Systemic chemotherapy options for metastatic bladder cancer

Systemic chemotherapy has reached a therapeutic plateau in the treatment of transitional cell carcinomas of the urothelium. Since the advent of the combination of methotrexate, vinblastine, adriamycin and cisplatin (MVAC) in the 1980s, no chemotherapy regimen has been proven to be superior to this therapy. Only one regimen, a combination of gemcitabine and cisplatin, has been equivalent. With a similar response rate and survival, plus the benefit of an improved toxicity profile, the gemcitabine cisplatin combination has largely supplanted MVAC in physician's practices. Although a recent dose-intense version of MVAC has shown an improved toxicity profile compared with traditional MVAC, it is clear that, for many patients, a full-dose cisplatin-based chemotherapy regimen may not be a tolerable option. Tobacco use, which is a common risk factor predisposing for the development of transitional cell carcinoma, may also cause morbidities that preclude treatment with aggressive combination therapy. Therefore, there is a clear need for regimens with improved toxicity, especially for the frequently frail or elderly patient population with poor renal function. There is an additional unmet requirement in rare bladder tumors, for which treatment has traditionally been based upon anecdotal evidence, limited by small patient numbers. Currently, there is newfound hope for all bladder cancer patients, with investigators studying new combinations and novel treatment paradigms, with recent studies focusing on frail, or 'cisplatin-unfit', patients and additional studies in the setting of rare small cell or urachal carcinoma patients.     

Determining patient preferences for improved chemotoxicity during treatment for advanced bladder cancer

Determining patient preferences for improved chemotoxicity during treatment for advanced bladder cancer Conventional treatment for advanced bladder cancer is methotrexate, vinblastine, doxorubicin plus cisplatin (MVAC), with a median survival of 1 year but significant toxicity. The newer combination of gemcitabine plus cisplatin (GC) has demonstrated comparable survival and an improved toxicity profile (Von der Maase et al. 2000). At present, the importance to patients of the toxicity of chemotherapy has not been widely studied. An earlier study in bladder cancer indicated that toxicity was an important determinant of treatment preference (Davey et al. 2000). A study of preferences for advanced bladder cancer therapy in the UK was proposed.     

Chemotherapy in Locally Advanced and Metastatic Bladder Cancer

Chemotherapy plays an important role in the management of patients with locally advanced and metastatic transitional cell carcinoma of the urothelial tract. Chemotherapeutic regimens have evolved from use of single drugs with low response rates and a short median survival to combination chemotherapy with inclusion of new active drugs which achieve response rates up to 75–80% and the possibility of cure in about 15% of patients with good performance status and without visceral metastases. Patients with a primary good response are candidates for subsequent surgery or radiotherapy of residual disease. A standard regimen in patients with good prognosis and normal renal function has, for a number of years, been the four-drug combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). However, this is now replaced in most centers with gemcitabine and cisplatin (GC), which has similar efficacy but less toxicity. New promising regimens include the combinations of gemcitabine and one of the taxanes, with or without cisplatin and the triple combination of cisplatin, paclitaxel and ifosfamide. The three-drug combination of gemcitabine, cisplatin and paclitaxel is presently being compared with the GC regimen in a large, international, randomized, phase III trial. Other two- and three-drug combinations have been proposed as alternative possibilities, but these regimens have to be compared with GC or MVAC in randomized trials to explore their potential use as a new standard of care in this patient group. No data so far have suggested the best treatment for patients with poor prognostic features, including impaired renal function. The use of drugs without renal toxicity (e.g. gemcitabine in combination with paclitaxel) is effective, but the rate of hematologic toxicity seems to increase profoundly in patients with poor prognosis. Thus, the goal for an appropriate chemotherapeutic regimen for these patients is to find an acceptable balance between efficacy and toxicity. Results of second-line chemotherapy have been disappointing, and treatment of patients requiring second-line therapy should primarily be performed as part of a clinical trial. An exception is gemcitabine, where efficacy seems to be independent of whether or not patients have received prior cisplatin-containing chemotherapy. Presently, new drugs such as pemetrexed and vinflunine are being investigated as second-line treatment. However, it should be emphasized that patients with a primary good response to chemotherapy such as MVAC or GC and a long recurrence-free interval generally should be offered re-induction combination chemotherapy and not included in trials with new second-line drugs.     

