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

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Article
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
User:Jackie.buck
Topic area
Guidelines:Melanoma
Clinical question
Form
Form:Critical appraisal
Study design
randomised controlled trial - Cochrane tool
Level of Evidence
II

Section below only relevant for Cancer Council Project Officer

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Critical Appraisal

Article being appraised

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.


Applicable clinical question

Key Facts

Study Design

randomised controlled trial - Cochrane tool

Study aims:

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

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.Jutta's question mark icon.png
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?Jutta's question mark icon.png
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.Jutta's question mark icon.png
computer program (with own algorithm)
What was the risk of bias from the allocation concealment?Jutta's question mark icon.png
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.Jutta's question mark icon.png
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?Jutta's question mark icon.png
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.Jutta's question mark icon.png
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?Jutta's question mark icon.png
Low
Selective outcome reporting
State how the possibility of selective outcome reporting was examined by the review authors and what was found.Jutta's question mark icon.png
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).Jutta's question mark icon.png
Low
Other sources of bias
Describe any other sources of biasJutta's question mark icon.png
No response
What was the risk of bias from other sources?Jutta's question mark icon.png
Low


Relevance of evidence
1 Additional comments: Please replace this text and briefly describe the reasons for your rating
Result of appraisal

Jutta's tick icon.png Included




Completed by

Jackie Buck