vinflunine and Urinary-Bladder-Neoplasms

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

The use of systemic immunotherapy targets is emerging as an important treatment option for metastatic urothelial carcinoma, particularly for patients who cannot tolerate or who fail cisplatin-based chemotherapy. One such target is the inhibition of the checkpoint protein programmed cell death-1 (PD-1) receptor and its ligand (PD-L1) by monoclonal antibodies.. To assess the effects of pembrolizumab monotherapy versus chemotherapy for treatment of advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy.. We performed a Cochrane Rapid Review, limiting our search to published studies in the English language. We searched databases of the medical literature, including the Cochrane Central Register of Controlled Trials and MEDLINE, as well as trial registries including ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). Our search extended from January 2000 to June 2018.. We included randomised controlled trials except cross-over trials and cluster randomised trials. We excluded all other study designs. Participants included had locally advanced or metastatic urothelial carcinoma of the bladder, with disease progression during or following platinum-containing chemotherapy (synonymous with second-/third-/fourth-line therapy). This review focused on pembrolizumab (synonyms: MK-3475, lambrolizumab, Keytruda).. Two review authors independently classified and abstracted data from the included study. The certainty of evidence was rated according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.. We identified one randomised controlled trial that included 542 participants, which compared the use of pembrolizumab monotherapy versus chemotherapy for the treatment of advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy. Results were reported after a median follow-up of 14.1 months (range 9.9 to 22.1 months).Primary outcomesPembrolizumab probably reduces the risk of death from any cause (hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59 to 0.90; moderate certainty evidence). This corresponds to 115 fewer deaths (191 fewer to 38 fewer) per 1000 participants with pembrolizumab at 12 months. We downgraded the certainty of evidence one level for imprecision.Pembrolizumab may slightly improve quality of life (change from baseline to week 15 assessed with the Core Quality of Life Questionnaire; higher value reflects better quality of life; scale 0 to 100) with a mean difference (MD) of 9.05, 95% CI 4.61 to 13.50; low certainty evidence). We downgraded the certainty of evidence two levels for study limitations and imprecision.Secondary outcomesPembrolizumab may have little or no effect on disease progression (HR 0.98, 95% CI 0.81 to 1.19; low certainty evidence). This corresponds to three fewer patients (42 fewer to 24 more) whose disease progressed per 1000 participants at 12 months. We downgraded the certainty of evidence two levels for study limitations and imprecision.Pembrolizumab probably improves treatment response (based on complete or partial radiologic response) with a risk ratio (RR) of 1.85, 95% CI 1.24 to 2.77; moderate certainty evidence). This corresponds to 97 more respondents (27 more to 202 more) per 1000 participants with pembrolizumab. We downgraded the certainty of evidence one level for imprecision.Pembrolizumab may have little or no effect on treatment-related mortality (RR 0.96, 95% CI 0.24 to 3.79; low certainty evidence). This corresponds to one fewer (12 fewer to 44 more) treatment-related deaths per 1000 participants with pembrolizumab. We downgraded the certainty of evidence two levels for study limitations and imprecision.Pembrolizumab may have little or no effect on discontinuations due to adverse events (RR 0.66, 95% CI 0.39 to 1.10). This corresponds to 54 fewer discontinuations per 1000 participants (95% CI 79 fewer to 7 more). We downgraded the certainty of evidence for study limitations and imprecision.Pembrolizumab may reduce serious adverse events (RR 0.83, 9. The use of pembrolizumab in men with advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy probably improves overall survival when compared with chemotherapy alone. At 12 months follow-up about 70% of those in the chemotherapy group had died, compared with 59% of those treated with pembrolizumab. We are very uncertain about the effects of pembolizumab on quality of life. Pembolizumab may also improve treatment response rates, and reduce the risk of serious adverse events, but may make little or no difference to discontinuations of treatment due to adverse events. These conclusions are based on a single trial that was sponsored by the producer of pembrolizumab.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Disease Progression; Docetaxel; Humans; Paclitaxel; Quality of Life; Taxoids; 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

To describe drugs used in bladder carcinoma.. Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies web sites (HAS and ANSM).. The drugs used in the treatment of bladder cancer are represented by the products referred to diagnosis (hexyl aminolevulinate), the intravesical instillations for the treatment of tumors not infiltrating the muscle and the infiltrating tumor chemotherapy (neo-adjuvant treatment or metastatic tumors). The hexyl aminolevulinate cystoscopy allows to identify a significantly greater number of lesions, including carcinoma in situ, compared to conventional white light cystoscopy. For intravesical instillations, BCG has a superior efficacy to mitomycin C with a lower tolerance. The chemotherapies for invasive tumors are effective in metastatic disease in 15-20% of cases with a mean survival of 12 to 14 months.. Except the use of hexyl aminolevulinate for improving the diagnosis, there was no emergence in recent years of new drugs for the treatment of bladder cancer. Targeted therapies currently available for many neoplasms were ineffective for bladder cancer.

