achievement of 2 3 cm margins often impractical. Consequently many authors report excision margins well below this recommendation. 11,19 The interpretation of many studies, using margins as a predictor of outcome, is often difficult when the contribution of adjuvant radiotherapy is unclear. In our experience it is an uncommon scenario that a small (<5 mm) lesion is removed with wide excision margins (2 3 cm) within acceptable functional and cosmetic constraints, particularly in the head and neck. It is more often the case that lesions are mm in size 10,11,19 similar to a median size of 12 mm in our study, and that wide excision margins (2 3 cm) are not achieved. 6,10,11,14 Kokoska et al. reported a significant difference in local relapse (27% vs 89%; P < 0.01) and 2-year survival (86% vs 28%; P = 0.03) between patients undergoing wide excision ( 2.5 cm) compared to simple excision. 16 The proportion of patients in each group receiving adjuvant radiotherapy was unclear. Gillenwater et al. while not showing any difference in disease control suggested a survival benefit to those with wider surgical margins. 6 Ott et al. reported no patient relapsing locally with excision margins >2 cm compared with seven of 24 relapsing with margins <2 cm although there was no difference in survival between the two groups. 10 The retrospective nature of our study precludes an accurate determination of excision margins in all patients. However, in all cases the aim was to achieve a negative surgical margin that often necessitated re-excision. Local treatment only fails to address the risk of subclinical nodal disease. Gillenwater et al. reported four of nine (44%) nodal relapses in patients with lesions <10 mm. 6 In 27 patients treated with local excision only we report regional relapse occurring in 33% and 50% of patients with lesions 5 10 mm and >10 mm in size, respectively. In a review of the literature of 181 patients undergoing local surgery a total of 83 (46%) experienced nodal relapse. 25 The elective treatment of first echelon lymph nodes may confer a survival benefit. Elective nodal dissection as reported by Allen et al. 11 and Kokoska et al. 16 resulted in improved survival, although one study incorporated adjuvant radiotherapy following surgery. Allen et al. suggested that information gathered by using sentinel node biopsy (SNB) could improve the sensitivity of detecting subclinical nodal metastases. 28 They identified five of 26 (19%) with subclinical nodal metastases and suggest this information is important in the recommendation of adjuvant treatment. The premise presumably being that some patients identified as SNB negative may not warrant further treatment, although this remains untested. We believe the use of SNB could negate the need for elective nodal dissection as a staging procedure. The role of elective irradiation to regional lymph nodes following a negative SNB is unclear. Some authors suggest surgery to both the primary and regional nodes as appropriate treatment in clinically node negative patients, yet the radioresponsiveness of MCC makes the addition of adjuvant locoregional radiotherapy an effective alternative that could negate the potential morbidity of nodal surgery. While elective nodal dissection may provide prognostic data the current usefulness of this information is limited. Since most patients will be recommended locoregional adjuvant radiotherapy the role of routine nodal dissection in clinically node negative patients is unclear. However, in patients with clinically involved nodes, nodal dissection and adjuvant locoregional radiotherapy are recommended. We have demonstrated far better regional control with this multimodality approach (14% vs 43%; Table 5). MCC is a radioresponsive disease with doses of Gy. In some circumstances patients may be treated with definitive radiotherapy and cured. 6,25 In a recent French study nine patients with node negative MCC were treated with radiotherapy alone (median dose 60 Gy) and with a median duration of follow up of 3 years none have relapsed, although three have died from unrelated causes. 29 We also treated 6 patients, most with advanced MCC, using definitive radiotherapy and despite obtaining tumour control most died from subsequent distant relapse. Such cases well illustrate the radiosensitivity of MCC to moderate dose radiotherapy even in the setting of gross disease. Poulsen and Harvey suggested in a review article on MCC published in this Journal that in the case of patients receiving adjuvant radiotherapy surgical margins to achieve a negative margin are usually adequate enough without the requirement to obtain wider (2 3 cm) excision margins. 30 While a few studies report no apparent benefit in local and/or regional control to the addition of adjuvant radiotherapy others report a dramatic improvement, especially in regional relapse, with the addition of adjuvant radiotherapy. Meeuwissen et al. reported a 100% relapse rate (majority regional) in 38 patients treated with surgery alone (local excision in majority) compared with only 29% in those that underwent surgery and adjuvant locoregional radiotherapy (50 in fractions). 