Carcinoma in Situ of the Bladder: Why Is It Underdetected?

José D. Subiela; Óscar Rodr&ıacute; guez Faba; Félix Guerrero-Ramos; Julia Aumatell; Alberto Breda; Joan Palou

Disclosures

Curr Opin Urol. 2020;30(3):392-399. 

In This Article

Treatment of Carcinoma in Situ of the Bladder

Intravesical instillation of BCG has been considered the standard therapy for CIS of the bladder.[22,23] The complete response rate (CRR) of induction and 3-week maintenance at 3, 6, 12, 18, 24, 30, and 36 months reaches 84%, compared with 69% with induction alone.[24,25] In fact, data from a meta-analysis with 403 CIS patients revealed that the use of BCG decreased the risk of progression by around 35%.[8] The use of maintenance BCG for CIS is supported by a randomized controlled trial (RCT) in which the CRR was found to be significantly lower for induction alone as compared with induction and maintenance (68.1 vs. 83.8%).[25] In a prospective registry study by Gofrit et al.[26] that included 104 CIS patients (half with maintenance), recurrence-free survival (RFS) rates were 63 and 54% and progression-free survival (PFS) rates were 79 and 77% at 5 and 10 years, respectively.

One of the first phase II trials using 8 weeks of induction therapy and 12 months of maintenance demonstrated a CRR of 68%.[23] Regarding treatment with induction therapy alone, Takenaka et al.,[27] reported a 5-year PFS rate of 78.5% and CRR of 86.5%. Chade et al.[28] found a CRR of 62%, a recurrence free-survival of 12% at 5 years (in responders) and progression free survival of 83% at 5 years to follow-up, moreover, a phase II trial conducted by EORTC in which CIS patients received only induction yielded a CRR of 83%, but the 5-year RFS in complete responders fell to just 60%.[29] Studies in which maintenance schedules were not completed still showed a benefit over induction therapy alone, suggesting that any kind of maintenance is better than none.[30]

With respect to BCG dose reduction, Mugiya et al.[31] published data on a series of 43 CIS patients in whom half-dose induction BCG provided a 5-year RFS of 61.9%. Moreover, two important RCTs comparing a reduced and a standard dose of BCG have been conducted by the Club urológico español de tratamiento oncológico (CUETO) group. The first, including 500 patients, showed that within the CIS subgroup (39 patients) the standard dose seemed to perform better in terms of recurrence.[32] The second trial included 155 patients (65 CIS patients) randomized to either standard or one-third dose and found a lower RFS in the reduced-dose group (49.8 vs. 61.9%) without any difference in PFS but with a significantly decreased adverse event rate in the reduced-dose group.[33] More recently, a trial by Yokomizo et al.[34] with mostly CIS patients (155 out of 171 patients) failed to demonstrate noninferiority of a half-dose BCG 8-week induction schedule. Finally, a meta-analysis of 2459 patients (of whom only 108 had CIS) concluded that low-dose BCG provides a better safety profile without affecting oncological outcomes.[35] Table 1 summarizes the outcomes of the most relevant studies using BCG in CIS patients.

Although cystectomy seems imperative in patients with persistent/recurrent disease after BCG, in daily clinical practice its use is limited by patients' desire to preserve the bladder or by lack of patient suitability for the surgery. Consequently, some old and new therapies have emerged as bladder conservation strategies. Thus, the American Urological Association (AUA) guidelines for NMIBC recommend a second induction course of BCG in patients with persistent/recurrent Ta or CIS disease.[36] In a heterogeneous series of patients with high-risk NMIBC(39 CIS patients out of 116), this strategy showed a CRR of 65% at 3 years with recurrence and progression rates of 37.9 and 3.4%, respectively, at 45 months of follow-up.[37]

As regards to other agents, intravesical chemotherapy has been used for CIS alone or in combination with BCG. Epirubicin was tested against BCG, showing worse outcomes in respect of recurrence rate (45 vs. 16%) without changes in progression or overall survival (OS).[38] In a meta-analysis comparing BCG with different chemotherapeutic agents, RFS was better with BCG (46.7 vs. 26.2% at 3.6 years).[39] The combination of BCG with other drugs (such as mitomycin C or IFN-alpha2B) has not proved to provide any benefit in either individual studies or meta-analyses.[40–43]

In view of the above findings, the role of these agents should be limited to certain scenarios, namely when there is contraindication to or failure after BCG and when cystectomy is considered too risky. Only valrubicin has been approved by the FDA for BCG failure, with discrete RFS rates of 18–21% at 6 months and 8% at 30 months.[44] Recently, an update of this pivotal phase III trial confirmed this rate of efficacy.[45] In addition, the results of an ongoing clinical trial to evaluate the efficacy and safety of maintenance with valrubicin are expected (ClinicalTrials.gov Identifier: NCT01310803).

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