title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Health and Medical Research Council of Australia, Cancer Council Australia, Melanoma Institute Australia, and the Cancer Council South Australia.
authors.affiliation: Division of Cancer Surgery, University of Melbourne Department of Surgery, East Melbourne, VIC, Australia; University of Melbourne, East Melbourne, VIC, Australia. Electronic address: michael.henderson@petermac.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Henderson
authors.affiliation: Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Burmeister
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Jill
authors.initials: J
authors.lastname: Ainslie
authors.affiliation: Centre for Biostatistics and Clinical Trials, East Melbourne, VIC, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Fisher
authors.affiliation: Centre for Biostatistics and Clinical Trials, East Melbourne, VIC, Australia.
authors.forename: Juliana
authors.initials: J
authors.lastname: Di Iulio
authors.affiliation: Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Smithers
authors.affiliation: Melanoma Institute of Australia, University of Sydney, Sydney, NSW, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Hong
authors.affiliation: Melanoma Institute of Australia, University of Sydney, Sydney, NSW, Australia.
authors.forename: Kerwin
authors.initials: K
authors.lastname: Shannon
authors.affiliation: Melanoma Institute of Australia, University of Sydney, Sydney, NSW, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Carruthers
authors.affiliation: Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Coventry
authors.affiliation: Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Scott
authors.initials: S
authors.lastname: Babington
authors.affiliation: Hospital Do Cancer, Sao Paulo, Brazil.
authors.forename: Joao
authors.initials: J
authors.lastname: Duprat
authors.affiliation: University Medical Centre Groningen, Groningen, Netherlands.
authors.forename: Harald J
authors.initials: HJ
authors.lastname: Hoekstra
authors.affiliation: Melanoma Institute of Australia, University of Sydney, Sydney, NSW, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000473:pathology* / Q000528:radiation effects; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000473:pathology / Q000532:radiotherapy*; D008875:Middle Aged; D018714:Radiotherapy, Adjuvant; D012008:Recurrence