The role of the pathologist is most important, and the pathological report must contain data on the type of tumor, stage, grade, vascular invasion, lymphatic invasion, perineural invasion, the presence of carcinoma in situ (CIS) and presence of molecular markers -P-53, Ki-67, BcL2, and ploidy. Following adequate TURBT, adjuvant intravesical therapy is usually administered to reduce recurrence and progression. Nevertheless, despite adjuvant intravesical therapy, approximately 40-50% of will recur with time. NMIBC includes both Ta-T1 single, or multiple low-grade tumors, and Ta-T1, single or multiple high-grade tumors, with or without CIS.
The rationale for adjuvant treatment of recurrent Ta-T1 disease is the destruction of circulating tumor cells after TURBT, and the ablation of residual tumor cells at the resection site and on small overlooked tumors. The risk of progression/recurrence depends on several clinical, molecular and pathological characteristics of the tumor. The European Organization for Research and Treatment of Cancer (EORTC) has looked at patient prognostic factors several times and found that the most important prognostic factors for recurrence were the number of tumors, prior recurrence rate, tumor size, and Grade. In contrast, for progression, the most important factors were tumor grade, response rate at entry, and whether the size of the tumor was larger than 3 cm. The EORTC initially divided patients to three risk categories according to prognostic factors: low, intermediate and high risk. Later, a more precise scoring system was developed with the EORTC tables and nomograms. (1,2) The CUETO group formed the CUETO scoring system as well in 20093 This enables tailoring adjuvant instillation therapy according to the risk of each patient.
The European Association of Urology (EAU) guidelines propose a risk stratification of the disease, with tumors being defined as low, intermediate or high-risk tumors. Low – primary solitary tumor, Ta, grade 1, less than 3 cm, and no CIS. High – should have any of the following: T1 tumor, high grade, CIS, multiple, recurrent and large tumors (over 3 cm). Intermediate – all tumors not defined in the low and high-risk categories.
When assessing recurrent tumors, it is important to remember that: Intermediate risk tumors are defined as Recurrent Ta, single, or multiple low-grade tumors. High-risk tumors- Recurrent T1 single or multiple high-grade T1 tumors, or recurrent multiple Ta low-grade tumors less than 3 cm. Very high-risk tumors - Recurrent multiple T1 high-grade tumors with associated CIS, or LVI, or variant histology.
Next, Dr. Brasui discussed some controversies in recurrent NMIBC. These included the usage if either BCG or chemotherapy in intermediate-risk disease, BCG therapy in high-risk patients – which dose? for how long? And device assisted therapy. The first controversy discussed was the therapy for the intermediate disease. In a meta-analysis of randomized trials comparing BCG to Mitomycin C in NMIBC patients, no significant difference in progression and survival was seen, but in BCG there was a 32% reduction in the risk of recurrence.4 Another study compared the long-term results of the comparison between BCG and Epirubicin in intermediate risk patients with a median follow-up of 9.2 years.5 The results demonstrated that BCG is more effective than Epirubicin with respect to time to first recurrence, time to distant metastasis, and time to death.
The next controversy discussed was the appropriate treatment for recurrent high-risk patients who previously received chemotherapy instillations. For these patients, BCG is considered the optimal therapy. The full dose of BCG was compared to a 1/3 dose in another study.6 With a median follow-up of 7.1 years intermediate-risk patients who received 1/3 dose of BCG maintenance for one year had a higher recurrence rate than those who received full dose. High-risk patients who received full-dose maintenance for three years had the best results. However, no significant differences were noted in the time to progression, duration of survival, or treatment toxicity in 1/3 and full dose of BCG. The authors summarized that 1/3 dose is not associated with less toxicity and has a higher recurrence rate, therefore full dose should be given to both intermediate and high-risk patients.
The last controversy discussed was the usage of device assisted therapy as an improved treatment, compared to BCG. The electromotive drug administration (EMDA) system entails iontophoresis and electroosmosis/electrophoresis (solute-solvent and solute-solute coupling). The rationale is to enhance the penetration of mitomycin C into the bladder wall (4-7 fold). In a study comparing sequential BCG and EMDA with MMC vs. BCG alone7, there was a statistically significant difference in favor of the sequential therapy in response rate, death from any cause and death from bladder cancer. These results were later replicated by other studies.
In very high-risk patients, as defined by the EAU guidelines (multiple high-grade T1 diseases, associated with CIS, LVI, or variant histology) the appropriate treatment is radical cystectomy. In these patients who have failed BCG therapy and who refuse or are unable to undergo radical cystectomy, the alternative treatments include EMDA, hyperthermia Mitomycin C, and Gemcitabine.
Dr. Brausi summarized his talk emphasizing the appropriate treatment for the different risk categories of NMIBC patients. For intermediate risk disease- BCG maintenance for one year with a full dose is required. For high-risk disease, the treatment is BCG maintenance full dose for three years or sequential therapy with BCG and MMC/EMDA. Lastly, for very high-risk disease, radical cystectomy is the most appropriate therapy. If patients are not fit for surgery or refuse to undergo surgery, it is possible to offer bladder sparing alternatives with BCG, hyperthermia/MMC, MMC/EMDA, or gemcitabine.
Presented by: Maurizio Brausi, MD Italy
1. Sylvester et al. Eur Urol 2006
2. Cambier et al. Eur Urol 2016
3. Fernandez-Gomez J Urol 2009
4. Malmstom PU et al. Eur Urol 2009
5. Sylevester RJ et al. Eur Urology 2010
6. Oddens J et al. Eur Urol 2013
7. Di stasi et al Lancet Oncol 2006
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre Twitter: @GoldbergHanan at the 38th Congress of the Society of International Urology - October 4- 7, 2018 - Seoul, South Korea