Metastatic Bladder Cancer: Role of Chemotherapy and New Agents

Metastatic Bladder Cancer: Role of Chemotherapy and New Agents

EAU Update Series 1 (2003) 108–117 Metastatic Bladder Cancer: Role of Chemotherapy and NewAgents Cora N. Sternberg* Department of Medical Oncology, S...

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EAU Update Series 1 (2003) 108–117

Metastatic Bladder Cancer: Role of Chemotherapy and NewAgents Cora N. Sternberg* Department of Medical Oncology, San Camillo Forlanini Hospital, Circonvallazione Gianicolense, 87, Padiglione Cesalpino II8, Rome 00152, Italy

Abstract The M-VAC chemotherapy regimen has been widely used in locally advanced as well as in metastatic disease. Since only a proportion of patients with advanced disease will survive, there is a dire need to identify patients who will respond to chemotherapy and to identify new agents, targets and strategies to improve treatment outcome. Approaches to the management of advanced urothelial cancer include: intensifying the dose intensity, doublet and triplet combination chemotherapy, sequential regimens, reducing toxicity in unfit or elderly patients, and the use of biologic targeted therapies and promising new chemotherapeutic agents. These include MTA, the epothilones, topoisomerase inhibitors and vinflunine which act upon folate metabolism or upon different phases of the cell cycle. New agents that are coming into clinical trials include farnesyl transferase inhibitors, several growth factors receptor inhibitors, anti-sense therapy and COX-2 inhibitors. Significant progress has been made in understanding the molecular biology of cancer. Numerous novel agents, many of which are in clinical trials, have been developed to target various processes of tumor progression. The rationale behind application of these molecularly targeted therapies is to overcome resistance to cytotoxic therapies. Bladder cancer represents a unique model for targeted therapy. As our understanding increases, integration of newer biologic agents will condition future trials, and our ability to target bladder and urothelial cancers will be enhanced. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Bladder cancer; Urothelial cancer; Chemotherapy; Gemcitabine; Paclitaxel; Cisplatin; Molecular targeted therapy; Novel or new agents

1. Chemotherapy Systemic chemotherapy is the only current modality which in phase III trials has been shown to improve survival in responding patients with advanced bladder cancer [1,2]. Carcinomas arising in the ureter and renal pelvis are mainly transitional cell carcinoma (TCC) and are usually treated with the same strategies directed towards metastatic bladder cancer. The M-VAC regimen came onto the scene in 1985, with the enthusiasm of investigators from Memorial Hospital, who demonstrated that TCC was sensitive to chemotherapy [3]. Patients with measurable lesions were found to have a remarkably high response rate of 72%, and 36% attained complete remission (CR) [4]. Long-term survival was achieved in the CR patients. *

Tel. þ39-06-5870-4580; Fax: þ39-06-663-0771. E-mail address: [email protected] (C.N. Sternberg).

In addition, patients who achieved a CR with the combination of chemotherapy and surgery had twice the survival of patients who had only a partial remission (PR) to chemotherapy and no further surgery [4]. Overall survival for the whole group was 13.1 months. Chemotherapy was more effective against nodal disease than visceral metastases [2,4]. The place of post-chemotherapy surgery was further addressed in a follow-up report on 203 patients treated with several M-VAC regimens. At a median follow-up of 47 months, 46 parents attained a CR with chemotherapy alone, and 5-year survival was 40%. Meanwhile, in 30 patients who had a CR with M-VAC plus surgery, 5-year survival was 33% [5]. Post-chemotherapy resection of viable tumor appeared to improve survival in selected patients. Bajorin et al. evaluated prognostic factors predictive of response and survival in these 203 patients [6]. Three risk categories were established on the basis

1570-9124/03/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1570-9124(03)00019-9