Topics: Aminolevulinic Acid; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Carcinoma; Cisplatin; Cystoscopy; Deoxycytidine; Doxorubicin; Fluorescence; Gemcitabine; Humans; Methotrexate; Mitomycin; Photosensitizing Agents; Urinary Bladder Neoplasms; Vinblastine

The perioperative use of chemotherapy regimens in urinary bladder carcinoma is still under debate. Evidence from clinical trials has not changed over the last decade and therefore current guidelines lack high grade recommendations for the use of perioperative chemotherapy, especially with regard to adjuvant chemotherapy. Neoadjuvant chemotherapy is capable of downsizing locally advanced tumors which leads to better operability. However, the quality of the surgical procedure has a major impact on the risk of recurrence and prognosis of patients and may therefore negatively influence the results of perioperative chemotherapy trials. A number of retrospective studies analyzing the outcome of patients after radical cystectomy have demonstrated that especially patients with node positive bladder carcinoma may benefit from adjuvant chemotherapy. Gemcitabine plus cisplatin still represents the gold standard in the treatment of metastastic bladder carcinoma. Vinflunin has become the standard therapy in second-line treatment and should represent the comparator for further clinical trials in this setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cystectomy; Deoxycytidine; Gemcitabine; Guideline Adherence; Humans; Lymphatic Metastasis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Retrospective Studies; Urinary Bladder Neoplasms; Vinblastine

Accounting for 14,000 deaths in the USA last year, research informs us that advanced bladder cancer is a lethal disease with a median survival that has remained a little over 1 year for the past two decades. For the majority of patients with metastatic disease, chemotherapy with cisplatin-based combinations is the standard first-line treatment. Although initial response rates are high, disease progression is common, creating a growing number of patients in need of effective second-line chemotherapy. For this population, no standard of care currently exists. Salvage chemotherapy is associated with low response rates and studies exploring potential clinical benefit over supportive care alone are limited to nonrandomized Phase II trials. Vinflunine, a novel anti-mitotic drug from the Vinca alkaloid class, is the first and only agent that has been compared with supportive care in the second-line setting. In Europe, vinflunine is approved as a treatment option for patients with advanced urothelial cancer who have failed a prior platinum-containing regimen. To date, in the USA, there is no FDA-approved second-line chemotherapy for patients with metastatic bladder cancer and treatment continues to emphasize patient enrollment into a clinical trial.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Urinary Bladder Neoplasms; Vinblastine

Vinflunine is a novel third-generation bifluorinated semisynthetic vinca alkaloid that has been shown to have activity against a variety of solid tumor types including advanced transitional cell carcinoma of the urothelium. In contrast to other vinca alkaloids, vinflunine shows superior antitumor activity and an excellent safety profile. Vinflunine interacts with tubulin and has a lower affinity to tubulin; it has a high intracellular accumulation rate and therefore significant effects on microtubule dynamics. A large, phase III trial comparing vinflunine with best supportive care versus best supportive care alone showed an improvement in overall survival in the vinflunine arm in preplanned secondary analyses. In addition, the drug has shown a moderate adverse event profile in the phase II and III trials. In September 2009, vinflunine was approved as a second-line treatment for patients with urothelial carcinoma resistant to first-line platinum-containing chemotherapy by the European Medicines Agency.

