Elsevier

The Lancet Oncology

Volume 17, Issue 6, June 2016, Pages 757-767
The Lancet Oncology

Articles
Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial

https://doi.org/10.1016/S1470-2045(16)00141-8Get rights and content

Summary

Background

Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation.

Methods

In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients.

Findings

Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20–54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9–82·1; 55 events) in the observation group and 74·9% (69·5–80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported.

Interpretation

Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller.

Funding

German Cancer Aid.

Introduction

It has been a traditional dogma of surgical oncology that radical surgery results in improved survival. In melanoma surgery, this conviction has been eroded step by step for safety margins in the excision of primary tumours, resulting in smaller excision margins. However, lymph node surgery for patients with primary tumours and intermediate to high risk of recurrence is still under debate.

In two-thirds of patients with melanoma, metastasis mainly develops in the regional lymph node basin, whereas in a third of patients, direct development of distant metastases has been observed. In this context, the concept of elective lymph node dissection was developed.1, 2, 3, 4, 5, 6 In 1992, Morton and colleagues7, 8 proposed sentinel lymph node biopsy as an alternative to elective lymphadenectomy. The major surgery of complete lymph node dissection became restricted to those patients in whom tumour deposits were detected by sentinel lymph node biopsy.

The MSLT-1 trial (NCT00275496) comparing sentinel lymph node biopsy followed by immediate complete lymph node dissection in positive patients with observation only showed no benefit for melanoma-specific survival or distant-metastasis-free survival.9, 10 Particularly, the role of complete lymph node dissection in extending survival in patients with positive sentinel lymph node biopsies remains unclear.9, 10 We designed this randomised multicentre trial to test the hypothesis that complete lymph node dissection in patients with positive sentinel nodes improves survival.

Research in context

Evidence before this study

We did an extensive search of PubMed for studies comparing complete lymph node dissection with observation for patients with melanoma with micrometastases in the sentinel lymph nodes. Search terms were “micrometastases AND SLNB AND CLND AND melanoma”. There were no date or language restrictions to the search. Retrospective, non-randomised studies reported data in patients with melanoma that are in line with our analyses. A prospective, randomised non-inferiority phase 3 trial in patients with breast cancer found no difference in disease-free or overall survival between patients who did and did not have complete lymph node dissection. We also identified a couple of randomised controlled trials comparing elective lymph node dissection with observation in the era before sentinel lymph node biopsy. These studies did not support superiority of elective lymph node dissection compared with observation.

Added value of this study

To our knowledge, this is the first randomised controlled trial comparing complete lymph node dissection and observation in patients with micrometastasis in the sentinel lymph node in melanoma. By contrast with the initial assumption that complete lymph node dissection is superior to observation, no significant difference was found in distant metastasis-free survival, recurrence-free survival, or overall survival with complete lymph node dissection compared with observation. Moreover, the adverse events profile was less favourable for complete lymph node dissection compared with observation.

Implications of all the available evidence

Overall, these findings did not show a benefit of complete lymph node dissection compared with observation in patients with melanoma and micrometastases in the sentinel lymph node. Therefore, complete lymphadenectomy should not be recommended in patients with melanoma with micrometastasis, at least in those with single cells or micrometastases of 1 mm diameter or less, who were the majority of patients in our study.

Section snippets

Study design and patients

DeCOG-SLT is a multicentre, randomised, phase 3 trial comparing survival of sentinel lymph node biopsy positive patients with melanoma with and without complete lymph node dissection. Patients were recruited from 41 German skin cancer centres (appendix, p2,3). Patients eligible for this trial had primary cutaneous melanoma of the torso, arms, or legs and were aged between 18 and 75 years, and had a tumour thickness of at least 1 mm with micrometastasis in the sentinel lymph node, including

Results

Between Jan 1, 2006, and Dec 1, 2014, we screened 5547 patients before they underwent sentinel lymph node biopsy. Of these, 1269 (23%) patients presented with positive sentinel lymph node biopsy (figure 1). 314 patients did not meet the inclusion criteria, 227 refused to be randomly assigned, and for 245 we have no information about the reason for not participating. 483 patients were randomly assigned to either the complete lymph node dissection group (242 patients) or the observation group

Discussion

In this randomised, prospective, multicentre study comparing complete lymph node dissection with observation in sentinel lymph node positive patients with melanoma, we found no survival benefit for the primary endpoint of distant metastasis-free survival, or for recurrence-free survival or overall survival in the complete lymph node dissection group compared with the observation group. Only a slight improvement of disease control in the regional lymph node basin was detected (20 [8%] patients

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