EDITORIAL

Intravesical Therapy for Bladder Cancer: Empiricism at the Helm

James E. Montie

Correspondence to: James E. Montie, M.D., Department of Urology, University of Michigan, Ann Arbor, MI 48109–0330.

For more than 40 years, most patients with superficial bladder cancer have received one or more courses of intravesical chemotherapy or immunotherapy treatments during the course of their disease. Despite widespread use, reliable data to confirm the benefit of such treatment were generally lacking until the last 10–15 years. Kilbridge and Kantoff (1), in a 1994 editorial, noted several problems with the many intravesical treatment publications: underpowered sample size, poor endpoints, poorly controlled or uncontrolled studies, and the grouping of primary tumor stages Ta, Tis, and T1 together and grades I–III together. A recent comprehensive review of the literature by the American Urological Association Bladder Cancer Clinical Guidelines Panel (2) found that only 181 of 5712 articles examined met minimum criteria, which included a study design with the randomization of patients and an appropriate control group for inclusion into data analysis and extraction. The data reviewed demonstrated that intravesical chemotherapy and immunotherapy modestly decrease recurrence rates but that intravesical chemotherapy does not substantially alter disease progression. In the same vein, dose and concentrations used in these studies were empirically derived and rarely tested systematically.

The article by Au et al. (3) in this issue of the Journal offers unique observations by bringing laboratory data to the bedside in a clinical trial with an "optimized" mitomycin C treatment protocol on the basis of earlier studies of drug sensitivity, plasma and urine pharmacokinetics, and tissue distribution both in animals and in humans. Five variables were then altered from traditional treatment by the following: 1) increasing dose, 2) reducing dose volume, 3) minimizing residual urine during treatment, 4) reducing urine production during treatment, and 5) alkalinizing the urine. One potential criticism is that, because so many variables were changed compared with traditional treatment, the relative importance of each intervention is uncertain. However, given the difficulty in performing prospective trials on this disease in the United States, it is understandable that the authors chose to go for a "home run," with changes that would likely produce enough of an effect to be detectable with a realistic sample size.

Appropriate stratification variables of grade and stage were used; however, as with many bladder cancer studies, the population studied included patients with cancers that were remarkably heterogeneous. Grades I–II, Ta (noninvasive) cancers recur commonly but rarely progress to a lethal disease. The inclusion of T1 (invasive) cancers with Ta or Tis cancers in any study of intravesical chemotherapy or immunotherapy is, therefore, now recognized as problematic, and the term "superficial" bladder cancer should be abandoned because depth or any invasion is not clear (4). Several studies (58) indicate that incomplete resection of T1 cancer, with or without understaging, is present in 20%–40% of the patients subjected either to reresection or to pathologic examination of the bladder after a cystectomy. Grade III, T1 cancers are very dangerous, with 30%–40% of the patients ultimately requiring a cystectomy and many dying of bladder cancer (9). If the study by Au et al. were being designed now rather than 10 years ago, the issue of incomplete resection of T1 cancers would need to be addressed more critically. Inclusion of patients with T1 cancer, who are more likely to recur or progress because of incomplete resection, may dilute the salutary effect seen in patients with Ta cancer.

The mechanisms of the recurrences may also differ greatly in patients with different disease grades and stages. Low-grade papillary cancers may well have implantation of cells into the mucosa as a common mechanism for recurrence (1012). Animal studies done years ago documented such a phenomenon, and the clinical observation that recurrent tumors are much more common at the dome of the bladder, where dispersed tumor cells may aggregate at the "air bubble" interface than at the time of initial resection (12), supports this mechanism. If implantation is a valid cause of recurrent tumors, then early intravesical chemotherapy within 24–48 hours of the resection (termed "immediate") becomes logical (10). Indeed, clinical studies (1012) demonstrate that immediate chemotherapy with a single dose of mitomycin C or even thiotepa is better than no treatment and is likely to produce results comparable to those seen with the more intense but delayed 6-week regimen. Immediate chemotherapy is widely used in Europe but is being adopted more slowly in the United States. The cost differential between a single dose and a 6-week treatment program of a relatively expensive agent, such as mitomycin C, is obvious.

Carcinoma in situ, on the other hand, is more likely to be associated with widespread mucosal abnormalities, at least on a molecular level, and is known to spread in the mucosa via a pagetoid pattern (1315). With such disease, a more prolonged course of treatment may well be necessary. Intravesical bacille Calmette-Guérin (BCG) therapy, generally viewed in the United States to be more effective than mitomycin C for carcinoma in situ, has uncertainty regarding concentration, dose, and timing (16). If another trial comparing BCG and mitomycin C is to be considered, an optimized BCG regimen would need to be compared with the optimized mitomycin C schedule proposed by Au et al.

The endpoint chosen for bladder cancer therapy studies, including that of Au et al., is also of some concern. For low-grade cancers, the risk of needing a cystectomy or of dying of bladder cancer is very low. Delay in recurrence is, therefore, an important endpoint relative to patient convenience, health care utilization, and cost. For patients with high-grade, T1, or Tis cancers, however, delay in recurrence is not the desired endpoint; complete elimination of the cancer is a necessity. A persisting high-grade cancer will eventually kill the patient. Urologists, in my opinion, have long been too complacent in their approach to such potentially lethal cancers. Every urologist has in his or her practice patients who are given intravesical therapy, while the bladder cancer becomes incurable. Such a disturbing outcome is not for lack of trying; rather, it occurs because we don't understand the disease or can't find the disease until it is too late. A T1 cancer is particularly worrisome because, at that stage, the cancer has the necessary biologic machinery to invade into the bladder wall and is certainly more dangerous in the short term if it is not totally eliminated. For patients with grade III or stage T1 or Tis cancers in the study by Au et al., the number of patients who developed a recurrence was similar between the control and optimized mitomycin C arms. Neither arm worked well enough.

Integration of data from this study into practice dictates that urologists be more diligent in optimizing administration of intravesical chemotherapy, with a goal of decreasing recurrences in patients with low-grade and noninvasive cancers. However, I believe that it is a mistake to extrapolate these data to high-grade, stage T1, or stage Tis cancer when the goal of treatment in such cancers is complete elimination.

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