A similar Canadian meta-analysis of 16 eligible trials was reported in 2004. Eight trials used cisplatin(Drug information on cisplatin)-based combination chemotherapy, and the absolute overall survival benefit was described to be 6.5%. A major pathologic response was associated with improved overall survival in four trials, and it was concluded that neoadjuvant cisplatin-based chemotherapy improved overall survival in muscle-invasive urothelial carcinoma, though with only a modest effect. Overall there seemed to be more benefit for higher-risk patients (cT3 vs cT2) with neoadjuvant therapy.
The authors also discuss in detail the rationale and trials utilizing postoperative adjuvant chemotherapy. Unfortunately, current adjuvant data are limited, and attempts to prospectively study this question have met with poor patient accrual. Although postoperative adjuvant therapy may be common practice for high-risk patients, this approach is not based on level 1 evidence.
Cystectomy vs Bladder Preservation
As mentioned in the review, transitional cell carcinoma is an aggressive disease, for which cystectomy is considered the gold standard of treatment. A review by Stein et al demonstrated that aggressive surgical treatment can achieve good long-term results. Operating techniques have improved with the development of continent urinary diversions, leading to greater patient satisfaction.
The goal of bladder preservation is to achieve survival equivalent to that associated with radical cystectomy while maintaining the patient's quality of life. Hence, a multimodality approach including neoadjuvant chemotherapy with or without radiation therapy is undertaken. The review describes the data available in this setting, none of which are robust. No randomized trials have compared transurethral resection of the bladder tumor (TURBT) with cystectomy, nor does the addition of radiation to chemotherapy seem to provide a survival advantage.
The take-home message is that patients who undergo bladder preservation need to be a highly selected group of patients who are willing to undergo close routine follow-up with multiple cystoscopies and understand the possibility that cystectomy may be required in the course of the disease.
Finally, a discussion of biologic markers that may predict outcomes and/or tumor response and facilitate patient selection for adjuvant treatment is important. Takata et al characterized gene-expression profiles of 27 invasive bladder cancer specimens prior to administration of preoperative MVAC. They were able to identify 14 genes that were differentially expressed in responding vs nonresponding tumors.
The authors proposed a numerical prediction scoring system for chemotherapy response. Whether such approaches will allow clinicians to tailor therapy will depend upon further studies. In addition, p53 gene expression has been studied as a tool with which to identify poor-prognosis patients. A trial comparing MVAC to observation in cystectomy patients with mutant p53 has completed accrual.
In summary, substantial evidence supports the use of neoadjuvant chemotherapy for clinical stage T2–T4a muscle-invasive bladder cancer. The development of additional markers will improve our understanding of the disease, be useful for prognostication, and aid in selection of appropriate treatment modalities.
—Ila Tamaskar, MD
—Ronald M. Bukowski, MD