Neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin for histologically proven lymph node positive bladder cancer

PURPOSE: We gained insight into the effect of neoadjuvant chemotherapy and subsequent surgery in patients with bladder cancer with tumor positive lymph nodes. MATERIALS AND METHODS: A total of 52 patients with histologically proven positive lymph nodes (by lymph node dissection or aspiration cytology) were treated with chemotherapy and post-chemotherapy surgery in case of partial or complete response. We evaluated response in the primary tumor and lymph nodes, long-term clinical outcome, and clinicopathological features potentially predictive of survival. RESULTS: Complete response, partial response and stable/progressive disease were attained in 29%, 57% and 14%, and resulted in a 5-year survival of 42%, 19% and 0%, respectively. Objective response (HR 4.1), especially complete response (HR 8.0), was independently associated with survival. The prognostic values of lymph node status and bladder tumor status after methotrexate, vinblastine, doxorubicin and cisplatin were evaluated separately. A tumor negative bladder combined with tumor negative nodes were associated with improved survival (HR 4.4) as was a tumor negative lymph node region in the presence of residual bladder disease (HR 2.8). All patients with post-chemotherapy tumor positive nodes died within 2 years. In resected specimens residual disease was found in 4 of 15 clinically complete responders while no tumor could be detected in 3 of 29 clinically assessed as partial responders. CONCLUSIONS: Response to chemotherapy is associated with improved survival, and our data suggest that lymph node status after methotrexate, vinblastine, doxorubicin and cisplatin is more important than local tumor status in this aspect. In the absence of reliable noninvasive methods, post-chemotherapy surgery in this series was the most adequate method of response evaluation and in limited partial responders led to long-term progression-free survival.     

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinoma

What’s known on the subject? and What does the study add? Metastatic bladder cancer is a devastating disease that often proves fatal. Systemic chemotherapy with MVAC (methotrexate, vinblastine, adriamycin, cisplatin) has been the first choice of treatment for many years but toxicity can be severe and overall survival poor. The search for more effective drug combinations continues. Clinical data indicate that gemcitabine has activity in this disease in terms of tumour response and overall survival. This systematic review comprehensively presents the available clinical evidence on gemcitabine chemotherapy for the management of metastatic bladder cancer. Limited data from randomized trials suggest that cisplatin plus gemcitabine may be considered a viable first‐line option for this disease and that the less toxic combination of gemcitabine plus carboplatin may be suitable for patients with poor renal function or low performance status. Data from observational studies highlight the wide variation in drug combinations and schedules used and the need for a systematic approach to clinical research with gemcitabine.

OBJECTIVE

? To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer.

MATERIALS AND METHODS

? The Medical Literature Analysis and Retrieval System Onlinedatabase (MEDLINE), the Excerpta Medicadatabase (EMBASE), the Cumulative Index to Nursing and Allied Health Literature database(CIHNAL), the Cochrane database of randomized trials, the Literatura Latino‐Americana e do Caribe emCiências da Saúdedatabase (LILACS), and Web of Science were searched to identify trials of gemcitabine for metastatic bladder cancer. Also searched were international guidelines on metastatic prostate cancer, trial registries, and recent systematic reviews. Data on trial design, survival, tumour response and toxicity outcomes were extracted from relevant studies.

RESULTS

? This review identified six randomized trials of combined chemotherapy with gemcitabine for the management of unresectable, locally advanced or metastatic bladder cancer. ? One trial compared gemcitabine plus cisplatin (GCis) with methotrexate/vinblastine/doxorubicin/cisplatin(MVAC) and found no difference in overall survival (OS; hazard ratio 1.09) but a better safety profile with GCis, which was suggested as the treatment of choice. ? A second trial evaluated GCis against gemcitabine plus carboplatin (GCarbo) and reported similar median OS (12.8 vs 9.8 months), disease progression (8.3 vs 7.3 months) and tumour response rates (66% vs 56%) for the two patient groups. ? A third trial compared GCis with GCis plus paclitaxel (GCisPac) and showed no significant difference in median OS (12.3 vs 15.3 months) and response rates (44% vs 43%) but greater toxicity with GCisPac. ? A fourth trial assessed GCarbo against methotrexate plus carboplatin plus vinblastine in patients unfit for cisplatin‐based chemotherapy and found similar tumour response rates for each regime (38% vs 20%) but the triplet regime was more toxic. ? Two other randomized studies compared a 2‐weekly maintenance regime of gemcitabine plus paclitaxel with a 3‐weelky regime given for a maximum of six cycles and found that the maintenance schedule did not confer any additional survival benefit. ? In all, 53observational studies of gemcitabine chemotherapy were identified that varied considerably in the drug combinations used and schedules. Overall response rates (17–78%) and median OS (6.4–24.0 months) were variable with no combination being clearly superior.

