Control of Non-Muscle Invasive Bladder Cancer Recurrence With TURBT and Beyond

Jacques Irani, MD, PhD

“The aim of treating NMIBC is avoid the loss of the bladder and to prevent recurrence and progression to muscle-invasive disease,” said Jacques Irani, MD, PhD, during a presentation at the 2017 Global Congress on Bladder Cancer.

Irani discussed the treatment and management of non-muscle invasive bladder cancer (NMIBC), which comprises 75% of bladder cancer cases. NMIBC is staged Tis, Ta, and T1 with an incidence in this patient population of 10%, 70%, and 20%, respectively.

“Foremost is to counsel smokers with confirmed bladder cancer to stop smoking,” emphasized Irani, of the Bicêtre Hospital, Universitie Paris-Sud, in Paris, France.

Management of NMIBC begins with standard initial treatment using transurethral resection of bladder tumor (TURBT), an in-office endoscopic treatment to diagnose, stage, and treat small, visible tumors.

“There is no optimal intra-vesicle instillation without a first optimal TURBT,” he commented.

Following TURBT, intra-vesicle instillation and monitoring are employed to prevent recurrence or to control low-risk lesions. Although many drugs are under investigation, including valrubicin, gemcitabine, taxanes, interferon, and apaziquone (EOquin; Qapzola), the standard chemotherapy currently used is mytomycin C, with alternate choices of epirubicin (Ellence) or doxorubicin (Adriamycin).

Irani commented: “There is no optimal intravascular treatment because there is no one type of NMIBC or one type of patient; several approaches are being used.”

Intra-vesicle immunotherapy may also be used in early-stage NMIBC, which consists of directly inserting the live Bacillus Chalmette-Guerin (BCG) vaccine into the bladder through a catheter, causing cells of the immune system to converge on the bladder and be activated by the BCG to attack the bladder cancer cells. Although BCG can be used for long-term maintenance, its use may be limited by unavailability or patient intolerance, according to Irani.

He outlined a trial being conducted by his team that is currently enrolling patients with recurrent or BCG-refractory NMIBC that is studying a combined immunotherapy approach. Patients will receive pembrolizumab (Keytruda) on day 14 following TURBT during a pre-induction phase, followed by an induction phase of combined pembrolizumab and BCG weekly for 6 weeks, then maintenance with pembrolizumab every 2 weeks for a total of 6 doses, followed by every-4-week dosing, all delivered intravesically.

Intra-vesicle installations deliver the chemotherapy or immunotherapy directly into the blabber via catherization and currently used approaches may involve electromotive drug administration (EMDA) that may be delivered with or without heat or be device assisted. With EMDA, either BCG or mytomycin is delivered without hyperthermia. Sole BCG was compared to BCG plus electromotive mytomycin in a randomized controlled trial that demonstrated that patients receiving the combination experienced lower recurrence rates (41.9% vs 57.9% with BCG alone; log-rank P = .0012).¹

These investigators also found that EMDA of mytomycin immediately prior to TURBT provided a lower rate of recurrence (38%) compared with patients receiving mytomycin after TURBT (59%) and compared with those receiving TURBT alone (64%; log-rank P <.0001).²

Chemotherapy is also delivered with hyperthermia, based on findings that bladder cells were more sensitive to antibiotics at 43°C resulting in synergism between the hyperthermia and the drug.³

“Promising data have been reported on enhancing the efficacy of mytomycin C using microwave-induced hyperthermia in patients with high-risk tumors,” Irani said. An example he gave was the Synergo method, in which the bladder wall is first heated using radiofrequency followed by intravesical delivery of mytomycin C or BCG.

A randomized controlled trial of radiofrequency-induced thermochemotherapeutic effect (RITE) demonstrated that chemohyperthermia with mytomycin C was feasible and provided a higher rate of recurrence-free survival at 24 months over BCG (81.8% vs 64.8% per protocol, respectively; P = .02).⁴

A variation of chemohyperthermia, according to Irani, is hyperthermic intravesical chemotherapy (HIVEC). This approach recirculates mytomycin C between the bladder and a device that heats the drug to 43°C. Initial efficacy data are promising and show that the approach is safe and well tolerated, but final results are still awaited.

Irani discussed a head-to-head comparison trial of hyperthermia plus mytomycin C versus mytomycin C monotherapy that ends recruitment this month, which may resolve the optimal use of mytomycin C for NMIBC. “Different technologies which increase the temperature of instilled mytomycin C are available, but data about their efficacy are still lacking,” he summarized.

Irani reviewed a case history of a 72-year-old woman who had been an active smoker, and had a single 1-cm papillary growth on the left bladder wall that had been completely resected. He polled the audience on whether they agreed that 1 installation of mytomycin C following TURBT was appropriate; 96% of the audience was in agreement.

He then provided data supporting a single post-operative installation of chemotherapy for several trials showing this was superior to TURBT alone.⁵

Further study evaluating the optimal timing of post-operative chemotherapeutic installation showed that chemotherapy should be delivered within 24 hours and optimally within 6 hours of TURBT.⁶

“A single installation has demonstrated a low rate of recurrence in patients with NMIBC compared to TURBT alone but is contraindicated in the presence of bladder perforation or extensive tumor,” he remarked.

Another ongoing trial from his team is a phase II trial evaluating immediate pre-operative instillation of mytomycin C as compared to early post-operative instillation in patients with NMIBC (NCT02075060).

References

1. Di Stasi SM, Giannantoni A, Giurioli A, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol. 2006;7(1):43-51. doi: 10.1016/S1470-2045(05)70472-1.
2. Di Stasi SM, Valenti M, Verri C, et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial. Lancet Oncol. 2011;12(9):871-879. doi: 10.1016/S1470-2045(11)70190-5.
3. Hahn GM, Braun J, Har-Kedar I. Thermochemotherapy: synergism between hyperthermia (42-43 degrees) and adriamycin (of bleomycin) in mammalian cell inactivation. Proc Natl Acad Sci U S A. 1975;72(3):937-940.
4. 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. doi: 10.1016/j.eururo.2016.01.006.
5. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol. 2004;171(6 Pt 1):2186-2190.
6. Kaasinen E, Rintala E, Hellström P, et al; FinnBladder Group. Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma. Eur Urol. 2002;42(2):167-174.