Immediate adjuvant intravesical chemotherapy after transurethral resection of bladder tumor

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Abstract
At the Fifth International Congress in Japan in October 1997, a randomized study was presented which illustrated the benefit of immediate intravesical chemotherapy after transurethral resection of bladder tumor (TURBT) [1] The group of patients who received post‐resection intravesical chemotherapy experienced a significantly lower incidence of new tumors at the 3‐month cystoscopy than did the control group who received no adjuvant intravesical instillation. Adjuvant intravesical chemotherapy following resection of superficial bladder cancer, as used in this study, has experienced a re‐awakening of interest as a result of several large randomized trials which have investigated and supported the efficacy of this strategy. The mechanisms for tumor recurrence/persistence after a transurethral resection can be enumerated as follows: (1) implantation of tumor cells at the time of resection, (2) incomplete resection, (3) unrecognized synchronous carcinoma in situ with subsequent macroscopic tumor development, and/or (4) subsequent new tumor occurrences. Immediate intravesical chemotherapy might be of benefit in reducing the recurrences secondary to the first three mechanisms. Subsequent new tumor occurrences that may appear months to years later would not be affected by adjuvant chemotherapy. The first mechanism mentioned, namely implantation, is of particular interest because it will escape the therapeutic effect of bacillus Calmette‐Guérin (BCG), the most commonly used agent for intravesical therapy in North America. Intravesical BCG must be delayed for a minimum of 1–2 weeks after resection because of the potential of systemic toxicity by tissue intravasation and/or vascular dissemination if instilled immediately after resection. BCG may be effective in eliminating tumors which result from the implantation process, but, by virtue of delayed administration, will not interfere with the process itself. The effort to prevent post‐resection tumor cell implantation after TURBT presumes that this is an important mechanism for tumor recurrence. There is both clinical and laboratory evidence to support this. Soloway and Martino, using the FANFT‐induced MBT2 bladder tumor, developed a model for bladder tumor recurrence by instilling cell suspensions of tumor cells into bladders which had been previously traumatized with a chemical, methyl‐CCNU [2]. On subsequent histological examination, they demonstrated a much higher incidence of bladder tumors in these mice compared to those without induced bladder injury. Using this model, various intravesical chemotherapeutic substances could be instilled following the tumor cell suspension to determine their effect in reducing the bladder tumor incidence. Instillation of some agents did provide a statistically significant reduction in bladder cancer occurrence. Clinical experience suggests that implantation is a mechanism of bladder tumor recurrence. While primary tumors are more frequently encountered in the posterior wall and trigonal areas, subsequent recurrences are much more frequently at the dome and anterior bladder wall. Boyd and Burnand reported that only 3% of primary tumors occurred on the dome but fully 60% of recurrences were located there [3]. This observation raises the hypothesis that, during transurethral resection, single cells or clusters of cells are released and float with the air bubble to the dome where they can be held in contact with traumatized epithelium and implant. Based on these clinical and laboratory observations, it was reasonable to postulate that instillation of chemotherapeutic substances immediately following resection would alter the cells such that the implantation process might be prevented or significantly reduced. Several studies in the 1970s and 1980s suggested that this was the case [4–6]. These studies were prospective and randomized but included relatively small numbers of patients with differing tumor histories and variability in the definition and inclusion of carcinoma in situ. Prognostic/risk factors were unevenly balanced between arms and may have influenced outcome.

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