Elsevier

The Lancet Oncology

Volume 16, Issue 9, September 2015, Pages 1049-1060
The Lancet Oncology

Articles
Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial

https://doi.org/10.1016/S1470-2045(15)00187-4Get rights and content

Summary

Background

Adjuvant radiotherapy is recommended for patients with melanoma after lymphadenectomy. We previously showed this treatment reduced risk of repeat lymph-node field cancer in patients with a high risk of recurrence but had no effect on overall survival. Here, we aim to update the relapse and survival data from that trial and assess quality of life and toxic effects.

Methods

In the ANZMTG 01.02/TROG 02.01 randomised controlled trial, we enrolled patients who had undergone lymphadenectomy for a palpable lymph-node field relapse and were at high risk of recurrence at 16 hospitals (11 in Australia, three in New Zealand, one in Netherlands, and one in Brazil). We randomly assigned patients (1:1) to adjuvant radiotherapy (48 Gy in 20 fractions, given over a maximum of 30 days) or observation, stratified by institution, areas of lymph-node field (parotid and cervical, axilla, or groin), number of involved nodes (≤3 vs >3), maximum involved node diameter (≤4 cm vs >4 cm), and extent of extracapsular extension (none, limited, or extensive). Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation, but participants were unaware of each other's treatment allocation. In this follow-up, we assessed outcomes every 3 months from randomisation for the first 2 years, then every 6 months up to 5 years, then annually. The primary endpoint was lymph-node field relapse as a first relapse, assessed in patients without major eligibility infringements (determined by an independent data monitoring committee). We assessed late adverse effects (occurring >90 days after surgery or start of radiotherapy) with standard criteria in the as-treated population. This study is registered with ClinicalTrials.gov, number NCT00287196.

Findings

Between March 21, 2003, and Nov 15, 2007, we randomly assigned 123 patients to adjuvant radiotherapy (109 eligible for efficacy assessments) and 127 to observation (108 eligible). The final follow-up date was Nov 15, 2011. Median follow-up was 73 months (IQR 61–91). 23 (21%) relapses occurred in the adjuvant radiotherapy group compared with 39 (36%) in the observation group (adjusted hazard ratio [HR] 0·52 [95% CI 0·31–0·88], p=0·023). Overall survival (HR 1·27 [95% CI 0·89–1·79], p=0·21) and relapse-free survival (0·89 [0·65–1·22], p=0·51) did not differ between groups. Minor, long-term toxic effects from radiotherapy (predominantly pain, and fibrosis of the skin or subcutaneous tissue) were common, and 20 (22%) of 90 patients receiving adjuvant radiotherapy developed grade 3–4 toxic effects. 18 (20%) of 90 patients had grade 3 toxic effects, mainly affecting skin (nine [10%] patients) and subcutaneous tissue (six [7%] patients). Over 5 years, a significant increase in lower limb volumes was noted after adjuvant radiotherapy (mean volume ratio 15·0%) compared with observation (7·7%; difference 7·3% [95% CI 1·5–13·1], p=0·014). No significant differences in upper limb volume were noted between groups.

Interpretation

Long-term follow-up supports our previous findings. Adjuvant radiotherapy could be useful for patients for whom lymph-node field control is a major issue, but entry to an adjuvant systemic therapy trial might be a preferable first option. Alternatively, observation, reserving surgery and radiotherapy for a further recurrence, might be an acceptable strategy.