Topics: Antineoplastic Agents, Phytogenic; Humans; Prognosis; Urinary Bladder Neoplasms; Vinblastine

New data regarding treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC.. To review the new EAU guidelines for MiM-BC with a specific focus on treatment.. New literature published since the last update of the EAU guidelines in 2008 was obtained from Medline, the Cochrane Database of Systematic Reviews, and reference lists in publications and review articles and comprehensively screened by a group of urologists, oncologists, and a radiologist appointed by the EAU Guidelines Office. Previous recommendations based on the older literature on this subject were also taken into account. Levels of evidence (LEs) and grades of recommendations (GRs) were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence.. Current data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC. RC remains the basic treatment of choice in localised invasive disease for both sexes. An attempt has been made to define the extent of surgery under standard conditions in both sexes. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. In contrast to neoadjuvant chemotherapy, current advice recommends the use of adjuvant chemotherapy only within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for medical or personal reasons. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy. With the advent of vinflunine, second-line chemotherapy has become available.. In the treatment of localised invasive bladder cancer (BCa), the standard treatment remains radical surgical removal of the bladder within standard limits, including as-yet-unspecified regional lymph nodes. However, the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups. A new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended.

Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Cisplatin; Cystectomy; Disease-Free Survival; Drug Administration Schedule; Evidence-Based Medicine; Female; Humans; Male; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Patient Selection; Radiotherapy, Adjuvant; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Urinary Bladder Neoplasms; Urinary Diversion; 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

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

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Cystectomy; Female; Humans; Male; Middle Aged; Muscle, Smooth; Neoadjuvant Therapy; Neoplasm Invasiveness; Urinary Bladder Neoplasms; Vinblastine; Young Adult

Vinflunine is recommended in the European guideline for the treatment of advanced or metastatic urothelial cell carcinoma (UCC) after failure of platinum-based therapy.. This prospective, non-interventional study investigated the safety and efficacy of vinflunine in platinum-pretreated UCC patients in routine clinical practice. Data were prospectively collected on patients with advanced or metastatic UCC undergoing vinflunine treatment in 39 German hospitals and medical practices. Dosing of vinflunine, tumor assessments and concomitant medications followed physician's routine clinical practice. Primary endpoints were toxicity and assessment of vinflunine treatment modalities. Secondary aims included overall response rate (ORR), overall survival (OS) time and a prognostic risk-model.. Seventy-seven platinum-pretreated patients were recruited. Vinflunine was predominantly administered as second-line (66%) therapy or in subsequent treatment lines (21%). One third of the patients received at least six cycles of vinflunine and the average number was 4.7 cycles. A vinflunine starting dose of 320 mg/m2 was chosen in 48% of patients and 280 mg/m2 in 39%. Grade 3/4 toxicities were leucopenia 16.9%, anemia 6.5%, elevated liver enzymes 6.5% and constipation 5.2%. ORR was 23.4% and OS was 7.7 (CI 4.1 to 10.4) months. Patients with zero, one, two or ≥three risk factors displayed a median OS of 18.2, 9.5, 4.1 and 2.8 months, respectively (p=0.0005; HR=1.82).. Vinflunine delivers a meaningful benefit to an unselected population of advanced platinum-pretreated UCC patients managed in routine clinical practice.

Topics: Adult; Aged; Carcinoma; Disease-Free Survival; Female; Germany; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Urinary Bladder Neoplasms; Urothelium; 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

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: Clinical Trials as Topic; Humans; Immune Checkpoint Inhibitors; Survival Rate; Urinary Bladder Neoplasms; Vinblastine

Vinflunine is a microtubule inhibitor of the vinca alkaloid class approved for the treatment of urothelial bladder carcinoma after a platinum-containing regimen.. To evaluate the effectiveness of vinflunine, we enrolled 80 subjects with a histologically confirmed diagnosis of metastatic urothelial bladder carcinoma that had previously undergone chemotherapy with a platinum-containing regimen and had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST). The patients (n = 80) received vinflunine (Javlor®) every 3 weeks at 320 mg/m2 via 20-min intravenous infusion. The endpoints were progression-free survival (PFS), objective response rate, overall survival (OS), and tolerability. The cumulative survival of the patients was analyzed using the Kaplan-Meier method.. In this retrospective study, vinflunine treatment was well tolerated and resulted in a good level of disease control (complete response + partial response + stable disease >50%), with a manageable toxicity profile. The median PFS and OS were 3.2 and 6.8 months, respectively. A significant correlation between pain and PFS was also noted. The major hematologic adverse event was neutropenia, observed in 47% of the patients. The most common nonhematologic adverse events were constipation in 48% of the patients and fatigue in 26%.. In this real-word non-randomized clinical trial setting, the data showed that vinflunine is an efficacious and safe therapeutic option for second-line treatment of patients with metastatic urothelial carcinoma of the bladder after a platinum-containing regimen.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Urinary Bladder Neoplasms; Vinblastine

