Background: The efficacy of intravesical chemotherapy maintenance for patients with non-muscle invasive bladder cancer (NMIBC) is inferior compared to intravesical bacillus Calmette-Guerin (BCG). How intravesical chemohyperthermia (CHT) compares with BCG is under investigation. Objective: To compare the oncological outcomes and safety profile between intravesical CHT and BCG treatment for intermediate- and high-risk NMIBC. Methods: We performed a systematic review and meta-analysis of clinical studies comparing CHT with BCG for intermediate- and high-risk NMIBC patients. A comprehensive literature search on OVID MEDLINE, EMBASE, and Cochrane Library was conducted. Risk of bias was assessed by the Cochrane RoB tool and ROBINS-I. Certainty of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Results: A total of 2,375 articles were identified and five studies were finally included. Among them, four randomised trials comprising 327 patients (CHT group: 156 patients; BCG group: 171 patients) were included in the meta-analysis. There were no significant differences in the 24-36 months recurrence rates (CHT: 29.5%, BCG: 37.4%; RR: 0.83, 95% CI 0.61-1.13; moderate certainty of evidence) and the 24-36 months progression rates (CHT: 4.4%, BCG: 7.6%, RR = 0.62, 95% CI 0.26-1.49; low certainty of evidence). There were also no significant differences in grade 1-2 adverse events (CHT group: 59.9%, BCG group 54.5%; RR = 1.10, 95% CI 0.93-1.30; moderate certainty of evidence) and grade 3 or above adverse events (CHT group: 23.2%, BCG group 22.5%; RR = 0.99, 95% CI 0.69-1.43; low certainty of evidence). Conclusions: Intravesical CHT had equivalent oncological outcomes and similar safety profile when compared to BCG maintenance therapy for patients with intermediate- and high-risk NMIBC. CHT is a possible alternative treatment in the times of BCG shortage.

Department of Urology and Oncologic Urology Wrocław Medical University Wrocław Poland

Department of Urology Charles University Prague Czechia

Department of Urology Comarcal Hospital Monforte Spain

Department of Urology Hertfordshire and Bedfordshire Urological Cancer Centre Lister Hospital Stevenage School of Medicine and Life Sciences University of Hertfordshire Hatfield United Kingdom

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology Penang General Hospital George Town Malaysia

Department of Urology Radboud University Medical Centre Nijmegen Netherlands

Department of Urology Royal Free Hospital London United Kingdom

Department of Urology University College London Hospital London United Kingdom

Department of Urology University Hospital 12 de Octubre Madrid Spain

Department of Urology University Hospital of Tours Tours France

Department of Urology University of Texas Southwestern Dallas TX United States

Department of Urology Urla State Hospital Izmir Turkey

Department of Urology Weill Cornell Medical College New York NY United States

Division of Surgery and Interventional Sciences University College London London United Kingdom

Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Klinik für Urologie Luzerner Kantonsspital Lucerne Switzerland

S H Ho Urology Centre Department of Surgery The Chinese University of Hong Kong Shatin Hong Kong SAR China

School of Medicine Faculty of Medicine and Health University of Leeds Leeds United Kingdom

Unit of Urology Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona Polytechnic University of the Marche Region Ancona Italy

See more in PubMed

Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. . Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. (2013) 63:234–41. 10.1016/j.eururo.2012.07.033 PubMed DOI

Teoh JY, Huang J, Ko WY, Lok V, Choi P, Ng CF, et al. . Global trends of bladder cancer incidence and mortality, and their associations with tobacco use and gross domestic product per capita. Eur Urol. (2020) 78:893–906. 10.1016/j.eururo.2020.09.006 PubMed DOI

Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, 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) 49:466–5. 10.1016/j.eururo.2005.12.031 PubMed DOI

Cambier S, Sylvester RJ, Collette L, Gontero P, Brausi MA, van Andel G, et al. . EORTC nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1-3 years of maintenance bacillus calmette-guérin. Eur Urol. (2016) 69:60–9. 10.1016/j.eururo.2015.06.045 PubMed DOI

Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, et al. . EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol. (2017) 71:447–61. 10.1016/j.eururo.2016.05.041 PubMed DOI

Xylinas E, Kent M, Kluth L, Pycha A, Comploj E, Svatek RS, et al. . Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder. Br J Cancer. (2013) 109:1460–6. 10.1038/bjc.2013.372 PubMed DOI PMC

