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Recent Research Progress in Taxol Biosynthetic Pathway and Acylation Reactions Mediated by Taxus Acyltransferases.
Wang, T, Li, L, Zhuang, W, Zhang, F, Shu, X, Wang, N, Wang, Z
Molecules (Basel, Switzerland). 2021;(10)
Abstract
Taxol is one of the most effective anticancer drugs in the world that is widely used in the treatments of breast, lung and ovarian cancer. The elucidation of the taxol biosynthetic pathway is the key to solve the problem of taxol supply. So far, the taxol biosynthetic pathway has been reported to require an estimated 20 steps of enzymatic reactions, and sixteen enzymes involved in the taxol pathway have been well characterized, including a novel taxane-10β-hydroxylase (T10βOH) and a newly putative β-phenylalanyl-CoA ligase (PCL). Moreover, the source and formation of the taxane core and the details of the downstream synthetic pathway have been basically depicted, while the modification of the core taxane skeleton has not been fully reported, mainly concerning the developments from diol intermediates to 2-debenzoyltaxane. The acylation reaction mediated by specialized Taxus BAHD family acyltransferases (ACTs) is recognized as one of the most important steps in the modification of core taxane skeleton that contribute to the increase of taxol yield. Recently, the influence of acylation on the functional and structural diversity of taxanes has also been continuously revealed. This review summarizes the latest research advances of the taxol biosynthetic pathway and systematically discusses the acylation reactions supported by Taxus ACTs. The underlying mechanism could improve the understanding of taxol biosynthesis, and provide a theoretical basis for the mass production of taxol.
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Safety and Effectiveness of Paclitaxel Drug-Coated Devices in Peripheral Artery Revascularization: Insights From VOYAGER PAD.
Hess, CN, Patel, MR, Bauersachs, RM, Anand, SS, Debus, ES, Nehler, MR, Fanelli, F, Yeh, RW, Secemsky, EA, Beckman, JA, et al
Journal of the American College of Cardiology. 2021;(18):1768-1778
Abstract
BACKGROUND Paclitaxel drug-coated devices (DCDs) were developed to improve lower extremity revascularization (LER) patency in peripheral artery disease (PAD) but have been associated with long-term mortality. OBJECTIVES This study assessed DCD safety and effectiveness in LER for PAD. METHODS VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) randomized patients with PAD who underwent LER to rivaroxaban or placebo. The primary VOYAGER PAD study efficacy and safety outcomes were composite cardiovascular and limb events and Thrombolysis In Myocardial Infarction major bleeding. For prespecified DCD analyses, primary safety and effectiveness outcomes were mortality and unplanned index limb revascularization (UILR). Major adverse limb events (MALE) were a secondary outcome. Inverse probability treatment weighting was used to account for each subject's propensity for DCD treatment. Effects of rivaroxaban were assessed with Cox proportional hazards models. RESULTS Among 4,316 patients who underwent LER, 3,478 (80.6%) were treated for claudication, and 1,342 (31.1%) received DCDs. Median follow-up was 31 months, vital status was ascertained in 99.6% of patients, and there were 394 deaths. After weighting, DCDs were not associated with mortality (HR: 0.95; 95% CI: 0.83-1.09) or MALE (HR: 1.08; 95% CI: 0.90-1.30) but were associated with reduced UILR (3-year Kaplan-Meier: 21.5% vs 24.6%; HR: 0.84; 95% CI: 0.76-0.92). Irrespective of DCD use, consistent benefit of rivaroxaban for composite cardiovascular and limb events (Pinteraction = 0.88) and safety of rivaroxaban with respect to bleeding (Pinteraction = 0.57) were observed. CONCLUSIONS In >4,000 patients with PAD who underwent LER, DCDs were not associated with mortality or MALE but were associated with persistent reduction in UILR. These findings provide insight into the safety and effectiveness of DCDs in PAD. (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD [VOYAGER PAD]; NCT02504216).
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Results of paclitaxel-drug-coated balloons (Pantera Lux) for coronary in-stent restenosis: Italian experience from REGistry of Paclitaxel Eluting Balloon in ISR study.
Galli, S, Troiano, S, Tespili, M, Ielasi, A, Niccoli, G, Sommariva, L, Amico, F, Pasquetto, G, Ceravolo, R, Forlani, D, et al
Journal of cardiovascular medicine (Hagerstown, Md.). 2021;(6):469-477
Abstract
AIMS: Drug-eluting stent (DES) implantation is an effective treatment of in-stent restenosis (ISR). However, literature data indicate that drug-coated balloons (DCBs) may be a valid alternative, particularly for recurrent ISR. We sought to evaluate clinical results on the long-term efficacy of a new DCB for ISR treatment. METHODS One hundred and ninety-nine patients were treated with paclitaxel drug-coated balloons (Pantera Lux, Biotronik, Switzerland) in the Italian REGistry of Paclitaxel Eluting Balloon in ISR (REGPEB study). Clinical follow-up was scheduled at 1 and 12 months. A subgroup of patients received adjunctive 5-year follow-up. Primary end point was Major Adverse Cardiac Events (MACE) at 1 year. RESULTS A total of 214 ISR coronary lesions were treated (75.4% DES-ISR). Mean time between stent implantation and DCB treatment is 41 months. DCBs were successfully delivered in 99% of the cases; crossover to a DES occurred in 3% of cases. Procedural success rate was 98.5%. Clinical success rate was 98.5%. First-month follow-up compliance was 98% and freedom from MACE was 96.9%. Twelve-month follow-up compliance was 89.3% with a freedom from MACE rate of 87.3% (CI: 81.3-91.5%). Five-year long-term follow-up showed 65.2% of freedom from MACE. CONCLUSION Our study confirms that Pantera Lux treatment is effective and well tolerated in ISR, showing good acute and long/very long-term results in the treatment of complex lesions (DES and late ISR).
