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Biomedical subjects

J Bellmunt

Publications and source records attributed to J Bellmunt.

At least 19 recordsLinked to original sources
PubMed2007

Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy.

BACKGROUND: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival. PATIENTS AND METHODS: Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response. RESULTS: Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival. CONCLUSION: The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.

Adult↗
PubMed2006

Gemcitabine in the treatment of advanced transitional cell carcinoma of the urothelium.

M-VAC (cisplatin, methotrexate, adriamycin, vinblastine) combination chemotherapy has been for long time the standard of care in fit patient with advanced urothelial tumors. Gemcitabine/cisplatin with similar results and an improved toxicity profile has proved to be a new standard alternative. Whether or not we can improve survival with newer triplet regimens will depend upon the results of ongoing phase III trials. In addition to the new active drug combinations and targeted therapies, new approaches are emerging for treatment. Chemotherapy optimization using molecular markers predicting chemosensitivity are being applied. There is an obvious need to incorporate in clinical trials a systematic translational approach to explain both our successes and our failures.

Aged↗
PubMed2006

[Peripheral cholangiocarcinoma: results of surgical treatment].

INTRODUCTION: Peripheral cholangiocarcinoma (PC) is an uncommon primary hepatic tumor that represents 10% of hepatic resections for primary malignant tumors in our experience. PATIENTS AND METHODS: From 1988 to 2004, 29 patients with a diagnosis of PC were treated in our unit. One patient was treated with chemoembolization and the remainder underwent surgery. In 7 patients, hepatectomy was not performed due to the presence of an extrahepatic tumor or massive hepatic invasion. The resectability index was 75%. Twenty-one patients underwent radical excision of PC and comprised the study group. RESULTS: The mean age was 60 years with a slight predominance of women. Sixty-two patients were symptomatic and tumoral markers were elevated in 58%. PC developed in normal liver in 15 patients, in cirrhotic liver in 2 patients and in the context of chronic hepatitis in 4 patients. The mean tumoral size was 7 cm (between 1.6 and 13 cm). Multiple tumors were found in 3 patients, invasion of the hepatic hilum lymph nodes was found in 8 patients and vascular invasion was observed in a further 8 patients. Major hepatectomy was performed in 90% of the patients; radical lymphadenectomy of the hepatic hilum was performed in 15 patients and excision of the extrahepatic biliary tract followed by Roux-en-Y hepaticojejunostomy in 4 patients. Operative mortality occurred in 3 patients (14%); one cirrhotic patient died 4 days after surgery from cardiovascular causes and 2 patients died from liver failure after extensive hepatectomies that included resection of the inferior vena cava and suprahepatic veins. Complications occurred in 33% of the patients. Ten patients (47%) died. Of these, 6 died from tumoral recurrence. Tumoral recurrence occurred in 9 patients (5 hepatic and 4 extrahepatic). Hepatic recurrences were treated with radiofrequency ablation in 2 patients and chemotherapy in 5 patients. The median survival was 11 months. Actuarial survival at 1, 3 and 5 years was 60%, 47% and 47% respectively. Disease-free survival at 1, 3 and 5 years was 50%, 31% and 31% respectively. In univariate analysis, significant risk factors for mortality were lymphatic invasion and a resection margin of less than 1 cm. In multivariate analysis, negative factors for tumoral recurrence were lymphatic invasion, satellitosis, and poor tumoral delimitation. CONCLUSION: Surgical treatment of PC through radical hepatic resection with margins of more than 1 cm in patients without nodal invasion provides good results with a 5-year survival of 79%.

Adult↗
PubMed2003

Novel approaches with targeted therapies in bladder cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor family.

The improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new targets and prognostic indices that can direct the most appropriate choice of treatment for advanced disease. Many human tumors express high levels of growth factors and their receptors that can be used as potential therapeutical targets. Tyrosine-kinase receptors, including many growth factor receptors such the receptors for epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and Her2/neu, have been found overexpressed in urothelial tumors. For many of these growth factor receptors, the degree of expression has been associated with the progression of cancer and a poor prognosis. Among the best studied growth factor receptors are the two members of EGF receptor familiy EGFr (ErbB-1), and Her2/neu (ErbB-2). Several preclinical studies in bladder cancer models, have confirmed that systemic administration of growth factor inhibitors inhibits the growth and metastasis of human transitional cell carcinoma established in the bladder wall of athymic nude mice. Additional studies indicate that therapy with EGFR inhibitors enhances the activity of conventional cytoreductive chemotherapeutic agents, in part by inhibiting tumor cell proliferation, angiogenesis, and inducing apoptosis. Novel targeted therapy hold promise to improve the current results of bladder cancer treatment. Based on the success seen with anti-HER2 monoclonal antibodies (Herceptin) and the promising results with EGFR targeted agents (IMC-C225 Cetuximab, ZD1389 Iressa, OSI-774 Tarceva, GW 57016) in other tumor types, and based on the results obtained in preclinical models, there is a great interest in assessing these agents in patients with bladder cancer. Several trials are now ongoing testing these new agents alone or in combination with chemotherapy in bladder cancer patients. The integration of these newer biologic agents, probably to supplement rather than to supplant chemotherapeutic drugs, should be a primary direction of research with the objective to interfere with multiple aspects of bladder cancer progression. However, the value of integration of biologically targeted agents into combined modality treatment for patients with bladder cancer has still to be proven.

Animals↗
PubMed2003

New drugs and new approaches in metastatic bladder cancer.

The median survival of patients with metastatic cancer of the urothelium who receive best supportive care only in 4-6 months. With the introduction of combination chemotherapy regimens including cisplatin and methotrexate for the management of metastatic urothelial cancer, median overall survival has doubled. Nevertheless, death due to cancer ultimately occurs in more than 80% of these patients, thus more effective therapy is required. The new available treatment modalities range from new combinations of conventional chemotherapeutic agents to combinations incorporating novel drugs like gemcitabine and the taxanes. These new combinations incorporate the new active agents in two, three or multiple drug combinations, administered either in one regimen or sequentially in various combinations and schedules intended to improve the outcome of bladder cancer patients. Ongoing phase III studies will help to define the role of these new combinations in the treatment of advanced bladder cancer. The improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new prognostic indices that can direct the most appropriate choice of treatment for advanced disease. In addition, advances in the molecular biology of urothelial malignancies may allow identification of specific genetic lesions and biochemical pathways upon which future therapeutic approaches can be focused. The integration of newer biologic agents, probably to supplement rather than to supplant chemotherapeutic drugs, should be a primary direction of research with the objective to interfere with multiple aspects of bladder cancer progression.

Antineoplastic Agents↗
PubMed2002

Bone alkaline phosphatase serum level predicts the response to antiandrogen withdrawal.

OBJECTIVE: To analyze if the biochemical response to antiandrogen withdrawal correlates with total and percent free serum prostate specific antigen (PSA) and bone alkaline phosphatase (BAP). MATERIALS AND METHODS: A group of 46 patients in whom maximal androgen blockade (MAB) failed was included in this study. Flutamide was used in 32 patients and bicalutamide in 14. Total and free PSA and BAP were determined in serum the same day in which antiandrogen was withdrawn. Thereafter, serum PSA was determined every 15 days. A biochemical response was established when a decrease in serum PSA greater than 50% was observed. The duration of biochemical response was considered until the first of two consecutive PSA serum elevations. RESULTS: The rate of biochemical responses was 23.9%. The mean duration of responses was 5.2 months. The mean serum PSA in patients who responded to the antiandrogen withdrawal was 86.4 ng/ml, while it was 98.6 ng/ml in those who did not respond, P > 0.05. The mean of percent free PSA was 13.9 and 17.7%, respectively, P > 0.05. However, the mean BAP in responder patients was significantly lower, 18.9 ng/ml versus 100.6 ng/ml, P < 0.03. The rate of responses to flutamide withdrawal was 25% and to bicalutamide withdrawal 21.4%, P > 0.05. Other factors as age, Gleason score, initial clinical stage and the period of antiandrogen exposure were also analyzed. However, none of them had statistical significance. Serum BAP was the only predictor of response in the logistic regression analysis and a cut-off point of 50 ng/ml provided a relative risk of 1.46 (95% CI 1.17-1.83). CONCLUSIONS: Lower serum levels of BAP seems to correlate with a better response to antiandrogen withdrawal. Moreover, a level of BAP higher than 50 ng/ml would predict strongly the absence of response.

