Review question
How does immunotherapy (a newer medicine that works through the body's immune system) compare to chemotherapy (a medicine that kills cancer cells) in people with cancer of the bladder or upper urinary system that has spread throughout the body or a surgical procedure is not feasible due to an advanced stage.
Background
Until a few years ago, the treatment of bladder cancer that has spread to other organs outside the urinary tract (metastatic bladder cancer) consisted of one of only a few chemotherapies using medicines called cisplatin or carboplatin (platinum-containing chemotherapy). Now the treatment of metastatic bladder cancer includes several new immunotherapies. Immunotherapies use the body's immune system to prevent the tumor from growing, or may even shrink it. This review looked at the evidence for immunotherapies as the first (first-line) or later (second-line) treatment for metastatic bladder cancer, and compared it to chemotherapy.
Study characteristics
We considered non-randomized studies and randomized controlled trials (in which people are assigned to a group by chance) in this Cochrane Review, as some of the approvals by responsible authorities are based on non-randomized trials. We only included randomized controlled trials in our analyses.
Key results
We identified five randomized trials and seven non-randomized studies addressing our review question, but only analyzed the randomized trials. People in these trials had locally advanced (cancer that has spread from where it first started to nearby tissue and could not be removed by surgery) or metastatic bladder cancer.
First-line treatment: immunotherapy for the treatment of advanced or metastatic bladder cancer, compared to chemotherapy, probably has little to no effect on the risk of death from any cause (if 750 out of 1000 people on chemotherapy died within three years, there would be 11 fewer [between 45 fewer and 26 more] people out of 1000 on immunotherapy who died). Immunotherapy probably has little to no effect on health-related quality of life (measured using a point scale from 0 to 156, the quality of life in people with immunotherapy was only 4.1 points better on average). Immunotherapy probably reduces serious side effects (if 908 out of 1000 people on chemotherapy had serious side effects within one year, there would be 481 fewer [between 644 fewer and 227 fewer] people out of 1000 on immunotherapy with serious side effects).
Second-line treatment: immunotherapy may reduce the risk of death from any cause (if 920 out of 1000 people on chemotherapy died within three years, there would be 59 fewer [between 95 fewer and 28 fewer] people out of 1000 on immunotherapy who died). Health-related quality of life may not be affected by immunotherapy (measured using a point scale from 0 to 100, the quality of life in people with immunotherapy was only 4.8 points better on average). Immunotherapy may reduce serious side effects (if 630 out of 1000 people on chemotherapy had serious side effects within 15 months, there would be 76 fewer [between 126 fewer and 25 fewer] people out of 1000 on immunotherapy with serious side effects).
Main limitations of the evidence
Depending on the outcome, we have little to moderate confidence in the evidence.
Compared to chemotherapy, immunotherapy for treating advanced or metastatic urothelial carcinoma probably has little to no effect on the risk of death from any cause when used as first-line therapy. Still, it may reduce the risk of death from any cause when used as second-line therapy. Health-related quality of life for participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce adverse events grade 3 to 5 when used as first- and second-line therapy, respectively.
Immune checkpoint inhibitors are increasingly important in the treatment algorithm for locally advanced and metastatic bladder cancer. Numerous ongoing studies are investigating these agents as first- and second-line therapies, both alone and in combination with chemotherapy or in a maintenance therapy setting.
To assess the effects of immune checkpoint inhibitors compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma.
We performed a comprehensive search including the Cochrane Library, MEDLINE, Embase, three other databases, several trial registers, other sources of gray literature, and conference proceedings, with no restrictions on language of publication. We limited the search period to run from 2000 until August 2022.
We included randomized controlled trials (RCTs) using immunotherapy versus chemotherapy and would have considered non-randomized trials in the absence of randomized trial data. Participants had locally advanced inoperable (cT4b or N+, or both) or metastatic (M1) (or both) urothelial carcinoma of the bladder or upper urinary tract. We excluded studies of people in whom immunotherapy was used in combination with chemotherapy or in a surveillance setting.
Two review authors independently classified studies for inclusion and abstracted data from included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence on a per-outcome basis.
We included five RCTs and identified seven single-armed studies. The RCTs included 3572 participants comparing immunotherapy versus chemotherapy for the treatment of locally advanced and metastatic bladder cancer.
First-line therapy
Immunotherapy probably has little to no effect on the risk of death from any cause when used as first-line therapy compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87 to 1.07; I2 = 0%; 3 studies, 2068 participants; moderate-certainty evidence). This corresponds to 750 deaths per 1000 participants with chemotherapy and 11 fewer (45 fewer to 26 more) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy probably has little to no effect on health-related quality of life (mean difference (MD) 4.10, 95% CI 3.83 to 4.37; 1 study, 393 participants; moderate-certainty evidence), when assuming a minimal clinically important difference (MCID) of at least 6 points (using the Functional Assessment of Cancer Therapy – Bladder [FACT-BL] tool; scale 0 to 156 with higher scores representing better quality of life). Immunotherapy probably reduces adverse events grade 3 to 5 (RR 0.47, 95% CI 0.29 to 0.75; I2 = 97%; 3 studies, 2046 participants; moderate-certainty evidence). This corresponds to 908 grade 3 to 5 adverse events per 1000 participants with chemotherapy, with 481 fewer (644 fewer to 227 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy.
We found no evidence for the outcome time to death from bladder cancer. Immunotherapy probably increases the risk of time to disease progression (HR 1.33, 95% CI 1.17 to 1.50; I2 = 0%; 2 studies, 1349 participants; moderate-certainty evidence). This corresponds to 660 events per 1000 participants with chemotherapy and 102 more (57 more to 152 more) events per 1000 participants with immunotherapy at 36 months. Immunotherapy may reduce discontinuations due to adverse effects (RR 0.47, 95% CI 0.20 to 1.10; I2 = 94%; 3 studies, 2046 participants; low-certainty evidence). This corresponds to 338 discontinuations per 1000 participants with chemotherapy and 179 fewer (271 fewer to 34 more) discontinuations per 1000 participants with immunotherapy.
Second-line therapy
Immunotherapy may reduce the risk of death from any cause when used as second-line therapy (HR 0.72, 95% CI 0.63 to 0.81; I2 = 0%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 920 deaths per 1000 participants with chemotherapy (vinflunine, paclitaxel, docetaxel) and 59 fewer (95 fewer to 28 fewer) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; I2 = 85%; 2 studies, 727 participants; low-certainty evidence), assuming an MCID of at least 10 points (using the EORTC QLQ tool; scale 0 to 100 with higher scores representing better quality of life). Immunotherapy may reduce adverse events grade 3 to 5 in participants undergoing second-line therapy (RR 0.89, 95% CI 0.81 to 0.97; I2 = 9%; 2 studies, 1423 participants; low-certainty evidence). This corresponds to 630 grade 3 to 5 adverse events per 1000 participants with chemotherapy and 76 fewer (126 fewer to 25 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy.
We found no evidence for the outcome of time to death from bladder cancer. We are very uncertain if immunotherapy reduces the risk of disease progression (HR 0.99, 95% CI 0.84 to 1.16; I2 = 0%; 2 studies, 1473 participants; very low-certainty evidence). Immunotherapy may reduce discontinuations due to adverse events in participants undergoing second-line therapy (RR 0.35, 95% CI 0.17 to 0.72; I2 = 69%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 110 discontinuations per 1000 participants with chemotherapy and 72 fewer (91 fewer to 31 fewer) discontinuations per 1000 participants with immunotherapy.