Combined-Modality Therapy for Bladder Cancer

Introduction

Muscle-invasive transitional cell carcinoma (TCC) of the urinary bladder is most commonly treated by radical cystectomy. This time-honored procedure leads to accurate staging and cures many patients. However it leaves the patient with a wet appliance on the skin and results in impotence in men. Distant metastases develop in a substantial proportion of patients with disease pathologically proven to invade the deep muscularis or beyond and, in a large majority, when nodal metastases are detected at operation.

Alternatives to radical cystectomy include recently developed operations providing continent urinary diversion, and combined-modality approaches with transurethral resection (TUR) of tumor or partial cystectomy, in conjunction with chemotherapy with or without radiation therapy. As monotherapy, none of the alternatives is as effective as cystectomy, but the cumulative results of studies incorporating two or more modalities show a trend toward higher response rates.[1]

In this paper we review the status of multimodality treatment for muscle-invasive disease and consider the progress made in elucidating the role of chemotherapy in the management of locally advanced bladder cancer.

Background

Treatment of the Primary Tumor

Historical surgical series of radical cystectomy demonstrate that both higher T-stage and the presence of lymph node metastasis have a negative impact on overall survival (Table 1).[2-12] Improved supportive care over the past 3 decades with the associated reduction in postoperative mortality has resulted in higher survival proportions in contemporary cystectomy series.[2,3,6,7,11] In addition, the development of continent urinary diversion procedures has enhanced quality of life and reduced the negative body image associated with radical cystectomy. Two types of continent diversion are available: the first is a continent reservoir still requiring a stoma but evacuated by repeated catheterization, and the second is an orthotopic bladder substitute anastomosed to the urethra.

Not all patients are suitable candidates for continent urinary diversions. Diffuse carcinoma in situ (CIS) and tumor involvement of the bladder neck or prostatic urethra are relative contraindications, and urethral anastomosis with preservation of continence is extremely difficult to accomplish in women, in whom it is rarely attempted. The rate of complication for continent diversions is also greater in the obese or elderly patient.[13]

In unselected patients, partial cystectomy is associated with a very high local relapse rate. If patient selection is based on a solitary lesion at the bladder dome, an absence of CIS or a prior history of transitional cell carcinoma, a bladder of normal function and capacity, and a 2-cm margin of resection, then only 6% to 19% of patients are potential candidates for a partial cystectomy. Although some series have survival rates equivalent to those for radical surgery, others have reported recurrence rates ranging from 38% to 78%.[14] Therefore partial cystectomy is rarely indicated as monotherapy.

A number of studies have shown that maximal or aggressive transurethral resection (TUR) alone may control some muscle-invasive bladder tumors.[15,16] One study evaluated 118 patients who had a diagnosis of transitional cell carcinoma made by transurethral resection and who were followed conservatively after a repeat TUR failed to document residual disease.

Of the 118 patients, 77 (65%) remained free of muscle-invasive disease beyond 5 years. The overall 5-year disease-free survival was 83%. Other investigators have reported similar bladder control rates following transurethral resection alone, when cases are selected for low T-stage and low histologic grade.[17,18] However, in general practice, the indication is in frequent and possible routinely only with small primary tumors.

In the United States, historically, radiation therapy alone has been reserved for patients who are medically unfit for radical cystectomy. In Europe and Canada, external-beam radiation therapy, given in fractionated doses over 4 to 7 weeks to a total dose ranging from 50 to 65 Gy, has been widely used as primary therapy. The largest series (Table 2) have included patients with T1 to T4b lesions and are associated with local control in 35% to 45% of patients and 5-year survival rates ranging from 23% to 40%.[19-23] These results appear to be worse than those achieved with primary surgery, although case selection and other biases probably exist.

Treatment of Metastatic Disease

Transitional cell carcinoma is a chemotherapeutically responsive neoplasm.[24] One of the principles underlying the development of effective systemic treatment is to combine agents with independent activity and nonoverlapping toxicities. Cisplatin(Drug information on cisplatin) (Platinol) is the agent common to nearly all active regimens. With cisplatin-based combination chemotherapy regimens, complete responses plus partial responses are observed in 50% to 75% of cases.[25]

Although the optimal combination has not been defined, data from two randomized trials support the use of the M-VAC (methotrexate, vinblastine(Drug information on vinblastine), doxorubicin(Drug information on doxorubicin), and cisplatin) combination as one form of standard therapy. In a randomized trial of 224 evaluable patients that compared M-VAC with single-agent cisplatin, M-VAC was superior to cisplatin in overall response proportion (39% vs 9%; P < .0001) and survival (12.5 months vs 8.2 months; P = .0002).[26]