Oddens J, Brausi M, Sylvester R, Bono A, van de Beek C, van Andel G, et al. . Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. (2013) 63:462–72. 10.1016/j.eururo.2012.10.039 PubMed DOI

Brausi M, Oddens J, Sylvester R, Bono A, Van De Beek C, Van Andel G, et al. . Side effects of bacillus calmette-guerin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. Eur Urol. (2014) 65:69–76. 10.1016/j.eururo.2013.07.021 PubMed DOI

Ojea A, Nogueira JL, Solsona E, Flores N, Gomez JMF, Molina JR, et al. . A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus calmette-guerin (27 mg) versus very low-dose bacillus calmette-guerin (13. 5 mg) versus Mitomycin C. Eur Urol. (2007) 52:1398–406. 10.1016/j.eururo.2007.04.062 PubMed DOI

Bandari J, Maganty A, MacLeod LC, Davies BJ. Manufacturing and the Market: rationalizing the Shortage of Bacillus Calmette-Guerin. Eur Urol Focus. (2018) 4:481–4. 10.1016/j.euf.2018.06.018 PubMed DOI

Fankhauser CD, Teoh JY, Mostafid H. Treatment options and results of adjuvant treatment in nonmuscle-invasive bladder cancer (NMIBC) during the Bacillus Calmette-Guerin shortage. Curr Opin Urol. (2020) 30:365–9. 10.1097/MOU.0000000000000739 PubMed DOI

Malmstrom PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, et al. . An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol. (2009) 56:247–56. 10.1016/j.eururo.2009.04.038 PubMed DOI

Shang PF, Kwong J, Wang ZP, Tian J, Jiang L, Yang K, et al. . Intravesical Bacillus Calmette-Guerin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst Rev. (2011) CD006885. 10.1002/14651858.CD006885.pub2 PubMed DOI

Schaaf L, Schwab M, Ulmer C, Heine S, Murdter TE, Schmid JO, et al. . Hyperthermia synergizes with chemotherapy by inhibiting PARP1-dependent DNA replication arrest. Cancer Res. (2016) 76:2868–75. 10.1158/0008-5472.CAN-15-2908 PubMed DOI

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. (2009) 339:b2535. 10.1136/bmj.b2535 PubMed DOI PMC

National Cancer Institute . Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Available online at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf (accessed December 12, 2020).

Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. (2007) 8:16. 10.1186/1745-6215-8-16 PubMed DOI PMC

Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0. 0 [updated February 2008]. London: The Cochrane Collaboration; (2008).

Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. . RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. (2019) 366:l4898. 10.1136/bmj.l4898 PubMed DOI

Nasser M. Cochrane handbook for systematic reviews of interventions. Am J Public Health. (2020) 110:753–4. 10.2105/AJPH.2020.305609 PubMed DOI

Sterne JAC, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. . ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. Brit Med J. (2016) 355:i4919. 10.1136/bmj.i4919 PubMed DOI PMC

Schünemann H, Brozek J, Guyatt G, Oxman A. GRADE Handbook. Available online at: https://gdt.gradepro.org/app/handbook/handbook.html#h.ged5uqebmir9 (accessed August 8, 2021).

Debruyne FM, van der Meijden AP, Franssen MP. BCG-(RIVM) versus mitomycin intravesical therapy in patients with superficial bladder cancer. EORTC GU Group and the Dutch South-East Collaborative Group. Prog Clin Biol Res. (1989) 303:435. PubMed

Tan WS, Panchal A, Buckley L, Devall AJ, Loubiere LS, Pope AM, et al. . Radiofrequency-induced thermo-chemotherapy effect versus a second course of bacillus calmette-guerin or institutional standard in patients with recurrence of non-muscle-invasive bladder cancer following induction or maintenance bacillus calmette-guerin therapy (HYMN): a phase III, open-label, randomised controlled trial. Eur Urol. (2019) 75:63–71. 10.1016/j.eururo.2018.09.005 PubMed DOI

Arends TJ, Nativ O, Maffezzini M, de Cobelli O, Canepa G, Verweij F, et al. . Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guerin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. Eur Urol. (2016) 69:1046–52. 10.1016/j.eururo.2016.01.006 PubMed DOI

Sousa A, Gonzalez-Valcarcel I, Mata JL, De La Morena JM, Martinez-Pineiro L. Chemo-resection with hyperthermic intravesical instillation (HIVEC-R) vs standard treatment in patients with intermediate-high risk NMIBC: comparative, prospective, randomized, controled study of efficacy and tolerability: preliminary results. J Urol. (2020) 203:e1123. 10.1097/JU.0000000000000959.06 DOI

