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


Curr Opin Urol. 2020;30(3):392-399. 

In This Article

New Perspectives in the Treatment of Carcinoma in Situ

In addition to conventional intravesical therapies, new approaches have been designed in an attempt at a bladder preservation strategy.

With respect to intravesical device-assisted therapies, a recent Cochrane meta-analysis that assessed the effects of intravesical electromotive drug administration (EMDA) showed that in T1/CIS patients the time to recurrence was not significantly different after induction with mitomycin-EMDA compared with BCG induction (RR: 1.06; 95% CI: 0.64–1.76). On the other hand, in T1 patients with or without CIS, mitomycin-EMDA with sequential BCG showed, in comparison with postoperative BCG induction and maintenance, a longer time to recurrence [heart rate (HR): 0.51; 95% CI: 0.34–0.77] and a longer time to progression (HR: 0.36; 95% CI: 0.17–0.75).[46] It should be noted, however, that the heterogeneity of the population in respect of bladder cancer stage may limit the validity of the results in CIS patients.

A recent retrospective multicenter analysis included 150 patients with CIS (50 BCG-unresponsive, 50 BCG-treated, 50 BCG-naïve) who underwent intravesical radiofrequency-induced chemohyperthermia (RF-CHT). In these three groups, there was, respectively, a CRR of 46.0, 71.7, and 83.0%, a 2-year recurrence rate of 17.4, 27.3, and 12.8%, and a cystectomy-free rate of 71.4, 84.1, and 86.7% without any differences in progression rate or OS.[47] Therefore, the authors suggested that RF-CHT shows efficacy in both naïve and unresponsive CIS patients, and proposed RF-CHT as an alternative to cystectomy in selected patients. In contrast, the results of a current phase III RCT (the HYMN trial) showed no significant differences between RF-CHT vs. a second induction course of BCG or standard care (control) with regard to CRR at 3 months (RF-CHT vs. control: 30 vs. 47%, P = 0.15) or disease-free survival (HR: 1.33; 95% CI: 0.84–2.10, P = 0.23) in CIS patients.[48] Therefore, the role of RF-CHT remains unclear and new trials are needed.

The fact that previous studies have shown that Programmed cell death protein 1 (PD-1) is expressed in NMIBC,[49] coupled with the enhanced Programmed death ligand 1 (PD-L1) expression on tumor tissue after BCG exposure, has given rise to the hypothesis that new immunotherapeutic agents (immune checkpoint inhibitors) could be a treatment option.[50] In this context, a phase II, single-arm trial (KEYNOTE-057) investigating pembrolizumab in 148 patients with high-risk NMIBC (including 96 BCG-unresponsive CIS patients) reported promising results, with a 3-month CRR of 40.2%. Of the 41 patients who achieved complete response (CR) at 3 months, 58.5% maintained CR at last follow-up (median 16.7 months), and during follow-up none of the patients had progressed to MIBC or metastatic disease.[51] These results have allowed recent Food and drug administration (FDA) approval of pembrolizumab in BCG-unresponsive NMIBC. Moreover, there are currently numerous RCTs combining BCG with immune checkpoint inhibitors for high-risk BCG-naïve and BCG-unresponsive NMIBC (including patients with CIS), and results of these trials in the coming years may promote a paradigm shift in treatment. Table 2 summarizes the ongoing clinical trials with immune checkpoint inhibitors that have included CIS patients.