Single Institutional Experience of Bladder-Preserving Trimodality Treatment for Muscle-Invasive Bladder Cancer

Radical cystectomy is considered the standard treatment for muscle-invasive bladder cancer, and over recent years surgical techniques have improved and urinary diversion has been introduced, which have undoubtedly improved quality of life. However, even the construction of a neobladder with continent urinary diversion cannot substitute for the original bladder. Resultantly, trimodality treatment, including transurethral resection of bladder tumor (TURBT) and chemoradiotherapy (CRT) has been suggested as a bladder-preserving therapy in invasive bladder cancer over the past two decades (1-4). To my knowledge, no study has been reported on a prospectively designed trimodality protocol for muscle-invasive bladder cancer in Korean patients. To determine the clinical effectiveness of this trimodality treatment, we designed the present study of concurrent CRT incorporating cisplatin following TURBT for the treatment of muscle-invasive bladder cancer.

Traditionally, transitional cell carcinoma (TCC) is known to be sensitive to cisplatin-based chemotherapy (5). In addition, radiation therapy has been administered to patients who appear to be unsuitable for radical cystectomy (6). However, in the case of muscle-invasive bladder cancer, adequate cancer control cannot be achieved by TURBT, chemotherapy, or radiotherapy alone. Over the last two decades, some centers in the United States and Europe adopted a trimodality treatment (1-4).

The rationale for combining radiotherapy with chemotherapy after TURBT is twofold. First, certain cytotoxic agents may have the ability to sensitize cancer cells to radiation and to inhibit repopulation during radiotherapy. Second, high rates of occult metastases require that efforts to eradicate occult metastases that have already developed in as many as 50% of muscle-invasive cancer (7).

There are two main concerns about CRT. The selection of optimal regimens and ideal candidates are main issues following bladder-preserving therapy, but optimal regimens have not been established. In general, cisplatin and 5-FU (fluorouracil) are still recommended by many investigators, because both agents have been shown to have radiosensitizing activities and acceptable toxicities (8). In addition, to these two drugs, newer chemotherapeutic agents, particularly gemcitabine and taxanes, have also been shown to be potent radiation sensitizers (9). Furthermore, recent studies have established that gemcitabine in combination with radiotherapy as a feasible regimen for bladder sparing treatments, and other series have shown that concurrent CRT using platinum and paclitaxel or docetaxel was also an effective regimen (10, 11). Recently, the relation between radiosensitization and the inhibition of oncogene products, such as, H-ras and c-erbB-1, has been the focus of attention (12, 13).

The selection of ideal candidates for CRT is another important issue for successful bladder-preserving treatment. Some studies have been undertaken to identify clinical factors that help distinguish candidates for trimodality treatment. Rodel et al. concluded that the completeness of TURBT is one of the most potent factors of survival after CRT for patients with invasive bladder cancer (14). In our patients with complete TURBT, the rate of CR was 87.5% and the 5-yr disease-specific and overall survivals were 71.6% and 53.5%, respectively. Our patients with complete TURBT were found to be more likely to respond to CRT and to have a higher survival rate than the 4 patients with incomplete TURBT. These findings are comparable with those of other studies on CRT, which achieved overall survivals of 45-60% (7, 14-16). Other clinical factors that have been considered when choosing patients for bladder preserving surgery include; small tumor size (<5 cm), early tumor stage, absence of ureteral obstruction, and no evidence of pelvic lymph node metastases (7). In addition to clinical factors, several promising molecular markers, such as p53, bcl-2, bax, and pRB may help predict response to specific cytotoxic therapies (17-19).

In terms of the timing of evaluating initial response to CRT, there are two strategies, i.e., early and delayed evaluation. In our study, delayed evaluation was performed at 4 weeks post-CRT. In a study by Erlangen and several others, responses were evaluated 4 to 6 weeks post-CRT by restaging TURBT (1-3). Conversely, according to the Massachusetts General Hospital (MGH) and Radiation Therapeutic Oncology Group (RTOG) protocols, response evaluation should be performed much earlier, i.e., after approximately 40 Gy of induction radiation therapy (20-22). In the literature, salvage cystectomy plays an important role in patients with a persistent tumor after CRT. In this study, we also preferentially recommended cystectomy, but the majority of patients with a persistent tumor at initial evaluation after CRT refused a salvage operation. Thus, we performed cystectomy as a salvage treatment in only 1 of the 5 patients with a persistent tumor at initial evaluation after CRT. In the Erlangen series, which used a late-response evaluation at 4 to 6 weeks post-CRT (1-3), the disease-specific survival rate at 5 yr for patients treated by salvage cystectomy for invasive relapse was 51%. Similarly, in the Boston series, the 5-yr disease-specific survival rate for patients that ultimately underwent salvage cystectomy, but after early-response evaluation, was approximately 50% (23). Thus, available findings reveal no difference in survival after salvage cystectomy according to the time of initial evaluation after CRT.

In our subjects, 4 of 15 patients that achieved CR at initial evaluations after CRT developed a recurrent tumor at the preserved bladder. Of these 4 patients, 2 had a superficial cancer and 2 had an invasive cancer. Two patients with superficial recurrence were easily managed by TURBT and survived with bladder preservation at the time of analysis. Of two patients with superficial recurrence, one patient showed experienced a single recurrence at 48 months post-CRT. Moreover, 3 of 15 patients that achieved CR at initial evaluations after CRT developed isolated distant metastasis. Thus, close follow-up of patients after organ-preserving treatment is mandatory in patients who achieve CR at initial evaluations after CRT for a long time. Generally, 30% of patients who achieved initial CR after CRT developed a recurrent tumor in the preserved bladder, and about a half of these recurrent cancer were superficial (7).

We found that the common acute side effects by CRT are transient diarrhea and voiding symptoms (frequency and urgency), which were common but easily managed with supportive treatment. Moreover, these symptoms usually resolved within 2 or 3 weeks of completing treatment. In this study, 55% and 35% of patients experienced voiding symptoms and diarrhea, respectively. At the time of analysis, no patient required cystectomy for bladder contraction by radiation, but in the largest series conducted to date by Erlangen, 2% of patients required cystectomy for bladder shrinkage, 10% reported some degree of incontinence or increased micturition frequency, and 1.5% of patients experienced a late gastrointestinal toxicity (bowel obstruction) requiring surgical intervention (14).

The present study is limited by the small number of patients recruited, which is why we could not analyze results with respect to clinical factors, especially the completeness of TURBT. A study with a greater number of patients is required to identify factors that distinguish candidates for bladder-preserving treatment. In our study, we could not perform salvage cystectomy on patients with a persistent tumor after CRT, and number of patients with incomplete TURBT was too small to reach the conclusion of survival differences with respect to the completeness of TURBT. However, considering that salvage cystectomy was performed in only 2 patients, 5-yr disease-specific and overall survivals for the 16 patients with complete TURBT were better than those reported by large studies in the US and Europe (1-4). Furthermore, the 5-yr overall survival rate was comparable to the results of radical cystectomy from large surgical series, which showed 48% from the University of Southern California and 45% from Memorial Sloan-Kettering Cancer Center (24).

The trimodality treatment was found to be an effective treatment option for patients with a muscle-invasive bladder cancer who underwent complete TURBT. Close follow-up of patients after CRT is mandatory even in those patients who achieved CR at initial response evaluations.