Treatment options can be limited in patients with recurrent non-muscle invasive bladder cancer who refuse cystectomy, are unsuitable for surgery, or in those who fail or are intolerant of BCG intravesical therapy. In this case series, gemcitabine and MMC were administered intravesically and produced a complete and durable response in 60% of patients with a median overall follow-up of 14 months (4–34 months). This response rate was achieved in a group of patients at high risk for recurrence and progression. Most patients in our series had high-grade disease or carcinoma in situ (9/10) and a median of 5 recurrences (2–14) prior to gemcitabine/MMC therapy. Interestingly, the 2 patients who went on to have a cystectomy had no evidence of carcinoma in their bladder after resection.
Overall, the complications were minor and the incidence low (20%). This rate of minor complications was similar to single agent intravesical gemcitabine from phase I and II studies that were approximately 27% and 29%, respectively[7
]. Similarly, in a recent study of intravesical epirubicin, the rate of minor chemical cystitis was 25% [10
]. While local toxicity from MMC alone was 30% [11
Gemcitabine has been administered in clinical trials as a single agent to treat non-muscle invasive bladder cancer. In 2002, Dalbagni and colleagues reported minimal toxicity in a phase I trial of gemcitabine in the treatment of BCG refractory TCC of the bladder [8
]. Patients experienced some minor grade 2/3 dysuria and minimal systemic nausea and vomiting. A complete response was observed in 39% of patients (7/18). In 2006, the same group published phase II trial results [7
]. Thirty patients with BCG refractory TCC who refused cystectomy were given gemcitabine twice weekly for 3 weeks. Surveillance was performed at 8 weeks and then every 3 months. While complete response was achieved in 50% on first surveillance, the 1-year recurrence-free survival was only 10% (95% CI, 0%–21%).
MMC therapy is often administered as a single post-operative dose after transurethral resection of bladder tumor or on a weekly basis for 6 to 8 weeks. Malmstrom and colleagues found only 4 of 21 BCG-refractory patients treated with MMC were disease-free at 3 years [12
]. Combining MMC with BCG does not appear to increase the regimen’s effectiveness [13
Another intravesical agent that has been employed to treat BCG refractory bladder cancer is valrubicin (N-trifluoroacetyladriamycin-14-valerate, AD 32), an analogue of doxorubicin [15
]. Phase I trials demonstrated the agent has minimal toxicity [15
]. Steinberg and colleagues reported a multi-institutional open label noncomparative trial on the use of intravesical valrubicin in patients with BCG refractory non-muscle invasive bladder cancer [16
]. Patients received 6 weekly instillations of 800 mg of valrubicin. Of 90 patients, 19 (21 %) had a complete response at 6 months and 7 (8%) at 30 months.
Hyperthermia combined with MMC for treatment of non-muscle invasive bladder cancer has shown promise[17
]. Hyperthermia produces increased cellular permeability, increased MMC cellular distribution and increased MMC reaction with DNA [19
]. In one study, compared to BCG (64%) and passive MMC (58%), electromotive MMC (31%) had reduced recurrence rates at 6 months after therapy [20
The main findings of this study are that a few select patients who have failed intravesical immunotherapy may be salvageable by sequential intravesical gemcitabine and MMC. This therapy may offer a potential alternative to cystectomy particularly for those patients with high risk non-muscle invasive disease who refuse or are unfit for cystectomy. The treatment appears to be well tolerated and the responses durable. More long-term follow-up is necessary before we can assess the effect of such treatment on local or systemic progression. These data do appear encouraging enough to perhaps warrant further investigation of this approach. Combination chemotherapy is used routinely for treatment of metastatic bladder cancer or in a neoadjuvant or adjuvant setting in those with muscle invasive disease. Single agent therapy has not been efficacious in these settings. Hence it is logical to assume that the same may be true in the case of intravesical chemotherapy for bladder cancer.
The data from our series corroborate that of an earlier report by Maymi and colleagues who demonstrated efficacy of sequential intravesical chemotherapy with gemcitabine and MMC used as third line therapy in patients with recurrent non-muscle invasive disease [21
]. They compared patients with non-muscle invasive urothelial carcinoma who had failed multiple intravesical agents treated with gemcitabine (n
= 12) versus gemcitabine and MCC (n
= 27). Interestingly, the 12 patients treated with single agent gemcitabine failed at a median five months (range 2–27). While, 15/27 (55%) patients treated with a combination of gemcitabine and MMC remained disease-free with median follow up of seven months (range 2–24). Overall, the median disease-free survival was 6.5 months with gemcitabine alone vs. 20 months with combination therapy. While the median follow-up in the study is short and no biopsy or cystectomy data are presented, their response rates are similar to the present series and underline the potential benefit of sequential therapy.
Recent data has demonstrated the ability of maintenance intravesical therapy to increase recurrence-free rates compared with short-term administration [22
]. Friedrich and colleagues randomized 495 patients with intermediate to high risk non-muscle invasive disease to either short-term BCG, short-term MMC, or MMC long-term administered monthly for 3 years [22
]. The long-term regimen had significantly lower 3-year recurrence-free rates (86.1%) compared with short-term BCG (65.5%) and short-term MMC (68.6%). The 12-month maintenance regimen the patients in the present series underwent likely has contributed to their disease-free rates.
The present study is limited by the small number of patients and the short duration of follow-up. Longer follow-up is needed in the responders to determine if the treatment effect is durable. A prospective, multi-center Phase II trial is needed to fully evaluate the validity of this approach in patients with BCG refractory bladder cancer as well as to determine its ability to limit progression and enhance disease specific survival.