CONCLUSIONS

? Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer. ? GCis may be considered an alternative regime to MVAC. ? GCarbo should be considered for patients unfit for cisplatin‐based therapy.     

Complete long-term survival data from a trial of adjuvant chemotherapy vs control after radical cystectomy for locally advanced bladder cancer

OBJECTIVES: To report the long-term follow-up of patients with locally advanced bladder cancer treated with either adjuvant combined chemotherapy with methotrexate, vinblastine, doxorubicin/epirubicin, and cisplatin (MVAC/MVEC) or no additional treatment after radical cystectomy, to examine various survival endpoints and factors associated with long-term survival. PATIENTS AND METHODS: Between May 1987 and December 1990, 49 patients undergoing radical cystectomy for locally advanced bladder cancer were randomized to observation only or adjuvant systemic chemotherapy with three cycles of MVAC/MVEC (methotrexate 30 mg/m(2) on day 1, 15 and 22; vinblastine 3 mg/m(2) on day 2, 15 and 22; doxorubicin 30 mg/m(2) or epirubicin 45 mg/m(2) on day 2; and cisplatin 70 mg/m(2) on day 2 of a 28-day cycle). Data were obtained for progression-free, overall and tumour-specific survival. RESULTS: In all, 23 patients were randomized to the control arm and 26 to treatment with adjuvant chemotherapy. The trial intended to accrue 100 patients but was stopped after an interim analysis showed a marked difference in progression free-survival when these first 49 patients had been randomized. The intent-to-treat analysis, including hazard ratios (HR) with 95% confidence intervals and point estimates at 10 years for control vs adjuvant chemotherapy, was as follows: progression-free survival HR 2.84 (1.46-5.54; P= 0.002), 13.0% vs 43.7%; overall survival HR 1.75 (0.95-3.23; P= 0.069), 17.4% vs 26.9%; and tumour-specific survival HR 2.52 (1.28-4.99; P= 0.007), 17.4% vs 41.7%, respectively. CONCLUSIONS: The long-term results further support the use of adjuvant-combined chemotherapy with cisplatin-based regimens after radical cystectomy for locally advanced bladder cancer, as this significantly improves progression-free and tumour-specific survival.     

Chemotherapy in the post-MVAC era: the case for adjuvant chemotherapy

Radical cystectomy for muscle invasive and locally advanced bladder cancer is the standard treatment modality in most of the Western industrialised countries. Rates of perioperative mortality from radical cystectomy have decreased to less than 2% over the past two decades due to advances in surgical technique and perioperative care. However, at least 40% of patients with pT3 bladder cancer and 70% of patients with lymph node-positive disease develop tumour recurrence after radical treatment within the first 5 years when treated with radical cystectomy alone. After the efficacy of combination chemotherapy for metastatic urothelial cancer using methotrexate, vinblastine, adriamycin and cisplatin (MVAC) was first described in 1985, several cisplatin-based systemic regimens have been investigated as adjunctive treatment before or after therapy for locally advanced bladder cancer by radical surgery or radiation therapy. Three randomised studies have reported superior results of postoperative adjuvant systemic chemotherapy compared to radical cystectomy alone for locally advanced bladder cancer. All three studies demonstrated a significant survival benefit for bladder cancer patients receiving adjuvant combination therapy. Studies have been criticised for small patient numbers and statistical shortcomings. New effective antineoplastic agents, such as paclitaxel and gemcitabine, have evolved during the past decade as promising substances for the treatment of urothelial cancer. This article reviews adjuvant studies from the era of MVAC combination chemotherapy, as well as contemporary studies that discuss new antineoplastic agents for systemic adjuvant chemotherapy of locally advanced bladder cancer.     

