Chemotherapeutic Prophylaxis of Superficial Bladder Tumors

In a recent issue of ONCOLOGY (15:85-88, 2001), Drs. Edgar C. Baselli and Richard E. Greenberg presented a brief overview of maintenanceintravesical chemotherapy for superficial bladder cancer.[1] Along with twoaccompanying reviews,[2,3] this article highlights the continuing controversysurrounding the management of this disease. While numerous drugs have been andcontinue to be used in the treatment of superficial bladder cancer, the trueimpact of such treatment on recurrence, progression, and survival remainsunclear. Some investigators (eg, Lamm et al[4]) suggest that intravesicalchemotherapy has only a minor effect on tumor recurrence rates and question theadvisability of its routine use (as opposed to immunotherapy with bacillusCalmette-Guérin, or BCG). In fact, Lamm et al reported that the addition ofchemotherapy produced only a 14% decrease in the recurrence rate at 1 to 3 yearspost-transurethral resection of the bladder (TURB).

Literature Limitations

The literature related to this topic suffers from multiple limitations,making interpretation problematic. For instance, the summary published by Lammet al[4] combined studies in patients with primary and recurrent bladder tumors,without stratifying this parameter. Biological differences may exist betweenprimary and recurrent disease, which may be reflected in the response tochemotherapy. Thus, stratification of this parameter would be informative.Second, this analysis failed to calculate recurrence rates at specific endpoints (eg, 1 or 2 years post-TURB). Third, and most importantly, the analysiswas not performed via standard statistical methods designed specifically forcombining data from multiple randomized clinical trials (ie, meta-analyses).[5]

More Recent Analyses

In an attempt to clarify the ambiguities in the existing published database,our group performed two meta-analyses using 1-, 2-, and 3-year recurrence ratesas end points.[6,7] The relevant clinical trials were pooled using acceptedmeta-analytic techniques.[5] Combined data from 11 trials enrolling over 3,703patients with primary superficial bladder cancer showed a 30% to 80% reductionin the incidence of recurrence at 1 to 3 years following TURB plus intravesicalchemotherapy vs TURB alone.[6] Of all the chemotherapeutic agents used,mitomycin-C (Mutamycin) appeared to be the most effective. Also, long-termtreatment protocols (ie, 2 years) were more effective than short-term orsingle-instillation schedules.

Among patients treated for recurrent bladder tumors, intravesicalchemotherapy reduced recurrence by 38% at 1 year compared with TURB alone, while2- and 3-year recurrence rates were decreased by 54% and 65%, respectively.Doxorubicin was shown to be significantly less effective than all other drugsstudied.

Heterogeneity across the available studies, in terms of tumor stage, grade,treatment schedule, chemotherapeutics employed, clinical end points, andtreatment durations, makes the translation of existing information into clinicalpractice guidelines difficult. In order to distill clinically useful informationfrom such data, appropriate statistical techniques must be employed.[5] Thesetechniques not only allow calculation of a summary estimate of effect but alsoenable evaluation of statistical heterogeneity. Such analyses can provideimportant insight into potential biases in study design or elucidate confoundersthat may produce spurious results.

We feel that intravesical chemotherapy probably has a greater impact on tumorrecurrence in this setting than previously suggested and that prior estimates ofits biological impact are questionable. We are currently designing furtheranalyses of chemotherapy and immunotherapy in superficial bladder cancer andagree that, in the future, molecular markers of aggressive biological behaviormay eventually be integrated into clinical decision-making.

References:

1. Baselli EC, Greenberg RE: Maintenance therapy for superficial bladdercancer. Oncology 15(1):85-88, 2001.

2. Keane TF: The Baselli/Greenberg article reviewed. Oncology 15(1):88-90,2001.

3. Bochner BH, Skinner DG: The Baselli/Greenberg article reviewed. Oncology15(1):90-91, 2001.

4. Lamm DL, Riggs DR, Traynelis C, et al: Apparent failure of currentintravesical chemotherapy prophylaxis to influence the long-term course ofsuperficial transitional cell carcinoma of the bladder. J Urol 153:1444-1450,1995.

5. Cooper H, Hedges LV: The Handbook of Research Synthesis. New York, RussellSage Foundation, 1994.

6. Huncharek M, Geschwind JF, Witherspoon B, et al: Intravesical chemotherapyprophylaxis in primary superficial bladder cancer: A meta-analysis of 3,703patients from 11 randomized trials. J Clin Epidemiol 53:676-680, 2000.

7. Huncharek M, McGarry R, Kupelnick B: Impact of intravesical chemotherapyon recurrence rate of recurrent superficial transitional cell carcinoma of thebladder: Results of a meta-analysis. Anticancer Res 21(1B):765-769, 2001.