vinflunine and Carcinoma--Transitional-Cell

This review summarises the treatment strategies of the last five decades for metastatic urothelial cancer. The introduction of combination chemotherapy in the mid-1980s led to clinically significant response rates and prolonged survival. Two years ago, the results of a phase-3 clinical trial with the PD1 inhibitor pembrolizumab for second-line treatment of metastatic urothelial carcinoma were published. These data were the first to show an overall survival benefit in comparison with a conventional chemotherapy with vinflunine, docetaxel or paclitaxel. Currently, PD1/PD-L1 inhibitors are also tested within randomized phase-3-trials for first-line treatment using different approaches either as a monotherapy or a combination with conventional chemotherapy or CTLA-4 inhibitors. Whereas data from single-arm phase-2 clinical trials have already been published, first phase-3 data are expected in 2019.. Dieser Übersichtsartikel stellt die Ergebnisse verschiedener Behandlungskonzepte für das metastasierte Urothelkarzinom in den letzten fünf Jahrzehnten zusammen. Mit der Einführung von verschiedenen Kombinations-Chemotherapien wurde ab Mitte der 80er Jahre eine signifikante Überlebensverlängerung und potenzielle Heilbarkeit auch fortgeschrittener Erkrankungsstadien in dieser Tumorentität postuliert. Vor zwei Jahren wurden Studiendaten zur Zweitlinientherapie des metastasierten Urothelkarzinoms mit dem PD1-Antikörper Pembrolizumab publiziert, die erstmals einen Vorteil im Gesamtüberleben gegenüber einer konventionellen Chemotherapie mit Paclitaxel, Docetaxel oder Vinflunin zeigen. Aktuell wird in randomisierten Phase-3-Studien der Einsatz von PD-1/PD-L1 gerichteten Substanzen auch in der Erstlinientherapie des metastasierten Urothelkarzinoms untersucht. Dabei werden verschiedene Therapiestrategien verfolgt: Monotherapien mit PD-1/PD-L1-Inhibitoren sowie deren Kombinationen mit CTLA-4-Inhibitoren oder konventioneller Chemotherapie. Es liegen bereits Daten aus einarmigen Phase-2-Studien zur Monotherapie vor. Erste Daten aus randomisierten Studien werden im Laufe des Jahres 2019 erwartet.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Transitional Cell; Clinical Trials as Topic; CTLA-4 Antigen; Docetaxel; Humans; Immunotherapy; Neoplasm Metastasis; Programmed Cell Death 1 Receptor; Randomized Controlled Trials as Topic; Survival Rate; Urinary Bladder Neoplasms; Vinblastine

We comprehensively reviewed current efforts and advances in the field of chemotherapeutic and biologically targeted treatment options after the failure of cisplatin based, first line regimens for urothelial carcinoma.. We searched MEDLINE®, Central®, and meeting abstracts of ASCO (American Society of Clinical Oncology) and ESMO (European Society for Medical Oncology) to identify original articles, reviews and retrospective analyses on second line treatment of urothelial carcinoma. Articles were included in analysis if they described prospective phase II/III studies or larger high quality retrospective studies of second line treatment of urothelial carcinoma.. Although considered a chemosensitive disease, most patients with advanced or metastatic urothelial carcinoma relapse after cisplatin based first line treatment. Today none of the commonly used drugs, ie paclitaxel, carboplatin and/or gemcitabine, are approved by the FDA (Food and Drug Administration) for second line systemic treatment. In Europe vinflunine plus best supportive care is the only option approved by the EMA (European Medicines Agency) with moderate clinical efficacy. Responses to combined chemotherapy approaches are often better but associated with remarkable toxicity. In patients who respond well to first line treatment and, thus, are considered cisplatin sensitive readministration of a platinum based combination regimen may be an option. To date targeted therapies do not have a role in second line treatment of urothelial cancer. Immunotherapeutic strategies to target the PD-1/PD-L1 axis are emerging. In a recent phase I trial evaluating the PD-L1 targeted monoclonal antibody MPDL3280A a promising 43% response rate with good tolerability was achieved, which led to an immediate breakthrough therapy designation by the FDA. Combining chemotherapy with targeted agents, eg weekly paclitaxel and pazopanib, also shows promising activity in this prognostically poor treatment situation.. Response rates and survival are poor after second line chemotherapy for advanced or metastatic urothelial carcinoma. To improve outcomes of salvage treatment novel biologically targeted drugs as monotherapy or as part of a combination with conventional cytostatics are urgently needed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Factors; Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Gemcitabine; Humans; Indazoles; Neoplasm Recurrence, Local; Paclitaxel; Pemetrexed; Pyrimidines; Salvage Therapy; Sulfonamides; Urinary Bladder Neoplasms; Vinblastine

The novel third-generation bifluorinated semisynthetic vinca alkaloid, vinflunine, is a microtubule inhibitor that shows superior antitumor activity and a favorable safety profile compared with other vinca alkaloids. The main antineoplastic effects of vinflunine arise from its interaction with tubulin, the major component of microtubules in mitotic spindles. Vinflunine is known to have low affinity for tubulin, high intracellular accumulation, and important effects on microtubule dynamics. It has been shown to have activity against transitional cell carcinoma of the urothelial tract. Vinflunine was investigated in a randomized phase III clinical trial comparing vinflunine and best supportive care versus best supportive care alone in patients with advanced transitional cell carcinoma of the urothelial tract, who were progressive after first-line platinum-containing therapy. At an acceptable safety profile without cumulative toxicity, second-line treatment with vinflunine has shown a survival advantage and has therefore been approved in 2009 for this indication. This review gives a brief outline on vinflunine as a second-line treatment for platin-resistant advanced urothelial carcinoma; it describes pharmacology, efficacy studies, tolerance, and side effects and briefly discusses future clinical perspectives.

