Critical appraisal:Burdett SS, Stewart LA, Rydzewska L 2007 3

systematic review — This is a systematic review and quantitative meta-analysis based on aggregate data extracted from trial publications. It evaluated evidence only from randomised controlled trials, and aimed to evaluate the effect of pre-operative chemotherapy on survival in NSCLC patients. If adequate data were available, then the aim was also to investigate whether or not pre-defined patient subgroups, such as disease stage, benefit more or less from pre-operative chemotherapy.

Number of Patients:

988

Includes an economic evaluation

no

Evidence ratings

Level of evidence

I

Risk of bias

Moderate risk of bias

Comments: The systematic review asked a clear question: "To evaluate the effect of pre-operative chemotherapy on survival in patients with non-small cell lung cancer". An appropriate search strategy and inclusion criteria were used.

Included in the analysis was 988 patients who represented 75% of the randomised evidence. The 7 randomised controlled trials (RCTs) included were assessed as having fairly good methodological quality. All of the RCTs appeared to be randomised but none gave full details; 6 of the RCTs did not reach their accrual targets; and only 2 of the RCTs reported patient exclusions.

No statistical heterogeneity was found between the studies indicating that were similar enough to be combined.

Since a literature-based systematic review and meta-analysis rather than an individual patient data (IPD)-based meta-analysis (although this project is ongoing) was done, a less reliable estimate of the treatment effect is given and the subgroup analyses conducted to address whether pre-operative chemotherapy is more or less effective in certain disease stages is not reliable.

Size of effect

2

Reason for decision: Although this systematic review was described by the authors as limited, it represented a comprehensive and up to date systematic review of published data. It suggested a significant survival benefit for NSCLC patients with stage 1-3 disease who had received pre-operative chemotherapy versus those who did not. All but one hazard ratio estimate was in favour of pre-operative chemotherapy although the confidence intervals for individual trial results were wide and the results of all trials were inconclusive.

There was a significant increase in survival associated with use of pre-operative chemotherapy with hazard ratio (HR) 0.82 (95% CI, 0.69 to 0.97). This was equivalent to an absolute survival improvement of 6% at 5 years, increasing overall survival (OS) from 14% to 20%. The absolute 5 year survival for stage 3a was 6-7% (increasing from 15-35% to 21-42%) and for stage 3b it was 3-5% (increasing from 5-10% to 8-15%). The test for interaction showed that there was no difference in treatment effect for trials that only recruited stage 3 patients and those that had a wider range of stages.

Relevance of evidence

1	Additional comments: The results of this systematic review suggested that there may be a survival benefit from pre-operative chemotherapy in all NSCLC patients with stage 1-3 disease although the extent of that benefit in stage 3 patients was less clearly defined.

Result of appraisal

Included

Completed by

Professor Michael Brown MBBS PhD FRACP FRCPA