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.