Introduction: Hyperthermic mitomycin (HM) is a novel treatment modality for selected patients with high-risk non-muscle invasive bladder cancer (NMIBC). We sought to determine predictors of response to this therapy. Patients and Methods: A longitudinal, cohort study of 97 patients with high-risk NMIBC treated with ≥4 HM instillations on a prophylactic schedule was conducted. The primary outcome was time-to-progression survival; secondary outcomes were overall survival, cancer-specific survival, and adverse events. Descriptive statistics, Kaplan-Meier survival analyses, Cox proportional hazards modelling, and univariate and multivariable regression were performed. Results: The presence of initial complete response (CR; no evidence of disease at first check video-cystoscopy and urine cytology) post-HM treatment was an independent predictor of good response to HM. Female patients and those without carcinoma in situ (CIS) also appeared to respond better to the intervention. The overall bladder preservation rate at a median of 27 months was 81.4%; 17/97 (17.5%) patients died during the course of the study. Conclusions: High-risk NMIBC patients can be safely treated with HM and have good oncological outcome. However, those without an initial CR have a poor prognosis and should be counselled towards adopting other treatment methodologies such as cystectomy. Female gender and lack of CIS may be good prognostic indicators for response to HM.

Keywords:
Hyperthermic mitomycin, High-risk non-muscle invasive bladder cancer
1.
Rampersaud EN, Vujaskovic Z, Inman BA: Hyperthermia as a treatment for bladder cancer. Oncology (Williston Park) 2010;24:1149-1155.
2.
Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R: The health economics of bladder cancer: a comprehensive review of the published literature. PharmacoEconomics 2003;21:1315-1330.
3.
Sylvester RJ, van der Meijden AP, 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;49:466-475; discussion 475-477.
4.
Freeman JA, Esrig D, Stein JP, et al: Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 1995;76:833-839.
5.
Nadler RB, Catalona WJ, Hudson MA, Ratliff TL: Durability of the tumor-free response for intravesical bacillus Calmette-Guerin therapy. J Urol 1994;152(2 pt 1):367-373.
6.
Witjes JA, Hendricksen K: Intravesical pharmacotherapy for non-muscle-invasive bladder cancer: a critical analysis of currently available drugs, treatment schedules, and long-term results. Eur Urol 2008;53:45-52.
7.
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;63:466-471.
8.
Colombo R, Salonia A, Leib Z, Pavone-Macaluso M, Engelstein D: Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). BJU Int 2011;107:912-918.
9.
Lammers RJ, Witjes JA, Inman BA, et al: The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review. Eur Urol 2011;60:81-93.
10.
van der Heijden AG, Verhaegh G, Jansen CF, Schalken JA, Witjes JA: Effect of hyperthermia on the cytotoxicity of 4 chemotherapeutic agents currently used for the treatment of transitional cell carcinoma of the bladder: an in vitro study. J Urol 2005;173:1375-1380.
11.
Paroni R, Salonia A, Lev A, et al: Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. Br J Clin Pharmacol 2001;52:273-278.
12.
Herr HW, Sogani PC: Does early cystectomy improve the survival of patients with high risk superficial bladder tumors? J Urol 2001;166:1296-1299.
13.
Babjuk M, Burger M, Zigeuner R, et al: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013;64:639-653.
14.
Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-383.
15.
Stoltzfus JC: Logistic regression: a brief primer. Acad Emerg Med 2011;18:1099-1104.
16.
Shuster JJ: Median follow-up in clinical trials. J Clin Oncol 1991;9:191-192.
17.
MacLennan GT, Kirkali Z, Cheng L: Histologic grading of noninvasive papillary urothelial neoplasms. Eur Urol 2007;51:889-897; discussion 897-898.
18.
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;21:4270-4276.
19.
Colombo R, Da Pozzo LF, Lev A, et al: Local microwave hyperthermia and intravesical chemotherapy as bladder sparing treatment for select multifocal and unresectable superficial bladder tumors. J Urol 1998;159:783-787.
20.
Moskovitz B, Meyer G, Kravtzov A, et al: Thermo-chemotherapy for intermediate or high-risk recurrent superficial bladder cancer patients. Ann Oncol 2005;16:585-589.
21.
Nativ O, Witjes JA, Hendricksen K, et al: Combined thermo-chemotherapy for recurrent bladder cancer after bacillus Calmette-Guerin. J Urol 2009;182:1313-1317.
22.
Halachmi S, Moskovitz B, Maffezzini M, et al: Intravesical mitomycin C combined with hyperthermia for patients with T1G3 transitional cell carcinoma of the bladder. Urol Oncol 2011;29:259-264.
23.
van der Heijden AG, Kiemeney LA, Gofrit ON, et al: Preliminary European results of local microwave hyperthermia and chemotherapy treatment in intermediate or high risk superficial transitional cell carcinoma of the bladder. Eur Urol 2004;46:65-71; discussion 71-72.
24.
Arends TJ, van der Heijden AG, Witjes JA: Combined chemohyperthermia: 10-year single center experience in 160 patients with nonmuscle invasive bladder cancer J Urol 2014;192:708-713.
25.
van Rhijn BW, Burger M, Lotan Y, et al: Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 2009;56:430-442.
26.
Maffezzini M, Campodonico F, Canepa G, Manuputty EE, Tamagno S, Puntoni M: Intravesical mitomycin C combined with local microwave hyperthermia in non-muscle-invasive bladder cancer with increased European organization for research and treatment of cancer (EORTC) score risk of recurrence and progression. Cancer Chemother Pharmacol 2014;73:925-930.
27.
Cookson MS, Chang SS, Wells N, Parekh DJ, Smith JA Jr: Complications of radical cystectomy for nonmuscle invasive disease: comparison with muscle invasive disease. J Urol 2003;169:101-104.
28.
Volpe A, Racioppi M, Bongiovanni L, et al: Thermochemotherapy for non-muscle-invasive bladder cancer: is there a chance to avoid early cystectomy? Urol Int 2012;89:311-318.
29.
Kiss B, Schneider S, Thalmann GN, Roth B: Is thermochemotherapy with the Synergo system a viable treatment option in patients with recurrent non-muscle-invasive bladder cancer? Int J Urol 2015;22:158-162.
30.
Chen C, Qi XJ, Cao YW, et al: Bladder tumor heterogeneity: the impact on clinical treatment. Urol Int 2015, Epub ahead of print.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.