Urothelial carcinoma of the bladder are rare but aggressive tumors with a high metastatic potential. The prognosis of these tumors has not drastically changed over the past 30 years, with an overall survival of less than two years in advanced or metastatic situations. Even though immune checkpoints inhibitors have changed this picture, it is beneficial for less than 30% of patients and there is no reliable biomarkers to identify this specific population of responders. Vinflunine is a vinca-alkaloid that was specifically developed as second line treatment post-platinum. As of today, it is the sole anticancer agent for which clinical trials have been pushed to phase III and that was approved for patients in good conditions. Unfortunately, it has been withdrawn from the list of reimbursed drugs, which impairs its prescription. Based on the results of phase III clinical trials with immunotherapies, this review provides the reader with argumentations in favor of patients' and clinicians' request to reimburse vinflunine for the treatment of advanced or metastatic urothelial carcinoma of the bladder.

Topics: Humans; Neoplasm Metastasis; Neoplasm Staging; Urinary Bladder Neoplasms; 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

Perioperative chemotherapy is likely to improve survival in both the neoadjuvant and the adjuvant setting. Therefore, it is an integral part of the modern treatment of patients with muscle-invasive urothelial bladder cancer. All patients who are suitable for cisplatin-based chemotherapy should be involved in a corresponding concept.Cisplatin-based combinations are standard regimens in the perioperative and palliative systemic treatment of urothelial cancer. Carboplatin is only an inferior substitute for "unfit" patients in the palliative treatment situation. Vinflunine may be used as a second-line agent in case of recurrence after palliative first-line treatment or in patients presenting with rapid progression after perioperative treatment. Alternatively, taxane or taxane-based combinations can be used in these situations.New therapeutic options may include the use of immune checkpoint inhibitors, which have shown promising results in early studies. Two substances have already been approved by the FDA for the treatment of advanced/metastatic urothelial cancer following platin-based upfront treatment. Other future options may be "tailored" treatment concepts based on the molecular pathogenesis of the individual patient. However, extensive pre-clinical work is still required for this approach.. Eine perioperative Chemotherapie verbessert wahrscheinlich sowohl in einem neoadjuvanten als auch in einem adjuvanten Konzept das Überleben des Patienten. Damit ist sie ein integraler Teil der modernen Therapie von Patienten mit einem muskelinvasiven Harnblasenkarzinom. Jeder Patient, der für eine Cisplatin-basierte Chemotherapie geeignet ist, sollte in ein entsprechendes Konzept eingebunden werden.Standard sowohl in der perioperativen als auch in der palliativen Systemtherapie des Urothelkarzinoms sind Cisplatin-basierte Kombinationstherapien. Carboplatin stellt nur bei „unfitten“ Patienten in der palliativen Therapiesituation einen möglichen Ersatz dar, in der perioperativen Systemtherapie besitz es keinen Stellenwert. Im Falle eines Rezidivs nach einer palliativen Erstlinientherapie oder bei einem schnellen Progress nach perioperativer Therapie kann eine Zweitlinientherapie mit Vinflunin durchgeführt werden. Alternativ dazu können auch Taxane oder Taxan-basierte Kombinationen zum Einsatz kommen.Neue Therapiemöglichkeiten sind der Einsatz von Immuncheckpoint-Inhibitoren, welche in ersten Studien vielversprechende Ergebnisse zeigten. Erste Zulassungen durch die FDA sind für die Therapie des metastasierten/fortgeschrittenen Urothelkarzinoms bereits erfolgt. Andere zukünftige Optionen sind „maßgeschneiderte“ Therapiekonzepte, die auf der Molekularpathogenese des individuellen Patienten beruhen. Hier sind jedoch noch weitreichende präklinische Arbeiten erforderlich.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Cisplatin; Humans; Neoadjuvant Therapy; Taxoids; Urinary Bladder 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