Topics: Animals; Antineoplastic Agents; Carcinoma, Transitional Cell; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Organoplatinum Compounds; Urologic Neoplasms; Vinblastine

There is currently no curative treatment for advanced-stage or metastatic transitional cell carcinoma of the uretholial tract. Chemotherapy generally only prolongs survival by a few months. Cisplatin is often used, but there is no consensus protocol. Vinflunine, a fluorinated vinblastine derivative, has been tested in many types of cancer since the 1990s. It was finally authorised in the EU in 2009, but only for second-line treatment of urothelial carcinoma of the bladder. Clinical evaluation of vinflunine in this setting is based on a single unblinded trial in 370 patients with treatment failure. It compared vinflunine plus individually tailored palliative care versus palliative care alone. Vinflunine increased the median overall survival time by 2 months (from 4.6 months to 6.9 months), a difference that was not statistically significant in the protocol-specified primary analysis. Other analyses showed a significant difference, but the gain in survival was still only about 2 months, which is no better than with other cytotoxic drugs. Vinflunine has the same profile of adverse effects as other vinca alkaloids, including frequent, often serious and sometimes fatal haematological disorders, severe constipation, and ileus. Other adverse effects include QT prolongation and cardiac ischaemia. * In practice, vinflunine has an unfavourable risk-benefit balance in patients with bladder cancer. It is better to continue to use better-assessed treatments.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Transitional Cell; Humans; Neoplasm Metastasis; Neoplasm Staging; Survival Rate; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Vinflunine is a novel bifluorinated vinca alkaloid that appears to differ from other class members in terms of its tubulin-binding properties and inhibitory effects on microtubule dynamics. Notably, it demonstrated superior in vivo antitumour activity to that of vinorelbine in a range of transplantable murine and human tumours. In a randomized, open-label, multicentre phase III trial in adult patients with advanced transitional cell carcinoma of the urothelium who experienced progression after first-line platinum-containing chemotherapy (n = 370), median overall survival (OS; primary endpoint) was 6.9 months for intravenous vinflunine plus best supportive care (BSC) recipients versus 4.6 months for BSC alone recipients in the intent to treat (ITT) population. The difference in OS between treatment groups was not significant in the ITT population; however, there was a significant improvement in OS for vinflunine plus BSC recipients in the ITT population after adjusting for prespecified prognostic factors, and in the analysis of the eligible population (ITT population excluding baseline protocol violations). In the latter, median OS was 6.9 months with vinflunine plus BSC versus 4.3 months with BSC alone after a median follow-up of approximately 1.8 years and again after a median follow-up of approximately 3.6 years. Progression-free survival, objective response rate and disease control rate were significantly improved with vinflunine plus BSC versus BSC alone. The most frequent treatment-related adverse events in vinflunine recipients included myelosuppression (e.g. neutropenia) and gastrointestinal symptoms (e.g. constipation). In general, adverse events with vinflunine were noncumulative and medically manageable.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Transitional Cell; Drug Resistance, Neoplasm; Humans; Randomized Controlled Trials as Topic; Salvage Therapy; Urinary Bladder Neoplasms; Vinblastine

To review new developments in second-line treatment for transitional cell carcinoma of the urinary bladder focusing on advances and findings within the last year.. So far no standard therapy has been established for pretreated patients with transitional cell carcinoma. Prognostic and predictive factors for response and outcome in pretreated patients have been studied retrospectively and will help to identify those who might benefit from intensive therapy and those who would rather improve their quality of life with best supportive care. Single-agent chemotherapy in this setting provided low response rates, short progression-free and overall survival. Vinflunine, a novel vinca-alkaloid, and best supportive care had a modest, but still significant benefit at a very moderate toxicity rate in a randomized phase III trial. As for second-line combination chemotherapy, response rates as well as potential toxicities are higher and the progression-free survival and overall survival benefits are still poorly understood. New chemotherapeutics and approaches like metronomic chemotherapy and novel agents are under investigation.. With vinflunine there is reasonable hope for a new standard chemotherapy in second-line management of transitional cell carcinoma. However, due to the reported results with single agents and combination chemotherapy, treatment within clinical trials is still the best choice in patients progressing after first-line chemotherapy.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Drug Therapy, Combination; Folic Acid Antagonists; Humans; Neoplasm Recurrence, Local; Salvage Therapy; Urinary Bladder Neoplasms; Vinblastine

Vinflunine is a novel microtubule inhibitor of the vinca alkaloid class currently in development for the treatment of advanced transitional cell carcinoma of the urothelium (TCCU) and other solid tumors. This review summarizes the clinical activity of vinflunine as a single agent or in combination with other antineoplastic drugs. Vinflunine is active against a variety of tumor types, including advanced TCCU, metastatic breast cancer, advanced non-small cell lung cancer, and malignant pleural mesothelioma. It has a manageable and noncumulative toxicity profile, and its specific mechanism of action has been linked to a reduced potential for peripheral sensory neuropathy. The activity and tolerability of this agent warrant further investigation. Phase 3 trials are underway to further define the extent of clinical benefit provided by vinflunine in patients with advanced solid malignancies.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Transitional Cell; Clinical Trials as Topic; Humans; Mesothelioma; Mice; Pleural Neoplasms; Tubulin Modulators; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Vinflunine (Javlor) is the first fluorinated microtubule inhibitor belonging to the Vinca alkaloids family. Vinflunine is obtained by semisynthesis using superacidic chemistry to selectively introduce two fluorine atoms at the 20' position of the catharanthine moiety. This compound has been selected for clinical development on the basis of encouraging preclinical activity that warrants study in patients with a wide spectrum of solid tumors. Clinically significant activity has been seen in phase II studies, mainly in the treatment of transitional cell carcinoma of the urothelial tract, non-small cell lung cancer, and carcinoma of the breast. Vinflunine is currently in phase III trial assessment in patients with (second line) transitional cell carcinoma of the urothelium and first-line advanced breast cancer. The efficacy of vinflunine in patients with advanced non-small cell lung cancer previously treated with a platinum-containing regimen was confirmed by a large phase III trial.