Aged↗
PubMed2002

Feasibility trial of methotrexate-paclitaxel as a second line therapy in advanced urothelial cancer.

To evaluate the clinical value of the concurrent use of methotrexate administered immediately before paclitaxel, we investigated the efficacy and toxicity of this two-drug combination administered as palliative second line therapy in patients with advanced urothelial cancer. The design of the schedule and sequence used was based on our previous preclinical data from a comparative study on sequential combinations of paclitaxel and methotrexate in a human bladder cancer cell line. As a confirmation study, we further extended our analysis of in vitro synergism. Twenty patients with advanced transitional cell carcinoma of the urinary tract previously treated with platinum-based therapy, with adequate renal function and a performance status > or = 60 were considered eligible. They received therapy with methotrexate 30 mg/m2 administered as an intravenous bolus, followed immediately by paclitaxel 175 mg/m2 given as a 3-hr infusion, both on day 1 every 21 days. Therapy was given on a compassionate-use basis until either disease progression was documented or the patient became intolerant to therapy. In vitro data were further analyzed using the median-effect principle and the combination index method. Twenty patients with metastatic (16 patients) or locally advanced disease (four patients) received a median of three cycles of therapy. Of the 19 patients assessable for response, there were six partial responses and seven disease stabilizations with no complete responses. Median duration of response was 3 months (range, 2-7) and median survival was 5 months. Three patients developed grade 3-4 neutropenia, one patient had grade 3 anemia, four patients had grade 2-3 sensory neuropathy, and three patients had myalgias. Eighteen patients developed alopecia. Gastrointestinal toxicity was mild. One patient died after the first cycle due to pulmonary thrombo-embolism and could not be evaluated for response. The synergistic in vitro effect of the concurrent combination was confirmed in analyses performed under mutually exclusive and mutually nonexclusive criteria. In conclusion, the combination of methotrexate and paclitaxel at this dose and sequence is feasible and active as a palliative therapy in patients with advanced urothelial cancer previously treated with platinum-based therapies. This schedule merits further investigation in a phase-II trial.

Adenocarcinoma↗
PubMed2001

A feasibility study of carboplatin with fixed dose of gemcitabine in "unfit" patients with advanced bladder cancer.

For the purpose of a subsequent phase II/III European Organization for Research and Treatment of Cancer (EORTC) trial, a gemcitabine/carboplatin feasibility study in "unfit" patients with advanced urothelial cell cancer was conducted. Gemcitabine was given at 1000 mg/m(2) days 1 and 8 with carboplatin (area under the curve (AUC) 4.5 or 5) day 1 every 21 days. 16 patients were treated, median age 68 years (47-75) years, performance status (PS) 0/1/2 in 3/10/3 patients. Creatinine clearance was >1 ml/s in 3 patients, 0.5-1 ml/s in 9 and <0.5 ml/s in 4 patients. Half of the patients had visceral disease. Median number of cycles given was 4 (range 2-6), for a total of 69 cycles. The first 8 patients received 33 cycles using a carboplatin AUC of 5. World Health Organization (WHO) grade 3-4 toxicity was: haemoglobin 5 patients, platelets 6 patients, neutrophils 5 patients and febrile neutropenia 2 patients. In view of this haematological toxicity in subsequent patients, the carboplatin AUC was decreased to 4.5. At this dose level, 8 patients received 36 cycles. WHO grade 3-4 toxicity was: anaemia 1 patient, platelets 4 patients, neutrophils 4 patients with no febrile neutropenia. Thus, this dose level was regarded to be feasible. For the 16 evaluable patients, overall response rate was 44%, (1 complete response (CR), 6 partial response (PR)). In conclusion, the combination of gemcitabine with carboplatin at an AUC of 4.5 appears to be an active and well tolerated regimen with acceptable toxicity in this unfit patient population. Based on these data, a randomised trial in the framework of the EORTC-Genitourinary (GU) group of gemcitabine/carboplatin versus carboplatin/methotrexate/vinblastine (MCAVI) is ongoing.

