Combined-Modality Therapy for Bladder Cancer

September 1, 1997
John A. Mccaffrey, MB, MRCPI

,
Dean F. Bajorin, MD

,
Howard I. Scher, MD

,
George J. Bosl, MD

Oncology, ONCOLOGY Vol 11 No 9, Volume 11, Issue 9

Radical cystectomy remains standard management for patients with locally advanced T2 through T4, N0, M0 transitional cell carcinoma of the urinary bladder.

ABSTRACT: Radical cystectomy remains standard management for patients with locally advanced T2 through T4, N0, M0 transitional cell carcinoma of the urinary bladder. Although radical cystectomy results in excellent local control, 50% or more of patients relapse. Studies have shown that multidrug cisplatin (Platinol)-based chemotherapy prolongs disease-free survival in 10% to 15% of cases and is superior to single-agent cisplatin. These studies led to the application of these regimens in conjunction with surgery and/or radiation therapy in an attempt to preserve bladder function. With this approach, the decision to leave the bladder in place, remove a portion (partial cystectomy), or perform a radical cystectomy is made after assessing the initial response to therapy. Results from neoadjuvant studies have shown that: major responses are observed in at least 50% of patients; bladder preservation can be achieved in 25% to 50%; a pathologic complete response predicts long survival; and patients with deeply invasive lesions (T3b to T4) usually are not candidates for bladder preservation. Whether overall survival is improved has been difficult to ascertain due to such issues as small sample size and case selection. Concurrently, newer surgical approaches with continent diversions have reduced, to some extent, the need for ileal conduits, a factor influencing the bladder preservation approach. Adjuvant chemotherapy, although less well studied, suggests a possible survival benefit for selected patients with a high likelihood of relapse. To optimize patient selection, new prognostic factors are necessary. Many biologic variables based on expression of tumor-related proteins are under study. Combined-modality therapy is not standard management for the majority of bladder-cancer patients. However, it is a viable alternative for those who are committed to preserving bladder function. Additional research is required to determine whether these approaches improve survival and to identify better markers of treatment outcome. [ONCOLOGY 11(Suppl 9):18-26 1997]

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 (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, 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 and Adriamycin), M-VAC showed a survival advantage (48.3 vs 36.1 weeks; P =.0003).[27]

Other regimens such as CMV (cisplatin, 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) 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.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy allows for in vivo assessment of chemosensitivity, and nonrandomized trials have demonstrated pathologic complete responses in up to 30% of patients.[45-48]Pathologic response to neoadjuvant chemotherapy has prognostic significance: 5-year survival rates of 75% vs 20% for a major response (complete response or partial response) vs the lack of such a response (pT ³ 2).[49-51]

 

Combined-Modality Treatment Plus Radiation Therapy

A number of factors have influenced the incorporation of radiation therapy into combined-modality programs. Radical cystectomy provides excellent local control, but more than 50% of patients with T2-T4 tumors develop distant metastases and die of disease. The combination of cisplatin with radiation therapy results in more effective control than does radiation therapy alone. Two randomized trials of 99 and 189 patients have been performed. In the first, a 67% vs 45% local control rate (P = .023) favored the combination arm[66] and in the second, a 76% vs 45% local control rate (P value not stated) also favored the combination.[67] However, a joint Australian/United Kingdom trial of 288 patients with T2 to T4 transitional cell carcinoma randomized to receive cisplatin/radiation or radiation therapy alone with salvage surgery for nonresponders demonstrated no differences between the two arms with respect to survival or organ preservation.[53]

Multiagent Chemotherapy Plus Radiation-Since multiagent chemotherapy is superior to single-agent cis-platin, many studies of radiation therapy and combination chemotherapy, with or without conservation surgery, have been conducted (Table 6).[49,65,67-72]Rates of bladder preservation at 5 years ranged from 18% to 44%, and 5-year survival, irrespective of local control, was equivalent to that seen with historical cystectomy series. Synergistic bladder and bowel toxicity was not observed, and most patients completed the planned therapy without dose attenuation. Reversible nephrotoxicity and myelosuppression were the main toxicities encountered.

The most frequently quoted series was reported by investigators at the Massachusetts General Hospital Cancer Center.[64] Their study included patients with T2-T4 tumors who underwent TUR followed by two cycles of chemotherapy with MCV (methotrexate, cisplatin, and vinblastine). Further management depended on the response of the bladder tumor to induction chemotherapy followed by concomitant radiation therapy (40 Gy over 5 weeks) to the pelvis and cisplatin 70 mg/m2 on days 0 and 21. Depending on response, additional radiation therapy to the primary tumor site (to a total dose of 64.8 Gy) was delivered with concomitant cisplatin. An incomplete response was treated with radical cystectomy.

