Use of Neoadjuvant Intravesical Therapy for NMIBC

Is there a role for neoadjuvant intravesical therapy in the treatment of patients with non-muscle invasive bladder cancer (NMIBC)? According to a recent phase 2 trial published in the Journal of Urology, there may be.¹ The current standard for the management of NMIBC is transurethral resection of bladder tumor (TURBT) followed by the instillation of intravesical bacille Calmette-Guérin or a chemotherapy-based agent.² The authors note that recurrence rates vary but range from 15% to 61% at 1 year and 31% to 78% at 5 years.³ Recurrence of NMIBC is typically attributed to 4 mechanisms, including incomplete resection, tumor cell reimplantation, microscopic tumor growth, and new tumor formation.⁴ By administering immediate single-dose intravesical chemotherapy, there is a 15% absolute risk reduction in tumor recurrence.⁵

Intravesical mitomycin-C (MMC) has a generally good systemic toxicity profile due to poor systemic absorption across the urothelium; however, the authors caution that its potential systemic toxicities should not be ignored. There have been some studies evaluating the use of MMC in the neoadjuvant setting, but many aspects of its use in this context, including dosing and scheduling, remain unknown. The purpose of this study was to assess the feasibility and potential efficacy of 2 doses of intravesical MMC administered 1 day and 4 hours prior to TURBT.

Phase 2 Study of Neoadjuvant Intravesical MMC

The study was designed as an open-label prospective, single-center, parallel-group, randomized phase 2 clinical trial over a 4-year period. Patients included in this study had previous cystoscopy with evidence of bladder tumors. The primary endpoint was to compare the recurrence-free survival (RFS) of those who underwent 2 doses of neoadjuvant intravesical MMC with those who underwent TURBT alone. In the MMC cohort, patients received instillation of MMC 40 mg at 1 day and 4 hours before undergoing TURBT. MMC was instilled via an 8-Fr urethral catheter and left in place for 1 to 2 hours.

Following this, patients underwent surveillance and further intervention in line with the recommendations of the European Association of Urology, American Urological Association, or Society of Urologic Oncology guidelines for NMIBC. RFS was defined as the time between TURBT and the date of first positive pathology. Secondary endpoints included progression-free survival and adverse events (AEs) attributed to treatment.

A total of 99 patients were initially included in the study and randomly assigned to neoadjuvant intravesical MMC plus TURBT (intervention arm) or TURBT alone (control arm) in a nearly 1:1 ratio. After application of the exclusion criteria, 71 patients were included in the study: 33 in the intervention arm and 38 in the control arm. More than 85% of patients had a follow-up of at least 10.4 months. Patients were well-balanced between the 2 cohorts. The median time of follow-up was 36 months for the intervention arm versus 26 months for the control arm, and the median age was 65 years in the intervention group versus 70 years in the control arm.

The control arm had a higher incidence of multiplicity multifocal tumor burden at 63% compared to 46% for the intervention arm. The authors used a per-protocol analysis and reported incidence of recurrence in 3 patients who underwent neoadjuvant intravesical MMC intervention arm compared with 8 in the control group, translating into an RFS rate of 97% versus 89%. No patients in the intervention group experienced recurrence compared with 3 patients in the control cohort. Additionally, 15% of patients who received neoadjuvant intravesical MMC experienced a grade 1 or 2 drug-related AE, specifically urinary frequency (9.1%) and hematuria 6.1%). There were no allergic reactions, systemic toxicities, or grade r3 or AEs reported.

The authors began their discussion by emphasizing that the standard of care—an immediate single dose of intravesical MMC after TURBT—is generally well tolerated and reduces recurrence by 25% to 38%. However, they noted that given that following TURBT there may be areas of thinned muscularis propria in areas of deep resection, there is a risk for extensive “MMC-induced transmural necrosis/ulceration” that can result in secondary perforation. For this reason, a single immediate intravesical instillation of MMC should not be used in certain cases, including extended or deep resection or suspected bladder perforation, because extravasation of MMC into the subperitoneal or intraperitoneal space and perivesical fat necrosis may be so significant as to require intensive care monitoring, surgical debridement, and cystectomy.

Study Limitations and Results

This study did not address the optimal timing and interval of neoadjuvant intravesical MMC administration. In this study, patients were hospitalized 1 day in advance of TURBT and given the maximum dose of 50 mg/20 mL, followed by a second dose 4 hours before TURBT. Effective delivery was demonstrated by confirmed measurements of MMC in tumor tissue.

The study lends evidence that neoadjuvant intravesical MMC can reduce the risk of post-TURBT intravesical instillation of MMC. The authors note that these findings are consistent with the PRECAVE randomized control trial interim analysis, which showed an 80% reduction in the risk of early recurrence for patients who received neoadjuvant intravesical MMC compared with patients who did not receive any neoadjuvant or adjuvant therapy.⁶ Regarding recurrence or progression, although the study reported decreased recurrence and progression in the intervention arm, it was not sufficiently powered to fully analyze its potential benefits.

Limitations of this single-center, randomized phase 2 clinical trial include its small patient population and lack of an arm for standard of care of immediate post-TURBT intravesical MMC. Although the study demonstrated a safe profile for neoadjuvant intravesical MMC, the authors cited a significant need for a “prospective, phase III, large-scale, long-term follow-up, multicenter trial comparing neoadjuvant MMC versus a single immediate post-TURBT intravesical MMC group, especially for patients with intermediate or high risk NMIBC.”¹

The article was accompanied by several editorial comments. Woodson Smelser, MD, from Washington University in St. Louis, made the point that the study was performed before approval for gemcitabine in South Korea, where it was conducted. Dr Smelser quotes the findings of the SWOG S0337 trial that gemcitabine is less caustic, safer to handle, and typically more cost-effective than MMC⁷ and may impact whether the use of neoadjuvant intravesical MMC is likely to dramatically shift the current standard of care.

However, given the comfort that urologists have with intravesical MMC, it may be worthwhile to add it to the management of NMIBC. Kyle Rose, MD, from the H. Lee Moffitt Cancer Center, largely agreed with Dr. Smelser and added that caution should be exercised when generalizing the findings of the study since its patients were admitted the day before undergoing TURBT, which may not reflect standard practice.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

1. Lee HW, Lee HH, Park EY, et al. Clinical efficacy of neoadjuvant intravesical mitomycin-c therapy immediately before transurethral resection of bladder tumor in patients with nonmuscle-invasive bladder cancer: preliminary results of a prospective, randomized phase II study. J Urol. 2022; Oct 12. doi: 10.1097/JU.0000000000003002. [Online ahead of print.]
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3. Sylvester RJ, van der Meijden APM, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466-475. discussion 475-7. doi: 10.1016/j.eururo.2005.12.031
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5. Sylvester RJ, Oosterlinck W, Holmang S, et al. Systematic review, and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa-pT1 urothelial carcinoma of the bladder: which patients benefit from the instillation? Eur Urol. 2016;69(2):231-244. doi: 10.1016/j.eururo.2015.05.050
6. Carrión DM, Gómez Rivas J, Aguilera Bazán A, et al. The benefit of a neoadjuvant instillation of chemotherapy in non-muscle invasive bladder cancer: interim analysis of the PRECAVE randomized clinical trial. Arch Esp Urol. 2021;74(9):883-893. PMID: 34726625
7. Li R, Li Y, Song J, et al. Intravesical gemcitabine versus mitomycin for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized controlled trial. BMC Urol. 2020;20(1):97. doi: 10.1186/s12894-020-00610-9