Intravesical hyperthermia with high-dose mitomycin-C shows promise as BCG alternative for NMIBC

Treatment for high-risk non–muscle-invasive bladder cancer (NMIBC) with hyperthermic intravesical chemotherapy (HIVEC) using high-dose mitomycin-C (MMC) is safe, well tolerated, and appears efficacious after short-term follow-up, according to a report from Duke University urologists.¹ In a paper presenting the first North American clinical experience with this modality, the investigators summarized outcomes from a cohort of 14 patients who received MMC HIVEC because of the BCG shortage. The median number of instillations received was 6, and the median follow-up for the series was 11 months.

The MMC HIVEC was well tolerated by 11 (79%) patients. Seven patients (50%) developed adverse events (AEs), but all were grade 1 or 2. During the available follow-up, 2 patients (14%) experienced a cancer recurrence, but both had discontinued MMC HIVEC after only 2 treatments.

Scott P. Campbell, MD, third-year urology resident at Duke University Medical Center, Durham, North Carolina, told Urology Times®, “Given the limited supply of BCG and the lack of reliable treatments in the post-BCG setting, our biggest priority is to continue to identify therapies for bladder cancer that are safe and effective alternatives to BCG. Our study demonstrates the feasibility of HIVEC MMC and suggests it is a reasonable substitute for BCG during global shortages. We hope that clinical trials stem from this series to help the urologic oncology community better understand how to optimize HIVEC, including testing alternative agents to MMC.”

The 14 patients included in the MMC HIVEC series comprised 4 with intermediate-risk disease and 10 with high-risk NIMBC. Twelve patients had recurrent tumors of which 11 had been previously treated with intravesical BCG (median, 6 treatments). Three patients were BCG-naïve.

The MMC HIVEC was administered at a concentration of 2 mg/mL (120 mg diluted in 60 mL sterile water) using a convective hyperthermia system (Combat BRS) with an induction course of 6 weekly instillations followed by up to 12 additional monthly treatments in the setting of a negative postinduction cystoscopy. Dwell time was 60 minutes heated and 30 to 60 minutes unheated following catheter removal.

MMC was chosen because it had been used in nearly all clinical trials investigating hyperthermia as an adjunct to intravesical chemotherapy, said first author Dominic C. Grimberg, MD, urology resident at Duke University Medical Center. “MMC has the best track record as an alternative to BCG, and although in prior studies of hyperthermic chemotherapy, MMC was administered at a concentration less than or equal to 1 mg/mL, we used the higher dose that is the accepted standard concentration in the United States based on a phase 3 trial,” he said.2

Grimberg added, “There are multiple hyperthermia systems, but the convective system we chose is small, reliable, low maintenance, widely available, affordable, and easy to use. Therefore, it could be rapidly implemented into clinical practice in our cancer center.”

AEs occurred during the instillation in 3 patients (bladder spasms in all and hematuria in 1) and led 2 patients to discontinue treatment. Four patients developed a pruritic rash thought to be MMC allergy as a delayed AE, and another developed leukopenia that resolved after the treatment was stopped. The investigators postulated that the higher-than-expected rate of systemic AEs reflected increased drug delivery using hyperthermia. Patient follow-up is continuing, and the investigators plan to report on longer-term outcomes over the next several months.

Brant A. Inman, MD, MS, Cary N. Robertson, MD, Associate Professor of Urologic Oncology at Duke University School of Medicine, is senior author of the paper. He told Urology Times®, “Many patients have already been seen at a 12-month visit, and preliminarily the data show that durable oncologic control is possible when patients are able to receive full induction courses of high-dose HIVEC MMC.”

References

1. Grimberg DC, Dudinec J, Shah A, Inman BA. Clinical trial of high dose hyperthermic intravesical mitomycin C for intermediate and high-risk non–muscle invasive bladder cancer during BCG shortage. Urol Oncol. Published online January 20, 2021. doi:10.1016/j.urolonc.2020.12.025

2. Au JL, Badalament RA, Wientjes MG, et al; International Mitomycin C Consortium. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst. 2001;93(8):597-604. doi:10.1093/jnci/93.8.597