Aged↗
PubMed2001

New chemotherapy combinations for advanced bladder cancer.

Transitional cell carcinoma of the urothelium is considered a chemosensitive malignancy. Until recently, the methotrexate, vinblastine, doxorubicin and cisplatin combination has been considered the standard for treating this disease. The development of new chemotherapeutic agents such as gemcitabine and the taxanes has opened up promising new perspectives in the treatment of this disease. However, the preliminary phase II data must be confirmed in adequately conducted phase III trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. Spanish Oncology Genitourinary Group.

PURPOSE: To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with measurable, previously untreated, locally advanced or metastatic TCC and with Eastern Cooperative Oncology Group performance status < or = 2 and creatinine clearance > or = 55 mL/min were eligible. Cisplatin was given on day 1 at a fixed dose of 70 mg/m(2). Paclitaxel and gemcitabine were given on days 1 and 8 at increasing dose levels. Cycles were repeated every 21 days to a maximum of six cycles. RESULTS: Sixty-one patients were registered. In phase I, 15 patients were entered at four different dose levels. Dose-limiting toxicity consisted of early onset (after the first cycle) grade 2 asthenia (two of six patients) and grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dose of 80 mg/m(2) and gemcitabine 1,000 mg/m(2) was recommended for phase II, and 46 additional patients were entered at this level for a total of 49 patients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients, respectively. Overall, febrile neutropenia was seen in 11 patients, and one toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assessable for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed for an overall response rate of 77.6% (95% confidence interval, 60% to 98%). The median survival time (MST) available for the phase I part of the study is 24.0 months. MST has not been reached for the whole group with the current follow-up. CONCLUSION: This combination of paclitaxel, cisplatin, and gemcitabine is feasible and highly active in patients with advanced TCC of the urothelium. Further evaluation of this regimen in patients with TCC is warranted.

Adult↗
PubMed2000

Gemcitabine/paclitaxel-based three-drug regimens in advanced urothelial cancer.

Transitional cell carcinoma (TCC) of the urothelium is a highly chemosensitive tumour. Combination chemotherapy can provide both palliation and a modest survival advantage in patients with advanced disease. At present, the combination of cisplatin, methotrexate, doxorubicin and vinblastine (M-VAC) is the most widely used for advanced TCC with an overall response rate of 40-72% in phase II, and 35-45% in phase III studies, and a median survival of approximately 12 months. These modest results and the unsuccessful attempts to increase efficacy with dose intensive M-VAC schedules have prompted the identification of new active agents in TCC, such as the taxanes and gemcitabine. The overall response rates for two-drug regimens of cisplatin-paclitaxel, carboplatin-paclitaxel and cisplatin-gemcitabine range from 63 to 72%, 14 to 65% and 42 to 66%, respectively. The overall response rates for platinum-paclitaxel-gemcitabine three-drug regimens range from 58 to 80%. The potential clinical benefit of these new three-drug combinations in the treatment of TCC needs to be tested in future phase III studies.