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of Karnofsky performance status (KPS) and the presence or absence of visceral metastases. Two factors had independent prognosis: Karnofsky performance status (KPS) less than 80% and visceral (lung, liver, or bone) metastasis. Median survival times for patients who had zero, one, or two risk factors were 33, 13.4, and 9.3 months, respectively ( p ¼ 0:0001). The median survival time of patient cohorts could vary from 9 to 26 months simply by altering the proportion of patients from different risk categories. With M-VAC, prior prognostic factor models for predicting lower response rates, increased toxicity and poor overall survival included: the presence of visceral metastases, the presence of abnormal levels of alkaline phosphatase and a low KPS [1,7,8]. In the years since M-VAC was developed, it has been considered the standard therapy for ‘‘fit’’ patients with advanced disease. Nonetheless, M-VAC and other cisplatin-based chemotherapy regimens have been associated with toxicity and long-term survival in only 15% of patients with visceral metastases and in 30% with nodal disease. An Intergroup study showed that M-VAC was superior to cisplatin [1], yet long-term follow-up of the M-VAC patients was quite poor [7]. The need for improved efficacy and reduced toxicity has led investigators to continue to seek less toxic and more effective regimens. More recent combination regimens have shown better survival than what was seen in the original M-VAC series (in the range of 14–15 months) [9–13]. This may be the case for multiple reasons: 1. case selection, 2. stage migration (patients with locally-advanced disease mixed together with advanced metastatic disease, 3. better radiological techniques, 4. increased patient awareness, 5. increased use of post-chemotherapy surgery, and 6. newer active agents [14,15]. 1.1. Single agents Anti-tumor activity has been demonstrated with several single agents, although these have rarely produced an improvement in survival [12,13]. Response rates (RR) to platinum single agents are: 17% for cisplatin (12% in phase III trials) [1], and 12% for carboplatin [16]. Based on the activity of cisplatin, carboplatin has been widely used due to its ease of outpatient administration and milder toxicity profile. Phase II studies in advanced urothelial cancer have shown a 14% RR for carboplatin [17]. In an EORTC trial, lobaplatin, a thirdgeneration platinum complex, was assessed in previously treated patients with urothelial cancer, and a response rate of 10% was reported [18]. Studies of oxaliplatin, another promising platinum complex alone or in combination with gemcitabine are ongoing [19].

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Since methotrexate has activity in advanced bladder cancer, other anti-folates and anti-metabolites have been evaluated. Trimetrexate revealed a 17% RR in patients who had prior chemotherapy [20]. Piritrexim, an oral second-generation antimetabolite, was studied in 2 trials of 50 previously treated and untreated patients [21,22]. The RR was 23%. Pemetrexed (Alimta, MTA, LY231514) is a novel drug with activity in a variety of solid tumors. MTA, is a multi-targeted antifolate that inhibits multiple folatedependent enzymes [23–26]. A clinical trial in TCC revealed activity comparable to that of other active single agents [26]. Paz-Ares, Cortes-Funes and other Spanish investigators treated 33 (31 evaluable) chemotherapy-naı¨ve patients with pemetrexed 500 mg/m2 iv every 3 weeks without folic acid or B-12 supplementation. Seven had received prior adjuvant chemotherapy, 6 were PS 2 and 19 (61%) had visceral metastases. Twenty eight patients completed 2 courses and were evaluable for response; 9 had a PR for a median of 8 months. Most responses were in nodal and soft tissue disease. The median survival was 11 months. Modern trials with MTA utilize both folic acid and B-12 supplementation which have substantially lowered the toxicity of this drug [27]. Trials combining MTA with gemcitabine are in progress in TCC. Several other novel chemotherapeutic agents have activity in urothelial carcinoma including gemcitabine, the taxanes (paclitaxel and docetaxel), the epothilones and vinflunine [12–14,23,28]. Gemcitabine is a new antimetabolite, a deoxycytidine analog which after intracellular activation, the active metabolite is incorporated into DNA, resulting in inhibition of further DNA synthesis. Gemcitabine may also inhibit ribonucleotide reductase and cytidine deaminase as part of its cytotoxic activity. Gemcitabine is usually given weekly for 3 weeks, followed by a one week rest, in a 4-week schedule. When administered as a single agent, gemcitabine response rates from 23% to 28% have been obtained in both pretreated patients and in those who have not had prior therapy [9,14]. Following several phase II studies, Gemcitabine and cisplatin (GC) were combined in a randomized international trial. In an industry sponsored trial, GC was compared to M-VAC. Eligibility criteria include patients with T4b, N2, N3, and M1 disease. The trial was designed to detect a difference in survival from 12 months with M-VAC to 16 months with GC. The study revealed that GC was less toxic with survival of 13.8 months as compared to 14.8 months in patients treated with M-VAC [29]. Based primarily upon quality of life parameters, many investigators