Systemic chemotherapy in locally advanced and/or metastatic bladder cancer

Transitional cell carcinoma of the bladder is a common malignancy. Advanced urothelial cancer is a chemosenstive neoplasm. Whereas the MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen was long-considered the standard of care for patients with advanced disease, the evaluation of newer agents with retained activity and improved tolerability has been the focus of much investigation over the past decade. Combinations such as cisplatin-gemcitabine (GC) and intensified, G-CSF supported MVAC have shown more favourable toxicity profile and equal or even improved efficacy. Specific groups of patients (elderly, patients with renal dysfunction or poor performance status or co-morbidities) who cannot tolerate cisplatin-based therapy, should receive carboplatin, gemcitabine or taxane-based treatment. Continuing improvements in our understanding of the molecular phenotype of individual patient tumors may lead to the appropriate therapies that target molecular aberrations unique to this malignancy. This review will summarize recent developments in the management of locally advanced (T4b, N 2-3) and/or metastatic (M1) bladder cancer.     

Chemotherapy in Metastatic Urothelial Cancer

For more than a decade, the cisplatin plus doxorubicin and methotrexate plus vinblastine (MVAC) regimen has been the gold standard chemotherapy in bladder cancer, although the toxicity associated with this therapy has hampered its use in many older patients with metastatic disease. In recent years, new active agents have been identified, combinations of new agents with established drugs followed and results have become available on the combination of gemcitabine and cisplatin vs MVAC that have revealed an efficacy-toxicity profile in favor of the gemcitabine-cisplatin regimen. Other new doublet and triplet combinations, comprising new agents as well as incorporating one or two new agents into established regimens have demonstrated significant activity in phase II studies. However, there are no randomized data to show that any of these regimens improves patient survival as compared with either MVAC or cisplatin-gemcitabine. Advances in the understanding of the molecular biology of urothelial cancer will help to identify new biochemical targets for the development of novel therapeutic approaches to treat this cancer.     

New approaches to treatment of metastatic bladder cancer

The combination of methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) has been the standard therapy for transitional cell carcinoma for over a decade. Despite evidence that MVAC can improve outcome in comparison with single drugs or other combinations in this disease, only a small fraction of patients (less than 4%) become long-term survivors, and the regimen is quite toxic. Attempts to improve upon the MVAC regimen have partially ameliorated its toxicity, but they have not clearly improved outcome. Recently, a number of new chemotherapeutic agents have become available. This report summarizes the current experience with these agents and combinations.     

Gemcitabine in transitional cell carcinoma of the urothelium

Gemcitabine has become one of the key drugs in the treatment of patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The overall response rate for single-agent gemcitabine is 25% with a complete response rate of 9% and toxicity is mild-to-modest. The overall response rate for gemcitabine combined with cisplatin (GC) in Phase II studies is 47% with a complete response rate of 18% and a median survival ranging from 12.5 to 14.3 months. A randomized Phase III study comparing GC and methotrexate, vinblastine, adriamycin and cisplatin (MVAC) has demonstrated similar efficacy with respect to response, time-to-progression and overall survival, whereas GC is associated with less toxicity than MVAC. Thus, GC is now considered a standard of care for patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine together with one of the taxanes with or without cisplatin.     

Gemcitabine in transitional cell carcinoma of the urothelium

Gemcitabine has become one of the key drugs in the treatment of patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The overall response rate for single-agent gemcitabine is 25% with a complete response rate of 9% and toxicity is mild-to-modest. The overall response rate for gemcitabine combined with cisplatin (GC) in Phase II studies is 47% with a complete response rate of 18% and a median survival ranging from 12.5 to 14.3 months. A randomized Phase III study comparing GC and methotrexate, vinblastine, adriamycin and cisplatin (MVAC) has demonstrated similar efficacy with respect to response, time-to-progression and overall survival, whereas GC is associated with less toxicity than MVAC. Thus, GC is now considered a standard of care for patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine together with one of the taxanes with or without cisplatin.     