12 Similarly, Gillenwater et al. reported on 34 patients treated with wide local excision in which 59% experienced a regional relapse as the first site of relapse compared to a 27% regional relapse rate in 26 patients treated with local surgery and adjuvant radiotherapy (46 66 Gy to primary site and draining lymphatics). 6 Results from the MD Anderson Cancer Center, Texas, also strongly support the addition of adjuvant radiotherapy. In patients treated with surgery alone 33 of 37 experienced local (9/37), local + regional (7/37) or regional relapse (17/37). This compares to five of 12 patients relapsing after surgery and adjuvant radiotherapy (50 55 Gy), including one with a distant failure. 17 In another Australian study 10 of 16 patients treated with surgery experienced a local and/or regional relapse compared to 0 of 11 treated with surgery and adjuvant radiotherapy. 14 In our patients treated with surgery only (including seven with nodal dissections for clinical disease) 37% experienced regional relapse compared with 18% treated with surgery and locoregional adjuvant radiotherapy (median dose 50 Gy). This contrasts with local relapse, which was similar for patients undergoing surgery alone (5/37; 14%) compared with surgery and adjuvant radiotherapy (3/25; 12%). Despite no difference in local relapse in our study, in a large review of 1024 cases of MCC the authors identified 11 series that documented local relapse rates with, and without adjuvant radiotherapy. The mean relapse rate with the addition of radiotherapy was 10% vs 52% without adjuvant radiotherapy (P = ). 31 The routine addition of platinum based adjuvant combination chemotherapy in the treatment of MCC is unclear. MCC is a chemosensitive disease with response rates in the setting of metastatic disease of around 60 70%, including complete responses in 20 30%. 4,5 However, responses are often short lived and patients with distant metastatic MCC usually die within months. There are limited data from studies evaluating the potential benefit of adjuvant chemotherapy in MCC. There were too few patients in our

6 280 VENESS ET AL. study treated with the addition of adjuvant chemotherapy to make any meaningful conclusion. However, a recent Trans Tasman Radiation Oncology Group phase II trial using concurrent and adjuvant combination chemotherapy (etoposide/carboplatin) and locoregional radiotherapy (50 Gy) in high risk MCC patients indicated this to be a well-tolerated regimen with neutropenia the major side-effect. 32 In this landmark prospective study patients needed to have one or more unfavourable feature ( 10 mm primary, nodal disease, residual disease post surgery, surgical recurrence or recurrence outside an irradiated field). The authors reported a 3-year overall survival, local and/or regional control, and distant control rate of 76%, 75% and 76%, respectively. 33 These impressive results, in a group of patients with poor prognostic features, particularly the presence of nodal metastases in 33 (62%) patients, strongly suggests a potential benefit to the addition of combination chemotherapy in patients with unfavourable features. This is all the more impressive considering we report a 5-year OS and DFS of 47% and 25%, respectively, not too dissimilar from the Australian study of Meeuwissen et al. who reported 3 years OS and DFS of 68% and 29%, respectively. 12 In 1988 Bourne and O Rourke reported on 13 patients treated at the Queensland Radium Institute. All but one underwent local surgery and nearly all patients relapsed (eight local and two intransit). Eight patients developed further nodal relapse. Despite limited experience with treating MCC in the 1980s the authors felt that, pending further experience... a recommendation is made for wide excision of the primary site with elective postoperative radiation to both the primary site, the in-transit zone and where practicable the regional lymph nodes. 34 Although our retrospective study has the weaknesses of all similar studies we believe the weight of published evidence strongly supports the addition of adjuvant locoregional radiotherapy in improving the outcome of patients diagnosed with MCC by reducing the rate of local and/or regional relapse. A recent German study of 31 patients has also confirmed a significant improvement in local (6% vs 36%) and regional (19% vs 50%) control and median DFS (32 months vs 9 months; P = 0.023) to those patients receiving adjuvant locoregional radiotherapy. 35 Of note, the number of patients relapsing outside of radiotherapy fields in our study would also suggest that radiation oncologists should consider radiotherapy fields that encompass not just first echelon lymph nodes. Based not only on our data, but also on the accumulated results of others, we would strongly recommend a combined locoregional approach to treating patients diagnosed with MCC. Local treatment alone is associated with a high rate of relapse particularly in regional lymph nodes. It is likely that less radical local excision when combined with adjuvant locoregional radiotherapy (50 55 Gy) is adequate without the need to achieve wide excision (2 3 cm) margins. 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