Therefore, our study aimed to determine whether the addition of intravesical electromotive drug administration of mytomicin-C (EMDA-MMC) improved the efficacy of a second BCG cycle in high-risk NMIBC who failed first BCG treatment.
We identify 80 patients with high-risk NMIBC who failed first BCG treatment, refused radical cystectomy (RC) and therefore underwent a second BCG cycle with or without intravesical EMDA-MMC from January 2014 to February 2021 at our Institution.
The BCG only re-induction cycle was carried out as the first BCG course; sequential treatment consisted of a 9-weekly course with two BCG doses followed by a third one with EMDA-MMC (41 mg MMC in 100 ml normal saline, Physion EMDA®) instillation. Systematic bladder biopsies were performed at the end of each cycle, both first and re-induction one. After the second course, if negative or yielding low-grade Ta disease, patients underwent maintenance, which consisted in monthly instillations of BCG for the BCG-only group, or the sequence of EMDA-MMC for the first two months followed by BCG for the third month, for sequential treatment. In both cases, maintenance was carried out for at least one year.
Forty four (55%) patients underwent re-induction with BCG-only (group A) and 36 (45%) with sequential treatment (group B). At a median follow-up of 38 months, recurrent HG NMIBC occurred in 67.5% and progression to MIBC in 18.8%. Twentyone (27.3%) patients underwent RC. Pathologic upstage to extravesical disease (T stage > 3) and presence of nodal metastases occurred in 6/21 (29%) and 7/21 (33%) patients respectively, and all were found in those having undergone RC for progression to MIBC. Overall, cancer-specific survival (CSS) was 88.3%. Recurrence rate and progression rate were higher in group A than in group B (71% 31/44 vs. 64% 23/36, p = 0.7; 21% vs. 17%, p = 0.5; respectively). Ta patients (Fig. 1) receiving sequential treatment had statistically better RFS and PFS survival than those receiving BCG only (all p values < 0.009); this difference did not apply to T1 patients (Fig. 1). Multivariable analysis confirmed those findings in Ta patients, where sequential treatment was a significant predictor of recurrence, and none of the variables predicted progression in both Ta and T1 tumors, although treatment was close but did not reach statistical significance (p = 0.06) in this respect.
In the past, attempts to find alternative treatments to a second BCG course have been oriented towards the use of cytotoxic intravesical therapies such as gemcitabine and valrubicin, but with little success.3-5 Promising data were recently reported using novel immunotherapies. Systemic pembrolizumab achieved a 40% complete response rate in a prospective phase II study which was maintained in 48% of patients for up to 12 months, resulting in FDA approval of the study drug for this patient population.6 Similarly, a phase III multicenter RCT using intravesical nadofaragene firadenovec demonstrated complete response in 53.4% of patients with BCG-unresponsive CIS.7 The possibility to treat BCG failures with intravesical EMDA-MMC has recently been explored by Racioppi et al. in 26 patients. At the end of 3 years follow-up, PFS was 84.6% while 10 patients (38.4%) underwent radical cystectomy. In another similar cohort of 26 patients addressed by Juvet et al., 2-years PFS and RFS rates were 48.9% and 27.2% respectively.
To our knowledge, the present study is the first comparing the efficacy of second BCG treatment with that of a sequential intravesical instillations of EMDA-MMC and BCG in the setting of HG NMIBC failing BCG treatment. To date, no doubts regarding RC as the first option in BCG-failure setting remained. Our findings could be relevant in counselling patients with this challenging clinical condition and strongly motivated to preserve their bladder, albeit higher risk of progression and recurrence.
Written by: Gian Maria Busetto, Marco Finati, Marco Chirico, Francesco Cinelli, Nicola D'Altilia, Ugo G Falagario, Francesca Sanguedolce, Francesco Del Giudice, Ettore De Berardinis, Matteo Ferro, Felice Crocetto, Angelo Porreca, Luca Di Gianfrancesco, Beppe Calo', Vito Mancini, Carlo Bettocchi, Giuseppe Carrieri, Luigi Cormio
Department of Urology, University of Foggia, Policlinico Riuniti, Via Luigi Pinto, 1, 71122, Foggia, Italy., Department of Urology, University of Foggia, Policlinico Riuniti, Via Luigi Pinto, 1, 71122, Foggia, Italy., Department of Pathology, University of Foggia, Policlinico Riuniti, Foggia, Italy., Department of Urology, Sapienza Rome University, Policlinico Umberto I, Rome, Italy., Department of Urology, European Institute of Oncology (IEO)-IRCCS, Milan, Italy., Department of Urology, University of Naples Federico II, Naples, Italy., Oncological Urology, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy., Bonomo Teaching Hospital, Andria, BAT, Italy.
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