A phase II study of gemcitabine and oxaliplatin in advanced transitional cell carcinoma of the bladder

Cisplatin-based chemotherapy is recommended for use as first-line treatment for patients with advanced transitional cell carcinoma of the bladder. Unfortunately, 30–50 % of patients are ineligible for cisplatin due to renal insufficiency. Oxaliplatin is a less nephrotoxic platin which can be used for patients with impaired renal function. We carried out a phase II study of gemcitabine (1,200 mg/m²) in combination with oxaliplatin (100 mg/m²) given on days 1 and 14 every 28 days (GEMOX) in predominantly cisplatin-‘unfit’ stage IV transitional cell bladder cancer patients to determine whether this combination exhibited a clinical activity profile similar to cisplatin plus gemcitabine. Eighteen patients with a median GFR of 49 ml/min were enrolled. GEMOX treatment led to a 36 % response rate in assessable patients. Median progression-free survival was 4.9 months, with a median overall survival (OS) of 10.4 months and a one-year survival rate of 44.4 %. GEMOX in bladder cancer patients exhibited a tolerable side effects profile, with thrombocytopenia as the most frequent grade 3/4 toxicity. These findings suggest that GEMOX is an active combination in advanced bladder cancer patients with reduced renal function.     

Efficacy and safety of gemcitabine monotherapy in patients with transitional cell carcinoma after Cisplatin-containing therapy: a Japanese experience

BACKGROUND: In Japan, the standard chemotherapy for advanced transitional cell carcinoma (TCC) of the urothelium is MVAC (methotrexate, vinblastine, adriamycin, cisplatin). However, a second-line therapy is still required for patients with recurrent TCC who discontinued MVAC because of toxicity or have MVAC refractory tumors. METHODS: We evaluated gemcitabine monotherapy in patients with advanced TCC who were previously treated with a platinum-based regimen. Gemcitabine (1000 mg/m2) was given once a week for three consecutive weeks followed by a week of rest. This cycle was repeated at least three times, or until disease progression or intolerable adverse events were observed. RESULTS: Of the 46 patients entered into this study, 44 received gemcitabine. Performance status (PS) at study entry was: PS 0 (30 patients), PS 1 (12 patients) and PS 2 (2 patients). Stages III/IV were observed in 1/9 patients; the other 34 patients had relapsed after surgery. All 44 patients had been previously treated with a platinum-based regimen. The overall response rate was 25%, 1-year survival rate 52.3%, median survival time 12.6 months and median progression free survival 3.1 months. The major grade 3/4 hematological toxicity was neutropenia (47.7%), and the major grade 3/4 non-hematological toxicity was anorexia (9.1%). All adverse drug reactions seen in the study were manageable. CONCLUSION: Gemcitabine monotherapy is a sufficiently active and well-tolerated therapy for patients who have previously undergone chemotherapy with a platinum-based regimen.     

Management of bladder cancer

Bladder cancer is a paradigm of malignancy, representing the spectrum from localized to metastatic disease, and manifesting varied histologic types, including transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma. Preclinical and clinical data suggest that a common stem cell of origin gives rise to the different histologic types and that these patterns are of clonal origin. Localized bladder cancer is managed optimally by transurethral resection, with or without adjuvant intravesical chemotherapy. Invasive cancer or relapsed superficial disease may require more radical surgery or radical radiotherapy. In recent years, the evolution of techniques of continent urinary diversion or of bladder replacement has revolutionized the management of invasive disease. However, the 5-year survival for invasive bladder cancer is still approximately 50%, and innovative strategies have been developed, combining definitive local treatment and systemic chemotherapy, in an attempt to improve survival. For patients with metastatic disease, the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (the MVAC regimen) has achieved response rates as high as 70% but with a median survival of only 12 months. Until cure rates are improved, one of the hallmarks of effective management of metastatic disease will remain the provision of thorough and well-structured palliative treatment programs. Recently, the introduction of new agents (such as paclitaxel, gallium, ifosfamide, and gemcitabine) has led to promising response rates, and further clinical trials of these agents alone and in combination are in progress. In addition, an improved understanding of the mechanisms of resistance to treatment, including the implications of the expression of p-glycoprotein, p53 proteins, and other biochemical predictors of outcome, and of strategies to overcome such resistance, may lead to more effective management of advanced disease. Furthermore, real progress will be made only through the application of well-designed clinical trials to test the efficacy and toxicity of the new strategies of treatment.     

