Radiotherapy and Conservative Surgery For Merkel Cell Carcinoma - The British Columbia Cancer Agency Experience Poster No.: RO-0003 Congress: RANZCR FRO 2012 Type: Scientific Exhibit Authors: C. Harrington, W. Kwan Keywords: Neoplasia, Surgery, Radiation therapy / Oncology, Soft tissues / Skin, Oncology DOI: 10.1594/ranzcrfro2012/RO-0003 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply RANZCR's endorsement, sponsorship or recommendation of the third party, information, product or service. RANZCR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold RANZCR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies,.ppt slideshows,.doc documents and any other multimedia files are not available in the pdf version of presentations. www.ranzcr.edu.au Page 1 of 14
Purpose MCC is an uncommon neuroendocrine carcinoma of skin that has a propensity to recur after local excision. Lymph node involvement is present at diagnosis clinically in about 25% of patients and microscopically in a further 25% [1]. Tumours frequently occur at sites where wide excision can be disfiguring, and in patients whose comorbidity or frailty makes extensive resection difficult. Published case series of MCC have predominantly focussed on wide surgical excision for the treatment of primary MCC and for clinically involved nodes. At the BCCA a common approach has been more conservative surgery followed by radiotherapy. We present the British Columbia Cancer Agency (BCCA) experience of treating Merkel Cell Carcinoma (MCC) of skin with surgery, adjuvant radiotherapy and definitive radiotherapy (RT). Methods and Materials The BCCA was the sole provider of radiotherapy for the province during the study period. Patients were identified, and treatment details extracted, from the agency database and case records. We performed a retrospective review of patients with stage I-III MCC (AJCC 2010 [2]) treated at the BCCA between 1997 and 2007. Patients were excluded if distant metastases were present at diagnosis, if no follow up information was available or if no curative intent treatment was given. Survival estimates were determined using the Kaplan-Meier method and p values are for the log rank test. Cox regression was used for multivariate analysis. The study had approval from the Regional Ethics Board. Definitions Page 2 of 14
Definitive radiotherapy refers to treatment of macroscopic tumour (after biopsy or remaining after attempted excision). Radiotherapy applied to the surgical bed after excision of macroscopic tumour (including patients with microscopically positive resection margins) was termed adjuvant. Results Baseline Characteristics are listed in table 1. Stage and site distribution was similar to other series [1,3]. Treatment of primary and nodal disease is summarised in table 2. 69% of patients underwent attempted excision of the primary tumour. Positive margins or residual disease were present in at least 49%. Few patients had pathological staging of lymph nodes - 11 underwent node dissection and 6 had a sentinel node biopsy. Radiotherapy details The most common dose fractionation was 50Gy in 20 fractions, and doses were similar in the definitive and adjuvant setting. 30% of patients received <50Gy equivalent in daily 2Gy fractions (EQD2), 58% received 50-60Gy and 12% more than 60Gy. Dose response was observed for definitive RT but not for adjuvant RT Local relapse occurred in 23% of definitive patients after EQD2 <50Gy versus 4.2% after # 50Gy (p = 0.012). Field margins were available for 62% of patients. A margin of 3cm around the primary was most common (26%), 18% had <3cm margin and 18% >3cm. No effect of margin on local control was found. Local control Local and nodal recurrence rates are shown in table 3, and local relapse free survival (LRFS) for all patients in figure 1. Page 3 of 14
Local control was best for surgery plus adjuvant RT (94.7%), and five year LRFS favoured adjuvant RT over surgery alone (93% versus 85% respectively; p = 0.04); (Figure 2). Five year LRFS was 90% after definitive RT to the primary. When should RT follow surgery? 25% of patients with <1cm histological margin recurred locally (4 out of 16); (Table 4). Adjuvant RT reduced local recurrence in this group to 5.3%, but had no effect if the margin was #1cm. Nodal Control Elective nodal RT showed a trend towards reduction in nodal relapse free survival (p=0.07) but had no significant effect on cancer specific or overall survival. Nodal relapse free survival after definitive nodal RT was 75% at 5 years. Of the seven nodal relapses, two were infield, two at field edge, and three were at nodal sites outside the original field. Survival Five year cancer specific survival (CSS) was 77% for all patients and 24% had died from MCC (Table 5, figure 3). Increasing T stage and nodal positivity correlated with poorer relapse free, cancer specific and overall survival. Five year CSS was lower for definitively treated patients (68%), who were also more likely to have higher stage disease. The improvement in LRFS seen for adjuvant RT versus surgery alone did not translate to a difference in CSS (p=0.36) Survival Analysis Factors significantly associated with poorer CSS on univariate analysis include male sex, larger primary tumour diameter, RT duration <14 days or >43 days. Trends to worse CSS were observed in node positive patients (p=0.085) and those with a positive surgical margin (p=0.06). Page 4 of 14
Male sex and node positivity were significant poor prognostic factors on multivariate analysis (p<0.02). Images for this section: Table 2 Page 5 of 14
Table 3 Page 6 of 14
Fig. 1 Page 7 of 14
Fig. 2 Table 4 Page 8 of 14
Table 5 Page 9 of 14
Fig. 3 Page 10 of 14
Table 1 Page 11 of 14
Conclusion Local excision followed by adjuvant radiotherapy achieved excellent local control in the current series, including in patients with microscopic positive margins. This approach should be considered an alternative to wide excision, especially where concerns are present over cosmesis or comorbidity. We found that excision with narrow margins (<1cm) resulted in unsatisfactory local control unless adjuvant RT was added. Definitive radiotherapy also achieved good control, especially at the primary site. Infield or field-edge recurrence after definitive nodal RT occurred in 12%. This series did not find benefit for elective nodal RT (beyond reduction in nodal relapse) but numerous possible confounders exist. Few patients had sentinel node biopsy and its increasing use may help stratify patients who benefit most from node dissection and/or radiotherapy [4]. Overall survival, local recurrence and MCC death rate were similar to other series (Fields, Ghadjar) Prospective studies are needed to optimise management of primary MCC tumours and especially to address nodal disease. Personal Information Corresponding Author: Dr Chris Harrington Oncology dept. Christchurch hospital Private Bag 4710 Christchurch Page 12 of 14
New Zealand chris.harrington@cdhb.health.nz Dr Winkle Kwan British Columbia Cancer Agency Surrey Memorial Hospital 13750 96th Avenue Surrey, BC V3R 0Z7 Canada References [1] Merkel cell carcinoma. In: AJCC Cancer Staging Manual. 7th ed. Edge SB, Byrd DR, Compton CC, et al., eds. New York, NY: Springer, 2010, pp 315-23 [2] Merkel Cell Carcinoma: Prognosis and Treatment of Patients From a Single Institution Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. J Clin Oncol 23:2300-2309. [3] The essential role of radiotherapy in the treatment of Merkel Cell Crcinoma: a study from the rare cancer network Ghadjar P, Kaanders JH, Poortmans P et al. Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 4, e583-e591, 2011 Page 13 of 14
[4] Sentinel Lymph Node Biopsy for Evaluation and Treatment of Patients With Merkel Cell Carcinoma Gupta SG, Wang LC, Peñas PF, Gellenthin M, Lee S, Nghiem P. Arch Dermatol. 2006;142:685-690 Page 14 of 14