Intravesical chemotherapy with mitomycin C (MMC) or gemcitabine is frequently used immediately following TURBT to reduce the risk of recurrence in patients with presumed low-grade NMIBC. However, the use of these therapies for preventing recurrence in intermediate or high-risk patients is limited to cases of BCG-refractory disease or times of BCG shortage due to inferior efficacy. Various strategies have been used in an effort to boost the anti-tumor activity of these chemotherapies, including the application of heat to the intravesical solution. Different from thermal ablation, where intense heat is used to directly kill tumor cells, hyperthermia (HT) utilizes mildly elevated temperatures (40-44°C) to achieve its effects. HT is theorized to work through multiple mechanisms including improving drug delivery, creation of an unfavorable metabolic environment for tumor cell survival, intensifying local immune system activity, and increasing drug sensitivity.1-3
Hyperthermic intravesical chemotherapy (HIVEC) with MMC has been studied as a chemoablative therapy as well as in the adjuvant setting following TURBT, and the literature suggests that in both settings HIVEC MMC is safe, well-tolerated, and efficacious. Chemoablation refers to treatment in the absence of, or prior to, TURBT. Five phase I/II clinical trials have been conducted to evaluate HIVEC MMC as a chemoablative treatment with complete response rates ranging from 53-75% and recurrence rates of 13-39% with a median follow-up of 15-39 months.4-8 One notable trial compared MMC HIVEC to traditional MMC and MMC with electromotive drug administration (EMDA), and MMC HIVEC had higher complete response rates than the other therapies (66% MMC HIVEC, 22% MMC alone, 40% MMC with EMDA).6
There have been several reports of the use of MMC HIVEC for the treatment of NMIBC in the adjuvant setting, including three phase III clinical trials. The first phase III trial by Colombo et al suggested that MMC HIVEC was more effective than MMC without hyperthermia.9 The subsequent trial by Arends et al compared HIVEC MMC to intravesical BCG for intermediate- and high-risk NMIBC and found comparable effectiveness between the two therapies, and even a suggestion that HIVEC MMC was superior to BCG in preventing recurrence of papillary tumors when using a per-protocol analysis.10 The latest trial by Tan et al again compared HIVEC MMC to BCG, this time in patients with recurrence following initial BCG therapy, and again found the two treatments to be similar in efficacy.11 In all published literature on MMC HIVEC, the treatment has been generally well-tolerated with a Grade 3 or higher adverse event rate of 10-12%. Bothersome LUTS, infection, hematuria, and allergic reaction are the most clinically relevant adverse events and resolve with cessation of treatment.
To add to the literature, our group recently reported on an additional series of fourteen patients with intermediate or high-risk NMIBC treated with high-dose (120mg/60mL) HIVEC MMC due to the global BCG shortage.12 The treatment was generally safe and well-tolerated without any Grade 3 or higher adverse events. In addition, with follow-up approaching 12-months since the last treatment, oncologic outcomes are favorable with only two patients experiencing recurrence, both of whom were unable to tolerate the full allotment of treatments due to side effects. Among patients who completed treatments, no recurrences have occurred.
Overall, there is robust literature suggesting that hyperthermia enhances the efficacy of intravesical MMC for the treatment of NMIBC. Future studies need to further refine optimal treatment doses and schedules for HIVEC MMC, as well as begin to evaluate other chemotherapeutic agents in the setting of hyperthermia, such as gemcitabine.
Written by: Scott P. Campbell MD, Brant A. Inman MD, MS, Duke University Medical Center, Durham, NC
- Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol. 2002;43(1):33-56.
- Frey B, Weiss EM, Rubner Y, et al. Old and new facts about hyperthermia-induced modulations of the immune system. Int J Hyperthermia. 2012;28(6):528-542.
- Schildkopf P, Ott OJ, Frey B, et al. Biological rationales and clinical applications of temperature controlled hyperthermia--implications for multimodal cancer treatments. Current medicinal chemistry. 2010;17(27):3045-3057.
- Colombo R, Lev A, Da Pozzo LF, Freschi M, Gallus G, Rigatti P. A new approach using local combined microwave hyperthermia and chemotherapy in superficial transitional bladder carcinoma treatment. J Urol. 1995;153(3 Pt 2):959-963.
- Colombo R, Da Pozzo LF, Lev A, Freschi M, Gallus G, Rigatti P. Neoadjuvant combined microwave induced local hyperthermia and topical chemotherapy versus chemotherapy alone for superficial bladder cancer. J Urol. 1996;155(4):1227-1232.
- Colombo R, Brausi M, Da Pozzo L, et al. Thermo-chemotherapy and electromotive drug administration of mitomycin C in superficial bladder cancer eradication. a pilot study on marker lesion. Eur Urol. 2001;39(1):95-100.
- Gofrit ON, Shapiro A, Pode D, et al. Combined local bladder hyperthermia and intravesical chemotherapy for the treatment of high-grade superficial bladder cancer. Urology. 2004;63(3):466-471.
- Sousa A, Inman BA, Piñeiro I, et al. A clinical trial of neoadjuvant hyperthermic intravesical chemotherapy (HIVEC) for treating intermediate and high-risk non-muscle invasive bladder cancer. Int J Hyperthermia. 2014;30(3):166-170.
- Colombo R, Da Pozzo LF, Salonia A, et al. Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol. 2003;21(23):4270-4276.
- Arends TJ, Nativ O, Maffezzini M, et al. 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. Eur Urol. 2016;69(6):1046-1052.
- Tan WS, Panchal A, Buckley L, et al. Radiofrequency-induced Thermo-chemotherapy Effect Versus a Second Course of Bacillus Calmette-Guérin or Institutional Standard in Patients with Recurrence of Non-muscle-invasive Bladder Cancer Following Induction or Maintenance Bacillus Calmette-Guérin Therapy (HYMN): A Phase III, Open-label, Randomised Controlled Trial. Eur Urol. 2019;75(1):63-71.
- 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. Urologic oncology. 2021.
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