Introduction:

Bacillus Calmette-Guerin (BCG) is the standard of care for adjuvant intravesical therapy after transurethral resection (TURBT) of intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). However, up to 40% of high-risk patients treated with BCG will relapse. The preferred treatment for these patients is radical cystectomy (RC), though many patients refuse or are medically unfit for RC. Various intravesical therapies have been investigated for these patients, now more relevant than ever given the recent BCG shortages. Our institution recently reported a phase I study of combination cabazitaxel, gemcitabine, and cisplatin demonstrating encouraging recurrence-free rates of 89% and 83% at initial and 1-year evaluations, respectively, in a highly pretreated cohort. Off trial, our institution has begun using docetaxel in lieu of cabazitaxel given its high cost. The present study represents the first report of combination intravesical docetaxel, gemcitabine, and cisplatin (DGC) in the salvage setting for patients with BCG-refractory disease.

Methods:

This was a retrospective review of all patients at our institution receiving the DGC regimen from January 2018 to July 2019. This regimen included a 6-week induction of separate-day weekly docetaxel (80mg), weekly gemcitabine (1000mg or 2000mg), and biweekly cisplatin (100mg) to reduce risk of platinum-induced hypersensitivity. In patients with treatment response, a maintenance regimen of separate-day monthly docetaxel (80mg) and monthly gemcitabine (1000mg) was initiated. Cystoscopy and urine cytology were performed every 3 months. All patients had normal CT or MRI upper urinary tract imaging within 3 months of starting the DGC regimen. Primary outcome was recurrence, defined as biopsy-proven cancer of any grade or stage. Progression was defined as ≥T2 disease or metastases as detected by biopsy, RC pathology, or imaging.

Results:

A total of 10 patients received the DGC regimen, all of whom were male. Median age was 70 years (range 57-85 years). This highly pretreated cohort included 90% (9/10) of patients previously receiving at least two BCG induction courses +/- interferon and 30% (3/10) previously receiving intravesical chemotherapy. Prior to DGC, all patients had high-grade disease, with 2 patients having T1+Cis, 3 patients with Cis only, 1 patient with T1 only, 1 patient with Ta+Cis, and 3 patients with Ta only. Induction treatment was fully completed as planned in 80% (8/10) of patients, as one patient did not receive the last docetaxel and gemcitabine doses due to local symptoms (frequency, urgency, dysuria) and another patient stopped cisplatin after one treatment due to local symptoms (frequency, dysuria) and fatigue. Of the seven patients who have at least undergone the first surveillance cystoscopy (followup median 41 weeks, range 23-74 weeks), two patients have recurred: one at 17 weeks with LG Ta and was continued on maintenance, and the other at 26 weeks with HG T1 who underwent DGC reinduction with a response and was started on maintenance. At last followup, all seven patients were still on maintenance treatment. No patients have experienced progression nor undergone RC.

Conclusion:

This novel salvage regimen of triple intravesical therapy has promising short-term results in a highly pretreated BCG-refractory patient cohort, with all patients experiencing initial downgrading and/or downstaging and all continuing on maintenance treatment. In this period of recent BCG shortages, this regimen may prove to be a reasonable treatment for BCG-naïve and refractory patients.

Funding: N/A