Funding

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

Introduction

The most common site of first relapse in patients with melanoma is in the draining lymph-node field, and in the absence of distant metastases, lymphadenectomy is indicated. Patients with large deposits of tumour in the lymph node, an increasing number of involved lymph nodes, and extracapsular extension of tumour have a high risk of further relapse with associated morbidity including pain, ulceration, discharge, malodour, lymphoedema, and impaired function, especially in the lower limb.1, 2 Most, but not all, retrospective studies have showed that adjuvant radiotherapy reduces lymph-node field relapses but has no effect on survival.3, 4, 5, 6, 7, 8, 9, 10, 11 An attempted trial of adjuvant radiotherapy (RTOG 93.02) was closed early because of insufficient patient accrual, and has not been reported. A randomised study of 58 patients12 showed no effect of adjuvant radiotherapy on survival; however, this trial was underpowered and used outdated radiotherapy techniques. A previous phase 2 trial (TROG 96.06) of adjuvant radiotherapy for patients with melanoma who have completely resected lymph-node disease judged to be at significant risk of further melanoma relapse reported good regional control and limited toxicity. The present randomised, phase 3 study (ANZMTG 01.02 TROG 02.01) of patients assigned to adjuvant radiotherapy or observation only after lymphadenectomy was initiated based on the TROG 96.06 results, and the first results were published in 2012.13, 14, 15

Research in context

Evidence before this study

We did a systematic search of the Cochrane, PubMed, and Medline databases with the terms “melanoma”, “regional recurrence”, and “lymph-node field recurrence”, and the date restrictions 1970–2014. Only retrospective studies were available, and suggested that radiotherapy reduces lymph-node field recurrence but without an effect on survival. No reliable information on quality of life or toxicity of treatment was identified.

Added value of this study

To the best of our knowledge, our study is the first completed randomised trial with the primary endpoint of lymph-node field relapse. We report the final results from a trial of radiotherapy versus observation for patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy. The risk of lymph-node field relapse is significantly reduced, but overall survival is not altered. Patients in the observation group who developed an isolated lymph-node field relapse given surgery and or radiotherapy achieved similar outcomes to patients randomly assigned to radiotherapy. The addition of radiotherapy after lymphadenectomy had negligible effect on quality of life but specific lymph-node field symptoms were more common in patients receiving radiotherapy. Tissue fibrosis was the most common side-effect of radiotherapy and was usually minor in severity. Limb volumes slightly increased after radiotherapy more than after surgery but this was only significant in the lower limbs.

Implications of all the available evidence

Patients at high risk of lymph-node field (and distant) recurrence should be considered for adjuvant systemic therapy studies. Alternatively, adjuvant radiotherapy could be considered, although close observation might be a reasonable option reserving further surgery and radiotherapy if an isolated lymph-node field relapse occurs.

The first analysis13 of the primary endpoint—lymph-node field relapse—showed that patients in the adjuvant radiotherapy group had a significant reduction in the risk of lymph-node field relapse as a site of first relapse (hazard ratio [HR] 0·56) compared with those patients in the observation alone group, but no significant difference in survival. The number of early toxic effects due to radiotherapy was acceptably low. This final report provides updated follow-up analyses of lymph-node field relapse, relapse-free survival, and overall survival, and reports late toxic effects (occurring more than 90 days after surgery or initiation of radiotherapy), lymphoedema, and quality of life data for the first time.

Section snippets

Study design and participants

This study has already been described;13 briefly, we did a randomised, international, multicentre, phase 3 trial in 11 hospitals in Australia, three in New Zealand, one in Netherlands, and one in Brazil. Patients were eligible if they presented with palpable metastatic lymph-node field disease, had undergone a complete cervical, inguinal, or axillary lymphadenectomy, and had no evidence of either previous recurrence or recurrence elsewhere at the time of randomisation. Patients presenting with

Results

As previously described,13 between March 21, 2003, and Nov 15, 2007, we randomly assigned 250 patients to treatment; 123 to adjuvant radiotherapy and 127 to observation (figure 1). Two patients withdrew consent and 31 had a major eligibility infringement, as decided by an independent data monitoring committee, resulting in 109 eligible patients in the adjuvant radiotherapy group and 108 in the observation group. Two patients, both from the observation group, were lost to follow-up after 13 and

Discussion

In this multicentre, randomised controlled study to investigate the role of adjuvant radiotherapy in patients with melanoma with an isolated lymph-node field relapse who are at high risk of further lymph-node field relapse after complete surgical resection, we showed that radiotherapy given to the lymph-node field reduced the risk of both lymph-node field relapse as a first relapse and lymph-node field relapse at any time. In absolute terms, the reduction in the cumulative incidence of

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