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have come to consider this combination to be equivalent to the M-VAC regimen that has long been the only gold standard. Paclitaxel 250 mg/m2 by 24-hour continuous infusion every 3 weeks [30] resulted in an RR of 42%, including a 27% CR rate. Since the kidneys are only minimally involved in the excretion of paclitaxel, it can be utilized in patients with impaired renal function [31]. Regimens of combined paclitaxel and cisplatin, usually every three weeks, have been evaluated in several phase II studies [32–34] including more than 100 patients, with an overall RR rate ranging from 50% to 70% (CR rates from 15% to 32%). Docetaxel, another widely used taxane also has displayed activity in TCC. In previously treated patients the RR was 13% with a median overall survival of 9 months [35]. In untreated patients, the RR was higher; 38% with a median duration of response of 6 months [36]. The combination of docetaxel and cisplatin every 3 weeks has been evaluated in 3 studies [37–39]. In more than 120 patients, the overall RR was 52%–62% and the median overall survival ranged from 8.2 to 13.6 months. Although these phase II studies of 2 drug combinations of paclitaxel or docetaxel with cisplatin, have shown activity in untreated patients, with response rates that are similar to M-VAC, they have not been directly compared to M-VAC in a phase III trial. Other new agents act upon different phases of the cell cycle; for example the epothilones and vinflunine interfere with mitosis. The epothilones are semisynthetic analogues of natural epothilones B and D which have a mode of action similar to the taxanes (microtubular stabilization). They have activity in both paclitaxel-sensitive and refractory tumors, and are twice as potent as paclitaxel in inducing tubulin polymerization in vitro. Phase I trials are showing activity in a wide range of cancers. The ECOG is pursuing a phase II second line trial in TCC. Vinca alkaloids represent a chemical class of major interest in cancer chemotherapy. Vinflunine is a novel fluorinated vinca alkaloid. Modifications in the velbenamine part of the vinca alkaloids have major implications for tubulin interacting activities [40]. Activity has been seen in phase I trials, and a second-line international phase II trial is ongoing. Topoisomerase inhibitors such as J-107088, a new derivative of NB-506, an indolocarbazole anticancer agent, target topoisomerase I and induce single-strand DNA cleavage more effectively than NB-506 or camptothecin [41–43]. A phase II second line study is underway in the USA.