Chemotherapeutic and targeted biological agents for metastatic bladder cancer: A comprehensive review

The American Cancer Society estimates that 73 510 new cases of bladder cancer will be diagnosed and 15 000 deaths will result this year. The paper summarizes the clinical evidence for the use of platinum‐based, non‐platinum‐based and new targeted biological agents, while reporting the future directions in the treatment of metastatic bladder cancer. For cisplatin‐base regimens, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M‐VAC) has been the mainstream treatment for both advanced and metastatic bladder cancers. It showed significant improvement in the complete response rate and overall survival time in comparison with single‐agent cisplatin. For cisplatin‐ineligible patients, namely patients with renal impairment, symptomatic cardiac disease and poor performance status, alternative therapies consisting of paclitaxel, gemcitabine and carboplatin were shown to be of benefit. Pemetrexed and vinflunine have also shown effectiveness, with small but demonstrable overall survival benefits. Gemcitabine‐based doublet therapies (combined with paclitaxel, docetaxel, irinotecan, oxaliplatin or epirubicin) have all been shown to be effective and well‐tolerated. Several new targeted therapies, such as gefetinib, sorafenib and lapatinib, have received attention in recent years; however, their effectiveness as single agents in a relapse setting have not been optimal and more studies are warranted.     

The prognostic significance of human equilibrative nucleoside transporter1 (hENT1) expression in metastatic bladder cancer patients treated with gemcitabine-cisplatin based combination chemotherapy

Systemic combination chemotherapy, such as the methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) regimen, has shown certain activity in advanced bladder cancer, but is associated with a significant toxicity burden, with a treatment-related mortality of about 4%. Therefore, a great deal of interest has been focused on the gemcitabine-cisplatin (GC) combination chemotherapy which showed the same antitumor effect as MVAC chemotherapy with far less toxicity. Indeed, the GC regimen is now frequently administered as the first-line chemotherapy against metastatic bladder cancer. For the present, GC/MVAC regimens constitute alternative platform chemotherapy, until new evidence based strategy can be demonstrated. Accordingly it is important to be able to predict whether a regimen is effective in each patient with bladder cancer before the initiation of chemotherapy. Clinicopathological factors as the Karnofsky performance status and the presence of visceral metastases are well-established prognostic markers for poor survival. However, they are inadequate to predict the optimal therapeutic regimen for each individual patient. As for the predictive marker of cisplatin, ERCC1 may predict survival in bladder cancer treated by platinum-based therapy. The predictive potential of gemcitabine has not been previously considered in advanced bladder cancer treated by gemcitabine-combined systemic chemotherapy. In our retrospective study, the predictive value of a high expression level of hENT1 was assessed in bladder cancer treated by gemcitabine combined combination chemotherapy.     

Do mixed histological features affect survival benefit from neoadjuvant platinum‐based combination chemotherapy in patients with locally advanced bladder cancer? A secondary analysis of Southwest Oncology Group‐Directed Intergroup Study (S8710)

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? In a meta‐analysis of randomized trials, neoadjuvant platinum‐based combination chemotherapy administered before definitive local treatment improved survival of patients with muscle‐invasive bladder cancer compared with definitive local treatment alone. However, it was not known whether chemotherapy was equally effective for pure urothelial carcinoma versus urothelial carcinoma with mixed histological features, such as squamous or glandular differentiation. To address this question we performed a secondary analysis of the Southwest Oncology Group‐directed intergroup randomized trial S8710 of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy versus cystectomy alone for treatment of locally advanced urothelial cancer of the bladder. Our findings suggest that presence of squamous or glandular differentiation does not confer resistance to combination chemotherapy with MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.

OBJECTIVE

? To determine whether the effect of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) on the survival of patients with locally advanced urothelial carcinoma (UC) of the bladder treated with radical cystectomy varies with the presence of non‐urothelial components in the tumour.

PATIENTS AND METHODS

? This is a secondary analysis of the Southwest Oncology Group‐directed intergroup randomized trial S8710 of neoadjuvant MVAC followed by cystectomy versus cystectomy alone for treatment of locally advanced UC of the bladder. ? For the purpose of these analyses, tumours were classified based on the presence of non‐urothelial components as either pure UC (n= 236) or mixed tumours (n= 59). Non‐urothelial components included squamous and glandular differentiation. ? Cox regression models were used to estimate the effect of neoadjuvant MVAC on all‐cause mortality for patients with pure UC and for patients with mixed tumours, with adjustment for age and clinical stage.

