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Excision margins for melanomas: how wide is enough?

2016; Elsevier BV; Volume: 17; Issue: 2 Linguagem: Inglês

10.1016/s1470-2045(15)00556-2

1474-5488

Marc Moncrieff,

CAR-T cell therapy research

The main aim of surgery in treating any cancer is to completely excise the tumour, thereby preventing local recurrence. In the case of melanoma, the purpose of a wide excision is to remove local micrometastases and otherwise phenotypically normal tissue that might be harbouring genotypically abnormal cells located in either the surrounding cutis or superficial lymphatics, while at the same time trying to prevent unacceptable functional and cosmetic harm to the patient as a result. In The Lancet Oncology, Andrew Hayes and colleagues1Hayes AJ Maynard L Coombes G et al.the Scottish Cancer Therapy NetworkWide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial.Lancet Oncol. 2016; (published online Jan 11.)http://dx.doi.org/10.1016/S1470-2045(15)00482-9Summary Full Text Full Text PDF Scopus (93) Google Scholar report the long term follow-up data from the UK excision margins trial,4Thomas JM Newton-Bishop J A'Hern R et al.Excision margins in high risk malignant melanoma.N Engl J Med. 2004; 350: 757-766Crossref PubMed Scopus (379) Google Scholar which started in 1993. The original work has been included in meta-analyses, and the data have been key in producing international guidance on the surgical management of melanoma. The latest analysis of the data1Hayes AJ Maynard L Coombes G et al.the Scottish Cancer Therapy NetworkWide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial.Lancet Oncol. 2016; (published online Jan 11.)http://dx.doi.org/10.1016/S1470-2045(15)00482-9Summary Full Text Full Text PDF Scopus (93) Google Scholar suggests that the narrower excision margin of 1 cm is associated with worse disease-specific survival, estimated as an absolute difference of 5·95% (95% CI −0·54 to 12·44) at 10 years, compared with that in patients who had the wider 3 cm excision margin at a median follow-up of 8·8 years: (unadjusted hazard ratio [HR] 1·24 [95% CI 1·01–1·53], p=0·041). These data are important because they seem to contrast with findings from five other randomised trials suggesting that narrow margins around melanomas (1 cm or 2 cm) are just as safe as wide ones (3 cm, 4 cm, or 5 cm).2Sladden MJ Balch C Barzilai DA et al.Surgical excision margins for primary cutaneous melanoma.Cochrane Database Syst Rev. 2009; 4 (CD004835.)Google Scholar Currently, only the UK national guidelines3Marsden JR Newton-Bishop JA Burrows L et al.Revised UK guidelines for the management of cutaneous melanoma 2010.J Plast Reconstr Aesthetic Surg. 2010; 63: 1401-1419Summary Full Text Full Text PDF PubMed Scopus (109) Google Scholar continue to recommend 3 cm margins around thicker primary melanomas, compared with guidelines from other countries that recommend 2 cm as the maximum margin. Hayes and colleagues propose that the findings in their long-term analysis are linked directly to their previous finding of increased locoregional recurrence associated with the narrower 1 cm excision margin compared with the 3 cm excision margin.4Thomas JM Newton-Bishop J A'Hern R et al.Excision margins in high risk malignant melanoma.N Engl J Med. 2004; 350: 757-766Crossref PubMed Scopus (379) Google Scholar However, in both surgical groups, the incidence of nodal recurrence outweighed the incidence of local recurrence by at least 5 to 1. In view of the findings of the MSLT-1 study,5Morton DL Thompson JF Cochran AJ et al.Final report of sentinel-node biopsy versus nodal observation in melanoma.N Engl J Med. 2014; 370: 599-609Crossref PubMed Scopus (1031) Google Scholar in which the incidence of sentinel node positivity matched the number of nodal recurrences, especially for thick melanomas, most of these nodal metastases would probably have been detected by sentinel-node biopsy, if it had been done at the time of the intervention. Accordingly, a plausible alternative explanation is that the excess nodal disease in the narrow margin group was indicative of poor prognostic disease before the intervention, rather than resulting from the narrow margin intervention itself. The overall recurrence data, including data for in-transit metastases, from the primary analysis4Thomas JM Newton-Bishop J A'Hern R et al.Excision margins in high risk malignant melanoma.N Engl J Med. 2004; 350: 757-766Crossref PubMed Scopus (379) Google Scholar were remarkably similar between the 1 cm and 3 cm groups (5·7% vs 4·7%). However, when analysed as a specific secondary endpoint, the difference in local recurrence between the groups was greater, although not significantly (8·2% vs 5·6%; HR 1·51 [95% CI 0·91–2·51]; p=0·1).4Thomas JM Newton-Bishop J A'Hern R et al.Excision margins in high risk malignant melanoma.N Engl J Med. 2004; 350: 757-766Crossref PubMed Scopus (379) Google Scholar Since 2004, it has become clear that the presence of microsatellites—representing microscopic, discontiguous, intralymphatic extensions of melanoma directly adjacent to the primary tumour—is a poor prognostic indicator for melanoma, and is now classified as stage III disease.6Balch CM Gershenwald JE Soong SJ et al.Final version of 2009 AJCC melanoma staging and classification.J Clin Oncol. 2009; 27: 6199-6206Crossref PubMed Scopus (3726) Google Scholar Whether an excess of microsatellites was present in the 1 cm group before or at randomisation in the present study is unclear, because this information was not included in the standard synoptic report at the time. Nevertheless, the evidence could be signalling that the 1 cm excision margin might be inadequate to deal with microsatellites in particular. Data from the recent Scandinavian wide excision trial7Gillgren P Drzewiecki KT Niin M et al.2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: a randomised, multicentre trial.Lancet. 2011; 378: 1635-1642Summary Full Text Full Text PDF PubMed Scopus (146) Google Scholar is consistent with this notion, because local recurrence was higher in the narrow margin group (2 cm) than in the wide margin group (4 cm), although this was not significant. Data from a large, retrospective study investigating risk factors for locoregional recurrences8Read RL Haydu L Saw RPM et al.In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy.Ann Surg Oncol. 2015; 22: 475-481Crossref PubMed Scopus (107) Google Scholar have suggested that in-transit metastases and local recurrences are associated with an increased incidence of subsequent regional nodal relapse, despite an initially negative sentinel node. In summary, the implication of Hayes and colleagues' study is that high-risk melanoma phenotypes might be unmasked by a narrower, 1 cm wide-excision margin around tumours and these risks could manifest as clinically detectable local or regional recurrences (or both) in follow-up. Closer inspection of the data, however, suggests that this subgroup of patients is small and that most patients could be safely managed without creating 4–6 cm wide excision defects. A multinational, phase 3 clinical trial in progress aims to confirm this (NCT02385214). Accordingly, clinicians' efforts might be supported by the identification of biomarkers to recognise the high-risk minority of patients, especially those with a microscopic locoregional extension at the time of diagnosis of their primary melanoma. These patients might benefit from a wider, elective excision margin for their melanoma, or indeed, adjuvant therapies that might become the standard of care in the near future. I declare no competing interests. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trialOur findings suggest that a 1 cm excision margin is inadequate for cutaneous melanoma with Breslow thickness greater than 2 mm on the trunk and limbs. Current guidelines advise a 2 cm margin for melanomas greater than 2 mm in thickness but only a 1 cm margin for thinner melanomas. The adequacy of a 1 cm margin for thinner melanomas with poor prognostic features should be addressed in future randomised studies. Full-Text PDF Open Access