Topics: Animals; Breast Neoplasms; Carcinoma; Carcinoma, Transitional Cell; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Models, Biological; Neoplasms; Treatment Outcome; Tubulin Modulators; Urologic Neoplasms; Urothelium; Vinblastine

Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible. We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible. A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients).. Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Docetaxel; Humans; Immune Checkpoint Inhibitors; Receptors, Fibroblast Growth Factor; Urinary Bladder Neoplasms

The open-label, randomized, active-controlled KEYNOTE-045 study (NCT02256436) showed that second-line pembrolizumab significantly improved overall survival (OS) of patients with advanced/metastatic urothelial cancer (UC) that progressed after first-line platinum-containing chemotherapy, compared with standard chemotherapy (paclitaxel, docetaxel, or vinflunine). Pembrolizumab is approved for patients with bladder cancer in Japan.. Analysis was performed in the subgroup of Japanese patients enrolled in the KEYNOTE-045 study. Coprimary end points were OS and progression-free survival (PFS). Objective response rate (ORR) and safety were secondary end points.. Fifty-two Japanese patients (pembrolizumab, n = 30; chemotherapy, n = 22) were followed up for a median of 26.1 months. Patients who received pembrolizumab compared with chemotherapy had a 19% lower risk for death (hazard ratio [HR] 0.81, 95% CI 0.44-1.50); after adjusting for baseline covariates, the HR for OS was 0.61 (95% CI 0.32-1.15). The 24-month OS rate was higher with pembrolizumab (26.9% vs 14.3%). PFS was 2.0 and 4.9 months for pembrolizumab and chemotherapy, respectively (HR 1.71, 95% CI 0.95-3.08). ORR was similar for pembrolizumab and chemotherapy (20.0% vs 18.2%); durability of response was higher with pembrolizumab: 67% and 33% of patients, respectively, maintained a response for > 12 months. Treatment-related adverse events, including grade 3-5 events, occurred less frequently with pembrolizumab.. Pembrolizumab provided durable antitumor activity in patients with locally advanced/metastatic UC that progressed after platinum-containing chemotherapy in the overall population and in the Japanese subgroup; safety profile was consistent with that previously observed for pembrolizumab.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Docetaxel; Female; Humans; Japan; Male; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Survival Rate; Treatment Outcome; Urinary Bladder Neoplasms; Urologic Neoplasms; Vinblastine

The MAJA study compared vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in advanced urothelial carcinoma responsive to first-line chemotherapy. The primary end point of progression-free survival was achieved. We present the final overall survival (OS) and long-term follow-up safety analyses.. Patients were enrolled, and a subsequent post hoc analysis was performed on the basis of radiologic response or stabilization to first-line cisplatin/gemcitabine (CG) chemotherapy (4-6 cycles), according to Response Evaluation Criteria in Solid Tumors (RECIST). VFL + BSC versus BSC alone were randomly assigned until disease progression.. At final analysis, 58 patients (66.7%) had died while 29 (33.3%) had survived; the BSC arm had higher mortality (VFL + BSC, n = 26, 59.1% vs. BSC, n = 32, 74.4%). Median follow-up of surviving patients was 38.8 months (interquartile range, 23.8-61.6). Median OS was 16.7 months (95% confidence interval, 0-34.5) in VFL and 13.2 months (95% confidence interval, 6-20.4) in the BSC groups (hazard ratio, 0.736; 95% confidence interval, 0.44-1.24, P = .182). Post hoc group division did not affect median OS in either study arm.. Final analysis supported a benefit of VFL in maintenance therapy in patients with disease control after first-line treatment with CG, with no unexpected long-term adverse effects. The study was insufficiently powered to show a significant OS advantage.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Humans; Survival Analysis; Urinary Bladder Neoplasms; Vinblastine

Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Combined Modality Therapy; Disease-Free Survival; Europe; Female; Humans; Male; Middle Aged; Organoplatinum Compounds; Pemetrexed; Urinary Bladder Neoplasms; Urologic Neoplasms; Vinblastine

Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine.. This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III.. Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms.. This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously.. NCT01830231.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Disease-Free Survival; Europe; Female; Humans; Liver Neoplasms; Male; Middle Aged; Survival Analysis; Taxoids; Time Factors; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium; Vinblastine

There is no standard first-line chemotherapy for advanced urothelial carcinoma (aUC) in cisplatin-ineligible (cisplatin-unfit) patients. The study assessed the efficacy and tolerability profile of two vinflunine-based cytotoxic regimens in this setting.. Patients with aUC a creatinine clearance (CrCl) of <60 but ≥30 ml/min, performance status 0 or 1 and no prior chemotherapy for advanced disease were randomized (1 : 1). They received vinflunine 250 or 280 mg/m(2) (based on baseline CrCl) on day 1, plus either gemcitabine [750 mg/m(2) escalated to 1000 mg/m(2) in cycle 2 if no toxicity grade (G) ≥2 on days 1 and 8 (VG) or plus carboplatin area under the curve 4.5 day 1 (VC) every 21 days]. To detect a 22% improvement in each arm compared with H0 (41%) in the primary end point, disease control rate (DCR = complete response + partial response + stable disease), 31 assessable patients per arm were required (α = 5%, β = 20%).. Sixty-nine patients were enrolled (34 VG, 35 VC). Less G3/4 haematological adverse events (AEs) were reported with VG: neutropaenia was seen in 38% (versus 68% with VC) and febrile neutropaenia in 3% (versus 14% with VC) of patients. No major differences were observed for non-haematological AEs. DCR was 77% in both groups; overall response rate (ORR) was 44.1% versus 28.6%, with a median progression-free survival of 5.9 versus 6.1 months and median OS of 14.0 versus 12.8 months with VG and VC, respectively.. Both vinflunine-based doublets offer a similar DCR, ORR and OS. The better haematological tolerance favours the VG combination, which warrants further study. CLINICALTRIALS.GOV PROTOCOL IDENTIFIER: NCT 01599013.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Disease-Free Survival; Female; Gemcitabine; Humans; Male; Middle Aged; Treatment Outcome; Urinary Bladder Neoplasms; Vinblastine

