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Original Investigation
May 8, 2018

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

Author Affiliations
  • 1University of Rochester, Rochester, New York
  • 2SWOG Statistical Center, Seattle, Washington
  • 3Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 4Baylor College of Medicine, Houston, Texas
  • 5Oregon Health & Science University, Portland
  • 6Beaumont Health, Royal Oak, Michigan
  • 7University of California Davis, Sacramento
  • 8University of Texas–San Antonio, San Antonio
  • 9University of Michigan, Ann Arbor
  • 10University of Oklahoma, Oklahoma City
  • 11Madigan Army Medical Center, Tacoma, Washington
  • 12Urology Center of Colorado, Denver
  • 13University of Kansas Cancer Center, Kansas City
  • 14University of Colorado, Aurora
  • 15Comprehensive Cancer Centers of Nevada, Las Vegas
  • 16CHRISTUS Santa Rosa Medical Center, San Antonio, Texas
JAMA. 2018;319(18):1880-1888. doi:10.1001/jama.2018.4657
Key Points

Question  Does a single intravesical instillation of gemcitabine reduce risk of recurrence after resection of low-grade non–muscle-invasive urothelial cancer?

Finding  In this randomized clinical trial of 406 patients with suspected low-grade non–muscle-invasive urothelial cancer, intravesical instillation of gemcitabine, compared with saline, significantly reduced the risk of recurrence over a median of 4.0 years (recurrence rate: gemcitabine, 35%; saline, 47%; hazard ratio, 0.66).

Meaning  Intravesical gemcitabine immediately following tumor excision reduced risk of recurrence in patients with suspected low-grade non–muscle-invasive urothelial cancer.

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

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