1.2. Dose intensification In a phase III EORTC Genitourinary Group trial, high dose M-VAC (HD-M-VAC) given every 2 weeks with G-CSF was compared to classic M-VAC [44]. It was possible to deliver twice the dose of cisplatin and doxorubicin with less toxicity, fewer dose delays, and in half of the time, if G-CSF was routinely added. This trial revealed less toxicity with HD-M-VAC due to the addition of G-CSF. Although there was not a significant difference found in median survival (>14 months in both arms), there was a significant difference in favor of HD-M-VAC in response rate (RR) and CR rate. Of note, 2-year survival was 35% with HD-M-VAC compared to 25% with M-VAC (Fig. 1). One could conjecture that this regimen might be useful in the neo-adjuvant or adjuvant setting since it is given in 1/2 of the time of traditional M-VAC. 1.3. Reducing toxicity and unfit or elderly patients Strategies have been developed to minimize toxicity in patients who are unfit, elderly or have compromised renal function [45]. Unfortunately, there is not a general consensus as to who is considered ‘‘unfit’’. The EORTC is evaluating gemcitabine and carboplatin compared to methotrexate, carboplatin and vinblastine [46] in patients ineligible for platinum-based chemotherapy. Meanwhile, the Cancer and Leukemia Group B (CALGB) in the US has initiated a study for patients with impaired renal function with gemcitabine, carboplatin and Iressa (Gefitinib, ZD 1839). In a phase I trial, at MSKCC (Memorial Sloan Kettering Cancer Center), carboplatin and paclitaxel are given in sequence after gemcitabine and doxorubicin to patients with impaired renal function. The SWOG has opted to study gemcitabine and paclitaxel in patients >70 years of age with advanced or recurrent urothelial cancer. Cisplatin-related toxicity is not inconsequential in elderly patients. Renal insufficiency limits wide applicability and long-term survival remains poor. These protocols seek less toxic treatments for patients that cannot undergo cisplatin-based regimens, primarily for medical reasons. One major problem is that ‘‘unfit’’ or poor performance status (PS) patients are often mixed or confused with ‘‘elderly’’ and renal-impaired patients. PS 2 patients are a very poor prognosis group but may still respond to chemotherapy. Clinical trials should be designed to clearly distinguish among these 3 groups of patients. 1.4. Doublet combination chemotherapy Paclitaxel and carboplatin combination chemotherapy regimens have been routinely used in advanced

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Fig. 1. Survival with HD M-VAC versus M-VAC [44]. The median overall survival was 15.5 months on the HD- MVAC arm versus 14.1 months on the classic M-VAC arm. At 2-years, however, survival on HD-MVAC arm is 35% vs. 25% on the M-VAC arm.

TCC [47]. Several studies with carboplatin (AUC 5–6) and paclitaxel (150–225 mg/m2) have reported RR ranging from 21% to 63%, many of the responses were partial remissions [48–50]. In the SWOG study, the RR was only 14% with a very poor median survival of only 9 months [48]. This may have been due to a predominance of patients with poor PS and with visceral metastases, suggesting that the regimen was not necessarily to blame for the poor results. None-the-less, a number of investigators now question whether or not it is ethical to give ‘‘fit’’ patients this combination. Since no phase III trials have compared carboplatin and paclitaxel to the standard M-VAC regimen or to GC (the ECOG trial of M-VAC versus carboplatin and paclitaxel was closed early due to poor accrual), it is probably best not to use this regimen except in extremely patients with extremely poor renal function who cannot tolerate cisplatin. Gemcitabine and paclitaxel combination chemotherapy has been evaluated in several studies with excellent results, even in pretreated patients [51–56]. In a phase II Italian study, 40 patients who had been pre-treated with M-VAC had a 60% RR (28% CR and 33% PR) when treated with paclitaxel 150 mg/m2 and gemcitabine 2500–3000 mg/m2 every 2 weeks on an outpatient basis [51]. Of note, the RR was 27% in patients who had failed prior chemotherapy for metastatic disease

within the last year as compared to 80% for patients who received prior neo-adjuvant or adjuvant M-VAC. The median survival for all patients was 14.4 months, equal to that seen in another American study [52]. Of concern was the pulmonary toxicity observed in the Hoosier group study in which a weekly regimen of this combination (gemcitabine 1000 mg/m2 and paclitaxel 110 mg/m2 on days 1, 8, and 15 every 4 weeks) was utilized in un-pretreated patients [53]. The combination of docetaxel 40 mg/m2 and gemcitabine 800 mg/m2 on days 1 and 8 every 3 weeks has been recently evaluated in pretreated patients by the ECOG [57]. Of 29 patients, 25 were evaluable for response. The authors concluded that this regimen was active with 5 patients attaining a PR (20% RR), and 10 evaluated as having stable disease. A combination of doxorubicin and gemcitabine has been reported to lead to a 36% CR rate, but this has not been confirmed. In yet another feasibility trial in 20 patients previously treated with platinum-based therapy, the combination of methotrexate and paclitaxel was active as palliative therapy [58]. The combination of gemcitabine and a taxane is active and well tolerated as first- or second-line treatment of patients with advanced TCC, as well as in patients with compromised renal function. Response rate and duration compare favorably with those

