ABSTRACT: Invasive bladder cancer is a chemotherapy-sensitive neoplasm. Historically, the development of cisplatin (Platinol)-based chemotherapy regimens has represented an important advance for patients with metastatic disease. More recently, investigations of new agents, such as gemcitabine (Gemzar) and paclitaxel (Taxol), have resulted in further options for these patients. Randomized trials comparing new regimens with cisplatin-based therapies have been initiated. The role of chemotherapy in the adjuvant and neoadjuvant settings is an area that is undergoing active investigation. The application of prognostic biological markers to risk-stratify patients has resulted in new avenues of investigation in these ongoing early disease trials. [ONCOLOGY 15(6):763-780, 2001]
In the United States, radical cystectomy with bilateral pelvic lymph node dissection is the standard treatment for localized muscle-invasive bladder cancer. The prognosis of the patient depends primarily upon the tumor stage. The risk of recurrence for patients with extravesical extension or lymph node metastases is relatively high. Because transitional cell carcinoma is a chemotherapy-sensitive neoplasm, eradication of micrometastases with adjuvant or neoadjuvant systemic chemotherapy could potentially improve cure rates. An extensive discussion of adjuvant and neoadjuvant chemotherapy for bladder cancer is beyond the scope of this article; however, recent reviews have been published.[40,41] The ultimate benefit of recent advances in the development of new, active regimens for patients with advanced bladder cancer may be their application in the earlier perioperative setting.
Adjuvant therapy is based on knowledge of the pathologic stage of the patient’s tumor. To determine the benefit of this approach, there is a need for sufficiently powered randomized trials with a surgery-only control arm. Although there is no trial that definitively proves the benefit of adjuvant chemotherapy in bladder cancer, two trials suggest potential.
Skinner et al reported a randomized trial of surgery alone or surgery followed by adjuvant chemotherapy with the cyclophosphamide/doxorubicin/cisplatin regimen in 91 patients with pT3/pT4 and/or node-positive disease. This trial demonstrated a delay in the time to progression in favor of the chemotherapy arm (70% vs 46% disease-free survival at 3 years; P = .001).
Stockle et al randomized patients with pT3b-pT4a or node-positive disease to M-VAC/MVEC (methotrexate, vinblastine, epirubicin [Ellence], cisplatin) or observation. With only 49 patients treated, an interim analysis showed that the risk of recurrence was significantly decreased by adjuvant chemotherapy. Follow-up on these patients has been updated, and the patients who had been randomized to the chemotherapy arm continue to show an advantage with respect to event-free survival (40 vs 18 months; P = .004).[40,43] Other small trials have not demonstrated a benefit with adjuvant chemotherapy. Outside of the context of a clinical trial, some clinicians recommend treatment with a standard regimen, such as M-VAC, for patients with high-risk, resected disease (eg, patients with extravesical extension or micrometastases to regional nodes), if the patient can tolerate chemotherapy.
Clinical trials examining the role of adjuvant chemotherapy in bladder cancer continue (Table 4). A randomized trial has been initiated by the ECOG consisting of four cycles of paclitaxel/carboplatin vs four cycles of M-VAC for postcystectomy patients with pT3b-pT4 and/or node-positive disease. This trial was activated in March 1999, and the investigators plan to accrue 490 patients. At MSKCC, the use of sequential drug therapy in the adjuvant setting is under investigation. High-risk patients are receiving sequential gemcitabine and doxorubicin followed by paclitaxel plus cisplatin or carboplatin.
With respect to neoadjuvant chemotherapy for bladder cancer, published randomized trials to date have generally failed to demonstrate an effect on survival. The largest of these trials was the Medical Research Council/EORTC trial that randomized patients to three cycles of cisplatin/methotrexate/vinblastine followed by definitive local therapy vs definitive local therapy alone. This large prospective trial in 975 patients failed to demonstrate an improvement in overall survival with the use of neoadjuvant chemotherapy. The Intergroup trial of neoadjuvant M-VAC for three cycles followed by cystectomy vs cystectomy alone for patients with muscle-invasive disease has been completed. This trial accrued over 300 patients between 1989 and 1998. Results are forthcoming.