The role of pazopanib in the second-line setting of refractory metastatic transitional cell carcinoma of the urothelium has not been defined clearly. The aim of this phase I/II trial was to assess the safety, tolerability, and efficacy of combining pazopanib and vinflunine in patients with metastatic transitional cell carcinoma of the urothelium after failure of first-line platinum-containing therapy. From May 2011 to December 2011, five patients were enrolled in this trial. Pazopanib was the investigated compound; four levels were planned (200, 400, 600, and 800 mg/day). Vinflunine was dosed at 280 mg/m for the first dose and 320 mg/m every 3 weeks thereafter. After the definition of a tolerated dose for the combined therapy, a subsequent phase II study was planned. At the starting level, pazopanib 200 mg/day, dose-limiting toxicities were observed in two of five patients. One patient experienced grade 4 febrile neutropenia, which led to treatment discontinuation. A second patient showed grade 3 hepatobiliary disorder with an increase in γ-glutamyltransferase. The study was interrupted at dose level 1 for safety reasons. The initially planned phase II study was therefore not carried out. This phase I study showed that combined therapy of daily pazopanib (200 mg) and vinflunine (280/320 mg/m) every 3 weeks is poorly tolerated in patients with refractory advanced urothelial cancer.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cardiovascular Diseases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Early Termination of Clinical Trials; Humans; Indazoles; Male; Neutropenia; Organoplatinum Compounds; Palliative Care; Prospective Studies; Pyrimidines; Salvage Therapy; Sulfonamides; Thrombocytopenia; Urologic Neoplasms; Vinblastine

To compare long-term, updated overall survival (OS) of patients with advanced transitional cell carcinoma of the urothelium (TCCU) treated with vinflunine plus best supportive care (BSC) or BSC alone, after failure of platinum-based chemotherapy.. Three hundred and seventy patients were randomly assigned in a phase III trial and allocated (2:1) to vinflunine (320 or 280 mg/m(2)) plus BSC or BSC alone. The first report (Bellmunt J, Theodore C, Demkov T et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009; 27(27): 4454-4461) had a median follow-up of 22.1 m and the current report has a follow-up of 45.4 m.. Three hundred and fifty-two patients had died (censoring rate 5%). In the intention-to-treat (ITT) population, the median OS was 6.9 m and 4.6 m for vinflunine plus BSC versus BSC alone, respectively (n.s.). In multivariate Cox analysis, the addition of vinflunine was independently correlated with improved survival (HR: 0.719; 95% CI:0.570-0.906, P = 0.0052). In the eligible population, the median OS in both the arms was 6.9 and 4.3 m, respectively (HR: 0.78; 95% CI:0.61-0.96; P = 0.0227), indicating an estimated 22% reduction in the risk of death.. The updated OS data confirm the positive treatment effect of vinflunine on survival that was previously reported. These results are consistent over time and confirm that vinflunine is a valuable option for second-line treatment in patients with advanced TCCU after failure of platinum-based regimens.

Topics: Aged; Carcinoma, Transitional Cell; Cisplatin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Platinum Compounds; Prospective Studies; Survival Rate; Time Factors; Treatment Failure; Urinary Bladder Neoplasms; Urothelium; Vinblastine

A phase III trial demonstrated an overall survival advantage with the addition of vinflunine to best supportive care (BSC) in platinum-refractory advanced urothelial cancer. We subsequently examined the impact of an additional 2 years of survival follow-up and evaluated the influence of first-line platinum therapy on survival.. The 357 eligible patients from the phase III study were categorised into two cohorts depending on prior cisplatin treatment: cisplatin or non-cisplatin. Survival was calculated using the Kaplan-Meier method.. The majority had received prior cisplatin (70.3%). Survival was higher in the cisplatin group (HR: 0.76; CI 95% 0.58-0.99; P=0.04) irrespective of treatment arm. Multivariate analysis including known prognostic factors (liver involvement, haemoglobin, performance status) and prior platinum administration did not show an independent effect of cisplatin. Vinflunine reduced the risk of death by 24% in the cisplatin-group (HR: 0.76; CI 95% 0.58-0.99; P=0.04) and by 35% in non-cisplatin patients (HR: 0.65; CI 95% 0.41-1.04; P=0.07).. Differences in prognostic factors between patients who can receive prior cisplatin and those who cannot may explain the survival differences in patients who undergo second line therapy. Prior cisplatin administration did not diminish the subsequent benefit of vinflunine over BSC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cisplatin; Cohort Studies; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Vinflunine (VFL) has been approved in the European Union for second-line treatment of advanced transitional cell carcinoma of the urothelial tract (TCCU) in patients who progress after a platinum based regimen. However, very few patients achieve response by response evaluation criteria in solid tumours (RECIST). Therefore, another 'response' threshold may be more useful than RECIST 1.0 in this setting.. One hundred and seventy nine patients with advanced TCCU treated with second-line VFL therapy had chest Computed Tomography (CT) and abdominal/pelvic CT or MRI performed at baseline and at first follow-up (6 weeks ± 3 days) after therapy initiation. Tumour measurements and response by RECIST 1.0 were correlated with overall survival (OS). Kaplan-Meier and receiver operating characteristic (ROC) analysis were then used to determine the optimal size threshold to define 'responders'. Impact of adverse prognostic factors including Eastern Cooperative Oncology Group Performance Status (ECOG PS) >0, Hb <10 g/dL, and liver metastases was analysed.. Tumour response included 13 partial responses (PR) by RECIST 1.0 and 52 patients with ≥ 10% decrease in the sum of longest diameters. Responders by RECIST 1.0 did not have a statistically significant improvement in OS, while patients with sum long axis diameter (SLD) reduction of ≥ 10% had a longer OS than those with SLD reduction of <10%: 11.3 versus 6.9 months (log rank p=0.0224). ROC analysis yielded ≥ 10% decrease in SLD as the optimal size change correlating with OS. These results persisted on multivariate analysis.. In the study population, a ≥ 10% reduction in SLD at first follow-up imaging is a better early predictor of outcome than RECIST.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Transitional Cell; Diagnostic Imaging; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Image Processing, Computer-Assisted; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Metastasis; Prognosis; ROC Curve; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Disease Progression; Female; Gemcitabine; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Urinary Bladder Neoplasms; Vinblastine