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produced by other active, first-line regimens [47]. In Italy, this regimen is being evaluated as first-line therapy in a multi-centered study. Phase III trials will be required to judge the true value of this therapy in comparison to cisplatin-based combination chemotherapy. 1.5. Triplet combination chemotherapy Other combinations using the taxanes and gemcitabine have been put forth as possible alternatives to M-VAC. Both gemcitabine and paclitaxel have been incorporated into multi-agent chemotherapy combinations with cisplatin or carboplatin [10]. Phase II data from two gemcitabine-based triplets are currently available. The Spanish regimen of gemcitabine, paclitaxel and cisplatin (GCP) has led to a very high RR of around 78% (CR 28% and PR 50%) [59]. The first report from the phase I trial reported survival of 24 months, probably due to patient selection. In the multi-center phase II study, the median survival was 15.6 months, more consistent with other currently available regimens [60]. The American combination study of gemcitabine, paclitaxel and carboplatin ( rather than cisplatin) compared favorably to the Spanish regimen with a 14.7 month median survival, and 1-year survival of 59%. The RR was 68% (CR 32% and PR 36%) [61]. In a third study from MSKCC, the triplet ifosfomide, paclitaxel and cisplatin (ITP) revealed a 68% RR (CR 23% and 45% PR). Median survival was 20 months in this single center study [62]. Whether or not we are really improving upon survival with these new triplet regimens will depend upon the results of ongoing phase III trials. 1.6. Dose-dense sequential regimens Dose-dense sequential regimens have been piloted in a few institutions. At MSKCC doxorubicin (adriamycin) and gemcitabine (AG)  6 were followed by ITP (ifosfamide, taxol and cisplatin) every 3 weeks  4 [63]. Others have evaluated AG followed by paclitaxel and carboplatin. Stadler is evaluating docetaxel and methotrexate (DM)  3 cycles followed by 3 cycles of GC.

2. Targeted therapy Based upon aberrations in pathways or known markers, therapy can be tailored to benefit patients based both upon their risk of progression and molecular alterations specific to a patient’s tumor. Targeted therapy, is defined as treatment that targets both

mechanism and risk. Utilizing the available knowledge of the molecular biology of cell cycle regulation, signal transduction, metastases, apoptosis and angiogenesis in bladder cancer, potential therapeutic targets for drug development have already entered the clinic [64]. 2.1. Farnesyl transferase inhibitors Farnesyl transferase inhibitors (FTI) prevent processing of RAS protein, which is activated in some 30% of solid tumors. These agents were developed to inhibit cell signaling in RAS-transformed cells, however it has become evident that farnesylation is crucial in the cellular localization and function of many proteins including ras, the kinesins CENP-E, F, and other molecules. Therefore, even tumors without RAS mutations may also be targets [65–67]. Phase I and II trials in urothelial cancer with a variety of new FTIs such as BMS-214662, R-115777 (Zarnestra), and Sch-66336 are ongoing. These trials also combine FTIs with chemotherapy. Trials combine a FTI and gemcitabine as second line therapy, or with taxotere (Genitourinary Group of the EORTC). Encouraging results from early clinical trials have emerged, creating both enthusiasm and new challenges for the optimum clinical development of this important new class of anticancer agent. 2.2. Growth factor inhibitors Many oncogenes code for growth factors and their receptors. Growth factors are required for cell proliferation. Transfection of growth factors or their receptors can convert normal cells to a malignant phenotype. Unregulated stimulation of growth factor receptors is fundamental to malignancy. Many human tumors overexpress growth factors and their receptors. The epidermal growth factor receptor (EGFR) is expressed in TCC and its overexpression is associated with more aggressive clinical behavior. Aberrant signal transduction plays a crucial role in the biology of cancer. Therefore, inhibition of growth factor receptor kinase-dependent signaling pathways is one of the most promising new therapeutic approaches for treatment. Growth factor-induced signaling is also implicated in the activation of anti-apoptotic cell survival pathways [68]. Growth factor receptor kinases are inhibited by a new class of agents referred to as small molecules and also by monoclonal antibodies which block ligand binding to growth factor receptors such as the EGFR and other receptors of the ERB family [69,70]. Small molecule inhibitors of EGFR-associated tyrosine kinases include Iressa (ZD 1839, Gefitinib), Tarceva