RESULTS

? There was evidence of a survival benefit from chemotherapy in patients with mixed tumours (hazard ratio 0.46; 95% CI 0.25–0.87; P= 0.02). Patients with pure UC had improved survival on the chemotherapy arm but the survival benefit was not statistically significant (hazard ratio 0.90; 95% CI 0.67–1.21; P= 0.48). ? There was marginal evidence that the survival benefit of chemotherapy in patients with mixed tumours was greater than it was for patients with pure UC (interaction P= 0.09).

CONCLUSION

? Presence of squamous or glandular differentiation in locally advanced UC of the bladder does not confer resistance to MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.     

Lokal fortgeschrittenes oder metastasiertes Harnblasenkarzinom Aktuelle Aspekte in der Therapie

The prognostic factors for infiltrating tumors established by the TNM system in 1997 include: Depth of infiltration, degree of differentiation, status of lymph nodes distant metastases. Of the additional factors investigated, only tumor size and hydronephrosis appear to be of prognostic significance. In the scope of molecular markers, the loss of expression of the epithelial cell-cell adhesion molecule E-cadherin signals an unfavorable clinical course. In cases of carcinoma of the urinary bladder without metastases (T2-4,N0,M0), radical cystectomy is the therapy of choice. A preceding neoadjuvant systemic regimen of chemotherapy with three cycles of M-VAC (methotrexate, vinblastine, adriamycin, cisplatin) significantly improves the survival rate. In patients with locally advanced urinary bladder carcinoma, however, adjuvant systemic chemotherapy with M-VAC after cystectomy and lymphadenectomy offers no advantages for survival. Quality of life in patients with metastatic bladder cancer disease is improved by new cytotoxic drugs, i.e. gemcitabine or taxanes.     

The role of adjuvant chemotherapy in patients with locally advanced (pT3, pT4a) and/or lymph node–positive bladder cancer

Objective  

To report the long-term follow up of patients with locally advanced bladder cancer treated with either adjuvant chemotherapy with gemcitabine/cisplatin (GC) or methotrexate, vinblastine, epirubicin, and cisplatin (MVEC) or no additional treatment after radical cystectomy, to examine various survival endpoints and factors associated with long-term survival.     

The role of chemotherapy in the treatment of urothelial cell carcinoma of the upper urinary tract (UUT-UCC)

ObjectiveUrothelial cell carcinoma of the upper urinary tract (UUT-UCC) is a rare, aggressive urologic cancer with a propensity for multifocality, local recurrence, and metastasis. This review highlights the main chemotherapy regimens available for UUT-UCCs based on the recent literature.Materials and methodsData on urothelial malignancies and UUT-UCCs management in the literature were searched using MEDLINE and by matching the following key words: urinary tract cancer; urothelial carcinomas; upper urinary tract; carcinoma; transitional cell; renal pelvis; ureter; bladder cancer; chemotherapy; nephroureterectomy; adjuvant treatment; neoadjuvant treatment; recurrence; risk factors; and survival.ResultsNo evidence level 1 information from prospective randomized trials was available. Because of its many similarities with bladder urothelial carcinomas, chemotherapy with a cisplatin-containing regimen is often proposed in patients with metastatic or locally advanced disease. Most teams have proposed a neoadjuvant or an adjuvant treatment based either on the combination of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) or on gemcitabine/cisplatin (GC). These regimens have been shown to prolong survival moderately. All recent studies have included limited numbers of patients and have reported poor patient outcomes after both neoadjuvant and adjuvant chemotherapy. Regarding metastatic UUT-UCCs, vinflunine has demonstrated moderate activity in these patients with a manageable toxicity. Interestingly, specific molecular markers [microsatellite instability (MSI), E-cadherin, HIF-1α, and RNA levels of the telomerase gene] can provide useful information that can help diagnose and determine patient prognosis in patients with UUT-UCC.ConclusionChemotherapy with a cisplatin-containing regimen is often proposed in patients with metastatic or locally advanced disease. However, there is no strong evidence that chemotherapy is effective due to the rarity of the disease and the lack of data in the current literature. Thus, physicians must take into account the specific clinical characteristics of each individual patient with regard to renal function, medical comorbidities, tumor location, grade, and stage, and molecular marker status when determining the optimal treatment regimen for their patients. The ongoing identification of the oncologic mechanisms of this type of cancer might pave the way for the development of specific treatments that are targeted to the characteristics of each patient's tumor in the future.     

