One method thought to improve the efficacy of intravesical chemotherapy is by heating the solution during instillation. This has various acronyms, but here we will call it hyperthermic intravesical chemotherapy (HIVEC). Hyperthermia is proposed to enhance treatment efficacy through multiple pathways including 1) increasing urothelial permeability, 2) enhancing drug sensitivity, 3) augmenting anti-tumor immune response, and 4) creating an unfavorable environment for metabolically deranged malignant cells.3
Early clinical trials utilizing mitomycin c (MMC) HIVEC at a standard dose of 0.8 mg/mL (40 mg in 50 mL) demonstrated good safety and improved efficacy when compared to standard MMC.4,5 HIVEC using an empty and refill done at 30 minutes with fresh MMC solution (0.8 mg/mL) has also been successful.6 Importantly, one randomized trial found HIVEC to have comparable efficacy to BCG.7 In the United States, MMC is normally administered at 2 mg/mL based on the trial of Au et al. where 40 mg MMC in 20 mL sterile water was utilized.8 Little is known about the safety and efficacy of HIVEC MMC at this concentration, particularly when a higher total dose is instilled. As a result of a worldwide BCG shortage, we obtained FDA approval to use high-dose HIVEC at 2mg/mL (120 mg in 60 mL) as a humanitarian use exemption trial for the treatment of intermediate- and high-risk NMIBC.
High-dose HIVEC MMC (2 mg/mL) was administered to 14 patients total, with 13 patients receiving adjuvant treatment following transurethral resection and one patient receiving the treatment as an ablative therapy without undergoing surgery due to significant medical comorbidity. The treatments began with six weekly induction treatments followed by one year of monthly maintenance therapy. The cohort was heavily pretreated and generally had unfavorable disease characteristics with 71% being American Urological Association (AUA) high-risk, 86% having experienced at least one prior recurrence, a median of 3.5 (IQR 1-5.25) prior recurrences, and 79% having received BCG in some fashion prior to the start of the study.
Instillations were well-tolerated in 11/14 (78.6%) patients, the remaining three patients developed lower urinary tract symptoms during treatment leading to two of three discontinuing further treatment. Delayed adverse events (AEs) included a higher than expected incidence of MMC allergy presenting as a pruritic rash in 4/14 (28%), ankle edema in 1/14 (7%), and leukopenia in 1/14 (7%) of patients. All reactions were transient and resolved with cessation of treatment, and all were CTCAE Grade 1 or 2. Although mild, AEs related to MMC led to the withdrawal of six patients (43%) with an additional two self-withdrawing and switching back to BCG when it became available again.
During a median follow-up of 11 months, only two patients have experienced tumor recurrences however both of these patients had discontinued treatment after two instillations due to AEs. No disease progression to muscle invasion or metastatic disease has occurred.
Overall this was a small single-arm trial aimed at evaluating the safety and tolerability of high-dose HIVEC with MMC for the treatment of intermediate- and high-risk NMIBC during BCG shortage. While no Grade 3 or higher AEs were observed, 43% of patients discontinued treatment due to AEs. The rate of systemic AEs was higher than anticipated, suggesting that the higher dosage in combination with hyperthermia may have contributed to a physiologically relevant degree of systemic absorption. For the patients that tolerated this therapy, short-term oncologic outcomes are favorable, but further follow-up is needed. This trial will hopefully lay the groundwork for future studies to further delineate the optimal treatment parameters for HIVEC with MMC. Treatment dose, duration, dwell time, and frequency must continue to be refined to obtain maximal therapeutic benefit while minimizing side effects, and this trial suggests that high-doses at induction may lead to systemic side effects but offers a strong therapeutic effect when tolerated.
Written by: Scott P. Campbell, MD, Resident of Urology, Dominic C. Grimberg MD, Resident of Urology, Brant A. Inman, MD, MS, Surgical Oncologist, Urologic Oncologist, Urologist, Division of Urology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina
- Malmström, Per-Uno, Richard J. Sylvester, David E. Crawford, Martin Friedrich, Susanne Krege, Erkki Rintala, Eduardo Solsona, Savino M. Di Stasi, and J. Alfred Witjes. "An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non–muscle-invasive bladder cancer." European urology 56, no. 2 (2009): 247-256.
- Mostafid, A. Hugh, Joan Palou Redorta, Richard Sylvester, and J. Alfred Witjes. "Therapeutic options in high-risk non–muscle-invasive bladder cancer during the current worldwide shortage of bacille Calmette-Guérin." (2015): 359-360.
- Tan, Wei Phin, Thomas A. Longo, and Brant A. Inman. "Heated intravesical chemotherapy: biology and clinical utility." Urologic Clinics 47, no. 1 (2020): 55-72.
- Colombo, Renzo, Luigi Filippo Da Pozzo, Andrea Salonia, Patrizio Rigatti, Zvi Leib, Jack Baniel, Emanuele Caldarera, and Michele Pavone-Macaluso. "Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma." Journal of clinical oncology 21, no. 23 (2003): 4270-4276.
- Lammers, Rianne JM, J. Alfred Witjes, Brant A. Inman, Ilan Leibovitch, Menachem Laufer, Ofer Nativ, and Renzo Colombo. "The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review." European urology 60, no. 1 (2011): 81-93.
- Witjes, J. Alfred, Kees Hendricksen, O. Gofrit, O. Risi, and O. Nativ. "Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo® working party." World journal of urology 27, no. 3 (2009): 319-324.
- Arends, Tom JH, Ofer Nativ, Massimo Maffezzini, Ottavio De Cobelli, Giorgio Canepa, Fabrizio Verweij, Boaz Moskovitz, Antoine G. van der Heijden, and J. Alfred Witjes. "Results of a randomised controlled trial comparing intravesical chemohyperthermia with mitomycin C versus bacillus Calmette-Guérin for adjuvant treatment of patients with intermediate-and high-risk non–muscle-invasive bladder cancer." European urology 69, no. 6 (2016): 1046-1052.
- Au, Jessie L-S., Robert A. Badalament, M. Guillaume Wientjes, Donn C. Young, Jill A. Warner, Pieter L. Venema, David L. Pollifrone et al. "Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial." Journal of the National Cancer Institute 93, no. 8 (2001): 597-604.
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