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(OSI-774) and many others. In preclinical studies Iressa inhibited cancer growth in tumors expressing EGFR. In addition, Iressa may enhance the efficacy of cytotoxic agents against human tumors irrespective of EGFR status. The CALGB is testing the combination of gemcitabine, cisplatin and Iressa in TCC. A similar study is planned in Europe. The SWOG has initiated a phase II second line study of Iressa in progressive or recurrent TCC after 1 prior systemic chemotherapy regimen for advanced disease. Dual inhibition of ErbB1(EGFR) and ErbB2 (HER-2) may potentially be superior to inhibition of only one of these receptors. Since some 37% of bladder cancer express EGFR and some 31% express Her-2, a dual, reversible small molecule inhibitor of erbB2 and EGFR is of extreme interest. Clinical trials will be initiated with GW572016, a novel Glaxo 4-anilinoquinoline, which inhibits both the EGFR and HER-2 receptor. Anti-EGFR monoclonal antibodies compete with endogenous ligands, primarily EGF and transforming growth factor-alpha, for receptor ligand-binding sites. Binding to EGFR blocks critical signaling pathways and interferes with the growth of tumors expressing EGFR. Anti-EGFR monoclonal antibodies under study include Cetuximab (C225, Erbitux), EMD 55900, ICR 62, and ABX-EGF and others that directly block the EGFR. They have been successfully used in combination with chemotherapy in colon cancer [71] in head and neck cancer, and in lung cancer [72]. In one study, activity of paclitaxel was enhanced by the Cetuximab in mice with metastatic human bladder TCC. Therapy with paclitaxel increased the ability of C225 to inhibit metastasis. The combination of C225 and paclitaxel enhanced apoptosis in tumor and endothelial cells compared with either agent alone (p < 0:005). This effect was probably mediated by inhibition of angiogenesis and induction of apoptosis [73]. Increased activity of chemotherapy when combined with a monoclonal antibody against HER-2 (Herceptin; Trastuzumab) has been demonstrated in breast cancer [74–76]. HER-2 overexpression is detected by immunohistochemistry in anywhere from 36% to 48% of patients with high grade or metastatic TCC of the bladder. Its value in predicting metastasis or response to therapy has not been clearly established as yet in bladder cancer [77]. Hussain has initiated a phase II trial for patients with advanced TCC who overexpress HER-2. The patients are treated with Herceptin, paclitaxel, carboplatin and gemcitabine as first line therapy. Another second line trial with Herceptin in bladder cancer is underway.

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HER-2 (Erb-2) is a potent signaler that itself doesn’t bind ligands, but functions by dimerization with ligand bound receptors such as the EGFR and ERB-3 to activate signaling pathways such as the Akt survival pathway or the MAP kinase growth pathway. 2C4 is a new monoclonal antibody from Genentech and Roche that inhibits ligand initiated HER-2 signaling through two major signal transduction pathways: (1) the MAP kinase growth pathway (a major proliferative pathway) and (2) the PI3 kinase pathway (a major survival and anti-apoptotic pathway. The antibodies are making their way into the clinic. 2.3. Antisense therapy Targeting regulators of cell division and cell death is essential in the treatment of cancer. Bcl-2 is an antiapoptotic molecule that negatively regulates activation of caspases essential for apoptosis (programmed cell death) [78,79]. Selection for drug resistance in cancer cells is often concomitant with enhanced expression of Bcl-2. In a significant proportion of bladder tumors and in carcinoma in situ, Bcl-2 is overexpressed. Therefore, use of antisense oligonucleotides represents a viable strategy for Bcl-2 protein down-regulation [80]. Phase III clinical trials with antisense Bcl-2 deoxyoligonucleotides are underway [81]. There are several unresolved Bcl-2 testing issues such as IHC standardization, target validation in vivo, and the level of Bcl-2 downregulation needed to achieve clinical benefit. 2.4. Cell cycle regulation and the p53/Rb pathway Several studies have shown that p53 is an important indicator of bladder cancer progression increased risk of recurrence and decreased overall survival [82]. Alteration in both p53 and pRb may act in cooperative or synergistic ways to promote tumor progression. In fact, tumors altered in both p53 and pRb have significantly increased rates of recurrence (p < 0:0001) and survival (p < 0:0001) compared to patients with no alterations in either p53 or pRb [83]. Combined information can be used to stratify bladder cancer patients into distinct prognostic groups. It is also known that cyclin dependent kinase inhibitor p21 is a downstream target of p53. When p21 expression remain normal, even in p53 altered tumors, clinical outcome is similar to patients with altered p53. As knowledge of p53 alterations increases, it has become increasingly evident that in addition to cell cycle regulation, p53 is critical in several pathways such as angiogenesis. Furthermore, p53 alterations appear to identify patients that may respond better to chemotherapy. Genetic alterations in p53 may increase sensitivity to