Erstlinienchemotherapie beim Harnblasenkarzinom

The incidence of bladder cancer in Europe was estimated to be 133,700 cases in 2008 (104,600 males and 29,100 females) corresponding to 6.2?% of tumors in men and 1.9?% in women. The incidence of these tumors has therefore not substantially changed in 5 years (WHO Globocan project 2008). Cisplatin-containing combination chemotherapy has been the standard of care in the treatment of urothelial cancer (UC) since the late 1980s. Gemcitabine/cisplatin, MVAC, high-dose MVAC and the new triplet paclitaxel/cisplatin/gemcitabine are possible treatment options with different toxicity profiles. However, up to 50% of patients are unfit for cisplatin-containing chemotherapy, either due to a poor performance status (PS) and/or impaired renal function or due to co-morbidities that prevent high-volume hydration. These conditions increase with age. There is controversy about the definition of fit or unfit for cisplatin therapy. An international survey revealed five factors to be crucial: decreased PS, renal function impairment, peripheral neuropathy, hearing loss and heart failure. A standard chemotherapy has not yet been established for patients ineligible for cisplatin-based standard chemotherapy. Trials with clearly defined unfit patients or patients with multiple adverse prognostic factors are rare. The first randomized phase II/III trial in this setting compared carboplatin/vinblastin/methotrexate (M-CAVI) and carboplatin/gemcitabine (CG) in patients unfit for cisplatin. Overall survival (OS) was not statistically significantly different between the two treatment regimens with a median OS of 9.3 and 8.1 months for CG and M-CAVI, respectively. Severe acute toxicity was higher for the M-CAVI arm and therefore carboplatin/gemcitabine is the preferred treatment option in cisplatin ineligible patients.     

保留膀胱手术联合动脉化疗治疗浸润性膀胱癌的临床研究

目的 评价保留膀胱手术联合动脉化疗治疗浸润性膀胱癌的临床疗效.方法 2003年4月～2006年12月,对35例浸润性膀胱癌患者采用经尿道膀胱肿瘤电切或膀胱部分切除术联合GC(吉西他滨 顺铂)方案动脉化疗治疗,总结分析肿瘤控制情况、膀胱保存率和患者的生存率.结果 33例患者获随访,2例失访,平均随访24.3个月(3～45个月).27例无瘤生存,2例带瘤生存,4例死于肿瘤转移,2年生存率为88.8%;19例无复发及转移,5例浅表性复发,3例浸润性复发,6例转移;25例保留膀胱生存,4例行挽救性全膀胱切除,4例死亡,2年膀胱保存率为74.1%.全部患者对动脉化疗耐受良好,无严重全身和局部不良反应.结论 保留膀胱手术联合GC方案动脉化疗治疗浸润性膀胱移行细胞癌近期疗效满意,毒副作用轻,值得临床进一步观察研究.     

The role of taxanes in the management of bladder cancer

Transitional cell carcinoma of the bladder is a chemo-sensitive neoplasm. Whereas the MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen was long considered the standard of care for patients with advanced disease, the evaluation of newer agents with retained activity and improved tolerability has been the focus of much investigation over the past decade. Among the most important of these newer agents are taxanes. Whereas taxane-containing regimens have not yet been shown to improve the survival of patients with transitional cell carcinoma in randomized trials, ongoing phase III trials will further define the role of these agents in both the perioperative and advanced disease settings.     