Relapsed urothelial cancer represents an unmet medical need. Vinflunine is a third-generation antimicrotubuline inhibitor and is currently the only approved drug for second-line treatment across the European Union. We conducted a retrospective analysis assessing the efficacy and safety of vinflunine in 71 Greek patients with relapsed urothelial cancer who were treated between 2005 and 2014. An overall 84% of our patients received vinflunine as second-line treatment, 77% had a performance status of Eastern Cooperative Oncology Group scale 0 or 1, and 30% had liver metastasis at the time of vinflunine administration. A median of four cycles of vinflunine were administered (range 1-16). The most common reported adverse events were constipation, fatigue, and anemia. Median progression-free survival was 6.2 months (95% confidence interval: 4.4-8.8) and overall survival was 11.9 months (95% confidence interval: 7.4-21). Two patients (3%) achieved a complete remission, seven a partial remission (10%), and 22 (31%) had stable disease according to an intention-to-treat analysis. Hemoglobin level less than 10 g/dl and Eastern Cooperative Oncology Group performance status greater than 1 were independent adverse prognostic factors. Stratification according to the Bellmunt risk model was also associated with progression-free survival and overall survival in our population. Vinflunine appears to be a safe and effective treatment modality for relapsed urothelial cancer. More effective therapies and more accurate prognostic algorithms should be sought.

Topics: Aged; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Survival Analysis; Tubulin Modulators; 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

Patients undergone kidney transplantation present higher risk of Urothelial Carcinoma (UC) development and represent a subgroup of special interest. To date, vinflunine is the only drug approved in Europe for the treatment of advanced UC after failure of platinum-based chemotherapy. However, to our knowledge, no data on the concomitant administration of vinflunine and immunosuppressive agents are available.. The patient, a 45 years old Caucasian male, presented poorly differentiated UC of the bladder recurred after initial cystectomy with abdominal lymphadenopathies evidenced by FDG-PET/CT. Previously, at the age of 22, he had post-glomerulonephritis renal failure and underwent kidney transplantation from deceased donor. Since then, he has been in treatment with immunosuppressive therapy. At the time of UC recurrence, he was on treatment with cyclosporine. After progression to platinum-based chemotherapy, he received second-line therapy with vinflunine resulting in a complete metabolic response after two cycles. However, despite several dose reductions, the patient experienced severe hematologic toxicity. The pharmacological interaction between vinflunine and cyclosporine, both metabolized by CYP 3A4, may explain the excellent result and the concomitant severe toxicity.. Vinflunine is active on UC developed in kidney transplanted patients. However, special attention should be paid to concomitant administration with immunosuppressive agents that could result in increased toxicity.

Topics: Drug Interactions; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium; 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

Intravenous vinflunine 320 mg/m(2) every 3 weeks plus best supportive care resulted in better overall survival in comparison with best supportive care alone for eligible patients with failure of prior therapy with locally advanced or metastatic transitional cell cancer of urothelial tract (TCCU). The objective of the present study was to describe our real-life experience of vinflunine for treatment of patients with TCCU.. We retrospectively investigated all patients with TCCU who received at least 1 cycle of vinflunine.. Nineteen patients were treated between May 2010 and March 2014 in a compassionate-use program. Performance status was poor in our real-life cohort, with 6 patients (32%) with an Eastern Cooperative Oncology Group performance status of 2. Median duration of vinflunine treatment was 2.4 months (range, 0-4.3 months), and median number of cycles was 3 (range, 1-6). Total response rate was 32%, with partial responses only. Disease control rate was 53%, with a median duration of 7.7 months (range, 6.0-9.4 months). Median progression-free survival was 87 days, or 2.9 months (range, 0.7-11.7 months). After vinflunine treatment, 42% of patients received from 1 to 3 additional lines of chemotherapy. The most frequent grade 4 toxicities were constipation (26%), with 3 intestinal obstructions (16%) and 1 mechanical ileus (5%); and asthenia and fatigue (21%).. Vinflunine, as a TCCU second-line chemotherapy, brings benefits, particularly in cases where there is no alternative treatment.

Topics: Administration, Intravenous; Clinical Trials as Topic; Disease-Free Survival; Female; Humans; Male; Retrospective Studies; Survival Analysis; Treatment Outcome; Urinary Bladder Neoplasms; Vinblastine