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DNA-damaging chemotherapeutic agents [84]. Based upon this reasoning, an international bladder cancer trial has been initiated to evaluate if patients with localized invasive bladder cancer and altered p53 respond better to M-VAC chemotherapy. 2.5. COX-2 inhibition Cyclooxygenase-2 (COX-2) a key isoenzyme in conversion of arachidonic acid to prostaglandins, and is inducible by various agents such as cytokines, growth factors and tumor promoters. COX-2 frequently overexpressed in bladder cancer [85]. COX-2 is linked to cancer progression, it converts pro-carcinogens to carcinogens, inhibits apoptosis, promote angiogenesis, modulates inflammation and immune function, and increases tumor cell invasiveness [86]. In experimental models, inhibition of COX-2 activity suppresses bladder cancer. Clinical trials are underway using these agents both in the treatment and prevention of bladder cancers.

3. Conclusions Several new chemotherapeutic agents that work at different points in the cell cycle appear to show promise. Progress in understanding of the biology of bladder cancer is leading to a better understanding. The ultimate goal of which is to define the molecular basis for bladder cancer progression so that we can better define risk and prognosis for our patients. This knowledge is leading to the development of new therapeutic strategies aimed at specific defects which characterize bladder cancer. Molecular targeted small molecule therapy and monoclonal antibodies have begun to dominate contemporary studies. In addition, newer molecularly-targeted inhibitors are auspicious. With the caveat that the results must be corroborated in phase III trials, prospects for the future are encouraging. In conclusion, metastatic bladder cancer continue to be the focus of clinical trials for new chemotherapeutic and other novel agents.

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CME questions Please visit http://www.uroweb.org/updateseries to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. Prognostic factors predictive of response to chemotherapy and survival in metastatic TCC include: A. performance status. B. visceral metastases. C. alkaline phosphatase. D. LDH. E. A, B, and C.

2. Anti-tumor activity in TCC has been clearly demonstrated with the following single agents: A. cisplatin and carboplatin. B. piritrexim and ALIMTA. C. lobaplatin. D. gemcitabine and taxanes. E. A, B, and D. 3. Dose intensification with high dose M-VAC (HDM-VAC) was: A. given every 2 weeks with G-CSF.

C.N. Sternberg / EAU Update Series 1 (2003) 108–117

B. it was possible to deliver twice the dose of cisplatin and doxorubicin. C. toxicity was less due to growth factors. D. A clear difference in median survival. E. A, B, and C. 4. Active triplet combinations in advance TCC include: A. methotrexate, vinblastine, doxorubicin and cisplatin. B. gemcitabine, paclitaxel and cisplatin.

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C. gemcitabine, viniblastine and carboplatin. D. ketoconazole and adriamycin. E. ifosfomide and cisplatin. 5. Targeted therapy is defined as treatment that targets: A. angiogenesis. B. mechanism and risk. C. signal transduction. D. apoptosis. E. all of the above.