Elsevier

The Lancet Oncology

Volume 13, Issue 6, June 2012, Pages 589-597
The Lancet Oncology

Articles
Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial

https://doi.org/10.1016/S1470-2045(12)70138-9Get rights and content

Summary

Background

The use of radiotherapy after therapeutic lymphadenectomy for patients with melanoma at high risk of further lymph-node field and distant recurrence is controversial. Decisions for radiotherapy in this setting are made on the basis of retrospective, non-randomised studies. We did this randomised trial to assess the effect of adjuvant radiotherapy on lymph-node field control in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes.

Methods

This randomised controlled trial included patients from 16 hospitals in Australia, New Zealand, the Netherlands, and Brazil. To be eligible for this trial, patients had to be at high risk of lymph-node field relapse, judged on the basis of number of nodes involved, extranodal spread, and maximum size of involved nodes. After lymphadenectomy, randomisation was done centrally by computer and patients assigned by telephone in a ratio of 1:1 to receive adjuvant radiotherapy of 48 Gy in 20 fractions or observation, with institution, lymph-node field, number of involved nodes, maximum node diameter, and extent of extranodal spread as minimisation factors. Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation. The primary endpoint was lymph-node field relapse (as a first relapse), analysed for all eligible patients. The study is registered at ClinicalTrials.gov, number NCT00287196. The trial is now closed and follow-up discontinued.

Findings

123 patients were randomly allocated to the adjuvant radiotherapy group and 127 to the observation group between March 20, 2002, and Sept 21, 2007. Two patients withdrew consent and 31 had a major eligibility infringement as decided by the independent data monitoring committee, resulting in 217 eligible for the primary analysis (109 in the adjuvant radiotherapy group and 108 in the observation group). Median follow-up was 40 months (IQR 27–55). Risk of lymph-node field relapse was significantly reduced in the adjuvant radiotherapy group compared with the observation group (20 relapses in the radiotherapy group vs 34 in the observation group, hazard ratio [HR] 0·56, 95% CI 0·32–0·98; p=0·041), but no differences were noted for relapse-free survival (70 vs 73 events, HR 0·91, 95% CI 0·65–1·26; p=0·56) or overall survival (59 vs 47 deaths, HR 1·37, 95% CI 0·94–2·01; p=0·12). The most common grade 3 and 4 adverse events were seroma (nine in the radiotherapy group vs 11 in the observation group), radiation dermatitis (19 in the radiotherapy group), and wound infection (three in the radiotherapy group vs seven in the observation group).

Interpretation

Adjuvant radiotherapy improves lymph-node field control in patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for metastatic melanoma. Adjuvant radiotherapy should be discussed with patients at high risk of relapse after lymphadenectomy.

Funding

National Health and Medical Research Council of Australia, Cancer Australia, Melanoma Institute Australia, Cancer Council of South Australia.

Introduction

Standard treatment protocols for many solid tumours include adjuvant radiotherapy on the basis of data that show improved local control and, in some situations, improved survival. For primary cutaneous melanoma, the commonest and usually first site of recurrence after definitive excision of the primary tumour is in the draining lymph-node field. After therapeutic lymphadenectomy for isolated lymph-node field relapse, patients with substantial disease burden in the regional lymph-node field have a high risk of recurrence,1, 2, 3 which can cause morbidity including pain, ulceration, malodour, lymphoedema, and impaired function, particularly in the leg. Further lymph-node field relapse is predicted by extranodal spread of melanoma, increased number of tumour-positive lymph nodes, and increasing size of involved nodes.4, 5, 6 The use of adjuvant radiotherapy after lymphadenectomy to reduce the risk of further relapse is controversial. In many centres it is recommended in patients considered to be at high risk of further relapse; however, evidence from randomised studies is scarce. In 1993, the Radiation Therapy Oncology Group initiated a randomised trial of post-operative adjuvant radiotherapy (RTOG 93.02), but the trial was halted after failure to accrue sufficient patients, with no results reported. Some retrospective single institution studies and several reviews suggest that radiotherapy after therapeutic lymphadenectomy improves lymph-node field control; however, the effect of radiotherapy on survival is much less clear.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19

In 1996, the Trans-Tasman Radiation Oncology Group (TROG) initiated a phase 2 trial20 (TROG 96.06) of adjuvant radiotherapy for melanoma patients with completely resected lymph-node disease judged to be at substantial risk of further melanoma relapse. Regional control was good, with few toxic effects.20, 21

With the same radiotherapy regimen as TROG 96.06, we did a randomised trial to compare adjuvant radiotherapy with observation alone in patients at high risk of lymph-node field relapse who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes. The study was started in 2002, by the Australian and New Zealand Melanoma Trials Group and TROG (ANZMTG 01.02/TROG 02.01).

Section snippets

Patients

Patients from 16 hospitals in Australia, four in New Zealand, one in the Netherlands, and one in Brazil were considered for inclusion. Patients were eligible if they had palpable metastatic lymph-node field disease; had a complete cervical, axillary, or inguinal lymphadenectomy; were at high risk of further lymph-node field relapse; had an ECOG performance status of 0 or 1; were aged 18 years or older; had a life expectancy in the absence of melanoma of 2 years or more; were staged (by CT scan

Results

From March 20, 2002, to Sept 21, 2007, 250 patients from 16 institutions (six did not accrue any patients) in Australia (222 patients), New Zealand (14 patients), the Netherlands (12 patients), and Brazil (two patients) were randomly assigned. The accrual rate (average 3·7 patients per month) was generally uniform throughout the accrual period. Two patients (one from each group) withdrew consent soon after randomisation and were excluded from all analyses (figure 1). The intention-to-treat

Discussion

The results of our study suggest that the use of adjuvant radiotherapy after complete surgical resection for isolated lymph-node field melanoma relapse in patients at high risk of relapse substantially reduced the risk of further lymph-node field relapse, although there was no effect on overall survival. As used in this trial, adjuvant radiotherapy was associated with acceptable early toxic effects.

The first study to investigate the role of adjuvant radiotherapy in melanoma patients with

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