Guerrero-Ramos* F, González-Padilla Daniel A, González-Díaz A, Duarte-Ojeda José M, Miranda-Utrera N, Villacampa-Aubá F, et al. . MP43-08 BCG vs chemohyperthermia with mitomycin c for high-risk non-muscle invasive bladder carcinoma: preliminary results of hivec-hr randomized clinical trial. J Urol. (2019) 201:e620–e. 10.1097/01.JU.0000556231.44325.78 DOI

Ekin RG, Akarken I, Zorlu F, Tarhan H, Kucuk U, Yildirim Z, et al. . Intravesical bacillus Calmette-Guerin versus chemohyperthermia for high-risk non-muscle-invasive bladder cancer. Can Urol Assoc J. (2015) 9:E278–83. 10.5489/cuaj.2708 PubMed DOI PMC

Cabas P, Rizzo M, Giuffrè M, Antonello RM, Trombetta C, Luzzati R, et al. . BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review. Urol Oncol. (2020) 39:85–92. 10.1016/j.urolonc.2020.11.037 PubMed DOI

Serretta V, Scalici Gesolfo C, Alonge V, Cicero G, Moschini M, Colombo R. Does the compliance to intravesical BCG differ between common clinical practice and international multicentric trials? Urol Int. (2016) 96:20–4. 10.1159/000430501 PubMed DOI

Alcorn J, Burton R, Topping A. Patterns of patient withdrawal from BCG treatment for bladder cancer: a retrospective time interval analysis. Int J Urol Nurs. (2019) 13:63–74. 10.1111/ijun.12191 DOI

Westra A, Dewey WC. Variation in sensitivity to heat shock during the cell-cycle of Chinese hamster cells in vitro. Int J Radiat Biol Relat Stud Phys Chem Med. (1971) 19:467–77. 10.1080/09553007114550601 PubMed DOI

Mantso T, Goussetis G, Franco R, Botaitis S, Pappa A, Panayiotidis M. Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies. Semin Cancer Biol. (2016) 37–38:96–105. 10.1016/j.semcancer.2016.03.004 PubMed DOI

Tan WS, Kelly JD. Intravesical device-assisted therapies for non-muscle-invasive bladder cancer. Nat Rev Urol. (2018) 15:667–85. 10.1038/s41585-018-0092-z PubMed DOI

Lefor AT, Makohon S, Ackerman NB. The effects of hyperthermia on vascular permeability in experimental liver metastasis. J Surg Oncol. (1985) 28:297–300. 10.1002/jso.2930280412 PubMed DOI

Song CW. Effect of hyperthermia on vascular functions of normal tissues and experimental tumors; brief communication. J Natl Cancer Inst. (1978) 60:711–3. 10.1093/jnci/60.3.711 PubMed DOI

Kampinga HH. Cell biological effects of hyperthermia alone or combined with radiation or drugs: a short introduction to newcomers in the field. Int J Hyperthermia. (2006) 22:191–6. 10.1080/02656730500532028 PubMed DOI

Milani V, Noessner E, Ghose S, Kuppner M, Ahrens B, Scharner A, et al. . Heat shock protein 70: role in antigen presentation and immune stimulation. Int J Hyperthermia. (2002) 18:563–75. 10.1080/02656730210166140 PubMed DOI

Brace CL. Radiofrequency and microwave ablation of the liver, lung, kidney, and bone: what are the differences? Curr Probl Diagn Radiol. (2009) 38:135–43. 10.1067/j.cpradiol.2007.10.001 PubMed DOI PMC

Li K, Lin T, Chinese Bladder Cancer C, Xue W, Mu X, Xu E, et al. . Current status of diagnosis and treatment of bladder cancer in China–analyses of Chinese Bladder Cancer Consortium database. Asian J Urol. (2015) 2:63–9. 10.1016/j.ajur.2015.04.016 PubMed DOI PMC

Tan WS, Palou J, Kelly J. 662–Safety and tolerability analysis of hyperthermic intravesical mitomycin to mitomycin alone in HIVEC I and HIVEC II: An interim analysis of 307 patients. Eur Urol Suppl. (2017) 16:e1150–1. 10.1016/S1569-9056(17)30717-0 DOI