Adult↗
PubMed2000

Comparative study of sequential combinations of paclitaxel and methotrexate on a human bladder cancer cell line.

We investigated the cytotoxic effect of different sequential combinations of paclitaxel (Taxol, TX), an antimicrotuble agent, and methotrexate (MTX), a potent inhibitor of dihydrofolate reductase, on a human bladder cancer cell line (T24). The results obtained with a colony-forming assay 5 days after 24 hr of exposure to TX alone showed a strong decline in colony growth up to a concentration of 6 nM. There was a plateau phase at TX concentrations ranging from 6 to 10 nM. The IC50 values found with the different dosing sequences and 24-hr exposure to the drugs were 0.24 microM for MTX alone, 3.49 nM for TX alone, 3.84 nM for TX followed by MTX, 3.75 nM for TX and MTX simultaneously, and 2.10 nM for MTX followed by TX. The cytotoxic effect due to drug interactions in the different sequential combinations was evaluated by an algebraic method. All the combination sequences were found to be synergistic (combination index [CI] < 1) at low TX concentrations. An antagonistic effect (CI > 1) was obtained at higher TX concentrations. Our data demonstrate that the T24 cell line is sensitive to TX and that the cytotoxic effect is enhanced to different degrees depending on the treatment sequence when TX is combined with MTX. These findings could have implications in the design of appropriate administration schedules of these two drugs for the treatment of bladder cancer.

Antimetabolites, Antineoplastic↗
PubMed1998

Cyclophosphamide, methotrexate, and chronic oral tegafur modulated by folinic acid in the treatment of patients with advanced breast carcinoma.

BACKGROUND: Chronic oral tegafur (a 5-fluorouracil prodrug) modulated by folinic acid has antitumor activity in patients with metastatic breast carcinoma resistant to 5-fluorouracil or doxorubicin-based regimens. In this study, bolus 5-fluorouracil was substituted with chronic oral tegafur and folinic acid in a cyclophosphamide, methotrexate, and 5-fluorouracil-based regimen to study the activity of this novel regimen in patients with advanced breast carcinoma. METHODS: This study was comprised of patients with advanced breast carcinoma and measurable or evaluable disease. Patients with prior chemotherapy were eligible. The regimen was comprised of cyclophosphamide, 600 mg/m2, and methotrexate, 40 mg/m2, both given intravenously on Day 1, and tegafur, 750 mg/m2, with folinic acid, 45 mg/day, both given orally in 3 daily fractions on Days 2-14, every 3 weeks. RESULTS: Forty-seven patients were included, 44 of whom were fully assessable. Three patients (7%) achieved a complete remission and 17 (38.6%) achieved a partial remission, for an objective response rate of 45.5% (95% confidence interval, 29-59%). The median duration of response was 11 months. In previously untreated patients the response rate was 54.5%. In patients previously treated with anthracycline or 5-fluorouracil-based regimens the response rates were 41% and 39%, respectively. Sixteen patients (36.4%) had disease stabilization. The median overall time to progression was 10 months. Toxicities usually were mild and were comprised of leukocytopenia, mucositis, emesis, and diarrhea. CONCLUSIONS: Chronic oral tegafur and folinic acid combined with intravenous cyclophosphamide and methotrexate at the dose and schedule used in the current study has significant antitumor activity both as first-line chemotherapy as well as in other patients with advanced breast carcinoma who had prior chemotherapy. This regimen is well tolerated, with gastrointestinal toxicity being the most frequent and dose-limiting toxicity.