Recent progress in the treatment for urothelial cancer

Recent progress in the treatment for urothelial cancer is reviewed, especially concerning systemic chemotherapy and surgical techniques. A guideline for chemotherapy of urothelial cancer according to clinical stage is shown on the basis of evidence level in Japan. MVAC chemotherapy is regarded as the gold standard for advanced metastatic urothelial cancer. Randomized controlled trial revealed that gemcitabine in combination with cisplatin (GC therapy) has an efficacy similar to MVAC and is less toxic. Thus, GC therapy will become the standard treatment for advanced metastatic urothelial cancer instead of MVAC. Many chemotherapeutic regimens including gemcitabine and taxane have been introduced for patients with MVAC refractory or recurrent urothelial cancer. It was not yet clarified whether neoadjuvant chemotherapy provides survival benefits. Recent metaanalysis, however, revealed that neoadjuvant chemotherapy, especially cisplatin-based chemotherapy, has a survival advantage compared with total cystectomy alone. Intravesical BCG instillation is the standard treatment for carcinoma in situ and prophylaxis of recurrence for high-risk superficial bladder cancer. For higher efficacy and lower adverse effect, maintenance instillation and low-dose therapy are proposed, respectively, but further investigation is needed. Laparoscopic surgery in the urological field is widely performed and regarded as a minimally invasive surgery. Laparoscopic nephroureterectomy for patients with upper urinary tract cancer is reported to show the same efficacy at point of cancer control in comparison with traditional open surgery. Endoscopic treatment for upper tract urothelial cancer using laser can be safe and effective for a properly selected patient with a normal contralateral kidney.     

Neoadjuvant or adjuvant chemotherapy: what is the best treatment of muscle invasive bladder cancer?

Bladder cancer is the fourth most common cancer for men and the eighth most common cancer for women. Transitional cell carcinoma is the most predominant histological type. Bladder cancer is highly chemosensitive. In metastatic setting the treatment is based on cisplatin chemotherapy regimens type MVAC, MVAC-HD or gemcitabine plus cisplatin. The standard treatment of muscle invasive operable bladder cancer (T2–T4) used widely was radical cystectomy with pelvic lymph nodes dissection; the anatomical extent of pelvic lymphadenectomy has not accurately been defined so far. However, in the last decade, the treatment of tumors was improved by the introduction of chemotherapy as part of the management of the disease. Neoadjuvant chemotherapy should be considered at first, as standard treatment of choice, before local treatment for patients with good performance status (0–1) and good renal function–glomerular filtration rate (GFR) >60 mL/min. For patients treated with primary surgery, adjuvant chemotherapy is a valuable option in the case of lymph nodes involvement. This brief review would provide the evidence of the role of neoadjuvant chemotherapy in the management of operable muscle invasive (T2–T4) bladder cancer.     

Gemcitabine and cisplatin in locally advanced and/or metastatic bladder cancer

Although transitional cell carcinoma of the urothelium is chemosensitive, long-term disease-free survival is low. Accordingly, interest has focused on combining classically active agents like cisplatin with promising new drugs. Gemcitabine has evoked interest not only because of its intrinsic activity against this cancer, but also because of its effect of inhibiting repair of DNA that has been damaged by drugs like cisplatin. Four phase II studies have assessed the effect of a gemcitabine-cisplatin combination on advanced or metastatic bladder cancer. All the studies employed a gemcitabine dose of 1000 mg/m(2) given on days 1, 8 and 15, whereas the cisplatin dose and schedule varied, with total doses ranging from 70 to 105 mg/m(2). Overall response rates in these studies ranged from 42 to 66%, with complete responses from 15 to 28%. Toxicities, which were primarily haematological, were generally manageable. This promising two-drug combination has been compared with the standard MVAC regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) in a randomised phase III trial and the results are eagerly anticipated.     

Standard or accelerated methotrexate,vinblastine, doxorubicin and cisplatin as neoadjuvant chemotherapy for locally advanced urothelial bladder cancer: Does dose intensity matter?

BackgroundThere is continuing controversy regarding the optimal regimen for neoadjuvant chemotherapy (NAC) in bladder cancer.Patients and methodsWe performed a retrospective analysis of 241 consecutive bladder cancer patients who received a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) using a standard (52 patients) or an accelerated schedule (189 patients) as NAC before radical cystectomy in 17 centres of the French GEnito-urinary TUmour Group from March 2004–May 2013.ResultsThe median age was 62 years. As expected, the median number of cycles, the median total dose of cisplatin and the median cisplatin dose intensity were higher in patients treated with the accelerated regimen. Conversely, the median duration of chemotherapy was shorter. Regarding toxicity, grade III/IV neutropenia, grade III thrombocytopenia and grade III anaemia as well were more frequently observed in patients treated with the standard regimen. Among 211 (88%) patients who proceeded to cystectomy, 75 (35%) patients achieved an ypT0 pN0 status (no pathologic residual tumour cells) with no significant difference according to the MVAC schedule. Three-year overall survival rates were 66.5% (95% confidence interval [CI], 56–79) and 72% (95% CI, 59.5–88) in the standard and accelerated cohorts, respectively. In the multivariate analysis, two independent prognostic parameters were retained: the ypT0 stage and the ypN0 stage. Heterogeneity test did not show any interaction with NAC regimens.ConclusionSimilar pathological response and survival rates were observed whatever the chemotherapy regimen used. Haematological toxicity was greater in patients who received standard MVAC.     

