Elsevier

The Lancet

Volume 378, Issue 9803, 5–11 November 2011, Pages 1635-1642
The Lancet

Articles
2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: a randomised, multicentre trial

https://doi.org/10.1016/S0140-6736(11)61546-8Get rights and content

Summary

Background

Optimum surgical resection margins for patients with clinical stage IIA–C cutaneous melanoma thicker than 2 mm are controversial. The aim of the study was to test whether survival was different for a wide local excision margin of 2 cm compared with a 4-cm excision margin.

Methods

We undertook a randomised controlled trial in nine European centres. Patients with cutaneous melanoma thicker than 2 mm, at clinical stage IIA–C, were allocated to have either a 2-cm or a 4-cm surgical resection margin. Patients were randomised in a 1:1 allocation to one of the two groups and stratified by geographic region. Randomisation was done by sealed envelope or by computer generated lists with permuted blocks. Our primary endpoint was overall survival. The trial was not masked at any stage. Analyses were by intention to treat. Adverse events were not systematically recorded. The study is registered with ClinicalTrials.gov, number NCT01183936.

Findings

936 patients were enrolled from Jan 22, 1992, to May 19, 2004; 465 were randomly allocated to treatment with a 2-cm resection margin, and 471 to receive treatment with a 4-cm resection margin. One patient in each group was lost to follow-up but included in the analysis. After a median follow-up of 6·7 years (IQR 4·3–9·5) 181 patients in the 2-cm margin group and 177 in the 4-cm group had died (hazard ratio 1·05, 95% CI 0·85–1·29; p=0.64). 5-year overall survival was 65% (95% CI 60–69) in the 2-cm group and 65% (40–70) in the 4-cm group (p=0·69).

Interpretation

Our findings suggest that a 2-cm resection margin is sufficient and safe for patients with cutaneous melanoma thicker than 2 mm.

Funding

Swedish Cancer Society and Stockholm Cancer Society.

Introduction

The incidence of cutaneous melanoma is increasing in Scandinavia and other countries with predominantly white populations. In Sweden the average increase is 4·1% per year for men and 4·2% per year for women.1 Furthermore, the median age of patients diagnosed with a cutaneous melanoma is low compared with other cancers.2, 3 Deaths due to cutaneous melanoma have also increased in most light-skinned populations worldwide in the past few decades.4, 5 In the USA, cutaneous melanoma is the second greatest cause of lost productive years owing to cancer.6, 7

Surgical resection margins for patients with localised cutaneous melanoma thicker than 2 mm (T3–T4, N0, M0; American Joint Committee on Cancer system stage IIA–IIC) are still controversial.8 Surgery is the key treatment for patients with localised cutaneous melanoma, and the standard procedure is removal of the tumour with a safety margin from the edge of the tumour border. A trade-off exists between a wide excision, with consequent surgical difficulties, and the relapse-risk with a narrow excision, which could compromise disease-free survival or, worse, overall survival. Wide excisions might also lead to bad cosmetic results, lymphoedema, long hospital inpatient stay, frequent need for skin grafts, or complicated skin flap reconstructions. Historically, cutaneous melanoma has been excised with wide resection margins of 5 cm (sometimes extended to 10 cm towards the local lymph node basin). This treatment policy emerged from a recommendation by Handley in 1907 based on the findings of one autopsy.9 Not until more than 60 years later was the wide-excision policy questioned10 but clinical practice did not change until the late 1980s, when studies suggested that narrow excision margins might be appropriate for thin cutaneous melanomas.10 This finding was supported by subsequent data from randomised controlled trials.11, 12, 13, 14

In 1992—when our trial was started—data on optimum surgical margins for patients with cutaneous melanomas thicker than 2 mm were insufficient, and this uncertainty continues. Authors of a Cochrane meta-analysis15 concluded that the evidence on which to base a recommendation of surgical resection margin size for patients with thick tumours is weak. Most randomised controlled trials have generated data about treatment of patients with relatively thin tumours; the Intergroup Melanoma Surgical Trial has reported data for patients treated for intermediately thick cutaneous melanomas (1–4 mm),16, 17, 18 but most patients had tumours thinner than 2 mm. Only one randomised controlled trial has included patients with cutaneous melanoma thicker than 2 mm, comparing a 1-cm with a 3-cm excision margin.19 In Thomas and colleagues' trial,19 900 patients were randomly assigned and the study showed no statistically significant difference in the rate of local recurrence or in overall survival between the two groups, although the 1-cm margin group had more combined locoregional recurrences (p=0·05). These data do not lend support to the use of margins of 2-cm versus 4-cm.

Overall, evidence from randomised controlled trials is inconclusive in identifying the optimum excision margin for patients with cutaneous melanoma thicker than 2 mm. We aimed to test whether overall survival differs with 2-cm and 4-cm excision margins.

Section snippets

Patients

This trial was launched by the Swedish Melanoma Study Group in cooperation with the Danish Melanoma Group. Patients were enrolled between January, 1992 and May, 2004. Only patients 75 years or younger with a primary cutaneous melanoma thicker than 2 mm and with clinically localised disease on the trunk or upper or lower extremities were eligible. No patients who underwent surgical nodal staging before randomisation were included. We excluded patients with cutaneous melanoma of the hands, foot,

Results

Figure 1 shows the trial profile, and table 1 shows baseline characteristics. About 95% of patients approached agreed to take part in the trial. The median age of patients in the 4-cm group was slightly higher than in the 2-cm group. Median tumour thickness was the same in both groups.

Protocol deviations occurred in 145 (15%) of included patients (table 2). Patients who did not meet inclusion criteria after randomisation were not excluded from the study. The most common deviation was definitive

Discussion

We report no significant difference in overall survival, or in the risk of recurrence or death due to melanoma, between 2-cm and 4-cm surgical excision margins for cutaneous melanoma more than 2-mm thick. Furthermore, long-term follow-up of the Swedish patients did not reveal any differences in survival between the groups. No randomised controlled trial of equal size has been done comparing surgical excision margins of 2 cm and 4 cm for patients with cutaneous melanoma thicker than 2 mm (panel

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