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"In this era of BCG shortage, we may be forced to develop new standards and alternative strategies for bladder preservation," writes Badar M. Mian, MD.
“Journal Article of the Month” is a new Urology Times section in which Badar M. Mian, MD (left), offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, Albany, NY.
Depending on tumor characteristics and length of follow-up, recurrent nonmuscle-invasive bladder cancer (NMIBC) can develop in 20% to 40% of patients following initial intravesical Bacillus Calmette-GuÃ©rin therapy. Most experts recommend radical cystectomy for patients with BCG-unresponsive NMIBC. Yet, many patients are either not good candidates for major surgery or they desire to preserve a functioning bladder. Many bladder preservation strategies, including various immunotherapy and chemotherapy agents, in various combinations and schedules, have been tested over the years but most have not provided durable control of this disease.
Adopting the rationale from combination systemic chemotherapy used in advanced bladder cancer, some centers have utilized combination intravesical chemotherapy with sequential use of gemcitabine (Gemzar) and docetaxel (Taxotere) as a salvage strategy for patients with recurrent NMIBC. To determine the effectiveness of this approach, Steinberg et al performed a retrospective analysis of the data from multiple institutions showing promising results in this difficult cohort of patients (J Urol 2020; 203:1-8).
The authors pooled the data from 11 different centers and identified 276 patients with recurrent NMIBC (median age, 73 years) treated with sequential gemcitabine and docetaxel from 2009 to 2018. The patients had undergone a median of two previous intravesical induction courses and a median of one BCG induction course (range, 1-4). Of these, 38% were classified as BCG unresponsive, ie, early recurrence (within 6-12 months) of various NMIBC pathology.
The instillation protocol included gemcitabine, 1 gram in 50 mL saline or water instilled via Foley catheter and allowed to remain in the bladder for 60 to 90 minutes. After drainage of the gemcitabine, docetaxel, 37.5 mg in 50 mL saline, was instilled. The catheter was removed and patients were instructed to not void for 60 to 120 minutes. This induction regimen was administered once per week for 6 weeks.
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Most institutions used this combination intravesical chemotherapy once per month for 24 months. Side effects were reported by 41% of patients, requiring modification of schedule in 10%. The most frequently noted side effects included irritative urinary symptoms (22%), dysuria (16%), and hematuria (11%).
The data were presented separately for any recurrence or high-grade recurrence after treatment. Any recurrence-free survival (RFS) in all treated patients was 60% at 1 year and 46% at 2 years, with a median follow-up of 13.9 months. Median time to recurrence was 6.8 months (range, 2.0 to 67.3). RFS for patients with any carcinoma in situ was 60% at 1 year and 43% at 2 years, and RFS for those with papillary disease alone was 62% at 1 year and 51% at 2 years.
High-grade RFS in all patients was 65% at 1 year and 52% at 2 years. In the BCG-unresponsive group, 50% of those with carcinoma in situ and 58% of those with papillary disease were free of high-grade recurrence at 2 years. Using the maintenance protocol was associated with lower recurrence rate, both low grade and high grade (p<.01). Of the 43 patients undergoing cystectomy (at median of 11.3 months), 38 were due to recurrent disease. Final pathology showed stage T0 in seven patients and T2 or higher in 11 patients, four of whom had lymph node metastases.
Forty-four patients (16%) died at median follow-up of 22.9 months, and 13 (5%) died of metastatic bladder cancer. In patients dying of bladder cancer, carcinoma in situ was the initial diagnosis in eight of 13 patients. The bladder cancer-specific mortality rate was 1% at 1 year and 4% at 2 years, while the all-cause mortality rate was 3% and 13%, respectively.
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This report on sequential intravesical gemcitabine and docetaxel for BCG-recurrent NMIBC shows promising results. The recurrence-free rates appear to be better than many previously reported attempts at controlling recurrent or resistant disease. This may be due in part to the fact that these patients were treated early in the salvage paradigm (history of one or two inductions) and not heavily pre-treated with multiple induction or maintenance courses. This regimen appears to be well tolerated and with an acceptable rate of schedule modification. Because there was no standardized method for collecting the data, the rate and severity of adverse effects are likely underreported.
In this era of BCG shortage, we may be forced to develop new standards and alternative strategies for bladder preservation. Can the sequential intravesical chemotherapy replace BCG in patients with newly diagnosed NMIBC with sufficient efficacy? Or can it replace maintenance BCG so that the precious supply of available BCG can be reserved for patients with initial high-risk NMIBC?
Radical cystectomy is probably the most complex urologic surgery, with a high rate of short-term complications. While it can be a life-saving intervention, it can also be life-changing event with significant implications related to quality of life and survivorship. Thus, bladder preservation will always be desired by patients. The challenges created by the BCG shortages also provide the rationale and opportunity for prospective validation of this and other bladder preservation strategies.