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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The search for new Vinca analogues has led to the second-generation semisynthetic analogs vindesine (EldesineTM) and vinorelbine (NavelbineTM), and more recently a third-generation bi-fluorinated semisynthetic analog vinflunine (JavlorTM) has been introduced. Vinorelbine, which is used for the treatment of advanced breast and non-small-cell lung cancer, is unique among the five agents in that it can be administered orally as well as intravenously. Vinflunine is also unique in being approved as a monotherapy for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a platinum-based regimen.
Bladder Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
The role of second-line chemotherapy is debated. Patients who respond to first-line therapy and remain of good performance status may achieve reasonable response rates when retreated with the same chemotherapy or an alternative first-line therapy. For instance, in a French report, accelerated MVAC after first-line gemcitabine/platinum achieved response rates of over 50% though at the cost of significant toxicity including treatment deaths.111 (A number of other combinations such as gemcitabine/paclitaxel and paclitaxel/carboplatin have112 been tested in phase II studies and have achieved response rates of around 20–30% and median progression-free survival of around 4–6 months.) The only randomized trial in second-line therapy tested the third-generation vinca alkaloid, vinflunine, against best supportive care. Median survival was non-significantly improved from 4.6 months on best supportive care to 6.9 months with vinflunine (HR 0.88 CI 0.69–1.12; p = 0.29).113 This result was significant in the eligible patient population and on this basis is the first treatment licensed for use as second-line treatment. Recent interest has centered on emerging data on antibody conjugated therapy such as enfortumab vedotin which is targeted against nectin-4 that is expressed on most bladder cancers. A phase II trial reported a 44% ORR as third-line therapy.114
Vinca rosea (Madagascar Periwinkle) and Adhatoda vesica (Malabar Nut)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Rajib Hossain, Md Shahazul Islam, Dipta Dey, Muhammad Torequl Islam
Alkaloids with antitumor and anticancer effects are derived from the leaves and branches of V. rosea. Cancer is inhibited by alkaloids. Vinblastin is being used to treat chorio carcinoma, a kind of Hodgkin's disease tumor. Vincristine is a drug that is used to treat childhood leukemia. Oncovin is a medication that contains vinblastin, which is marketed as Velban or Vincristine. Moderate vinca alkaloids, like vinorelbine and vinflunine, have been created to enhance the treatment efficacy. Vinorelbine and vinflunine interact with microtubules and hence have cytotoxic effects. The alkaloids, commonly known as mitotic spindle poisons, prevent microtubules from entering the cell cycle, preventing mitosis cell division in the cell cycle. As a result, vinca alkaloids aid in the prevention of cancer (Moudi et al., 2013). Various fractions of raw methanolic extract of vinca have exhibited anticancer efficacy against such a range of cell types (Moreno-Valenzuela et al., 1998) and exert a pronounced effect on multi-drug-resistant malignancies (Wang et al., 2004). Anhydrovinblastine in the lung and cervico-uterine cancer cell lines exhibited significant effects (Tiong et al., 2013). In a variety of cancer cells, ursolic acid has been demonstrated to exhibit antiproliferative properties (Neto, 2007). Ursolic acid upregulates apoptosis cell death which was initiated through using Fas activation and caspase-3/8, and PARP breakage, which was accompanied by increasing Bax and decreasing Bcl-2, as well as the production of cytochrome c from mitochondria with the reduction in MMP (Kim et al., 2011).
Trimodal therapy for muscle-invasive bladder cancer
Published in Expert Review of Anticancer Therapy, 2018
Joachim Mathes, Steffen Rausch, Tilman Todenhöfer, Arnulf Stenzl
After a period of perceived stagnation, the approval of vinflunine in the second-line treatment of locally advanced and metastatic urothelial carcinomas provided a discrete improvement compared to best supportive care. The establishment of gemcitabine and cisplatin as an alternative to MVAC was another step. The introduction of checkpoint inhibitors raised the therapeutic potential of treating tumors to a higher level. Recently, PD-L1 inhibitors, atezolizumab, durvalumab, and avelumab, and PD-1 inhibitors, pembrolizumab and nivolumab, have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced or metastatic urothelial carcinoma of the bladder [105–108]. The clinical studies for the FDA approval showed overall objective response rate (regardless of PD-L1 expression) of 13–24% [108].
Avelumab for the treatment of urothelial cancer
Published in Expert Review of Anticancer Therapy, 2018
Alejo Rodriguez-Vida, Joaquim Bellmunt
Following disease progression on platinum-based chemotherapy, there was no internationally accepted standard of care second-line therapy because there was no Food and Drug Administration (FDA)-approved drug for this setting until 2017. Vinflunine, a third-generation vinca alkaloid derivative, is an approved treatment option in Europe after showing an improved but modest survival benefit as compared with best supportive care in a randomized phase III study [10]. Other agents such as docetaxel, paclitaxel, or pemetrexed have been tested as single agents with response rates between 9% and 20% and are considered valid second-line treatment options [11–13]. However, these results are based on evidence from phase II studies, and none of them has shown significant improvement in OS. Consequently, the median OS of patients with second-line therapy for advanced UCs is reduced to approximately 6 months [10]. Therefore, there is an important unmet need for effective anticancer treatment in UC both in first and second line.
Systemic treatments for metastatic urothelial carcinoma
Published in Expert Opinion on Pharmacotherapy, 2019
Aly-Khan A. Lalani, Guru P. Sonpavde
Larger studies examining agents with different targets than contemporary ICI have also been conducted in the platinum-treated space. The phase-III RANGE study evaluated docetaxel plus ramucirumab, a human IgG1 VEGFR-2, versus docetaxel plus placebo in 530 patients with platinum-refractory mUC [25]. The primary end point of PFS (ITT in first 430 patients) was only modestly improved by 1.3 months with ramucuriumab (median PFS 4.1 vs. 2.8 mos, HR 0.76, p = 0.0118). Due to its gate-keeping statistical design, the study does not allow for formal testing of response rate unless OS benefit reaches HR 0.75 (currently immature). There were limited number of patients who received prior ICI and subgroup analysis did not appear to show benefit in patients with visceral metastasis. At this time, ramucirumab is not approved in this setting. The Borealis-2 study evaluated docetaxel plus apatorsen, an antisense oligonucleotide (ASO) to heat-shock protein 27, compared to docetaxel alone in 200 patients [26]. The primary end point of this randomized phase-II study was OS where a one-sided p-value < 0.10 would indicate a positive result. While the addition of apatorsen met its predefined end point (HR 0.80, 80% CI 0.65–0.98, p = 0.0784) there was a marginal improvement in median OS compared to docetaxel alone (6.4 vs. 5.9 mos). Therefore, ASOs such as apatorsen may require further study in a later phase setting, ideally with biomarkers for better patient-selection, before informing clinical practice. Vinflunine and taxane chemotherapy continue to play a role as salvage systemic chemotherapy based on modest activity demonstrated in a phase-III trial and nonrandomized trials, respectively [27–30].