title: Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Health and Medical Research Council of Australia, Cancer Australia, Melanoma Institute Australia, Cancer Council of South Australia.
authors.affiliation: Princess Alexandra Hospital, University of Queensland, Brisbane, Australia. bryan_burmeister@health.qld.gov.au
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Burmeister
authors.forename: Michael A
authors.initials: MA
authors.lastname: Henderson
authors.forename: Jill
authors.initials: J
authors.lastname: Ainslie
authors.forename: Richard
authors.initials: R
authors.lastname: Fisher
authors.forename: Juliana
authors.initials: J
authors.lastname: Di Iulio
authors.forename: B Mark
authors.initials: BM
authors.lastname: Smithers
authors.forename: Angela
authors.initials: A
authors.lastname: Hong
authors.forename: Kerwin
authors.initials: K
authors.lastname: Shannon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Scott
authors.initials: S
authors.lastname: Carruthers
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Coventry
authors.forename: Scott
authors.initials: S
authors.lastname: Babington
authors.forename: Joao
authors.initials: J
authors.lastname: Duprat
authors.forename: Harald J
authors.initials: HJ
authors.lastname: Hoekstra
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016001:Confidence Intervals; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision / Q000379:methods* / Q000401:mortality; D008198:Lymph Nodes / Q000473:pathology / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary* / Q000601:surgery; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011793:Queensland; D018714:Radiotherapy, Adjuvant; D018570:Risk Assessment; D016037:Single-Blind Method; D012878:Skin Neoplasms / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D057832:Watchful Waiting / Q000379:methods*; D055815:Young Adult