Administration, Oral↗
PubMed1998

Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: a study of the Spanish Group for Research on Sarcomas (GEIS)

BACKGROUND: The agent Ifosfamide (IFOS) is active against soft tissue sarcomas (STS), and patients who progress to IFOS at doses < or = 10 g/m2 show remissions when exposed to high-dose ifosfamide (HDI) (i.e., doses > 10 g/m2), which supports a dose-response relationship for this drug. Because of a lack of first-line studies in adult STS patients, we decided to test the activity and toxicity of HDI in a phase II trial. PATIENTS AND METHODS: Forty-eight patients were enrolled in the study. IFOS was administered at a dose of 14 g/m2 by continuous infusion over six days every four weeks. Granulocyte-macrophage colony-stimulating factor (GM-CSF) at 5 micrograms/kg/day for 10 consecutive days was systematically administered after an episode of neutropenic fever or a delay in hematologic recovery. Patients were treated until progression or the occurrence of severe toxicity, and surgical rescue was attempted when possible. RESULTS: Six pathology-established complete remissions and 11 partial remissions were observed in 45 assessable patients with a response rate of 37.7% (95% CI: 25.5%-50%). Grade 3-4 toxicity (% of cycles) was noted by hemoglobin (17%), leukocyte (75%), granulocyte (75%) and platelet (13%) counts in 158 evaluable cycles. GM-CSF was administered to 28 patients, and 25 suffered one or more episodes of neutropenic fever. Renal toxicity was mild and reversible with some degree of tubular and glomerular dysfunction detected in up to 60% of patients. Grade 3 CNS toxicity was observed in 32% of patients but only one required interruption of therapy. Sixty-four per cent of the patients had asthenia grade 2-3 and 20% were excluded from the study due to excessive toxicity. There was one treatment-related death. CONCLUSIONS: HDI is an active drug in first-line therapy against adult STS. Different administration schedules should be evaluated in an attempt to improve its therapeutic index.

Adult↗
PubMed1998

Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

Administration, Oral↗
PubMed1997

Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma.

BACKGROUND: The carboplatin-based chemotherapeutic regimen M-CAVI (methotrexate, carboplatin, and vinblastine) is active against bladder carcinoma and can be administered to patients who are ineligible to receive cisplatin or doxorubicin. The authors designed a randomized study to evaluate whether M-CAVI offers a therapeutic advantage over the cisplatin-based regimen M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) in the treatment of patients with surgically incurable advanced bladder carcinoma. METHODS: Patients with surgically incurable advanced bladder carcinoma were enrolled on a randomized trial comparing M-CAVI, which consists of carboplatin (300 mg/m2 on Day 2, adjusted using Calvert's formula for an area under the curve of 5), methotrexate (30 mg/m2 on Days 1, 15, and 22), and vinblastine (3 mg/m2 on Days 2, 15, and 22) administered every 28 days, versus standard M-VAC. The eligibility criteria included histologically proven bladder carcinoma, surgically incurable disease, and no prior chemotherapy. Patients were treated until disease progression or unacceptable toxicity occurred. RESULTS: From January 1989 to January 1994, 47 assessable patients were included. Seventeen patients had lymph node disease and 30 had distant metastatic disease. Twenty-three patients were randomized to receive M-CAVI and 24 to receive M-VAC. Patient characteristics in the two groups were similar. Overall response rates were 39% (95% confidence interval [CI], 20-62%) for M-CAVI and 52% (95% CI, 30-73%) for M-VAC (P = 0.3), with 3 complete responses observed among patients treated with M-VAC and none among those in the M-CAVI group. M-VAC was associated with more gastrointestinal toxicity, stomatitis, alopecia, and Grade 4 neutropenia than M-CAVI. One toxicity-related death occurred in the M-VAC group. There was a statistically significant difference in median disease-related survival time favoring M-VAC (16 months; range, 6 to 22+) versus M-CAVI (9 months; range, 6 to 14+) (P = 0.03). CONCLUSIONS: M-CAVI is less toxic but less active than M-VAC in the treatment of patients with advanced bladder carcinoma. Carboplatin-based regimens in which carboplatin is administered at the dose range used in the current study should be reserved for patients who cannot tolerate cisplatin treatment. Further research is required to assess the impact of high dose carboplatin in the treatment of this disease.

Adult↗