The activity and safety of vinflunine was evaluated in patients with locally advanced or metastatic urothelial carcinoma (UC) who developed disease progression within 12 months of platinum-containing chemotherapy.. Patients with UC were eligible if they received a prior platinum-based regimen in the neoadjuvant/adjuvant setting or as first-line treatment for advanced/metastatic disease and had developed disease progression within 12 months. Vinflunine was administered intravenously every 3 weeks. Patients with Karnofsky performance status of 80 or 90, impaired renal function, prior pelvic irradiation, or age>or=75 years received an initial dose of 280 mg/m2, which was escalated to 320 mg/m2 in Cycle 2 if well tolerated. All other patients received an initial dose of 320 mg/m2. The primary endpoint was response rate defined by an independent response review committee (IRRC).. Per the IRRC, 22 patients achieved a partial response, with a response rate of 15% (95% confidence interval, 9%-21%) with a median duration of response of 6.0 months. Sixty-four (42%) patients had stable disease. The median progression-free survival was 2.8 months, and the median overall survival was 8.2 months. Myelosuppression was the most frequent adverse event, with grade 3 of 4 (adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria [version 2.0] guidelines) neutropenia reported in 58% of the patients. Grade 3 of 4 febrile neutropenia occurred in 10 (7%) patients. Nonhematologic treatment-related events (grade 3 of 4) were generally manageable and included constipation (17%), asthenia/fatigue (13%), ileus (5%), and abdominal pain (5%). No cumulative toxicity was observed.. Vinflunine demonstrates moderate activity in patients with platinum-pretreated UC. Toxicity is manageable and noncumulative.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Platinum Compounds; Retreatment; Urinary Bladder Neoplasms; Vinblastine

Vinflunine (VFL) is a new microtubule inhibitor that has activity against transitional cell carcinoma of urothelial tract (TCCU). We conducted a randomized phase III study of VFL and best supportive care (BSC) versus BSC alone in the treatment of patients with advanced TCCU who had experienced progression after a first-line platinum-containing regimen.. The study was designed to compare overall survival (OS) between patients receiving VFL + BSC (performance status [PS] = 0: 320 mg/m(2), every 3 weeks; PS = 0 with previous pelvic radiation and PS = 1: 280 mg/m(2) subsequently escalated to 320 mg/m(2)) or BSC.. Three hundred seventy patients were randomly assigned (VFL + BSC, n =253; BSC, n = 117). Both arms were well balanced except there were more patients with PS more than 1 (10% difference) in the BSC arm. Main grade 3 or 4 toxicities for VFL + BSC were neutropenia (50%), febrile neutropenia (6%), anemia (19%), fatigue (19%), and constipation (16%). In the intent-to-treat population, the objective of a median 2-month survival advantage (6.9 months for VFL + BSC v 4.6 months for BSC) was achieved (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12) but was not statistically significant (P = .287). Multivariate Cox analysis adjusting for prognostic factors showed statistically significant effect of VFL on OS (P = .036), reducing the death risk by 23% (HR = 0.77; 95% CI, 0.61 to 0.98). In the eligible population (n = 357), the median OS was significantly longer for VFL + BSC than BSC (6.9 v 4.3 months, respectively), with the difference being statistically significant (P = .040). Overall response rate, disease control, and progression-free survival were all statistically significant favoring VFL + BSC (P = .006, P = .002, and P = .001, respectively).. VFL demonstrates a survival advantage in second-line treatment for advanced TCCU. Consistency of results exists with significant and meaningful benefit over all efficacy parameters. Safety profile is acceptable, and therefore, VFL seems to be a reasonable option for TCCU progressing after first-line platinum-based therapy.

Topics: Aged; Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Humans; Middle Aged; Palliative Care; Platinum Compounds; Survival Analysis; Urologic Neoplasms; Urothelium; Vinblastine