Chemotherapy with gemcitabine, paclitaxel, and cisplatin in the treatment of patients with advanced transitional cell carcinoma of the urothelium

Chemotherapeutic agents are active in advanced bladder cancer, and various combinations have shown promising results. The objective of this study was to evaluate the efficacy of combination chemotherapy with gemcitabine, paclitaxel, and cisplatin in patients with advanced urothelial carcinoma. Fifty-nine patients with metastatic or locally advanced transitional cell carcinoma of the urothelium were treated between 2000 and 2005. No patient had received any previous systemic chemotherapy. All patients received chemotherapy intravenously with gemcitabine at a dose of 1000 mg/m(2) on days 1 and 8, paclitaxel at a dose of 80 mg/m(2) on days 1 and 8, and cisplatin at a dose of 50 mg/m(2) on day 2. Treatment courses were repeated every 21 days. After completion of four to six courses in this regimen an intravenous application of gemcitabine was repeated every 28 days at a dose of 1000 mg/m(2). Fifty-nine patients were treated between 2000 and 2005. Nine patients (15%) had >or=1 visceral site of metastases, and no patient had received any previous systemic chemotherapy. Forty-eight patients (81%) achieved objective responses to treatment (56% complete responses). The median actuarial survival was 22 months, and the actuarial 1-year and 2-year survival rates were 68% and 39%, respectively. After a median follow-up of 17.5 months, 29 patients remained alive and 25 were free of disease progression. The median progression-free survival for the entire group was 10 months. The median survival time for patients with an Eastern Cooperative Oncology Group (ECOG) status of 0, 1, and 2 was 37.5, 17, and 12 months, respectively. Grade 3-4 neutropenia occurred in 39% of the patients. The combination of gemcitabine, paclitaxel, and cisplatin is a highly effective and tolerable regimen for patients with advanced urothelial carcinoma. This treatment should be considered as a suitable option that deserves further prospective evaluation. The ECOG performance status is an important predictive factor for survival.     

Neoadjuvant chemotherapy with sequential methotrexate and 5-fluorouracil scheduling,epirubicin and cisplatin for locally advanced bladder cancer

INTRODUCTION: Transitional cell carcinoma of the bladder is moderately sensitive to chemotherapy. Notably, the methotrexate, doxorubicin, vinblastine and cisplatin regimen was found to produce a high overall response rate and a modest survival advantage. However, toxicity was significant and the therapy rarely results in long-term disease-free survival. In several clinical series, sequentially delivered methotrexate and 5-fluorouracil followed by leucovorin rescue in expectation of a biochemical modulation has a higher response rate. METHODS: The combination chemotherapy using sequential methotrexate and 5-fluorouracil scheduling, epirubicin and cisplatin (MFAP regimen) for locally advanced bladder cancer was evaluated in a neoadjuvant setting. Thirty-seven patients (32 males and 5 females) were enrolled in this study. RESULTS: Six (16.2%) of the patients had complete responses and 26 (70.3%) had partial responses to the therapy amounting to a response rate of 86.5%. At follow-up, 10 of 13 patients (76.9%) who underwent bladder preservation had not developed muscle-invasive recurrence of the disease and kept their bladder. There is no statistical difference of the survival rate between the cystectomy group and the bladder preservation group (p = 0.86). Toxicity was relatively mild but with some severe myelotoxic effects. CONCLUSIONS: MFAP represents an active regimen in the treatment of locally advanced bladder cancer with a moderate toxicity profile.