Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract: an evidence-based review of safety, efficacy, and place in therapy

Abstract

BackgroundA systematic review and meta-analysis of the use of systemic vinflunine (VIN) in the treatment of urothelial carcinoma (UC) was performed to evaluate its efficacy based on current available clinical data.MethodsThis review was prospectively registered at the International Prospective Register of Systematic Reviews, PROSPERO (registration CRD42016049294). Electronic databases including MEDLINE®, Embase®, Cochrane Central Register of Controlled Trials, and Web of Science were searched through December 2016. We performed a meta-analysis of the published data. Primary end points were progression-free survival (PFS) and overall survival (OS). Numerous secondary clinical outcomes were analyzed including response and toxicity data.ResultsWe identified 382 publications, of which 35 met inclusion criteria for this review representing 29 unique studies. A total of 2,255 patients received VIN for the treatment of UC in the included studies. OS and PFS were analyzed in a pooled Kaplan–Meier analysis. Response data were available for 1,416 VIN-treated patients with random effects proportion of complete response in 1%, partial response in 18%, and overall response rate of 21%. Toxicity analysis revealed fatigue (40.1%), nausea (33.9%), constipation (34.1%), and alopecia (26.0%) as the most prevalent overall non-hematologic adverse events (AEs). Most prevalent grade 3–4 AEs were fatigue (10.2%), abdominal pain (8.2%), myalgias (2.5%), and nausea (2.3%). Most common hematologic AEs of all grades were anemia (56.6%), neutropenia (46.0%), thrombocytopenia (25.5%), and febrile neutropenia (6.6%). Grade 3–4 hematologic AEs had the following pooled rates: neutropenia, 24.6%; anemia, 10.2%; febrile neutropenia, 5.4%; and thrombocytopenia, 3.0%.ConclusionVIN has been explored as a combination first-line treatment as well as a single-agent second-line, third-line, and maintenance therapy for advanced and metastatic UC. In first-line treatment of UC, either as a maintenance agent after cisplatin or as a primary combination therapy, VIN may be a promising alternative to current treatments. Further studies are needed to compare first-line combination VIN regimens to the current standard of care in order to assess long-term survival outcomes. Second- and third-line VIN monotherapy does provide a proven, although limited, survival benefit in platinum-refractory patients.

Vinflunine/gemcitabine versus carboplatin/gemcitabine as first-line treatment in cisplatin-ineligible patients with advanced urothelial carcinoma: A randomised phase II trial (VINGEM)

“…This response rate exceeds the numbers reported for other chemotherapy regimens in unfit patients, e.g. the phase III trial CG vs M-CAVI [5] (including the subgroup treated with CG unfit to cisplatin only due to impaired renal function, ORR 47%, CR 6%), the JASINT1 trial [16] and vinflunine in second-line treatment [14,15]. The response rate in our trial is comparable with the best response data reported for cisplatin-based chemotherapy in aUC [3,21,22].…”

“…In 2009, the European Medicines Agency (EMA) approved the third-generation anti-microtubule inhibitor vinflunine as second-line treatment after platinum-based chemotherapy in patients with aUC, improving mOS for vinflunine compared with best supportive care in the eligible population (but not in the intention-to-treat [ITT] population) [14]. Furthermore, the efficacy of vinflunine in second-line treatment has been confirmed in real-world studies [15]. Vinflunine combinations, vinflunine and gemcitabine (VG) versus vinflunine and carboplatin, were explored as first-line treatment for cisplatin-unfit patients in the randomised phase II trial JASINT1 [16], showing promising response rates and survival (ORR 53% with confirmed ORR 44% and mOS 14.0 months in the VG arm), although the trial did not include a non-investigational control arm.…”

Vinflunine in the treatment of relapsed metastatic urothelial cancer: A systematic review and meta-analysis of real-world series

“…For this reason, a critical review of these publications is necessary to extract useful information and reliable conclusions on the everyday utilization of VFL. Recently, a meta-analysis including RWD on VFL in mUC was published [36], however, this meta-analysis also included all published phase II and III clinical trials of VFL, thus neutralizing the important advantages of a pure RWD analysis. We therefore conducted a meta-analysis completely focused on RWD on VFL.…”

“…Risk factors: ECOG PS  1, liver metastases, Hb 10 g/dL[34]. ‡ Risk factors: ECOG PS  1, liver metastases, Hb 10 g/dL, time-from-prior-chemotherapy <6 months[36].…”

Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway

“…In line with the in vitro culture results, the in vivo xenograft model clearly supported the hypothesis that TSA works synergistically with paclitaxel. Although the cooperative antitumor effect between TSA and paclitaxel was observed in papillary serous endometrial cancer cells [ 32 ], whether the synergistic effect holds for other cancer types, especially those that exhibit drug resistance, is unclear. Our study results indicate that the synergistic antitumor effect is well preserved in high-grade UC cells despite their insensitivity to other chemotherapeutic agents.…”