The effect of cystectomy, and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer

PURPOSE: Trials have demonstrated decreased relapse with perioperative methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy in patients with muscle invasive bladder cancer. We evaluated whether the benefit of chemotherapy correlates with its effects on distant or pelvic relapse. MATERIALS AND METHODS: We retrospectively evaluated the records of all 107 patients who underwent cystectomy for muscle invasive bladder cancer at our institution between 1988 and 1994. Factors predicting relapse were identified and used to group patients at high or low risk. The outcome in each group with and without M-VAC chemotherapy was then analyzed in terms of overall, metastatic and pelvic relapse. Univariate analysis was performed using the Kaplan-Meier method and log rank statistic, and multivariate analysis was done using the Cox proportional hazards model. Median survival was 29 months for patients free of disease. RESULTS: Pathological stage T3 or greater according to the American Joint Committee on Cancer, tumor greater than 3 cm. and creatinine greater than 1.5-fold normal were independent poor prognostic factors in patients treated with cystectomy only. Patients with any of these factors or metastatic involvement of the pelvic lymph nodes were considered at high risk. All 35 low risk patients were treated with cystectomy only and had an excellent outcome with a 3-year relapse-free survival plus or minus standard error of 93% +/- 5%. The 3-year rates in 52 and 20 high risk patients treated without and with chemotherapy, respectively, were 42% +/- 8% versus 57% +/- 13% for relapse-free survival (p = 0.17), 38% +/- 9% versus 8% +/- 8% for pelvic failure (p = 0.02) and 39% +/- 9% versus 38% +/- 13% for distant metastases (not significant). Multivariate analysis of patients who underwent pelvic lymphadenectomy revealed that perioperative chemotherapy improved relapse-free survival and pelvic control but not metastatic control (p = 0.03, 0.02 and 0.31, respectively). CONCLUSIONS: Low risk patients have excellent disease control when treated with cystectomy only. Those with high risk features are at substantial risk for pelvic failure (38% at 3 years) after cystectomy only. Perioperative M-VAC chemotherapy has a profound impact on pelvic but not on metastatic failure.     

The efficacy of neoadjuvant chemotherapy in invasive bladder cancer

Radical cystectomy is the gold standard in the treatment of invasivebladder cancer. However, five-year disease-free survival is low mostprobably due to micrometastatic disease at the time of surgery. Theneoadjuvant chemotherapy may be performed as the first line managementfor invasive bladder tumors in order to treat micrometastases found at thediagnosis and improve resectability of larger neoplasms. A total of 43patients diagnosed with invasive bladder tumors and 11 patients receivedneoadjuvant chemotherapy. The mean age of patients was 64 (43–74) years,and mean follow-up period was 52 months (12–114). Neoadjuvantchemotherapy protocol consisted of methotrexate, vinblastine, doxorubicin,and cisplatin (MVAC) or cisplatin, methotrexate, and cisplatin (CMV). Allpatients in neoadjuvant chemotherapy group underwent radicalcystectomy. There was no significant difference between the groups withrespect to disease-free survival time and overall survival time. In patientswho received neoadjuvant chemotherapy, the respective disease-free andoverall survival times were 31 months and 36 months versus 30 months and35 months in patients who were treated with surgery only (p > 0.05). Five-year survival rates were 36% and 31% in the chemotherapy and no-chemotherapy groups, respectively. In the present study, 5-year survivalrate was not affected by neoadjuvant chemotherapy in invasive bladdertumor. Complete pathological remission (stage p0) was found in 28% andpathological downstaging (stage < T2) was seen in 9% of patients in theneoadjuvant chemotherapy group. Five-year survival rates were 75% and14.2% in patients who responded to chemotherapy, and in patients with noresponse, respectively (p < 0.05). The most favorable prognostic factor inthis study was the response to neoadjuvant chemotherapy revealed ascomplete remission or pathological downstaging. The most important issueremains the prediction of patients who would respond and benefit fromneoadjuvant chemotherapy.     