A multicentre phase II trial to determine the efficacy of vinflunine as second-line therapy in patients with advanced transitional cell carcinoma (TCC) of the bladder; secondary objectives were to assess duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients had tumours that failed or progressed after first-line platinum-containing regimens for advanced or metastatic disease, or had progressive disease after platinum-containing chemotherapy given with adjuvant or neoadjuvant intent. Response and adverse events were assessed according to WHO criteria and NCI-CTC (version 2), respectively. Out of 51 patients treated with 320 mg m(-2) of vinflunine, nine patients responded to the therapy yielding an overall response rate of 18% (95% CI: 8.4-30.9%), and 67% (95%CI: 52.1-79.3%) achieved disease control (PR+SD). Of note, responses were seen in patients with relatively poor prognostic factors such as a short (<12 months) interval from prior platinum therapy (19%, including an 11% response rate in those progressing <3 months after platinum treatment), prior treatment for metastatic disease (24%), prior treatment with vinca alkaloids (14%) and visceral involvement (20%). The median duration of response was 9.1 months (95% CI: 4.2-15.0) and the median PFS was 3.0 months (95% CI: 2.4-3.8). The median OS was 6.6 months (95% CI: 4.8-7.6). The main haematological toxicity was grade 3-4 neutropenia, observed in 67% of patients (42% of cycles). Febrile neutropenia was observed in five patients (10%) and among them two were fatal. Constipation was frequently observed (but was manageable and noncumulative) and was grade 3-4 in only 8% of patients. The incidence of grade 3 nausea and vomiting was very low (4 and 6% of patients, respectively). Neither grade 3-4 sensory neuropathy nor severe venous irritation was observed. Moreover, and of importance in this particular study population, no grade 3-4 renal function impairment was observed. Vinflunine is an active agent for the treatment of platinum-pretreated bladder cancer, and these results warrant further investigation in phase III trials, either as monotherapy or in combination with other agents as treatment of advanced/metastatic TCC of the bladder.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Carcinoma, Transitional Cell; Female; Humans; Male; Middle Aged; Organoplatinum Compounds; Urinary Bladder Neoplasms; Vinblastine

Topics: Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Gemcitabine; Humans; Urologic Neoplasms; Vinblastine

The treatment of metastatic urothelial cancer (mUC) following first-line standard platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) is not yet established.. We investigated the activity and toxicity of vinflunine at the dose, due to previous treatments, of 280 mg i.v. every 21 days until disease progression or limiting toxicity, with instrumental disease reassessment every 3 cycles, in 6 patients aged ≥18 years, with metastatic urothelial carcinoma of the upper or lower urinary tract, with performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) of 0-2, adequate hematologic function and progressive disease (PD) following first-line platinum-based chemotherapy and second-line ICI.. The median age of the 6 patients was 67.5 years (range 63-77) and median PS 1 (range, 0-2). Four patients (67%) had a disease partial response (PR). With a median follow-up of 4.5 months (range, 3-9), 3 patients are alive (50%). The median progression-free survival following vinflunine (PFS-3) was 4 months (range, 1-8), as compared to the PFS-2 (following ICI) of 4 months (range, 2-9) and the PFS-1 (after platinum-based chemotherapy) of 6 months (range, 2-13). The PRs were not associated with the length of PFS-2 of PFS-1, the histologic subtype, primary and metastatic site of the tumour. No grade 3-4 toxicity has been observed; grade 2 asthenia occurred in 3 patients (50%), grade 1 nausea and constipation were observed in one patient (17%), respectively.. Despite the low number of patients treated, the activity of vinflunine was substantial and suggests its role as chemotherapy line following previous chemotherapy and immunotherapy, deserving further retrospective or prospective investigations in this setting.

Topics: Aged; Antineoplastic Agents; Carcinoma, Transitional Cell; Disease-Free Survival; Follow-Up Studies; Humans; Middle Aged; Urologic Neoplasms; Vinblastine

Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy.. This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease.. The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy.. The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Transitional Cell; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nausea; Pilot Projects; Platinum Compounds; Prospective Studies; Treatment Outcome; Urologic Neoplasms; Urothelium; Vinblastine

Vinflunine is a microtubule inhibitor approved in Europe as second-line treatment of advanced transitional cell cancer of the urothelium (TCCU). The inability to continue with a first-line platinum-based regimen beyond 6 cycles suggested investigating the use of vinflunine as switch maintenance therapy in patients with response or stable disease after first-line therapy.. Patients with advanced TCCU and documented disease control after 3-6 cycles of first-line platinum-based chemotherapy received vinflunine maintenance therapy within 6 weeks of the last cycle. Our analysis aimed to examine the performance of vinflunine in terms of activity and safety in such a patient population.. 28 consecutive patients were studied. After a median follow-up of 25 months, vinflunine was associated with a median progression-free survival of 9 months (range 4 to > 16 months) and a disease control rate of 64%; median overall survival was not reached. Treatment was well tolerated, with no unexpected safety events. The most common adverse events of grade ≥ 3 were neutropenia (21%) and constipation (14%); no toxicity-related death occurred.. Our results suggest that vinflunine may be a suitable maintenance treatment option for TCCU patients who received a maximum of 6 cycles of platinum-based chemotherapy commonly used as first-line treatment.

Topics: Adult; Aged; Carcinoma, Transitional Cell; Female; Humans; Male; Middle Aged; Urinary Bladder Neoplasms; Vinblastine

The clinical case concerns a 72-years-old woman diagnosed with an urothelial carcinoma of the renal pelvis with hepatic and lymph node metastases. The disease was rapidly progressing to a first line of platinum-based chemotherapy and to a second line with immunotherapy; a clinical and instrumental benefit was then observed with vinflunine used as third line regimen.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Disease Progression; Female; Humans; Immunotherapy; Kidney Pelvis; Liver Neoplasms; Lymphatic Metastasis; Treatment Outcome; Urinary Bladder Neoplasms; Vinblastine

Despite an expected prognostic disadvantage for upper tract versus lower tract metastatic urothelial carcinomas (UTUC/LTUC), only few studies have been conducted to elucidate potential differences in chemotherapy treatment.. A post-hoc subgroup analysis of a non-interventional study investigating vinflunine after failure of a platinum-based chemotherapy in metastatic/locally advanced UC patients was performed.. A total of 18 and 59 out of 77 patients had UTUC and LTUC, respectively. The effectiveness of vinflunine treatment was comparable with an overall response rate of 22.2% and 23.7% respectively and a median progression-free survival of 2.76 months in both groups. Median overall survival was 5.0 months in UTUC compared to 8.2 months in the LTUC group (p=0.478). The safety profile was in accordance with previous vinflunine experiences, with a comparable frequency of adverse events in both groups.. Vinflunine can be applied in the 2nd line for UC regardless of the primary tumor localization.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Carcinoma, Transitional Cell; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prospective Studies; Survival Analysis; Treatment Outcome; Urologic Neoplasms; Vinblastine

