Urology guidelines recommend radical cystectomy (RC) after BCG failure in high-risk NMIBC. RC is surgically a highly destructive procedure with significant morbidity and mortality rates related to drastic lifestyle changes. While not all patients are fit for or accept radical cystectomy, bladder-sparing medical treatment for BCG-failure patients still represents an open issue.
Conservative treatments for BCG failure HR NMIBC include repeated BCG induction and maintenance therapy, intravesical chemotherapy, and device-assisted therapies aimed at improving the efficacy of intravesical treatment presented suboptimal results in terms of survival analysis.
The first intravesical chemotherapy approved by the US Food and Drug Administration (FDA) for the treatment of BCG-failure carcinoma in situ (CIS) was valrubicin and its use was limited due to its low availability and negligible efficacy. At the beginning of this year, the FDA approved pembrolizumab (KEYTRUDA®, Merck & Co. Inc.) in this setting. Pembrolizumab is an immune checkpoint inhibitor that has been investigated in patients with BCG-unresponsive HR NMIBC characterized as the presence of CIS with or without papillary tumors who are unfit for RC. In the KEYNOTE-057 trial, pembrolizumab showed a complete response of 41% at 3 months, with a durable response at 12 months in approximately 19% of patients. Adverse events of pembrolizumab are not negligible and it requires intravesical access such as chemotherapies.
While waiting for confirmatory results of a new intravesical compound, ONCOFID-P-B, showing exciting findings at the end of Phase I trial, conservative approaches remain welcome.
Gemcitabine (20,20-difluorodeoxycytidine) is a widely recognized chemotherapeutic agent that inhibits DNA synthesis in mitotic cells. In our study intravesical gemcitabine (2000 mg in 50 ml) was administered once a week for 6 consecutive weeks in the intensive phase and once a month for 12 consecutive months in the maintenance phase. Overall, 46 patients were enrolled, but the statistical analysis was performed for over 42 patients who completed the 6-week induction course. Among them, 29 (69.05%) patients showed a recurrence-free survival (RFS) after the induction phase. Midterm oncological outcomes also showed interesting results; the disease-free survival (DFS) at 12, 24 months, and 36 months was 47.62%, 38.14%, and 32.69%, respectively. Furthermore, progression-free survival at 36 months was 65.38%.
The two most interesting characteristics of gemcitabine are its advantageous adverse event profile and the intravesical route of administration that makes it well tolerated by the patients.
In our study, there was no life-threatening event or treatment-related death (grade 4 or 5). The most commonly mild and moderate adverse events reported were urinary symptoms (lower urinary tract symptoms) in 16 cases and fatigue in 13 (G1-G2).
In comparing gemcitabine with pembrolizumab therapy given as an intravenous infusion, 20.6% of patients experienced an immune-related adverse event, some of which may be clinically significant.
In conclusion, we think that gemcitabine might represent a valid medical therapy for patients with BCG failure, in the scenario of BCG shortage, in order to offer an organ-sparing approach.
Written by: Roberto Contieri, MD, PhD, Massimo Lazzari, MD, Rodolfo Hurle, MD, Department of Urology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
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