Critical appraisal:Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al 2015 2
- Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al. 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. Lancet Oncol 2015 Jul 20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26206146.
- Assigned to
- Topic area
- Clinical question
- Study design
- randomised controlled trial - Cochrane tool
- Level of Evidence
Section below only relevant for Cancer Council Project Officer
Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al. 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. Lancet Oncol 2015 Jul 20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26206146.
- What is the appropriate treatment for macroscopic (i.e. detectable clinically or by ultrasound) nodal metastasis?
randomised controlled trial - Cochrane tool
Adjuvant radiotherapy is recommended for patients with melanoma after lymphadenectomy. 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, aim to update the relapse and survival data from that trial and assess quality of life and toxic effects
Lymph-node field relapse
2 observation patients: lymph-node field relapse after 3 years. Observation group had more frequent first relapses (HR 0·52, 95% CI 0·31–0·88, p=0·023 adjusted for lymph-node field region). Lymph-node field relapse at any time was also more common in the observation group (0·54, 95% CI 0·33–0·89 p=0·021). Significant difference in cumulative incidence of lymph-node field relapse as a first relapse (p=0·0092). 5-year cumulative incidence of lymph-node field relapse as a site of first relapse: 18% (95% CI 11–26) adjuvant radiotherapy group and 33% (24–42) observation group (difference 15%: 95% CI 3·5–27 p=0·011). 5-year cumulative incidence for isolated lymph-node field relapse as a site of first relapse was 8·3% (95% CI 3·0–13·5) adjuvant radiotherapy and 23% (15–31) observation, p Gray's =0·0015 (difference 15%: 95% CI 5·4–25 p=0·002).
Apart from treatment group, only extracapsular extension was significantly related to risk of lymph-node field relapse as a first relapse in univariable analyses (relative HRs: no extracapsular extension 0·74, limited 1·02, extensive 2·04, p=0·0063; trend: HR 1·64:95% CI 1·17–2·30 per category increase, p trend =0·0037). Multivariable analysis, treatment arm (HR 0·49: 95% CI 0·28–0·85 p=0·011) and extracapsular extension (HR 1·69 per category increase 95% CI 1·21–2·36 p trend =0·0020) were independently predictive. Shorter interval from primary diagnosis to randomisation was associated with an increased risk of further lymph-node field relapse as a site of first relapse (HR 0·86: 95% CI 0·76–0·99 per doubling of time p=0·035), also after adjusting for extracapsular extension and treatment group (HR 0·87 0·76–0·99 per doubling p=0·044), but not with survival (HR 0·96: 0·88–1·05 per doubling p=0·30).
5-year survival for adjuvant radiotherapy 40% (31–50), observation 45% (36–55) (HR 1·27: 0·89–1·79 p=0·21). Univariable analysis, only the number of positive nodes (HR trend 1·35: 1·09–1·68 p trend =0·006) and extracapsular extension (HR trend 1·71: 1·36–2·15 p trend<0·0001) predictive of overall survival. Multivariable analysis, only extracapsular extension (HR 1·70: 95% CI 1·35–2·13 per category increase, p<0·0001), increasing number of positive nodes (HR 1·42: 1·13–1·79 per category increase, p=0·0029), being male (HR 1·68: 1·08–2·62 p=0·021) independently predictive of worse overall survival. Extracapsular extension (HR 1·46: 95% CI 1·18–1·8 per category increase, p=0·0004) and increasing number of positive nodes (HR 1·23: 1·01–1·51per category increase, p=0·042) were independently related to relapse-free survival.
26 patients: observation group developed isolated lymph-node field relapse. 20 (77%) treated with surgery/radiotherapy, 1 (4%) radiotherapy only, 4 (15%) surgery only, and 1 (4%) had no treatment. 23/26 patients were successfully salvaged. The survival of this group was 34% (95% CI 18–63) at 5 years; 8 remained without evidence of disease after definitive treatment and 18 developed distant relapse (including 3 who also had further lymph-node field relapse). 9 patients assigned to adjuvant radiotherapy who had an isolated lymph-node field relapse as a first relapse, 7 developed distant disease and 2 a local or in transit relapse; all have since died.
Quality of Life and Lymphadema: also reported on in results
|High risk of bias||Comments: Please replace this text and include any additional comments in regards to your risk of bias rating|
Risk of bias assessment: Randomised Controlled Trial (Cochrane risk of bias tool)
Random sequence generation
- Patients were randomised centrally with a computer program (with own algorithm). Randomisation was done with minimisation using random components, with balancing factors of institution
- computer program (with own algorithm)
- Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocations
Incomplete outcome data
- Review identified 41 major eligibility infringements in 31 patientS. The committee recommended that these patients be excluded from the primary analysis. Thus, two study populations were analysed; the intention-to-treat population, and the eligible population.
Two patients (one from each group) withdrew consent soon after randomisation and were excluded from all analyses
Selective outcome reporting
- Cutoff date for follow-up of Nov 15, 2008, and all living patients were followed up to this date; any follow-up after this date was ignored to minimise reporting bias
Other sources of bias
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