Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial

Abstract

Importance: Low-grade non-muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT).

Objective: To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non-muscle-invasive urothelial cancer compared with saline.

Design, setting, and participants: Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non-muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016.

Interventions: Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT.

Main outcomes and measures: The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause.

Results: Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90; P<.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non-muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35-0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower.

Conclusions and relevance: Among patients with suspected low-grade non-muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents.

Trial registration: clinicaltrials.gov Identifier: NCT00445601.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lerner reports receipt of personal fees for advisory board membership from BioCancell, Incyte, Nucleix, and UroGen and for consultancy from Vaxiion and clinical trial grants from UroGen, Endo, FKD, Viventia, JBL, and Roche/Genentech. Dr Koppie reports receipt of personal fees from Convergent Genomics. Dr Karsh reports receipt of personal fees for consulting and/or speaking and/or research funding to his institution from Astellas, Bayer, Janssen, Sanofi, Spectrum, Precision Biopsy, 3D Biopsy, Augmenix, Dendreon, Pfizer, Abbvie, Myriad Genetics, AstraZeneca, Vaxiion, and Arivan Research. No other disclosures were reported.

Figures

Figure 1.. Participant Flow Through the SWOG S0337 Randomized Clinical Trial

No data are available for number of patients approached to enroll in the trial; 23 sites participated. TURBT indicates transurethral resection of bladder tumor. aEastern Cooperative Oncology Group (ECOG) performance status scores: 0 = fully active, able to carry on all predisease performance without restriction; 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; eg, light housework, office work. bInadequate pathology specimen indicates that based on scantiness of the specimen, the pathologist was unable to assess to unequivocally diagnose a benign condition or bladder cancer.

Figure 2.. Time to Recurrence of Bladder Cancer

A, Cumulative incidence of recurrence in the primary analysis by randomized treatment group. All randomized patients who met eligibility criteria were included. B, Cumulative incidence of recurrence by randomized treatment group among patients who were found to have low-grade non–muscle-invasive urothelial cancer at transurethral resection of bladder tumor and received instillation as randomized.