Neo-adjuvant and adjuvant treatment of locally invasive bladder cancer

Since Sternberg et al. in 1985 first published preliminary results of polychemotherapy in patients with metastatic bladder cancer, it became apparent that transitional carcinoma of the bladder is highly responsive to chemotherapy. Response rates up to 70% with combination therapy regimens like methotrexate, vinblastine, doxorubicin or adriamycin and cisplatin promised that transitional carcinoma might be able to cure even in advanced stages. Chemotherapy has either been applied prior to the local treatment (such as radical cystectomy or radiotherapy) in a neo-adjuvant regimen, or after local therapy in an adjuvant regimen. Although a large number of studies have been published in the past 20 years, the role of the different chemotherapeutic approaches has not been clearly defined. Therefore, neither neo-adjuvant nor adjuvant chemotherapy can be recommended as 'gold standard' treatment for advanced bladder cancer.     

Gemcitabine plus cisplatin for advanced transitional cell carcinoma of the urinary tract: a phase II multicenter trial

PURPOSE: We determined the activity and toxicity of gemcitabine plus cisplatin in patients with inoperable or metastatic transitional cell carcinoma of the urinary tract. MATERIALS AND METHODS: A total of 54 patients with transitional cell carcinoma, measurable disease and Eastern Cooperative Oncology Group performance status 2 or greater were enrolled in this multicenter phase II trial. Previous adjuvant or neoadjuvant therapy for locally advanced disease was acceptable if it had been completed more than 1 year before study entry. Every 4 weeks patients received 1,000 mg./m.2 gemcitabine intravenously on days 1, 8 and 15, and 70 mg./m.2 cisplatin intravenously on day 2. RESULTS: All patients were evaluable for response and toxicity. Notably only 7 of the 54 patients (13%) previously received chemotherapy in an adjuvant or neoadjuvant setting. Overall we observed 26 objective responses (48%), of which 15% were complete. Median time to progression was 23 weeks and median survival was 54 weeks. Treatment was well tolerated. The main toxicities were leukopenia (grade 3 in 28% and grade 4 in 11% of patients), anemia (grade 3 in 34% and grade 4 in 6%) and thrombocytopenia (grade 3 in 14% and grade 4 in 6%). Other relevant side effects were nausea and vomiting in 20% of cases, fever in 24%, alopecia in 22%, renal failure in 7.4% and mucositis in 2%. CONCLUSIONS: Combined cisplatin plus gemcitabine is highly active in advanced transitional cell carcinoma of the urinary tract with manageable toxicity. The response rate, time to treatment failure and overall survival appeared to be comparable to those achieved with combined methotrexate, vinblastine, doxorubicin and cisplatin. Conversely toxicity appeared lower. Evaluation of this regimen in randomized studies with methotrexate, vinblastine, doxorubicin and cisplatin is strongly suggested.     

Current chemotherapeutic strategies against bladder cancer

Urothelial cancer is a chemotherapy-sensitive malignancy, with the regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) until recently considered to be the first choice for chemotherapy. Poor survival and substantial toxicity associated with M-VAC have led to investigations into alternative chemotherapy strategies, and the combination of gemcitabine and cisplatin (GC) may be promising. In addition, combination chemotherapy of taxanes along with gemcitabine and/or platinum-based agents is also considered to provide clinical benefits as second-line chemotherapy following M-VAC or GC therapy. In the near future, results of trials using molecular target therapies may bring improved outcomes for patients with bladder cancer.     

Gemcitabin in der Behandlung des fortgeschrittenen Urothelkarzinoms

MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) has been the standard treatment for patients with advanced urothelial cancer for more than 15 years. Combination chemotherapy including gemcitabine/cisplatin showed similar tumor response and survival rates with a more tolerable toxicity profile in a recent multinational phase III study when compared to MVAC. Effectiveness of gemcitabine as a single agent or in combination with other cytotoxic agents had been investigated before in several phase II studies treating patients with advanced urothelial cancers. The tumor response rate for single agent gemcitabine in advanced urothelial cancers is between 11% and 28%. Tumor response rates rise to 50% when combining gemcitabine with cisplatin, and median survival times between 12 and 15 months can be expected. Triplet therapy schedules including gemcitabine may yield response rates in up to 80% of patients, particularly when used sequentially with other regimens. Further improvement of tolerability during systemic gemcitabine/cisplatin combination therapy without compromising effectiveness was recently demonstrated by a German phase II study when the 4-week schedule was reduced to a 3-week schedule with gemcitabine given on days 1 and 8.     

