Intravesical Therapy and Dose Scheduling

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The traditional induction regimen of six weekly instillations of chemotherapy,initiated a week after resection, was based on original work using BCG immunotherapy. Delayed bladder instillation was intended as a prophylactic therapy for a secondary new occurrence, presuming that all previous tumors have been eradicated. It is now increasingly apparent that intravesical chemotherapy is best intended as an ablative therapy to "mop up" loose cells released at the time of extirpation and to prevent tumor reimplantation. Longitudinal studies have shown that tumor recurrences occur in two time-dependent peaks. The groups with early recurrence peaks are sensitive to chemotherapy, whereas those with delayed recurrences are generally resistant [35]. It is not surprising, therefore, that the influential study of the MRC demonstrated that immediate instillation of MMC within 24 hours of transurethral resection was as effective as conventional 6-week courses [61]. Indeed, more recent studies have suggested that intravesical chemotherapy should be administered as soon after resection as possible, with most of the advantage being lost within the first 24 hours [62]. Immediate bladder instillation appears to be safe as long as there is no risk of perforation and the bleeding has been adequately controlled. For those with extensive resection, the risk of systemic absorption and side effects should be considered. Cutaneous reactions often involving the genitalia and palms have been noted in up to 9% of patients receiving MMC [63]. BCG immunotherapy should never be given in the perioperative setting, as this increases the risk of systemic absorption and infection.

The optimal BCG treatment schedule remains a matter of some debate. A second 6-week cycle of BCG therapy improves the overall response rate from 50% to 70% [64], and 30% to 50% of those who fail an initial course of BCG respond to a second 6-week induction course [64,65]. As a result, many trials have attempted to improve BCG efficacy using "maintenance" regimens of continued weekly, biweekly, or monthly instillations [66], as well as longer induction courses [67]. Although one review of 14 such trials [68] suggested that response rates were maximized with additional BCG courses and led to a more durable long-term advantage over single-induction regimens, only one randomized study has proven any (statistically significant) advantage for progression. The SWOG 8507 study [69] showed a disease-free improvement from 40% to 61% and a 6% reduction in the rate of surgical intervention in patients receiving 3-week maintenance instillations at 3 and 6 months and every 6 months thereafter over 3 years. However, only 16% of the 243 patients were able to tolerate the complete 3-year regimen due to the local side effects. Overall, only a third to one half of the patients in these studies were able to tolerate regular BCG instillations due to the cumulative BCG-induced cystitis [68,69]. The toxicity of maintenance regimes (consisting of up to 27 instillations over a 3-year period) has also been addressed by the EORTC-GU group. The analysis of their own and other studies [19,70,71] suggests that the toxic-ity is mostly incurred during the induction phase, and lowering the dose of the maintenance (one-third dose) could reduce the limiting toxicity to 20%. It remains to be seen if the EORTC results can be translated into the common experience of most urology practices. For most, the therapeutic advantages of maintenance regimes are compromised by significant increases in local toxicity.

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