The high recurrence rate stems from genetic defects that exist in all cells lining the bladder, making it just a matter of time before tumors appears in the bladder. Another reason is derived from the surgical technique of the procedure used to extract tumors from the bladder -Transurethral resection of bladder tumor (TURBT) involves spread of tumor cells throughout the bladder, and disruption of the surface to allow possible seeding. An additional important point is tumor visualization – we do not see everything with standard cystoscopy and TURBT instruments, which mean that not all tumors are removed.
Enhanced vision of bladder lesions is therefore recommended and quite critical. Narrow band imaging (NBI) is one of the available image enhancing techniques, whereby the vasculature of various lesions is increased and given a greenish color. In a randomized study assessing the effect of NBI vs. standard white light cystoscopy no difference in the overall cohort was seen. However, while no difference was seen in the intermediate and high risk subgroups, lower recurrence rate were seen in low-risk patients with no carcinoma in situ (CIS) that were monitored with NBI.1 Another modality is the blue light cystoscopy (Cysview) which is a photodynamic diagnosis system used to visualize CIS lesions better. A meta-analysis including 9 studies with 2212 patients demonstrated that 24.9% and 40% of patients had at least one additional Ta/T1 tumor and additional one CIS lesion, respectively, detected using Cysview, that was not detected with white light cystoscopy.2 Cysview has been shown to save cost (15% savings) while improving expected clinical outcomes: improved accuracy, lower 5-year recurrence rates, less progression to muscle-invasive disease.3 Dr. Fradet then gave his own opinion on the usage of NBI an Cysview. According to him, there is more convincing data for the use of Cysview for both reducing the recurrence risk after TURBT, and for identification of CIS in patients with positive cytology. Cysview requires preoperative instillation of the product approximately 30-45 minutes before TURBT, which is quite compatible with the OR turnaround. NBI is more convenient for the diagnostic and follow-up cystoscopy and for upper tract investigation of CIS.
Treatments to prevent recurrence were the next topic discussed by Dr. Fradet. Intravesical chemotherapy (Mitomycin C, Epirubicin) prevent recurrence of low grade cancer, with monthly maintenance for one year. Mitomycin C instillation can be optimized by dehydrating the patient, administering sodium bicarbonate 1.3 gr the night before, and in the morning of the procedure, and making sure the bladder is empty. The optimized dose is 40 mg in 20 cc and it has shown an improved recurrence rate. Another intravesical option is immunotherapy with Bacillus Calmette-Guerin (BCG) therapy, that can be curative for CIS and preventative for Ta-T1 disease. A more novel option is Electro-Motive Drug Administration (EMDA) which delivers drug therapy (Mitomycin C) intravesically using an electrical current. In 2006 a study comparing BCG alone vs. sequential BCG and EMDA with Mitomycin C in high risk NMIBC patients was published.4 The sequential therapy showed a considerable reduction in progression from 21.9% in the BCG alone group to 9.4% in the sequential therapy group, a lower recurrence rate (42.1% vs. 58.1%), and with a lower rate of bladder cancer specific mortality (5.6% vs. 16.2%).
Summarizing the data presented so far, Dr. Fradet stated that NMIBC is initially treated by TURBT, and has a high rate of recurrence of 60% and a progression rate to muscle-invasive bladder cancer (MIBC) in 5-20% of cases. NMIBIC mandates long-term follow-up and is the most expensive cancer to treat. When microstaging pT1 disease, within 3 years of follow-up, the risk of progression is 0% and 42% for pT1a/pT1b and pT1c disease, respectively. It is most critical that physicians have all available knowledge and technology to differentiate aggressive from non-aggressive NMIBC. Using RNA sequencing, it is possible to identify 3 different molecular grades and immune checkpoint (ICP) cascades with distinct clinical behaviour in NMIBC.5 This led Dr. Fradet to discuss the topic of immunotherapy.
BCG immunotherapy with a minimum 3-cycle maintenance course is required to significantly reduce the recurrence rate of NMIBC.6 However, BCG therapy can fail, and this can be divided into several different types of failure7:
- Intolerant – recurrent disease in the setting of inadequate BCG treatment due to side effects
- Resistant – recurrence of lesser or improving disease that resolves with further BCG
- Relapsing – recurrences after achieving 6 months complete response
- Refractory – No complete response by 6 months after BCG, not improving or worsening disease despite two courses of BCG or maintenance.
The next topic discussed was the new era of cancer treatment - anti-immune checkpoint therapies. These therapies block the inhibitive effect tumor cells have on the immune cells, and enable the immune cells to attack tumor cells. For this discovery, the scientists who discovered PD-1, and CTLA-4, Tasuku Honjo, and James Allison, respectively, won the 2018 Nobel Prize. These therapies have been approved as different lines of therapy in bladder cancer. There is even data showing a good pathologic response to pembrolizumab, an anti-PD-1, as neoadjuvant treatment before radical cystectomy. There are currently trials assessing the role of immunotherapy specifically in BCG failures and BCG naïve NMIBC patients. These include seeing whether atezolizumab and pembrolizumab are effective in patients with BCG failure after 2 inductions, and a study analyzing whether BCG with Durvalumab after BCG failure, has improved outcomes.
The last topic discussed were the important modulators of response to NMIBC treatments. Androgen deprivation therapy (ADT) given to patients with prostate cancer has been sown to lower the risk of developing bladder cancer. A prospective study has also shown that men treated with 5 alpha reductase inhibitors (5ARI) for benign prostatic hyperplasia demonstrated a significantly reduced risk of bladder cancer..10 Several studies have shown that female mice have a higher immune response than males. Estradiol might be implicated in this response in mice with one study concluding that the hormone reduces responses associated with immunopathology and enhances responses associated with recruitment of innate immune cells.
Dr. Fradet summarized his talk reiterating that NMIBC is the most costly cancer and the incidence is increasing rapidly with the aging process. Improved TURBT is the first step to reduce recurrence and progression (Using Cysview). Intravesical chemotherapy for intermediate risk patients can be improved. BCG needs replacement by new and improved therapies. Modified viruses and immune checkpoint inhibitors and activators will change the paradigm for high-risk patients. Finally, sex steroids may prove to be important contributors to NMIBC treatment.
Presented by: Yves Fradet, MD Urologist and oncologistProfessor Department of surgery, Division of Urology, Université Laval Head of the Department of Urology at the CHU de Québec
CHU de Quebec-Universite Laval CHU de Quebec-Universite Laval
References:
1. Naito S et al. Eur Urol 2016
2. Burger M et al. Eur UROL 2016
3. Garfield et al. CUAJ 2013
4. Di Stasi S et al. Lancet Oncol 2006
5. Chandrasekar T. et al. ASCO-GU 2018
6. Decobert M et al. Cancer 2008
7. Nieder AM et al. Urology 2005
8. Skinner EC et al. J URol, 2013
9. Barlow et al. J Urol 2013
10. Morales et al. Eur Urol 2016
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 70th Northeastern Section of the American Urological Association (NSAUA) - October 11-13, 2018 - Fairmont Royal York Toronto, ON Canada