Outcome of treatment with surgical resection of the remaining tumor after modified M-VAC treatment for advanced urothelial carcinoma

We retrospectively evaluated the effect of the surgical resection of the remaining tumor after modified M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) (m-M-VAC) treatment for locally advanced or metastatic urothelial carcinoma. In m-M-VAC therapy, methotrexate and vinblastine on 15 and 22 days were omitted from the classical M-VAC to avoid the discontinuation and the dose reduction, and duration of 1 course was shortened to 21 days from 28 days of the classical M-VAC. Seven patients with locally invasive or metastatic carcinoma of the renal pelvis, ureter, and bladder, 6 males and 1 female, with a median age 64.1 years, ranging from 49 to 77 years received m-M-VAC chemotherapy without severe side effects. In all patients, the residual viable carcinoma was completely resected and they achieved complete remission. The median survival time was 20 months (range, 7 to 61). Five of these 7 patients were still alive. Two patients had no recurrence and achieved long-term survival (survival duration; 61 and 39 months). Although further studies and long-term follow up are required, these results suggest that patients who present with locally advanced or metastatic urothelial carcinoma may benefit from surgical resection after m-M-VAC.     

The fate of the bladder in patients with metastatic bladder cancer treated with cisplatin, methotrexate and vinblastine: a Northern California Oncology Group study

We report the efficacy and toxicity of combined cisplatin, methotrexate and vinblastine for the treatment of metastatic transitional cell carcinoma of the bladder in 50 evaluable patients. Of these 50 patients 17 had not undergone cystectomy and had residual invasive bladder cancer. Of these 17 patients 11 had complete response of the bladder lesions following cisplatin, methotrexate and vinblastine for metastatic disease, including 6 of 12 treated by cisplatin, methotrexate and vinblastine alone, and 5 of 5 treated with cisplatin, methotrexate and vinblastine plus palliative or preoperative pelvic irradiation. Complete response was confirmed in 10 of the 11 patients by endoscopy and biopsy, and in 1 by cystectomy. One patient whose liver metastasis responded to cisplatin, methotrexate and vinblastine had conversion to complete response by cystectomy for persistent bladder cancer. Of these 17 patients 7 are alive, including 5 without disease, 4 to 41 months after treatment. The bladder appears to be responsive to this combination chemotherapy for invasive transitional cell carcinoma. This experience underscores the need for regular pathological re-staging of the bladder cancer in patients receiving chemotherapy.     

Neoadjuvant and adjuvant chemotherapy of transitional cell carcinoma of the urothelium with cisplatin,methotrexate and vinblastine

Summary Cisplatin-based multiple-drug chemotherapy is currently considered to be the most effective treatment for advanced and metastatic urothelial cancers. The combination of cisplatin, methotrexate and vinblastine (CMV) has been used at our institution for neoadjuvant and adjuvant chemotherapy. A complete response rate of 50% has been achieved in 28 evaluable patients with metastatic or locally advanced transitional cell carcinoma treated according to a neoadjuvant protocol. Our impression, based on early data, is that adjuvant CMV can effect at least a delay in disease progression, and possibly a prolonged disease-free survival.     

Paclitaxel and cisplatin chemotherapy for metastatic urothelial carcinoma after failure of two courses of platinum‐based regimens

Objectives: We investigated the outcomes of paclitaxel and cisplatin chemotherapy as an optional regimen for patients with metastatic urothelial carcinoma after failure of two consecutive platinum‐based regimens. Methods: We retrospectively analyzed the data of 21 patients who had evidence of disease progression after two consecutive platinum‐based regimens, gemcitabine and cisplatin (GC course), and methotrexate, vinblastine, doxorubicin and cisplatin (M‐VAC course) as first‐line and second‐line treatments. As third‐line chemotherapy, patients received paclitaxel (175 mg/m²) and cisplatin (70 mg/m²) every 3 weeks until disease progression. Results: Complete remission occurred in one patient (4.8%), partial remission occurred in three patients (14.3%) and stable disease occurred in five patients (23.8%). The overall response rate was 19.0% and the overall disease control rate, including stable disease, was 42.9%. The median progression‐free survival (PFS) was 3 months (95% CI 3.0–5.0). The median overall survival was 9 months (95% CI 7.0–15.0). Grade 3 to 4 neutropenia appeared in 85.7% of patients. No life‐threatening complications were observed. Conclusions: Paclitaxel and cisplatin chemotherapy could be an optional regimen for patients with metastatic urothelial carcinoma after the failure of two consecutive standard platinum‐based regimens.