In an effort to better characterize the biology of bladder cancer, specific components of biochemical pathways, or structural molecules that are critical to cell architecture, have emerged as candidate tumor biomarkers. Comprehensive discussions of multiple potential biomarkers in bladder cancer have recently been published.[45,46] Although the clinical value of many of these markers will be minor, fairly large retrospective studies of archival material have demonstrated the potential clinical utility of some of these putative biomarkers. Several cell-cycle regulatory molecules, such as p53, p21WAF1/CIP1, and retinoblastoma (Rb), have emerged as biomarkers that can predict for disease progression and survival in patients with muscle-invasive disease treated by cystectomy. A prospective validation of these biomarkers has not yet been demonstrated.
p53 and p21
p53 has multiple functions, with a central role in tumor suppression by initiating either apoptosis or inducing cell-cycle arrest at G1/S following the detection of cellular DNA damage through the induction of p21WAF1/CIP1. Mutated p53 is dysfunctional and has a prolonged half-life, resulting in a nuclear accumulation of the abnormal protein. This can be detected by immunohistochemical (IHC) techniques.
A strong concordance exists between p53 IHC overexpression and documented p53 mutations in bladder cancer, thereby providing an accessible biomarker for analysis of bladder cancer lesions.[48,49] In a retrospective review of 243 patients undergoing radical cystectomy, patients with organ-confined disease and altered p53 nuclear staining had a higher risk for disease progression (60%-80% vs 7%-11%) and disease-related mortality compared to patients with wild-type staining. Furthermore, altered p53 expression was an independent predictor of these outcomes in organ-confined (P1 and P2) invasive lesions.
These findings have been confirmed in some but not all investigations. [51,52] Discrepancy in these analyses may in large part be due to the use of different antibodies for IHC among the studies and the use of different criteria for positivity among investigators. Such findings suggest the importance of standardizing criteria for biomarker positivity before employing such data in clinical decision making.
The effect of cell-cycle dysregulation on outcomes in advanced bladder cancer has been further demonstrated by the clinical analysis of p53 and p21WAF1/CIP1 expression. Cell-cycle arrest that is mediated by p53 is effected by the induction of p21WAF1/CIP1—a cyclin-dependent kinase inhibitor. Besides induction through p53, p21WAF1/CIP1 may be constitutively expressed through several p53 independent pathways.
In an analysis of 242 patients undergoing radical cystectomy with a median follow-up of 8.5 years, it was noted that outcomes (progression and death) could be predicted by the pattern of p53 and p21 expression. Patients positive for p21WAF1/CIP1 had a significant decrease in tumor recurrence (30% vs 76%) and an increase in overall survival (63% vs 25%). In a multivariate analysis, p21WAF1/CIP1 was an independent predictor of recurrence and survival among several pathologic features, including p53 status. Furthermore, patients with altered p53 and absent p21WAF1/CIP1 expression had a poor prognosis with regard to disease progression (85%) and survival (15%), while patients with preserved p21WAF1/CIP1 expression demonstrated outcomes similar to those seen in patients with p53 wild-type tumors (50%-70% overall survival).
Role of pRb
Alterations in the Rb gene are common in bladder cancer, and the expression of Rb protein (pRb) has been studied in cystectomy patients.[56,57] In a series of 185 cases, Rb nuclear reactivity was measured (and scored as absent, 1+, or 2+). Absent or elevated pRb reflected worse progression (60% vs 30%) and worse 5-year survival (33% vs 66%) than normal (1+) heterogeneous nuclear reactivity (< 50% nuclei stained). When p53 status was also considered, a pattern of outcomes at 5 years was noted for wild type in both biomarkers (22% recurrence, 71% survival), alteration in either biomarker (42% recurrence, 51% survival), or altered Rb and p53 (79% recurrence, 16% survival). The data support the value of pRb as a biomarker and provide evidence that alterations in p53 and pRb may be synergistic in promoting tumor progression.
