Abstract: We included five RCTs involving a total of 1231 participants with NMIBC in this review. Due to poor reporting, the risk of bias in the included studies was often unclear. We assessed the studies under two main comparisons: intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs), and intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT). Intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs): We observed no clear difference between BCG plus IFN-α and BCG alone for recurrence (average risk ratio (RR) 0.76, 95% confidence interval (CI) 0.44 to 1.32; 4 RCTs; 925 participants; very low-quality evidence) or progression (average RR 0.26, 95% CI 0.04 to 1.87; 2 RCTs; 219 participants; low-quality evidence). The included RCTs did not report on the other primary outcome of this review, discontinuation of therapy due to adverse events. Regarding secondary outcomes, we observed no clear difference for disease-specific mortality (RR 0.38, 95% CI 0.05 to 3.05; 1 RCT; 99 participants; very low-quality evidence). Two RCTs reporting contradictory findings for adverse events could not be pooled due to variation in definitions. There were no data from the included RCTs on time-to-death or disease-specific quality of life. Intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT): We observed shorter time-to-recurrence for participants in the BCG alternating with IFN-α group compared with the BCG alone group (hazard ratio (HR) 2.86, 95% CI 1.98 to 4.13; 1 RCT; 205 participants; low-quality evidence), but no clear differences in time-to-progression (HR 2.39, 95% CI 0.92 to 6.21; 1 RCT; 205 participants; low-quality evidence) and discontinuation of therapy due to adverse events (RR 2.97, 95% CI 0.31 to 28.09; 1 RCT; 205 participants; low-quality evidence). Regarding secondary outcomes, there were no clear differences between the BCG alternating with IFN-α and BCG alone groups for disease-specific mortality (HR 2.74, 95% CI 0.73 to 10.28; 1 RCT; 205 participants; low-quality evidence), time-to-death (overall survival) (HR 1.00, 95% CI 0.68 to 1.47; 1 RCT; 205 participants; low-quality evidence), or systemic or local adverse events (RR 1.65, 95% CI 0.41 to 6.73; 1 RCT; 205 participants; low-quality evidence). There were no data on disease-specific quality of life. We found low- to very low-quality evidence suggesting no clear differences in recurrence or progression with BCG plus IFN-α compared with BCG alone for people with NMIBC; there was no information to determine the effect on discontinuation of therapy due to adverse events. Low-quality evidence suggests BCG alternating with IFN-α compared with BCG alone may increase time-to-recurrence, however low-quality evidence also suggests no clear differences for time-to-progression or discontinuation of therapy due to adverse events. Additional high-quality, adequately powered trials using standardised instillation regimens and doses of both BCG and IFN-α, reporting outcomes in subgroups stratified by patient and tumour characteristics, and on long-term outcomes related not only to recurrence but also to progression, discontinuation due to adverse events, and mortality may help to clarify the ideal treatment strategy and provide a more definitive result.

Plain-language summary: The evidence is current to 25 August 2016. We included five studies with a total of 1231 participants with non-muscle-invasive bladder cancer. Four studies compared BCG given together with IFN-α versus BCG alone. One study compared BCG alternating with IFN-α versus BCG alone. The follow-up period in the studies ranged from two months to nearly 20 years. BCG combined with IFN-α (four studies):We found very low-quality evidence showing no clear difference in recurrence (four studies involving 925 participants) or progression (two studies involving 219 participants) between participants who received BCG combined with IFN-α and those who received BCG alone. None of the studies reported on the important outcome of stopping treatment due to adverse events. There was also very low-quality evidence showing no clear difference between groups for cancer-specific mortality (one study, 99 participants). There were mixed findings for adverse events (two studies, 120 and 670 participants, respectively). BCG alternating with IFN-α (one study):We found low-quality evidence showing a higher probability of recurrence when BCG was alternated with IFN-α compared with BCG alone (study involving 205 participants). We also found low-quality evidence that showed no clear difference in the probability of progression, risk of stopping treatment due to adverse events, and cancer-specific mortality between those participants receiving BCG alternating with IFN-α and those receiving BCG alone (one study involving 205 participants). There was also no clear difference between groups for overall survival or adverse events (one study involving 205 participants). None of the five studies reported on quality of life of the participants. As the included studies were often poorly conducted or reported, we rated the quality of the evidence as low overall. Further research is likely to have an important impact on our confidence in the accuracy of results.