In a second trial that compared M-VAC with CISCA (cisplatin, cyclophosphamide(Drug information on cyclophosphamide) and Adriamycin), M-VAC showed a survival advantage (48.3 vs 36.1 weeks; P =.0003).[27]

Other regimens such as CMV (cisplatin, methotrexate(Drug information on methotrexate), and vinblastine) also have high response proportions and a median survival of 8 months.[28] A direct comparison of M-VAC with CMV has not been attempted. However, a randomized trial of CMV demonstrated a survival advantage over MV (methotrexate and vinblastine) at 1 year (P = .045).[29]

Combined-Modality Therapy With Surgery

The finding of high response rates and occasional long-term disease-free survival with active multiagent combinations has led to the exploration of these regimens in the postoperative adjuvant and preoperative neoadjuvant settings. The primary aim of both approaches is to treat micrometastases, thereby reducing systemic relapse and disease-specific mortality. A secondary aim of neoadjuvant therapy is to permit organ preservation.

A number of difficulties hamper the interpretation of clinical trials of both adjuvant and neoadjuvant chemotherapy regimens. The first is the inability to predict pathologic stage accurately using clinical methods, which adversely affects patient selection for neoadjuvant therapy.[30,31]

Second, at least 50% of patients with muscle-invasive disease will have disease relapse, two-thirds at distant sites and one-third locally.[15,32] The lack of reliable factors predictive of relapse underscores the difficulty of selecting patients to receive adjuvant chemotherapy who may already be cured by cystectomy alone. The promise shown by newer biologic prognostic factors notwithstanding, to date patient selection for combined therapy relies on clinical factors alone. Only two factors have been shown to have predictive ability, and one of these—tumor stage—is inaccurate in over 50% of cases.

A third impediment to data interpretation is the clinical trial methodology itself, particularly sample size, which may not be large enough to detect the 10% to 15% difference in survival predicted for chemotherapy plus surgery over surgery alone.[33] This emphasizes the need for multicenter trials to complete their planned randomization so as to provide answers with statistical power.

Adjuvant Chemotherapy

A few nonrandomized adjuvant trials were reported in the pre-cisplatin era.[34-38] The agents used were the best available at that time, but are now known to be of limited efficacy. The delivery of planned therapy at full doses was the exception rather than the rule in the era before effective antiemetics and hematopoietic growth factors. These trials did not demonstrate a survival benefit for chemotherapy.

A retrospective comparative analysis of 339 patients classified on the basis of postcystectomy pathologic risk (unfavorable features included resected nodal metastases, extravesical tumor involvement, lymphovascular permeation of the primary tumor, and pelvic visceral invasion) was reported by investigators at The M.D. Anderson Cancer Center.[39] Patients who did not receive adjuvant chemotherapy were subdivided into low-risk (favorable pathology: N = 206) and high-risk (refusal of chemotherapy, medically unfit, or not referred: N = 62) subgroups and compared with a second high-risk group that received adjuvant chemotherapy with CISCA (N = 71).

The 5-year survival distributions for the three groups were 76%, 37%, and 70%, respectively, suggesting that adjuvant chemotherapy shifts the prognosis of high-risk treated patients to match that of low-risk controls. For patients with node-positive disease who received chemotherapy, 65% achieved long-term disease-free survival. The absence of randomization is an important deficit of this analysis.

Randomized Trials—Adjuvant therapy has been studied in five randomized trials (Table 3).[36,40-43] Two trials have suggested a survival benefit for chemotherapy over observation alone following cystectomy.[42,43] In one trial, 91 patients with pT3-4 or node-positive disease were randomized to either observation or four cycles of CAP (cyclophosphamide, doxorubicin, and cisplatin). A significant delay in time to progression was observed for patients who received chemotherapy (70% disease-free survival, as compared with 46% at 3 years; P = .001), but the improvement in survival (57 vs 29 months) only approached statistical significance (P = .062).[43] This trial has been criticized for the methodology it employed, the lack of standardization of chemotherapy (ie, use of a number of agents and schedules), and the fact that it was terminated prematurely.

In the other study, 49 patients with pT3a-4a or node-positive transitional cell carcinoma were randomized to receive M-VAC or M-VEC (methotrexate, vinblastine, cisplatin, and either doxorubicin or epirubicin(Drug information on epirubicin)) or to observation. A significant reduction in the risk of tumor recurrence was observed in the adjuvant chemotherapy arm; 3 (17%) of 18 patients who received chemotherapy relapsed, as compared with 18 (82%) of 22 untreated patients (P = .0006). The number of involved nodes was predictive of recurrence.[42]

In a follow-up report, a survival benefit was observed, with additional patients entered into the study.[44] It should be noted that patients who were observed did not receive chemotherapy at relapse.

Other randomized trials have shown no difference between observation and adjuvant therapy. However, the remaining trials used therapy now known to be less active.