There is no standard of care in the UK or Ireland for second-line chemotherapy for patients with advanced transitional cell carcinoma (TCCU). Vinflunine is approved for TCCU patients who have failed a platinum-based regimen, and is standard of care in Europe but is not routinely available in the UK. Data were collected retrospectively on patients who received vinfluine as a second-line treatment. The aims were to document the toxicity and efficacy in a real life setting. Data were collected on 49 patients from 9 sites across the UK and Ireland [median age, 64 (IQR, 57-70) years, 33 males]. All patients had advanced metastatic TCCU. Thirteen patients had bone or liver metastases, 4 patients had PS 2 and 11 patients had HB <10. Median vinflunine administration was 3.5 cycles (range 1-18). Most common grade 3-4 toxicities were constipation (4 patients) and fatigue (3 patients). Partial response rate was 29% (14 PR, 11 SD, 19 PD, 4 NE, 1 not available). Median OS was 9.1 (6.0, 12.7) months. Results are consistent with real life data from Europe. Toxicity is further reduced with prophylactic laxative and oral antibiotics. Vinflunine is an efficient and tolerable second line treatment in advanced TCCU.

Topics: Aged; Antineoplastic Agents, Phytogenic; Bone Neoplasms; Carcinoma, Transitional Cell; Disease-Free Survival; Female; Humans; Ireland; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Treatment Outcome; United Kingdom; Urinary Bladder Neoplasms; Urothelium; Vinblastine

A prognostic model for patients with metastatic urothelial carcinoma (UC) progressing after platinum-based therapy was constructed from data from the phase III vinflunine trial. However, prognostic information for patients treated with other regimens is limited.. We pooled individual patient data from 7 second-line studies and analyzed the influence of factors of interest on overall survival (OS) through univariate and multivariate analysis. A prognostic model was constructed, and data from an independent series were used for validation.. The data from 193 patients were pooled. The second-line chemotherapy regimen was single-agent taxane in 54 patients (28%), a platinum-based combination in 47 (24%), and a non-platinum combination in 92 (48%). On multivariate analysis, Eastern Cooperative Oncology Group performance status ≥ 1, hemoglobin < 10 g/dL, and metastatic patterns other than lymph node-only metastasis emerged as independent adverse prognostic factors. Patients with all 3 factors (poor risk), 1 to 2 factors (intermediate risk), and no factors (good risk) had a median OS of 3.1, 8.7, and 16.5 months, respectively (P < .0001). The corresponding median OS for the validation series (n = 44) was 3.3, 8.1, and 13.3 months (P = .023). Furthermore, platinum-based regimens were independently associated with an OS benefit compared with other regimens (hazard ratio, 0.31; 95% confidence interval, 0.18-0.53; P < .0001).. We have proposed and validated a prognostic model for patients with metastatic UC who were eligible for second-line therapy. The proposed model could prove helpful for risk stratification. Furthermore, our data suggest that testing second-line platinum-based regimens in randomized trials is warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Prognosis; Proportional Hazards Models; Retrospective Studies; Treatment Outcome; Urinary Bladder Neoplasms; Vinblastine

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Gemcitabine; Humans; Treatment Outcome; Vinblastine

The aim of this study was to evaluate the effectiveness and toxicity profile of the vinflunine chemotherapy regimen and to examine the cost-effectiveness relation in a real-world sample of patients with transitional cell carcinoma of the bladder. This is a multicenter, observational, retrospective cohort study. To assess the effectiveness and safety of vinflunine treatment, progression-free survival, overall survival, and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios were calculated. A total of 37 patients were included in the study, with a mean age of 67 (SD=9) years. The median progression-free survival was 2.61 months (95% confidence interval 1.79-4.23) and the median overall survival was 5.72 months (95% confidence interval 3.34-10.35). An objective response was achieved in eight (22%) patients. Statistically significant differences were found between patients treated with vinflunine as a second-line therapy and those treated with vinflunine as a third-line therapy (P=0.036). The most commonly reported analytical adverse event was anemia (n=34; 92%), and the most severe was neutropenia (n=19; 51%), with nine patients developing grade 4 neutropenia (9/19; 47%). The total cost of vinflunine treatment was &OV0556;553 873, with a median of &OV0556;8524 (interquartile range, &OV0556;9220) per patient. The median-based cost-effectiveness ratio was &OV0556;44 789 (&OV0556;31 706-58 022) per progression-free year gained and &OV0556;22 750 (&OV0556;14 526-34 085) per life-year gained. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness and might help achieve an optimal quality healthcare system.

Topics: Aged; Antineoplastic Agents; Carcinoma, Transitional Cell; Cost-Benefit Analysis; Female; Hospital Bed Capacity, 500 and over; Humans; Male; Middle Aged; Retrospective Studies; Spain; Survival Analysis; Urinary Bladder Neoplasms; Vinblastine

Vinflunine is the only drug tested in a phase III trial and, to date, approved for advanced or metastatic bladder cancer after failure of a prior platinum-containing regimen. We report a case of a man with metastatic bladder cancer treated with vinflunine after failure of an adjuvant chemotherapy with carboplatin and gemcitabine.

