(UroToday.com) The Canadian Urological Association joint session with the European Association Urology (EAU) at the 2021 annual EAU virtual meeting included a presentation by Dr. J. Alfred Witjes who discussed shorter maintenance regimens for patients receiving BCG therapy. When the guidelines discuss BCG “and/or alternative treatments”, this is an issue for patients with higher-end intermediate-risk NMIBC, high-risk NMIBC, the highest risk patients, and those that are failing BCG.
So, how maintenance is maintenance? Oddens et al.1 assess whether a one-third dose is not inferior to the full dose, if 1 year of maintenance is not inferior to 3 years of maintenance, and if one-third dose and 1 year of maintenance were associated with less toxicity among patients enrolled in EORTC 30962. The analysis included 1,355 patients with a median follow-up of 7.1 years, over which there were no significant differences in toxicity between one-third dose and full dose. However, one-third dose for 1 year was suboptimal compared with full dose for three years (HR 0.75, 95% CI, 0.59-0.94). Intermediate-risk patients treated with full dose BCG do not benefit from an additional 2 years of BCG, and in high-risk patients, 3 years of 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.
Over the last several years, safe options for giving less BCG than the SWOG maintenance schedule have emerged in order to “save” BCG. Safe options include:
- 1 year of maintenance instead of 3 years (more recurrences, but not more progressions)
- 2 instead of 3 maintenance treatments
- Maintenance therapy with 1/3 dose (more recurrences, not more progressions)
- For CIS, maintenance therapy should include 3 years, with 1 year at full dose and 1/3 dose given at year 2 and 3
Based on recommendations from the FDA and the International Bladder Cancer Group, adequate BCG therapy is defined as at least one of the following: at least five of six doses of an initial induction course of BCG plus at least two of three doses of maintenance therapy. Although it may be reasonable to decrease BCG maintenance therapy, it is important to not reduce dose/frequency too much.
With regards to side effects and patient compliance, less BCG toxicity is associated with better treatment. Prevention of toxicity does not include INH but rather ofloxacin is given 6 hours and 18 hours after BCG (improves tolerance and reduces dropout), which has also been validated with prulifloxin. Additionally, other ways to reduce toxicity include reducing dwell time, fewer instillations per course (omit the last dose), shorten treatment time (1 year instead of 3 years), and decrease the dose (1/3 dosing).
Mitomycin C has also been considered for intravesical chemotherapy and has been compared to BCG therapy. Malmstrom et al.,2 in 2009, performed an individual patient data meta-analysis of nine trials (n=2,820), finding that over a median follow-up of 4.4 months, 43% of patients recurred. Overall, there was no difference in the time to first recurrence (p=0.09) between BCG and MMC. In the trials with BCG maintenance, a 32% reduction in risk of recurrence on BCG compared to MMC was found (p<0.0001), while there was a 28% risk increase (p=0.006) for BCG in the trials without maintenance. As follows is a Forest plot of time to first recurrence by study:2
Chemotherapy combinations have also been considered, including intravesical gemcitabine plus docetaxel (with maintenance), which has been assessed retrospectively. Steinberg et al.3 reported the results of a multi-institutional analysis, including 276 patients that received treatment from 2009 to 2018. Over a median follow-up of 22.9 months, 1- and 2-year recurrence-free survival rates were 60% and 46%, and high-grade recurrence-free survival rates were 65% and 52%, respectively. Ten patients (3.6%) had disease progression on transurethral resection, and 43 patients (15.6%) went on to cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasion.
More recently, immunotherapy, specifically nadofaragene firadenovec, has been assessed in BCG unresponsive patients.4 Nadofaragene firadenovec is a non-replicating recombinant type-5 adenovirus vector-based gene therapy that delivers a copy of the human IFNα2b gene. Adenoviruses provide short-term, high but transient expression of the gene of interest in a relatively broad range of host cells. The Phase III trial of nadofaragene firadenovec for BCG unresponsive NMIBC was a multi-center study to investigate the safety and efficacy of intravesical nadofaragene firadenovec once every 3 months in 157 patients with high-grade, BCG-unresponsive NMIBC. Cytology and cystoscopy (with biopsy if clinically indicated) were performed at 3, 6, and 9 months to evaluate for recurrence of high-grade disease. At 12 months, all patients underwent urine cytology, cystoscopy, and mandatory biopsy. Patients free from high-grade recurrence were eligible for retreatment at 3-month intervals while they remained high-grade recurrence-free. The study met its primary endpoint with 53.4% of patients with CIS ± Ta/T1 achieving a complete response, all by 3 months, including 43.6% of these patients remaining free of high-grade recurrence at 15 months.
Device-assisted therapy has also recently gained attention, including conductive chemo-hyperthermia (Hyvec), and radiofrequency induced thermo-chemotherapy. Dr. Witjes highlighted that his group recently published their updated experience of 274 patients (234 were BCG pre-treated) treated with hyperthermia with Mitomycin C (n=239) or epirubicin (n=35).5 For patients with CIS, the 6-month complete response rate was 56.0%, and durable response rates were 79.7%, 66.5%, and 40.3% at one-, two- and five-year, respectively. Recurrence-free survival rates for papillary patients were 77.9%, 57.5%, and 37.2%, respectively.
Dr. Witjes notes that the future is most likely to include checkpoint inhibitors, including PD(L)-1 antagonists and CTLA-4 blockers. Indeed, the recently published KEYNOTE-057 trial of pembrolizumab for patients with BCG unresponsive CIS reported a 38.8% complete response rate at 3 months, of which 72.5% remained with complete response after a median of 14 months of follow-up.6 Based on these results, FDA approval for BCG unresponsive CIS was granted in January 2020.
Dr. Witjes concluded his presentation with the following take-home messages:
- Alternatives to full dose, 3-years of maintenance BCG include using chemotherapy in intermediate-risk patients, and adjusting the schedule to less BCG and/or less instillations (but not too few)
- For high-risk patients, other options include gemcitabine (combination with docetaxel), intravesical virus (nadofaragene firadenovec) in the near future, intravesical radiofrequency induced thermos-chemotherapy (if available), checkpoint inhibitors (ie. pembrolizumab), and radical cystectomy.
Presented by: J. Alfred Witjes, MD, PhD, Radboud University Medical Center, Nijmegen, Netherlands
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.
References:
- Oddens J, Brausi M, Sylvester R, 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 Mar;63(3):462-472.
- Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomized studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol. 2009 Aug;56(2):247-256.
- Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institutional Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer. J Urol. 2020 May;203(5):902-909.
- Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2020 Nov 27:S1470-2045(20)30540-4.
- Brummelhuis ISG, Wimper Y, Witjes-van Os HGJM, et al. Long-term experience with radiofrequency-induced hyperthermia combined with intravesical chemotherapy for non-muscle invasive bladder cancer. Cancers (Basel). 2021 Jan 20;13(3):377.
- Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): An open-label, single-arm, multicenter, phase 2 study. Lancet Oncol. 2021 May 26;S1470-2045(21)00147-9.