However, combination chemotherapy has found a niche as a salvage therapy for BCG failing patients, an unfortunately all too common occurrence. In this role, combination chemotherapy offers a 30-50% response rate, though with unclear long-term efficacy. While this may sound like an uncertain and ineffective therapy, especially given the high cure rates with cystectomy in this population, patient context must be strongly considered. Many patients with bladder cancer are frail, comorbid, or reject diversion or catheterization. Combination intravesical chemotherapy offers these patients an opportunity to avoid or delay radical surgery.
Critics of salvage combination chemotherapy contend that for biologically aggressive disease (determined by having failed BCG therapy), chemotherapy delays definitive surgical treatment and puts patients at risk of developing a progressive and incurable disease. Commonly cited evidence to support this viewpoint highlights worse overall survival in patients with progression to muscle-invasive bladder cancer (MIBC) as compared to those with primary MIBC1, as well as patients with metastasis in light of non-muscle invasive disease2. In this paradigm, each round of intravesical therapy represents a gamble of developing a dreaded progressive muscle-invasive cancer or an occult metastasis.
Our experience with patients undergoing salvage combination chemotherapy has not born out these concerns. In our initial cohort study of patients undergoing gemcitabine/docetaxel combination chemotherapy, bladder cancer-specific mortality was 11% at two years (4/45).3 Review of these four patients found that two were perioperative deaths following radical cystectomy (deemed “bladder cancer related”) and two were patients with recurrent non-muscle invasive disease who refused further therapy entirely. Thus, the rate of occult metastases or aggressive local disease leading to mortality in our series was essentially 0%. While this may be related to the combination chemotherapy, other practices additionally contribute to our ability to avoid bladder-cancer specific deaths in these patients. Some of these practices include:
- Aggressive initial transurethral resection (TUR), and frequent re-resection TUR, including all T1HG patients and many TaHG patients (larger tumors, multifocal, initial resection by referring provider). Evidence suggests that re-resection helps avoid understaging and also removes residual papillary disease4.
- Routine use of “blue-light” cystoscopy during operative procedures (including primary resections, re-resections, and restagings (see below)). Blue-light cystoscopy aids in achieving complete initial resections as well as diagnosing occult recurrences, particularly CIS.5
- Routine performance of operative restagings after induction therapy courses. This includes a white-light and blue-light cystoscopy, bilateral upper-tract cytology washings, bilateral retrograde pyelograms, random bladder biopsies (including the prostatic urethra), and a bladder cytology and UrovysionTM While evidence supporting this practice is currently limited, anecdotally we find that it helps diagnose recurrent or occult disease earlier (particularly upper-tract or prostatic CIS).
- Routine use of maintenance chemotherapy for responders, even though the duration of benefit and frequency of treatments is not well defined (we perform monthly instillations for two years with Gem/Doce).
- Finally, we consult extensively with our GU pathologist, particularly in regards to the presence of variant histologies (micropapillary, plasmacytoid, etc) and lymphovascular invasion. Failing to recognize these pathologic characteristics can lead to truly disastrous outcomes if intravesical treatments are pursued.
At this time the role of combination chemotherapy regimens in the treatment of NMIBC is still poorly defined. Historically, early regimens fell short in comparisons to BCG for treatment naïve patients. More recently, newer regimens have mostly been used in the salvage setting, and almost exclusively have been reported as single arm cohort series. Many questions exist regarding newer combination chemotherapy regimens including their efficacy as compared to BCG in treatment naïve patients, their long-term efficacy and side-effects, and the value and timing of maintenance regimens. Potentially more importantly, further bench-top and translational research is needed to elucidate the mechanisms of both BCG and chemotherapy resistance, and elucidate biomarkers that can be used to guide treatment selection for non-muscle invasive bladder cancer patients.
References:
1. Ge, P et al. Oncological Outcome of Primary and Secondary Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. Scientific Reports, 8:7543. May 2018
2. Wiesner, C et al. Lymph Node Metastases in Non-Muscle Invasive Bladder Cancer are Correlated with the Number of Transurethral Resections and Tumour Upstaging at Radical Cystectomy. BJU Int., 95:3: 2005
3. Steinberg, R et al.: Sequential intravesical gemcitabine and docetaxel for the salvage treatment of non-muscle invasive bladder cancer. Bladder Cancer, 1: 65, 2015
4. Herr, H et al. The Value of a Second Transurethral Resection in Evaluating Patients with Bladder Tumors. Journal of Urology, 162:1, 1999
5. Daneshmand, S et al. Blue Light Cystoscopy for the Diagnosis of Bladder Cancer: Results from the US Prospective Multicenter Registry. Urologic Oncology (In Press).
Written by: Lewis Thomas, MD, Department of Urology, University of Iowa, Iowa City, IA
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