The review found that immunotherapy was effective for treating advanced non-small cell lung cancer. Monoclonal antibodies had most potential but toxicity and allergenicity needed to be addressed. These conclusions require cautious interpretation due to limitations in the review that included a suboptimal search, differences between the studies and the small size of some subgroup analyses.

To evaluate the efficacy and safety of immunotherapy for treating advanced non-small cell lung cancer.

HighWire and PubMed were searched for studies published in English from January 1980 to April 2011. Search terms were reported. Relevant reviews were searched.

Eligible studies were randomised controlled trials (RCTs) of immunotherapy versus control therapy for non-small cell lung cancer stage IIIA, IIIB or IV. Outcomes of interest in the review were overall and progression-free survival, complete and partial response, total effective rate (complete and partial response) and adverse events.

Participants in the intervention groups of the included studies received various types of immunotherapy (cytokines, monoclonal antibodies and vaccines). Controls received either one of a range of chemotherapy regimens or best supportive care. Follow-up ranged from one to five years.

Three reviewers independently selected the studies. Disagreements were resolved by consensus.

Studies were categorised as having a low, moderate or high risk of bias, taking into account criteria for randomisation, allocation concealment, blinding and reporting of withdrawals and drop-outs.

The authors did not state how many reviewers performed the quality assessment.

Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes using Cox proportional hazards modelling. Weighted mean differences with 95% CIs were calculated for continuous outcomes.

Three reviewers independently extracted the data. Disagreements were resolved by consensus.

Data were combined to calculate pooled hazard ratios using a Mantel-Haenszel fixed-effect model unless there was significant heterogeneity in which case random-effects models were used. Heterogeneity was assessed using Χ² and Ι².

Subgroup analysis was performed according to drug type (cytokine, monoclonal antibody and vaccine). Sensitivity analyses omitted studies that did not use chemotherapy in both study arms. It appeared that the Begg test was used to assess the risk of publication bias.

Twelve RCTs were included (3,134 patients, range 28 to 1,125). All provided adequate information about allocation concealment and withdrawals and drop-outs and all were open-labelled. All trials were judged to be at low risk of bias.

Immunotherapy significantly improved overall survival, with higher death rates in the control groups (HR 0.95, 95% CI 0.92 to 0.98; 11 RCTs; Ι²=0%). Immunotherapy also improved progression-free survival (HR 1.08, 95% CI 1.03 to 1.12; seven RCTs; Ι²=32%), partial response rate (HR 1.23, 95% CI 1.08 to 1.40; eight RCTs; Ι²=1%) and total effective rate (HR 1.19, 95% CI 1.06 to 1.34; 10 RCTs; Ι²=2%). The complete response rate did not significantly differ between the groups (HR 1.00, 95% CI 0.77 to 1.31; nine RCTs; Ι²=0%).

Subgroup analysis showed that vaccines significantly improved overall survival compared to controls; cytokines and monoclonal antibodies did not produce a significant improvement. Monoclonal antibodies significantly improved progression-free survival and total effective rate; cytokines and vaccines did not produce a significant improvement or had no relevant studies.

For adverse events, eight RCTs reported that diarrhoea, hypomagnesaemia, leucopenia and thrombocytopenia occurred more frequently in the intervention group than among controls. These trials reported equal frequency in control and intervention groups for anaemia, neutropenia, nausea, hypertension, dyspnoea and neurosensory toxicity. In the other four RCTs adverse events were more frequent in the control group (two RCTs) or were poorly reported (two RCTs).

Subgroup analysis showed that cytokines were associated with significantly higher rates of diarrhoea, hypomagnesaemia and leucopenia than controls (four RCTs). Monoclonal antibodies were associated with higher rates of thrombocytopenia (three RCTs). Vaccines did not differ significantly from controls for any reported adverse event (one RCT).

There was no statistically significant heterogeneity for the main analyses. Detailed results of subgroup and sensitivity analyses were reported.

Immunotherapy was effective for treating advanced non-small cell lung cancer. Monoclonal antibodies had most potential, but toxicity and allergenicity needed to be addressed.

The objectives and inclusion criteria of the review were clear. Only two databases were searched, few search terms were used and the search was limited by language and publication status (a large number of meeting abstracts were excluded). It was possible that some relevant studies were missed but there was no evidence of significant publication bias. It was unclear whether adequate steps were taken to limit the risk of reviewer bias during validity assessment.

The methods used to assess study quality were generally appropriate but the assessment of attrition appeared to be based on clarity of reporting rather than risk of bias and details for individual trials (which might have clarified this) were not reported. Few details were provided about the methodological and clinical characteristics of the studies. Appropriate methods were used to combine studies and assess and explore heterogeneity. As the authors noted, the review was limited by the small number of studies and by differences between them. The authors' conclusions about the superiority of monoclonal antibodies over other immunotherapies were based on subgroup comparisons and may not be reliable. The direction of effect on some of the forest plots was inconsistent with the text.

The authors' conclusions require cautious interpretation due to limitations in the review that included a suboptimal search, differences between the studies and the small size of some subgroup analyses.

Practice: The authors stated that immunotherapy using monoclonal antibodies may be suitable as a standard complementary treatment for advanced non-small cell lung cancer.

Research: The authors stated that more studies were required to investigate the safety and efficacy of immunotherapy for treating advanced non-small cell lung cancer. There was a need for more effective treatments that caused fewer adverse and allergenic effects.

Guangdong Provincial Natural Science Foundation, National Natural Science Foundation of China.

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