Intravesical Therapy for Superficial Bladder Cancer

Despite being one of the more common genitourinary neo plasms, superficial transitional cell carcinoma involving the urinary bladder can be a confusing entity for the treating physician. This confusion stems, in large part, from the binary classification of transitional cell malignancies into broad categories of either superficial or invasive disease. Rather than being a single disease entity, urothelial malignancies that fall into the “superficial” classification actually constitute seven distinct stage/grade combinations. To imply that all of the entities that comprise this spectrum of urothelial malignancy have identical biological potential would be equivalent to saying that all leukemias are the same!

Estimating Risk for Tumor Recurrence and Progression

Although an element of unpredictability remains within single-stage and single-grade classifications, in general, the risk for tumor recurrence and/or progression can be estimated in a given case. Tumor recurrence may have a significant impact on patients’ quality of life. However, it is tumor progression to muscle-invasive disease that is associated with a potentially fatal outcome.

Given the relative importance of progression, when making decisions about treatment, superficial transitional cell carcinoma should be categorized into high- or low-risk groups based on the probability of disease progression. Ta, grades 1 and 2 tumors fall into the low-risk group, whereas carcinoma in situ, grade 3 tumors and T1 lesions constitute neoplasms at high risk for tumor progression.

Selecting an Intravesical Agent

The review article by Baselli and Greenberg provides an excellent overview of intravesical therapy for both high- and low-risk superficial transitional cell carcinoma. In some respects, the intravesical treatment options outlined in this article are as diverse as the disease category they are intended to treat. The available options differ widely not only in terms of efficacy but also with respect to associated toxicity and mechanism of action. The distinct efficacy and toxicity profiles of available intravesical agents, in combination with the variability of tumor biology, make it critically important to match the appropriate drug with the specific tumor.

The selection of an intravesical agent for a specific patient should be predicated on a risk-benefit analysis. The risks associated with a given therapy must be weighed against the potential benefit of the agent in treating the specific disease category.

For patients at high risk for disease progression, the increased morbidity and potential mortality associated with the use of intravesical bacillus Calmette-Guérin (BCG) “immunotherapy” are offset by its increased efficacy in preventing both recurrence and progression. However, for patients at low risk for progression, intravesical chemotherapeutic agents offer a better risk-benefit profile.

Endoscopic Tumor Removal and Disease Recurrence

Several additional points raised in this article merit emphasis. Although tumor progression may result in a potentially fatal outcome, tumor recurrence, independent of progression, carries the burden of significant morbidity. A growing body of evidence suggests that the majority of superficial bladder tumor recurrences are clonal in etiology.[1-3] Furthermore, strong circumstantial evidence suggests that endoscopic tumor removal may, in fact, contribute to tumor recurrence.[4,5] Single-dose perioperative intravesical chemotherapy appears to provide a clear benefit in preventing iatrogenic tumor recurrence.

Although endoscopic surgical tumor removal may contribute to metachronous tumor recurrence, the primacy of its role in the management of superficial transitional cell carcinoma has been clearly established. Complete tumor removal provides important stage/grade information on which the selection of adjuvant therapy is based. Also, intravesical therapy is more efficacious when used for prophylaxis rather than treatment. Finally, in the case of BCG, tumor resection may actually “target” adherence of the bacillus to the site of tumor involvement.[6]

Beyond the ‘Dump and Hope’ Philosophy

The last several decades have witnessed significant progress in our understanding of the use of intravesical therapies in the management of superficial bladder cancer. Despite this progress, a large element of empiricism characterizes current treatment approaches. Fundamental issues of optimal dose, frequency, and treatment duration remain undefined for many of the single agents, much less proposed combinations. Ease of access to the urinary bladder for both drug administration and treatment evaluation seems to have promulgated a “dump and hope philosophy” (ie, “dump it in and hope it works”) as it relates to superficial bladder cancer.

As Baselli and Greenberg emphasize, the future evaluation of treatment modalities must include a clearer definition of both primary and secondary outcome end points. At the same time, there is a pressing need for greater scientific rigor in defining optimal disease treatment strategies, as well as a need to target treatment based on the growing body of knowledge regarding the pathophysiology of both recurrence and progression of superficial transitional cell carcinoma.

References:

1. Takahashi T, Habuchi T, Kakehi Y, et al: Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. Cancer Res 58(24):5835-5341, 1998.

2. Habuchi T, Takahashi R, Yamada H, et al: Metachronous multifocal development of urothelial cancers by intraluminal seeding. Lancet 342(8879):1087-1088, 1993.

3. Sidransky D, Frost P, Von Eschenbach A, et al: Clonal origin bladder cancer. N Engl J Med 326(11):737-740, 1992.

4. See WA, Miller JS, Williams RD: Pathophysiology of transitional tumor cell adherence to sites of urothelial injury: Mechanisms mediating intravesical recurrence due to implantation. Cancer Res 49:5414-5418, 1989.

5. See WA, Chapman PH, Williams RD: Kinetics of transitional tumor cell line 4909 adherence to injured urothelial surfaces in (F-344) rats. Cancer Res 50:2499-2504, 1990.

6. See WA, Williams RD: Urothelial injury and clotting cascade activation: Common denominators in particulate adherence to urothelial surfaces. J Urol 147:541-548, 1992.