Topics: Aged; Antineoplastic Agents, Phytogenic; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cystectomy; Disease Progression; Humans; Male; Neoplasm Invasiveness; Urinary Bladder Neoplasms; Vinblastine

Patients with transitional cell carcinoma of the urothelial tract (TCCU) who fail initial platinum-based chemotherapy for advanced disease represent a challenge in daily clinical practice. Vinflunine is approved by the European Medicine Agency (EMA) but, up to now, limited experience has been reported outside clinical trials.. We assessed the efficacy and safety of vinflunine in an unselected group of 102 consecutive patients with metastatic TCCU.. The median age was 67 years (range 45-83). Among the most common comorbidities that patients presented at baseline were hypertension (50.5%) and diabetes (20.7%).Distant metastases were present in retroperitoneal nodes (58%), lung (29.3%), and bone (20.2%). The ECOG 0, 1 and 2 performance status at the start of vinflunine were 31.3%, 60.6% and 8.1%, respectively. The most commonly reported adverse events of any grade were constipation 70.6% (5.9% grade 3-4), vomiting 49.1% (2% grade 3-4), neutropenia 48.1% (12.8% grade 3-4) and abdominal pain 34.3% (4.9% grade 3-4). A median of 4 cycles of vinflunine was administered per patient (range 1-18). Median progression free and overall survival for all patients (N = 102) were 3.9 months (2.3-5.5) and 10 months (7.3-12.8), respectively. Time to tumor progression was 4.3 months (2.6-5.9). Two patients (2%) achieved CR, 23 (22.5%) patients had PR, and 42 (41.2%) presented SD as best response. The clinical benefit rate with vinflunine was 65.7%.. Our results show that the behavior of vinflunine in routine clinical practice resembles that of the pivotal phase III randomized study.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Retreatment; Survival Analysis; Treatment Failure; Treatment Outcome; Urinary Bladder Neoplasms; Vinblastine

Based on the results of phase III trial, vinflunine was approved by European Medicines Agency in 2010 as second line treatment of advanced urothelial cancer in patients with good performance status (ECOG 0- 1). The objective of this prospective observational study was to assess vinflunine treatment of advanced urothelial cancer patients in terms of progression free survival and overall survival, and to evaluate vinflunine toxicity.. From April 2011 to June 2014 a total of 16 patients (100%) with advanced urothelial cancer were treated with vinflunine. The median age was 62 years (range 43- 80) and the median Karnofsky index was 90% (range 80- 100%). Thirteen patients (81.25%) had urothelial bladder cancers, two patients (12.50%) suffered from urothelial cancers of ureter, and one patient (6.25%) had urothelial cancer of unknown origin (histology was obtained from liver metastasis). Histologically, all the lesions were grade 3 tumors (100%). The number of metastatic sites ranged from 1- 4 (median 3).. The effect of treatment was evaluated in accord with RECIST: two patients (12.50%) obtained partial remission, three (18.75%) stabilization, eight patients (50.00%) progressed, and treatment was suspended in one case at patients request. Vinflunine toxicity grade 3- 4 included neutropenia in six patients (37.50%), leukopenia in four patients (25.00%), anemia in one patient (6.25%), constipation in three patients (18.75%), and febrile neutropenia in one patient (6.25%). Median overall survival was 5.2 months (95% CI 3.4- 8.8) and median progression-free survival was 2.3 months (95% CI 2.1- 3.2).. This study summarizes the first Slovak experience with vinflunine therapy. Our data confirmed the efficacy of vinflunine and its acceptable toxicity in the treatment of patients with advanced urothelial cancer previously treated with a platinum-based regimen.Key words: advanced urothelial cancer -  vinflunine -  progression-free survival -  overall survival -  side effects.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Female; Gemcitabine; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasms, Unknown Primary; Prognosis; Slovakia; Survival Analysis; Treatment Outcome; Ureteral Neoplasms; Urinary Bladder Neoplasms; Urologic Neoplasms; Vinblastine

Topics: Aged; Carcinoma, Transitional Cell; Female; Humans; Posterior Leukoencephalopathy Syndrome; Urinary Bladder Neoplasms; Vinblastine

In the past few years, innumerable novel anti-cancer agents have been developed. Some of them have successfully entered into clinical practice while some of them have failed for different reasons. Although, nowadays, cancer treatment still relies heavily on conventional chemotherapy and surgery, with increasing evidence of novel biologic agents which demonstrate its higher anti-cancer activity and fewer side effects, more and more efforts have been spent on development of different types of novel agents. Vinflunine, a novel fluorinated vinca alkaloid, carries mitotic-arresting and tubulin-interacting properties and was just approved for treating transitional cell carcinoma of the urothelial tract (TCCU) in Europe. It, however, took quite a long time to get an approval. Needless to say, TCCU, similar to other types of cancer, is a very complex and heterogeneous disease and therefore, a single drug can hardly eradicate a cancer. Translational research, a new scientific research method, creates a link between clinical and laboratory studies. The link helps us to investigate the change in tumor environment in response to treatment, select patients who are more responsive to a particular treatment and predict prognosis of a group of patients with similar tumor characteristics. It can not only improve the success of a treatment, but also maximize the potential of novel anti-cancer agents.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Drug Design; Humans; Neoplasms; Patient Selection; Translational Research, Biomedical; Urologic Neoplasms; Urothelium; Vinblastine

Relapse after initial first-line chemotherapy shows a poor prognosis in metastatic urothelial cancer. Currently, several chemotherapeutic agents and targeted drugs are under evaluation for platin-resistant advanced urothelial carcinoma. Vinflunine has been approved for second-line treatment in this indication. We present a patient with initial T4 advanced and subsequently metastasized bladder cancer, who has shown prolonged survival of 44 months after radical cystectomy. During her clinical course, the patient received two different platinum-containing therapies, temsirolimus within a phase II protocol and subsequent vinflunine chemotherapy. Treatment duration was 15 weeks with temsirolimus and 9 weeks with vinflunine, respectively, with a stable disease period of 3.8 months under temsirolimus therapy. This case is an example of how patients can derive a survival benefit from adequate sequencing of surgery and medical treatment including the newest therapies, even in advanced disease.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Female; Humans; Middle Aged; Sirolimus; Time Factors; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms; Vinblastine

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Drug Approval; Evidence-Based Medicine; Humans; Platinum Compounds; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Treatment Outcome; Urologic Neoplasms; Vinblastine