In addition to cell-cycle regulators, the direct measurement of tumor angiogenesis (microvessel density) or biomarkers associated with angiogenesis may have potential as prognostic predictors for chemotherapy response. Tumors with low microvessel counts are associated with greater progression and decreased survival in patients with and without p53 alterations. Additionally, patients with low thrombospondin-1 (TSP-1) expression in tumor specimens demonstrate increased recurrence rates and decreased overall survival. However, the predictive power of this angiogenesis inhibitor is not independent of p53 expression, thereby suggesting that p53 may affect tumor angiogenesis by regulating the level of TSP expression.
Rationale for Retrospective Analysis
The findings in these series provided the rationale for applying this approach of retrospective molecular biomarker analysis to patients who received chemotherapy for bladder cancer. In one investigation of patients receiving neoadjuvant chemotherapy for muscle-invasive disease, altered p53 expression was associated with a significantly higher degree of disease progression and death, while those patients with wild-type p53 and other favorable features experienced a 77% 5-year survival.
In another review, patients who participated in an adjuvant chemotherapy trial were evaluated with regard to the p53 status of their lesions. In patients receiving adjuvant chemotherapy who displayed wild-type p53 expression, a 3-fold lower risk of tumor recurrence and a 2.6-fold improved survival was noted compared to the control group with altered p53 expression. In other smaller series of patients who received adjuvant chemotherapy, altered p53 expression was not informative with regard to response or outcome.[62,63] Results of these retrospective evaluations provide the basis for two recently initiated prospective chemotherapy trials in patients with localized bladder cancer.
Prospective Clinical Trials
At MSKCC, a trial has been initiated to demonstrate the use of neoadjuvant chemotherapy in patients with muscle-invasive lesions who have favorable clinical and molecular features. Patients with organ-confined, muscle-invasive disease, without hydronephrosis and wild-type p53 nuclear staining on IHC, will undergo complete transurethral resection of the tumor and then neoadjuvant M-VAC followed by conservative management of the primary bladder tumor when possible. The goals of this study are (1) to determine the feasibility of this treatment plan in these patients, and (2) to determine the proportion of patients (treated with this regimen) in whom bladder preservation, rather than radical cystectomy, is possible.
A multi-institutional study sponsored by the National Institutes of Health and based at the University of Southern California is investigating the effect of altered p53 expression on the adjuvant treatment of patients with organ-confined bladder cancer (Table 4). Approximately 540 patients will be studied among the different treatment arms. In this trial, patients who demonstrate organ-confined disease after cystectomy shall undergo IHC analysis of their tumor. Those patients with wild-type p53 tumors shall undergo routine follow-up, while patients with altered p53 expression tumors shall be randomized 1:1 to surgery alone or surgery followed by three cycles of adjuvant M-VAC. The study is designed to detect a 20% difference in survival between the groups.
As these investigations mature, other biomarkers may emerge as potential candidates for further prospective clinical trials. Nonetheless, at this time, it is apparent that a candidate biomarker must be measurable by IHC, since a certain level of technical ease and reproducibility must be available if the marker is to gain acceptance in broad clinical application. However, the rapid pace of biotechnology suggests that detailed and reproducible molecular phenotyping of tumors, with innovations such as microchip arrays, will allow us to accurately analyze candidate biomarkers in an effort to predict which patients with invasive bladder cancer will most likely derive benefit from chemotherapy.
In sum, the development of new agents, such as gemcitabine and paclitaxel, have resulted in new options for patients with advanced urothelial carcinoma. Randomized trials comparing gemcitabine/cisplatin and paclitaxel/carboplatin to M-VAC are important to further define the role of these regimens in the treatment of patients with advanced disease. The application of new regimens in early-disease, perioperative settings is currently under investigation.
Future advances in chemotherapy for patients with invasive bladder cancer may result from further investigations into the biology of the disease that aim to identify subsets of patient who may or may not benefit from chemotherapy. Clinicians are encouraged to offer patients the opportunity to participate in well-designed clinical trials that focus on the ongoing development of chemotherapy in bladder cancer.
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