The objective of this retrospective study was to investigate the efficacy and safety of vinflunine monotherapy and the utility of second-line prognostic factors in patients with advanced or metastatic urothelial cancer relapsing/progressing during or after a prior platinum-containing regimen under daily routine clinical conditions in Germany.. The selection was based on the marketing authorization indication and recommendations as well as on the evaluation of second-line prognostic factors issued from prior pivotal trials.. Eight centers across Germany provided a total of 21 patient records. Demographic and clinical characteristics were similar to the data previously reported in pivotal trials. Complete and partial response to vinflunine treatment was observed in 1 (4.8%) and 3 (14.3%) patients, respectively, resulting in an overall response rate of 19.1%. The disease control rate reached 47.7%. The median progression-free survival amounted to 4.4 months (95% CI 2.6-6.6), with a median overall survival of 6.2 months (95% CI 3.9-10.7). The observed toxicity profile was manageable and consistent with prior clinical trials: leukopenia (33.3%), neutropenia (9.5%), anemia (9.5%) and hyperglycemia (4.8%). The reported satisfaction rate with the treatment was 90.5 and 61.9% among patients and physicians, respectively.. This retrospective study confirms that the clinical outcomes obtained from routine medical practice in Germany with vinflunine in the treatment of advanced/metastatic urothelial cancer are in line with the data observed in prior clinical trials.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Disease-Free Survival; Female; Germany; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Platinum; Prognosis; Recurrence; Retrospective Studies; Risk; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Vinflunine (VFL) is a microtubule-targeting drug that suppresses microtubule dynamics, showing anti-metastatic properties both in vitro and in living cancer cells. An increasing body of evidence underlines the influence of the microtubules dynamics on the cadherin-dependent cell-cell adhesions. E-cadherin is a marker of epithelial-to-mesenchymal transition (EMT) and a tumour suppressor; its reduced levels in carcinoma are associated with poor prognosis. In this report, we investigate the role of VFL on cell-cell adhesions in bladder epithelial tumour cells.. Human bladder epithelial tumour cell lines HT1376, 5637, SW780, T24 and UMUC3 were used to analyse cadherin-dependent cell-cell adhesions under VFL treatment. VFL effect on growth inhibition was measured by using a MTT colorimetric cell viability assay. Western blot, immunofluorescence and transmission electron microscopy analyses were performed to assess the roles of VFL effect on cell-cell adhesions, epithelial-to-mesenchymal markers and apoptosis. The role of the proteasome in controlling cell-cell adhesion was studied using the proteasome inhibitor MG132.. We show that VFL induces cell death in bladder cancer cells and activates epithelial differentiation of the remaining living cells, leading to an increase of E-cadherin-dependent cell-cell adhesion and a reduction of mesenchymal markers, such as N-cadherin or vimentin. Moreover, while E-cadherin is increased, the levels of Hakai, an E3 ubiquitin-ligase for E-cadherin, were significantly reduced in presence of VFL. In 5637, this reduction on Hakai expression was blocked by MG132 proteasome inhibitor, indicating that the proteasome pathway could be one of the molecular mechanisms involved in its degradation.. Our findings underscore a critical function for VFL in cell-cell adhesions of epithelial bladder tumour cells, suggesting a novel molecular mechanism by which VFL may impact upon EMT and metastasis.

Topics: Apoptosis; Cell Adhesion; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Microtubules; 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

Topics: Antineoplastic Agents; Carcinoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Salvage Therapy; Scrotum; Urinary Bladder 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

Vinca alkaloids are an important class of anticancer agents and semisynthetic vinca alkaloids are developed to improve the therapeutic index of this class of drugs. In the present study, a direct comparison was made between vinflunine and vinorelbine regarding their radiosensitizing and cell cycle effects.. Four human tumour cell lines were tested under identical experimental conditions, using equitoxic concentrations of vinflunine and vinorelbine.. Vinflunine and vinorelbine induced a comparable radiosensitizing effect (p-value never below 0.01) when cells were incubated for 24 h immediately prior to radiation. Regarding the cell cycle effects, a statistically significant concentration-dependent G2/M block was seen after 24 h incubation with vinorelbine in all tested cell lines. Similar results, with small cell line-related differences, were observed with vinflunine.. The radiosensitizing effects of both semisynthetic vinca alkaloids were comparable (not statistically different) and nearly always cell line-specific and concentration-dependent. The cell cycle effects could be related to the observed radiosensitizing effects. Considering the more favourable toxicity profile of vinflunine, this agent might be more promising than vinorelbine for chemoradiation studies in the clinic.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Dose-Response Relationship, Drug; Female; Gamma Rays; Humans; Lung Neoplasms; Microtubules; Molecular Structure; Radiation-Sensitizing Agents; Structure-Activity Relationship; Tongue Neoplasms; Urinary Bladder Neoplasms; Vinblastine; Vinorelbine