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Bladder cancer is the fifth most common cancer diagnosed in theUnited States. Prognosis for this disease is dependent on both tumorstage and grade. Radical cystectomy has been the standard treatmentfor muscle-invasive local disease; however, combined-modality approacheswith the use of chemotherapy are gaining momentum withdata suggesting survival improvement. Patients with metastatic diseasehave poor long-term survival rates despite systemic multiagent chemotherapy.A variety of agents, including newer cytotoxic drugs and biologicallytargeted agents, are under investigation to determine the mosteffective regimen. The special needs of specific patient populations,such as the elderly, those with a suboptimal performance status, andpatients with medical comorbidities have gained more attention.Progress in the treatment of this disease is dependent on supportingongoing and future clinical trials.
Bladder cancer is the fifth most common cancer diagnosed in the United States. Prognosis for this disease is dependent on both tumor stage and grade. Radical cystectomy has been the standard treatment for muscle-invasive local disease; however, combined-modality approaches with the use of chemotherapy are gaining momentum with data suggesting survival improvement. Patients with metastatic disease have poor long-term survival rates despite systemic multiagent chemotherapy. A variety of agents, including newer cytotoxic drugs and biologically targeted agents, are under investigation to determine the most effective regimen. The special needs of specific patient populations, such as the elderly, those with a suboptimal performance status, and patients with medical comorbidities have gained more attention. Progress in the treatment of this disease is dependent on supporting ongoing and future clinical trials.
Bladder cancer is the fifth most common malignancy, with an estimated 63,210 newly diagnosed cases and 13,180 deaths in the United States in 2005. Approximately 75% of patients present with superficial disease and are managed primarily by urologists with cystoscopy and transurethral resection (TUR) with or without intravesicular therapy, depending on grade, presence of carcinoma in situ, and depth of invasion. The remaining patients- approximately 25%-have muscleinvasive disease on a biopsy specimen and have a worse prognosis. Outcomes in these patients are dependent upon tumor stage and grade, and high recurrence rates are seen even with disease confined to the bladder wall managed with cystectomy or primary radiotherapy. Patients who subsequently develop metastatic disease or present with it can expect a median survival of about 14 months with combination systemic chemotherapy. Current areas of clinical research for urothelial carcinomas are focused on improving the outcomes of patients with muscle-invasive disease with the use of local and systemic therapy, as mounting evidence suggests a role for chemotherapy in the perioperative setting. Work continues toward the de velopment of multimodality, bladdersparing approaches that incorporate surgery, radiotherapy, and chemotherapy with the intent of avoiding radical cystectomy. For patients with metastatic disease, the focus has been on new cytotoxic agents and combinations that have better therapeutic and toxicity profiles in addition to investigating the role of targeted therapies. Management of Locally Invasive DiseaseSurgery
The current standard approach for treatment of muscle-invasive bladder cancer involves radical cystectomy and bilateral pelvic lymphadenectomy. Long-term survival in this setting has been evaluated in multiple surgical series (Table 1).[2-4] The 5-year survival rate is 68% for patients with pathologically organ-confined bladder cancer (pT2), compared with about 25% to 30% for those with extravesicular extension. Analysis of subsets of patients with muscle-invasive disease has determined that both extravesicular disease and node-positive disease are predictive of decreased survival. The poor outcomes seen with surgical resection alone have provided the rationale for investigating a multimodality approach to the management of invasive bladder cancer patients. Learning from the positive outcomes with the utilization of adjuvant or neoadjuvant chemotherapy for a variety of other solid tumors, such trials evaluating perioperative chemotherapy for invasive bladder cancer have been conducted.
The goal of neoadjuvant chemotherapy is to improve survival via the "eradication" of micrometastatic disease. There are several potential advantages to the neoadjuvant approach, including the facilitation of bladdersparing strategies. In addition, because patients have the bladder in place, oncologists are able to monitor for response during treatment, which has prognostic value. Patients may also be better able to tolerate chemotherapy before surgery when their performance status is higher, whereas they may not be good candidates for chemotherapy following a major surgical procedure. One of the disadvantages of this approach is that patients with chemoresistant disease may progress while receiving neoadjuvant treatment and, therefore, risk progressing to a nonoperable stage due to the delay in providing definitive local therapy. Several randomized clinical trials have been performed to evaluate the use of neoadjuvant platinum-based regimens (Table 2).[6-15] Most of these trials failed to demonstrate a survival advantage, but many of the studies have shortcomings. They included small numbers of patients and are underpowered to detect a difference in survival. Some trials evaluated single-agent chemotherapy, which is known to be less efficacious than combination regimens. Other trials allowed patients to receive either radiation or cystectomy for local therapy, and these two modalities have not been directly compared. Poor local control may impact overall outcomes and affect the results of these studies. Three of these trials, however, strongly suggest an advantage for neoadjuvant chemotherapy.
