vinflunine and Carcinoma

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

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

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

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 retrospectively assess the efficacy and safety of Vinflunine (VFL) under routine conditions and identify overall survival (OS) prognostic factors.. Twenty centres participated in the retrospective study (minimum 4 patients undergoing VFL treatment for advanced/metastatic UC after platinum-based regimen progression. Primary endpoint was OS. Secondary endpoints: progression-free survival (PFS), radiological response rate (RR) RECIST criteria and toxicity (CTC NCI v3).. These centres enrolled 134 patients. Prior chemotherapy (CT) lines (≥ 1 palliative): 1 and ≥ 2 in 69% and 26% of patients, respectively. Performance status (PS): 0, 1, 2 in 25%, 46% and 23% of patients. Median OS = 8.2 months [6.5-9.4], PFS = 4.2 months and RR 22%, median number of 5 cycles. In risk groups based on 0-3 presence of adverse prognostic factors (PS ≥ 1, haemoglobin ≤ 10 g/dl and liver metastasis), median OS: 13.2, 9.9, 3.6, and 2.4 months (P < .0001), respectively; 3.3 months (1.9-5.6) in PS ≥ 2 subgroup.. This study reflects routine UC management and confirmed VFL patient efficacy. The drug is safe with gastro-intestinal and haematological prophylaxis. Analysis of prognostic factors for OS is consistent with pivotal trials.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Platinum; Retrospective Studies; Urologic Neoplasms; Urothelium; Vinblastine

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