Of the 53 patients treated, 11 withdrew from the study (eight of whom could not tolerate either chemotherapy or radiation therapy), 28 (53%) had a complete response to induction chemotherapy, and 14 (26%) had an incomplete response (eight of whom were referred for radical cystectomy and six of whom were deemed unsuitable for radical cystectomy). Among the 28 complete responders, 25 (89%) have continued to have bladders free of recurrent cancer.

With 4-year follow-up, 24 (45%) of the 53 patients are alive and disease free, and 20 (38%) have survived with a cancer-free, intact bladder, although nine patients have required repeat TUR and intravesical therapy for superficial disease. For the 15 patients with T2 tumors, the 5-year survival rate is 68%, as compared with a rate of 39% for the 38 patients with T3 or T4 disease (P = .02).

Multivariate analysis demonstrated that only tumor stage and hydronephrosis were independent prognostic factors for survival. The optimal predictor for successful bladder conservation was a complete response to the combination of transurethral resection followed by induction chemotherapy.

The recently reported European Organization for Research and Treatment of Cancer/Medical Research Council trial of neoadjuvant CMV chemotherapy followed by either cystectomy or radiation therapy showed no advantage over treatment with local therapy alone.[52] The addition of doxorubicin might be a significant factor, although M-VAC and CMV have not been compared in randomized fashion.

An ongoing Radiation Therapy Oncology Group trial is currently comparing the addition of combination chemotherapy (methotrexate, cisplatin, and vinblastine [MCV]) plus cisplatin/radiation therapy vs cisplatin/radiation therapy alone. The results of these trials should help define the roles of neoadjuvant chemotherapy and radiation.

Prognostic Factors for Bladder Preservation

Clinical factors reported to predict that a patient is not a suitable candidate for bladder preservation include the presence of solid, multiple, high-grade lesions, especially of the bladder neck or trigone; lymphovascular invasion; associated carcinoma in situ; higher T-stage (>T3a); hydronephrosis; and a poor response to neoadjuvant chemotherapy.[31]

In the two largest series of neoadjuvant chemotherapy and in the larger radiation/chemotherapy studies, only T- stage and lack of hydronephrosis identified patients who were candidates for combined-modality bladder preservation programs.[26,31,52,64] However, clinical factors alone are not sufficient since recurrent or metastatic disease frequently develops, despite the careful selection of patients. Newer prognostic factors based on biologic characteristics of the primary tumor may enhance patient selection. Mutations in tumor-suppressor genes are the most promising of these.

Status of p53 in Primary Tumor-An important new prognostic factor may be the status of the p53 tumor-suppressor gene in the primary tumor.[73]Mutation of the p53 gene is the most frequent genetic alteration in transitional cell carcinoma of the bladder. It is known that wild-type p53 has a short half-life and that mutant p53 forms resulting from certain mutations in the p53 gene have long half-lives. Thus, in immunohistochemical (IHC) studies, the presence of nuclear staining by p53 antibodies implies a mutant p53 gene. In transitional cell carcinoma of the bladder, the correlation between p53 nuclear staining and mutations in the p53 gene is high.

At Memorial Sloan-Kettering Cancer Center, the p53 status of the tumors of 90 patients treated with neoadjuvant chemotherapy was evaluated.[74] Patients whose primary tumors did not show nuclear staining of p53 protein by IHC (implying wild-type p53) were three times more likely to survive their disease than those whose tumors showed greater than 20% immunohistochemical nuclear staining. Patients with tumors that expressed wild-type p53 and had a low stage of disease (T2 and T3a tumors) had a 77% survival at 5 years following neoadjuvant chemotherapy.[74]

In an analysis of 243 patients who underwent radical cystectomy (pTa-pT4B), Esrig et al[75]examined the cystectomy specimens for immunohistochemical detection of p53 protein in relation to time to recurrence and overall survival. Rates of recurrence for pT1, pT2, and pT3a transitional cell carcinoma were 7%, 12%, and 11%, respectively, for those in whom nuclear p53 immunoreactivity was not detected. This contrasts with rates of 62%, 56%, and 80%, respectively, for the same disease stages in those with positive reactivity (P < .001). (No significant difference was noted for pT ³ 3B tumors).

Overall survival decreased when nuclear p53 reactivity was detected (P< .001). Lowe[73] demonstrated that tumors with wild-type p53 were more sensitive to chemotherapy than tumors with mutant p53.

Retinoblastoma Gene Product- The retinoblastoma (Rb) susceptibility gene product is a nuclear phosphoprotein thought to function as a cell-cycle regulator. This gene product can be examined by IHC using a monoclonal antibody (Rb-PMG-245) on frozen tissue sections, quantifying the level of Rb protein in individual tumor cells by computed image analysis. One report has suggested that bladder tumors exhibiting decreased expression of the Rb phosphoprotein have a more aggressive biologic behavior than those that express Rb protein in the majority of tumor cells.[76] The high rate of altered Rb expression found in advanced urothelial tumors strongly suggests that Rb functional loss may be associated with tumor progression.