Adjuvant chemotherapy has also been evaluated in an attempt to improve outcome in patients with muscle- invasive bladder cancer. By treating patients postoperatively, definitive local treatment is provided up front without delay. Because the surgery is performed first, complete pathologic staging information can be obtained for making treatment decisions, allowing better patient selection. Some of the limitations of the adjuvant approach include delay in initiating systemic therapy directed toward micrometastatic disease, an inability to assess response to chemotherapy postcystectomy, and difficulties in the delivery of chemotherapy in the adjuvant setting due to surgical complications and decreased patient tolerance.
Not all patients are candidates for radical cystectomy, either because of significant comorbidities or due to unresectable disease. Other patients refuse surgery for fear of compromising quality of life. As an alternative, these patients may be treated with definitive radiotherapy, but radiation alone has poor curative potential, as data indicate that up to 70% of these patients may experience a local recurrence and 5-year survival rates are generally suboptimal. The addition of chemotherapy to radiation has been shown to improve local control but not overall survival. Typically, a trimodality approach is used in which a maximum transurethral resection (TUR) is performed followed by bladder irradiation concurrent with radiosensitizing chemotherapy. In addition, either neoad- juvant or adjuvant chemotherapy is sometimes given. Periodic cystoscopies are performed to monitor for disease, and if recurrence is noted, patients undergo salvage radical cystectomy. To date, there has not been a randomized trial to address the issue of bladder preservation adequately.
Metastatic DiseaseSystemic Chemotherapy
Metastatic bladder cancer is a fatal disease, for which numerous chemotherapeutic regimens have been studied (Tables 3-5).[26-55] In randomized trials, MVAC resulted in superior survival rates as compared to either single-agent cisplatin or CISCA. Thus, MVAC was established as the gold standard against which other regimens are compared (Table 3). The experience with chemotherapy in general and MVAC in particular has been instructive as to the chemosensitivity of urothelial carcinoma, the importance of multiagent chemotherapy, the toxicities and treatment- related deaths associated with cisplatin-based therapy, the effects of clinical prognostic factors on outcome, and the inability of dose escalation with growth factor support in enhancing survival. (Attempts to improve the efficacy of MVAC by dose escalation with growth factor support failed to result in survival improvement.) In addition, although complete response rates are relatively high, cures are rare in advanced bladder cancer.
Clinically Relevant Prognostic Factors
As with locally advanced disease, significant prognostic factors have also been identified for patients with metastatic disease who have been predominantly treated with cisplatinbased regimens. Bajorin et al performed a retrospective trial of 203 patients treated with MVAC. The independent prognostic factors most predictive of poor survival included presence of lung, bone, or liver metastases and Karnofsky score < 80%. In patients with neither risk factor, 5-year survival was 33%, but in patients with both visceral metastases and poor performance status, 5-year survival was 0%. The investigators therefore recommended that phase III trials stratify patients according to the number of risk factors, to avoid imbalance in treatment arms. Similar results were seen in patients treated with the combination of paclitaxel, gemcitabine, and cisplatin.
