In 2016, the International Bladder Cancer group revamped BCG failure nomenclature [1]. They developed four distinct definitions for classifying BCG failure: (i) refractory – persistent high-grade disease at six months despite adequate BCG treatment, or any stage or grade progression by three months after the first BCG cycle; (ii) relapsing – recurrence of high-grade disease after achieving a disease-free state at six months after BCG; (iii) intolerant – disease persistence as a result of inability to receive adequate BCG therapy secondary to toxicity; (iv) unresponsive – BCG refractory and BCG relapsing disease, denoting a subgroup of patients that are at highest risk of recurrence/progression for whom additional BCG is not feasible.
The EAU and AUA guidelines suggest that high-risk recurrent disease should be recommended for radical cystectomy secondary to the poor long-term outcomes for these patients. Alternative therapies for these patients include chemotherapy, device assisted therapy, and clinical trials. Historical studies have suggested that conventional single chemotherapy agents (BCG re-induction, IFNa, mitomycin, valrubicin) do not work well when cancer recurs after BCG induction. Novel agents include gemcitabine, which has been studied as an intravesical chemotherapeutic option, with 2-year disease free rates of 21% and minimal toxicity. The recent Spanish CUETO 93009 RCT randomized patients to receive sequential MMC (1-day prior) and BCG (n=222) compared to BCG therapy alone (n=221) [2]. Patients treated with sequential therapy experienced an improved 5-year DFI (HR 0.57; p=0.003) compared to BCG therapy alone, although with 17.4% higher grade 3 toxicity, even after MMC dose reduction. Although these results are encouraging, increased toxicity may arguably limit sequential therapy from being widely adopted.
Chemohyperthermia includes delivery of hyperthermic chemotherapy with temperatures of 41-44ºC. The hypothesized mechanism is that there is a direct cytotoxic effect and hyperthermia enhances penetration of chemotherapeutic agent into the bladder wall with hyperthermia. Two common hyperthermia systems include Synergo and Combat BRS. Synergo is an intravesical microwave applicator, with five thermocouplers deliver hyperthermia to the bladder via direct contact. Combat BRS is a bladder recirculation system which acts as an external warmer. A recently published clinical trial randomized patients to chemotherapy with mitomycin C or chemotherapy with BCG [3]. The 24-month intention to treat RFS was 78.1% in the chemotherapy group compared with 64.8% in the BCG group (p=0.08). The 24-month RFS in the per-protocol analysis was 81.8% in the chemotherapy group compared with 64.8% in the BCG group (p=0.02). Progression rates were <2% in both groups. Regarding the side-effects, no new safety concerns were identified. A concern is that this study closed prematurely and thus is underpowered. Furthermore, blinding of treatment for patients and physicians was impossible.
Photodynamic therapy combines photosensitizers that selectively bind to bladder tumors and a powerful intravesical light source to destroy a complex of tumor and photo sensitizers. The high level of toxicity (skin hypersensitivity, excessive cardiotoxicity, detrusor scarring) limit the wide use in the bladder cancer population.
There are several checkpoint inhibitor trials ongoing. Atezolizumab in patients with PD-L1 antibody is an adjuvant therapy in patients with PD-L1 positive, high-risk muscle invasive bladder after surgery to removal all or part of the bladder. Atezolizumab was designative for breakthrough therapy with the FDA for bladder cancer.
Several authors have advocated for dose reduction BCG therapy. When comparing 1/3 dose vs full dose was assessed, in intention-to-treat analysis of 1355 patients with a median follow-up of 7.1 years, there were no significant differences in toxicity between 1/3 dose and full dose [4]. The null hypotheses of inferiority of the disease-free interval for both 1/3 dose and 1 year could not be rejected. 1/3 dose-1 year is suboptimal compared with full dose-3 year (HR 0.75; 95%CI, 0.59-0.94; p=0.01). Intermediate-risk patients treated with full dose do not benefit from an additional 2-year of BCG. In high-risk patients, 3-year maintenance is associated with a reduction in recurrence (HR: 1.61; 95% CI, 1.13-2.30; p=0.009) but only when given at full dose.
Dr. Kang concluded with several take home points:
- Traditional 2nd line single agent chemotherapy is an alternative, but few respond
- Mitomycin the day prior to BCG seems to be the most effective combination but is toxic
- Device assisted intravesical chemotherapy becomes common but larger trial data is needed
- New immunotherapy options have been successful for advanced bladder cancer – trials in BCG-unresponsive NMIBC are ongoing
Presented by: Seok Ho Kang, Korea University College of Medicine, Seoul, Republic of Korea
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, twitter: @zklaassen_md at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark
References:
1. Kamat AM, Sylvester RJ, Bohle A, et al. Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group. J Clin Oncol. 2016;34:1935-44.
2. Solsona E, Madero R, Chantada V, Fernandez JM, Zabala JA, Portillo JA, et al. Sequential combination of mitomycin C plus bacillus Calmette-Guerin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial. Eur Urol. 2015;67:508-16.
3. Arends T, Nativ O, Maffezzini M, et al. Results of a randomized 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(6):1046-1052.
4. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermedia- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-thrid dose versus full dose and 1 year and versus 3 years maintenance. Eur Urol 2013;63(3):462-472.