Critical appraisal:Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al 2015 2

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

Number of Patients:

217

109 to adjuvant radiotherapy and 108 to observation

Reported outcome(s):

Lymph-node field relapse
Survival

Results of outcome(s):

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.

Comments on results:

Quality of Life and Lymphadema: also reported on in results

Includes an economic evaluation

no

Evidence ratings

Level of evidence

II

Risk of bias

High risk of bias

Comments: Please replace this text and include any additional comments in regards to your risk of bias rating

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Risk of bias assessment: Randomised Controlled Trial (Cochrane risk of bias tool)

Random sequence generation

Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

Patients were randomised centrally with a computer program (with own algorithm). Randomisation was done with minimisation using random components, with balancing factors of institution

What was the risk of bias from the random sequence generation?

Low

Allocation concealment

Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of or during, enrolment.

computer program (with own algorithm)

What was the risk of bias from the allocation concealment?

Low

Blinding

Describe all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.

Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocations

What was the risk of bias from the blinding of participants and personnel and outcome assessors?

High

Incomplete outcome data

Describe the completeness of outcome data for each main outcome, including attrition and exlusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors.

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

What was the risk of bias from incomplete outcome data?

Low

Selective outcome reporting

State how the possibility of selective outcome reporting was examined by the review authors and what was found.

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

What was the risk of bias from selective outcome reporting? Assessments should be made for each main outcome (or class of outcomes).

Low

Other sources of bias

Describe any other sources of bias

No response

What was the risk of bias from other sources?

Low

Relevance of evidence

1	Additional comments: Please replace this text and briefly describe the reasons for your rating

Result of appraisal

Included

Completed by

Jackie Buck