Molecular Predictive/Prognostic Markers for Localized and Metastatic Disease
In various stages of bladder cancer, molecular markers are being evaluated as potential novel prognostic factors in order to better classify patients' risk of progression to invasive disease or systemic recurrence, and some are being evaluated as therapeutic targets (Table 6).[63-67] Other reviews have dealt with this subject in more detail.[63,68] Briefly, multiple genes have been evaluated,[64-67] but the most extensive data pertain to mutations of the tumor suppressor p53, which are associated with genomic instability and formation of carcinoma. Accumulation of p53 within tumor nuclei, when detected by immunohistochemical staining, has been associated with an increased risk of recurrence from bladder cancer in some studies but not others.[64,70] In a multivariate analysis stratified for tumor grade, pathologic stage, and nodal status, alteration in p53 was found to be an independent prognostic factor associated with increased recurrence and reduced survival. Other studies of p53 accumulation in both locally advanced and node-positive disease, however, have not demonstrated a correlation with disease-free survival.[64,70] Based on these observations, an ongoing National Cancer Institute (NCI)-sponsored trial is randomizing patients with invasive bladder cancer and mutations in p53 to adjuvant chemotherapy vs observation following radical cystectomy. The epidermal growth factor (EGF) receptor and HER2/neu are tyrosine kinases involved in cell proliferation, cell survival, angiogenesis, and metastasis.[ 63,71] The EGF receptor is overexpressed in high-grade invasive transitional cell carcinomas and is associated with more aggressive clinical behavior. Another member of the EGF receptor family, HER2/neu, has also been studied in urothelial tumors. In patients with metastatic bladder cancer, Jimenez et al demonstrated HER2/neu overexpression in 22 (37%) of 60 primary tumors, 20 (63%) of 32 regional lymph node metastases, and 6 (86%) of 7 distant metastases. Absence of overexpression of HER2/neu in the primary tumor failed to predict absence of HER2/neu overexpression in distant metastases. The increased expression in distant sites suggests that overexpression is an acquired feature during the metastatic process. Agents targeting the EGF receptor and HER2/neu have been developed, making these targets potentially of therapeutic value as well as prognostic significance. Preclinical studies in a murine model have suggested that the anti-EGF receptor antibody cetuximab (Erbitux) has activity in bladder cancer.[ 73] Based on prior results showing enhancement of antitumor activity of chemotherapy with the addition of trastuzumab (Herceptin) in patients with metastatic breast cancer overexpressing HER2/neu, studies are under way in advanced bladder cancer to evaluate both single-agent trastuzumab and the addition of trastuzumab to chemotherapy. The Cancer and Leukemia Group B (CALGB) is currently evaluating single-agent trastuzumab, and we have recently completed accrual to an NCI-sponsored trial designed to prospectively evaluate the frequency of HER2/neu overexpression and the feasibility of the combination of trastuzumab with paclitaxel, carboplatin, and gemcitabine. New Cytotoxic Therapies in Development
Other targeted therapies that are under investigation include the epothilone B analogs and the antifolate pemetrexed (Alimta). The epothilones comprise a new class of nontaxane tubulin-polymerizing agents that result in mitotic arrest at the G2/M transition. In both in vitro and in vivo tumor models of numerous solid tumors, epothilone B analogs have been shown to have a high level of antitumor activity, even in paclitaxel-resistant tumors.[75,76] The epothilone B analog ixabepilone is currently being evaluated in an Eastern Cooperative Oncology Group (ECOG) phase II trial (E3800) of previously treated patients with advanced transitional cell urothelial cancer. The antifolate agent pemetrexed has multiple enzyme targets involved in both purine and pyrimidine biosynthesis. It has previously been studied in other tumor types, both as a single agent and in combination with other chemotherapy agents, and it is now being evaluated in advanced urothelial cancer. A phase II trial of pemetrexed was conducted in 31 chemotherapy-naive patients with advanced bladder cancer, 61% of whom had visceral metastases.[ 77] The response rate was 32%, and median survival was 9.4 months. Toxicity was greater in pemetrexedtreated patients with bladder cancer compared to other primary tumors, which was thought to be due to a higher prevalence of renal insufficiency in these patients, resulting in delayed clearance of pemetrexed and higher rates of neutropenia. The other primary toxicity was hematologic, and therefore, subsequent studies have included folate and vitamin B12 supplementation along with pemetrexed. Pemetrexed is currently being evaluated in combination with gemcitabine in patients with advanced bladder cancer in a phase II study (ECOG-E4802). Conclusions Despite progress in the management of urothelial cancer, there remain several challenges that are driving research efforts. Transforming high response rates into cures, improving multiagent chemotherapy and multimodality treatment, investigating new agents, and defining second- line salvage therapy are some of the current research objectives. Improvement in understanding the biology of urothelial cancers has be- gun to define molecular markers that are not only prognostic but are also clinically relevant targets for existing or yet to be developed drugs. Progress in systemic therapy is the key to better outcome for newly diagnosed highrisk patients. Finally, particular attention to the toxicity of treatment is needed, as many bladder cancer patients are elderly or have comorbidities. Overall progress is only possible if all involved in the care of this disease support clinical trials.
Dr. Hussain receives research support from and is a consultant for Bristol-Myers Squibb, and has received research support from Genentech.
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