A second study found that altered Rb protein expression was independent of other known prognostic variables.[77] Therefore, patients with early-stage disease, wild-type p53, and increased Rb expression may be the ideal group to select for bladder-preserving therapy.

A clinical trial has been initiated at Memorial Hospital using p53 status to determine patient selection for radical cystectomy or bladder preservation using good-risk criteria (wild-type p53, T2 or T3a tumors, and no hydronephrosis). A transurethral resection is done to resect the primary tumor, followed by M-VAC chemotherapy and clinical restaging. Patients who achieve a clinical complete response at the completion of four cycles of therapy will be observed. Definitive surgery with radical cystectomy will be recommended for any patient with an incomplete response.

Conclusions

Radical cystectomy remains the standard treatment for muscle-invasive bladder cancer. Efforts at bladder preservation require more than one treatment modality, and the greatest benefit may be achieved by a program of conservation surgery, chemotherapy, and radiation therapy. Randomized data have yet to confirm this. The role of chemotherapy in improving survival in the patient undergoing cystectomy, when administered either before or after surgery, has yet to be confirmed, although benefit has been seen in some studies of adjuvant chemotherapy.

The exploitation of newer biologic prognostic markers may guide patient selection for such combined-modality approaches and improve both organ preservation and survival. Randomized studies are still required to ascertain which combination programs may allow for organ preservation and improve overall survival compared with standard therapy.

 Randomized Trials-The randomized studies of neoadjuvant chemotherapy (Table 4) also suffer from small sample size, and most studies have not been able to show a benefit for chemotherapy.[20,52-54]

 

One randomized trial conducted in Scandinavia showed an advantage for neoadjuvant chemotherapy.[55] Patients who received doxorubicin and cisplatin prior to preoperative radiation therapy and cystectomy had a 10% improvement in 5-year survival, as compared with the survival of patients who did not receive neoadjuvant chemotherapy.

Results from the ongoing Southwest Oncology Group trial of neoadjuvant chemotherapy are awaited. However, despite more than a decade of trials, the fundamental question of whether or not chemotherapy improves survival in the adjuvant and neoadjuvant settings has yet to be answered.

Neoadjuvant Chemotherapy Plus Less Radical Surgery-Some data support the use of chemotherapy as an adjunct to less radical surgery in selected patients [48,56-62]. In the largest series, reported from Memorial Hospital,[48] 111 patients received neoadjuvant M-VAC followed by reevaluation. Partial cystectomy was possible in 26 patients (23%); 7 (6%) were unresectable at laparotomy; 46 (41%) underwent radical cystectomy or radical prostatectomy (one patient with prostatic transitional cell carcinoma); one patient had a negative TUR and laparotomy and did not undergo radical resection; and one patient had autopsy staging. The remaining 30 patients (27%) were clinically staged only, the majority of whom refused surgery apart from transurethral resection.

Of the 26 patients who underwent partial cystectomy, 17 patients (65%) were alive and disease free with a minimum follow-up of 4 years, and 14 (54%) had an intact functioning bladder. Transurethral staging data were available for 27 of the 30 patients who were staged clinically. With a 31-month follow-up, 17 (63%) were alive, 16 (52%) with an intact bladder.[48]

Simon and Srougi[62] reported that 9 (30%) of 30 patients were selected as candidates for partial cystectomy based on clinical response following three cycles of M-VAC chemotherapy. With a minimum of 3 years follow-up, seven patients (78%) were alive with intact bladders.

Analyzing the other series that have used this combined approach (Table 5), the bladder-sparing rate ranged from 41% to 89% with 5-year survival rates varying from 63% to 89%.[56-61] In these series, some patients who had locally recurrent disease achieved long-term disease-free survival following salvage cystectomy. Distant metastases following transurethral resection and chemotherapy occurred in 0% to 32% of patients, with most appearing in the 2 years following diagnosis. This rate of distant metastasis is similar to that seen in patients treated with radical cystec-
tomy as initial surgery.[63]

Prognostic Factors-A complete response to chemotherapy rather than initial stage was the most important prognostic factor for outcome and survival in the Memorial Hospital trial.[48] Pathologic staging after neoadjuvant chemotherapy was available in 81 of the 111 patients. Among 47 patients with T2 to T3a disease, 20 (42.5%) were downstaged to pT0 or CIS alone; of 34 patients with T3a to T4b disease, only 4 patients (l2%) were similarly downstaged.

The postchemotherapy stage correlated with survival in patients with extravesical disease before chemotherapy; if downstaging to pT £ ƒ3b occurred, the median survival was 6.2 years, as compared with 1.1 years in patients who still had extravesical disease after chemotherapy. No survival difference was observed in those who initially had organ-confined disease (T £ 3a) whether or not downstaging was observed.[31-64] These observations have been confirmed by other investigators.[65]

These data suggest that neoadjuvant chemotherapy followed by an operation less radical than total cystectomy has value in selected patients with T2- T3 tumors, offering local control equivalent to radical cystectomy.

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