As indicated in the introduction international guidelines advise to treat CIS patients with maintenance intravesical BCG, since it appears to be able to prevent or delay disease progression. However, the possibilities in case of BCG-refractory CIS are limited.
Intravesical chemotherapy has been studied. Valrubicin is the only FDA approved drug for patients with CIS-failing intravesical therapy such as BCG. This was based on a phase-II study with 90 patients [9
]. After a year of follow-up 21% had a complete response, which decreased to 8% after 2 years. A marker lesion study in refractory patients confirmed initial potential of valrubicin, since 18/39 (46%) patients were free of disease after 3 months [20
]. However, due to several reasons, valrubicin is not used currently. Intravesical gemcitabine was also used in BCG-refractory patients resulting in three small series. In one study with 18 patients (of whom 12 had pure CIS, 2 T1 + CIS), 11 patients showed negative biopsies after treatment, of whom 7 also had negative cytology [10
]. In another recent phase-II study 7 of 16 high-risk patients (not specified) remained recurrence-free at 12 months [21
]. Fifteen of 30 patients (23 CIS, 4 Ta high grade, 3 T1) with NMIBC that were BCG refractory (27) or BCG intolerant (3) had a complete response in a study by Dalbagni et al. [22
]. The 1-year recurrence-free survival rate for patients with a complete response was 21%.
Immunotherapy in BCG failures is also reported. Bropirimine, an oral immunomodulator, was studied in BCG-resistant CIS in a phase-II trial [23
]. Fourteen out of 47 BCG-resistant patients showed a complete response with a median duration of more than 12 months. Unfortunately, no further evaluation of the drug has been done. The combination of interferon (IFN)-alpha and BCG for BCG failures has been the subject of a large multi-center phase-II trial [24
]. In all, 467 patients failing BCG were treated with low-dose BCG plus IFN. Twenty-seven percent of these patients had isolated or concomitant CIS. With a median follow-up of 24 months, 45% remained tumor-free, compared with 59% of the 536 patients in the BCG naïve group. Although there was no sub-analysis for CIS patients, CIS did not significantly affect outcome in a multivariate analysis. Patients treated with two or more courses of BCG did not respond well to BCG plus IFN, suggesting that this group of patients should go on to cystectomy.
A recent method of device-assisted intravesical therapy is PDT, which combines photo sensitizers that selectively bind to tumors and a powerful intravesical light source to destroy tumors. Waidelich et al. [25
] used PDT with oral 5-aminolevulinic acid (5-ALA) in five BCG-failing CIS patients, and found three patients recurrence-free after a median follow-up of 36 months. Intravesical 5-ALA was studied in 10 BCG failures (presence of CIS not specified) of which four remained tumor-free after an average follow-up of 11.8 months [13
]. EMDA is based on the concept of temporarily breaching the urothelial barrier of the bladder and enhancing penetration of drugs, among which MMC, in a controllable manner [26
]. Di Stasi et al. [14
] performed a randomized controlled trial in 212 patients with stage T1 NMIBC, comparing BCG alone (105 patients, 28 with concomitant CIS) with sequential BCG and MMC/EMDA (107 patients, 29 with concomitant CIS), with maintenance therapy in both arms. This study found a significantly higher disease-free interval, lower recurrence rate, lower progression rate and lower disease-specific mortality in favor of sequential BCG and MMC/EMDA. Although not designed to assess complete response rates of patients with CIS, 12/28 (42.9%) patients treated with BCG alone and 16/28 (55.2%) patients treated with sequential BCG and EMDA/MMC obtained a complete response at 3 months, and respectively 16/28 (57.1%) patients and 20/29 (69.0%) patients at 6 months.
Limited and disappointing information is available on the use of intravesical MMC in BCG failures. The Swedish-Norwegian bladder cancer group compared MMC and BCG in NMIBC patients and treatment failures were allowed to cross over [27
]. Twenty-one BCG failures changed to MMC therapy, but only four remained recurrence-free with a median follow-up of 64 months.
In all, conservative therapy in patients with BCG-refractory CIS remains largely experimental, and indeed guidelines advise cystectomy as a treatment of choice for CIS failing adequate BCG. On the other hand, cystectomy remains major surgery with mortality and morbidity. Prostate sparing cystectomy improves outcome of erectile function, but oncological outcome might be hampered [28
]. Another approach is an attempt to improve the efficacy of intravesical MMC with devices such as EMDA or intravesical bladder wall hyperthermia (Synergo®
). In patients with papillary tumors failing BCG thermochemotherapy showed promising results [18
]. In a group of 41 BCG-failing patients the 1 and 2 years recurrence rates after a year of thermochemotherapy were 23 and 41%, respectively. In this study, 34 of the 51 patients with CIS were BCG pretreated, with an initial CR rate after 3 months of 92%, which was still more than 50% after 2 years of follow-up.