Commentary (Shipley): Organ Preservation in Muscle-Invasive Bladder Cancer

Drs. Fernando and Sandler have written a thorough review that has documented why a bladder- conserving therapy can now be more widely accepted treatment for patients with muscle-invading bladder cancer. They have shown that this treatment approach, while selective, does have a high likelihood of eradicating the primary tumor, preserving good organ function, and not compromising patient survival. These successful approaches have evolved over the past 25 years following initial reports of the effectiveness of cisplatin against transitional cell carcinoma and then reports of added efficacy when cisplatin is given concurrently with radiation. Evolving Strategies
From 1981 to 1986, the National Bladder Cancer Group first used cisplatin as a radiation synthesizer in 68 patients with muscularis propria- invading bladder cancer who where unsuitable for cystectomy. This multicenter study showed the concurrent cisplatin/external-beam radiation therapy protocol to be feasible and safe.[1] The long-term survival rates for stage T2 tumors (64%) and stage T3/T4 tumors (22%) were encouraging. As Fernando and Sandler have indicated, the apparent added efficacy of this earlier result with concurrent cisplatin and pelvic irradiation was validated by the National Cancer Institute of Canada randomized trial of radiation (either definitive or precystectomy) with or without concurrent cisplatin in patients with T3 bladder cancer.[2] The Canadian study showed a significant improvement in pelvic tumor control (67% vs 47%) in patients who were assigned cisplatin. Single-institution studies reported that the combination of a visibly complete transurethral resection of the bladder tumor (TURBT) followed by radiation therapy, as well as radiation therapy concurrent with chemotherapy, safely improved bladder tumor eradication.[3,4] Based on these early studies, researchers developed the concept of trimodality therapy (TURBT, as complete as is safely possible, plus concurrent chemotherapy and external-beam radiation therapy). As reviewed in this article, this strategy was shown to be a safe and effective approach to eradicating the bladder of its cancer without requiring cystectomy in at least two-thirds of patients. Our patients, treated from 1986 to 1999, who had a visibly complete TURBT had a better complete response rate (74% vs 63%) and a lower rate of subsequently requiring a cystectomy than did patients whose resection was less than visibly complete.[5] However, those undergoing a visibly complete TURBT have no significant difference in overall or disease-specific survival or distant metastasis-free survival when compared by univariate or multivariate analysis. This is likely so because, using this approach, our patients have been willing to undergo lifelong cystoscopic surveillance and a promptly performed cystectomy should they have an incomplete response or if there is an invasive recurrence. The technique of administering radiation therapy to patients with muscle- invading bladder cancer is challenging because the bladder is not a fixed organ and its location and volume can vary considerably from day to day. Thus, there are logistic problems to ensure adequate coverage of the bladder and its tumor during fractionated external-beam treatment schedules. When using conventional or three-dimensional conformal radiation therapy, a minimum margin of 2.0 cm around the target volume is necessary.[6] Also, since a majority of patients are now being treated concurrently with cisplatin- containing chemotherapy, escalation of the total dose above 65 Gy should only be done under the umbrella of a phase I/II protocol. Brachytherapy
Interstitial radiation therapy allows for delivery of a higher biologic dose of radiation to a limited area of the bladder within a short period. This approach has been reported by investigators in the Netherlands, Belgium, and France. The majority of patients in these series underwent aggressive surgical tumor debulking either by partial cystectomy or by transurethral resection. In addition, many of these patients were given external-beam doses of 30 Gy or more combined with implant doses of 40 Gy.[7,8] Five-year survival rates of 72% to 84% have been reported, with disease- specific survival rates of approximately 80%. These results for solitary stage T2 tumors 4.0 cm or less in diameter suggest that in carefully selected patients with muscle-invading bladder cancer, interstitial radiation produces high local control rates and results in good survival. However, without a randomized trial comparing these results and the toxicity of brachytherapy with those of external-beam radiation therapy with or without concurrent chemotherapy, firm conclusions cannot be drawn. Treatment Comparisons
Any comparison of results from contemporary radical cystectomy series and trimodality therapy with selective bladder preservation (and prompt cystectomy for incompletely responding patients), as in the review by Drs. Fernando and Sandler, is confounded by the discordance between clinical (TURBT) and pathologic (cystectomy) staging. A recent prospective evaluation from Sweden[9] documented that clinical staging is more likely to underevaluate the extent of disease (with regard to penetration into the muscularis propria or beyond) than is pathologic staging. Thus, if any favorable outcome bias exists with such a comparison, it is in favor of the pathologically reported radical cystectomy series. For patients with pathologic stages T2-T4a bladder cancer undergoing radical cystectomy at either the University of Southern California[ 10] or Memorial Sloan-Kettering Cancer Center,[11] the 5- and 10-year overall survival results are similar to but not better than those from the contemporary series using trimodality therapy for clinical stage T2-T4a patients reported from our institution as well as from the University of Erlangen and the Radiation Therapy Oncology Group.[12] The review by Fernando and Sandler has described selective bladder preservation by trimodality therapy as one of the approaches that should be considered in the treatment of all patients with muscle-invading bladder cancer. Although it is not suggested that this strategy will replace radical cystectomy, sufficient data now exist from many national and international prospective studies demonstrating that it represents a valid alternative. This approach contributes to the quality of life of patients so treated and represents a unique opportunity for urologic surgeons, radiation oncologists, and medical oncologists to work hand-in-hand in a joint effort to provide patients with the best treatment for this disease. It must be understood, however, that lifelong bladder surveillance is essential because only prompt salvage cystectomy can prevent the focus of a new or recurrent invasive bladder cancer from disseminating.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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3. Shipley WU, Prout GR Jr, Kaufman SD, et al: Invasive bladder carcinoma. The importance of initial transurethral surgery and other significant prognostic factors for improved survival with full-dose irradiation. Cancer 60:514- 520, 1987.
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