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Rationale and design of a randomized study comparing the agent drug coated balloon to plain old balloon angioplasty in patients with In-stent restenosis.
Yeh, RW, Bachinsky, W, Stoler, R, Bateman, C, Tremmel, JA, Abbott, JD, Dohad, S, Batchelor, W, Underwood, P, Allocco, DJ, et al
American heart journal. 2021;:101-107
Abstract
BACKGROUND Drug-coated balloon (DCB) technology was developed as an alternative treatment for obstructive coronary artery disease (CAD) and in-stent restenosis (ISR). Management of coronary ISR is clinically challenging and frequently encountered in practice. The Agent DCB uses an inactive excipient to effectively deliver a targeted, therapeutic dose of paclitaxel to the vessel wall. STUDY DESIGN AGENT IDE is a prospective, multicenter, randomized controlled trial to evaluate superiority of the Agent DCB to balloon angioplasty in treating patients with ISR. A total of 480 patients with ISR of a previously treated lesion length <26 mm and reference vessel diameter >2.0 mm to ≤4.0 mm will be initially randomized. Subjects presenting with recent myocardial infarction (MI), complex lesions, or thrombus in the target vessel will be excluded. An adaptive group sequential design with one formal interim analysis for sample size re-estimation will be conducted, and the sample size may be increased to a maximum of 600 subjects. The primary endpoint is the rate of 12-month target lesion failure (TLF; composite of any ischemia-driven revascularization of the target lesion (TLR), target vessel related MI, or cardiac death) and will be tested for superiority in the test arm against the control. Functional status and general health-related quality of life will be measured by changes in the EQ-5D scores. Subjects will be followed for 5 years following the index procedure. CONCLUSION This study will prospectively evaluate the safety and efficacy of Agent DCB in patients treated for coronary ISR.
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Do Steroids Matter? A Retrospective Review of Premedication for Taxane Chemotherapy and Hypersensitivity Reactions.
Lansinger, OM, Biedermann, S, He, Z, Colevas, AD
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;(32):3583-3590
Abstract
PURPOSE Despite the widespread use of the taxanes paclitaxel and docetaxel for a variety of cancers and their well-known association with hypersensitivity reactions (HSRs), there is still significant variation in the prescribing practices of steroids for premedication. Premedication almost always includes dexamethasone, which can be associated with multiple adverse effects if taken for extended periods of time. This study reviews the pattern of steroid premedication in patients who received paclitaxel or docetaxel at Stanford Cancer Institute between January 2010 and June 2020. METHODS We used an electronic query of the electronic medical record followed up with a manual review of patient charts to ask whether we could find a correlation between steroid premedication dosing and the incidence or severity of HSRs with the first taxane dose. Variables considered included steroid dose and route, dose and type of taxane, clinical cancer group, sex, and race. RESULTS Five thousand two hundred seventeen patients were identified as having received paclitaxel or docetaxel, and 3,181 met criteria for our analysis. There were 264 (8.3%) HSRs. In adjusted multivariate analysis, we found no correlation of HSR rate or severity among any of the variables evaluated except gynecology oncology clinic patients, who had an increased risk (hazard ratio [HR] 1.34) of HSRs overall and high-grade HSRs (HR 2.34), and female patients, who had a higher rate of HSRs overall (HR 1.26), but not high-grade HSRs. CONCLUSION Neither dexamethasone dose nor route correlated with subsequent HSRs. Given the potential for adverse events from repeated high-dose steroids, our findings suggest that routine use of lower doses, such as a single 10 mg dose of dexamethasone, as premedication for taxanes to prevent HSRs is preferable to the current prescribing guidelines.
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Effect of early tumor response on the health-related quality of life among patients on second-line chemotherapy for advanced gastric cancer in the ABSOLUTE trial.
Fujitani, K, Shitara, K, Takashima, A, Koeda, K, Hara, H, Nakayama, N, Hironaka, S, Nishikawa, K, Kimura, Y, Amagai, K, et al
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2021;(2):467-476
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Abstract
BACKGROUND This study evaluated the association between early tumor response at 8 weeks, previously reported as a positive outcome prognosticator, and health-related quality of life (HRQOL) in advanced gastric cancer (AGC) patients enrolled in the ABSOLUTE trial. METHODS HRQOL was assessed using the EuroQol-5 Dimension (EQ-5D) utility index score in patients with complete response (CR) + partial response (PR) and progressive disease (PD) at 8 weeks, and time-to-deterioration (TtD) of the EQ-5D score, with the preset minimally important difference (MID) of 0.05, was compared between these populations. Among the enrolled patients, 143 and 160 patients were assessable in weekly solvent-based paclitaxel (Sb-PTX) arm and weekly nanoparticle albumin-bound paclitaxel (nab-PTX) arm, respectively. RESULTS Changes of the EQ-5D score from baseline to 8 weeks in the nab-PTX arm were 0.0009 and - 0.1229 in CR + PR and PD patients, respectively; the corresponding values for the Sb-PTX arm were - 0.0019 and - 0.1549. For both treatments, changes of the EQ-5D score from baseline at 8 weeks were significantly larger in patients with PD than in those with CR + PR. The median TtD was 3.9 and 2.2 months in patients with CR + PR and PD, respectively, for nab-PTX [hazard ratio (HR) = 0.595, 95% confidence interval (CI) 0.358-0.989]. For Sb-PTX, the corresponding values were 4.7 and 2.0 months (HR = 0.494, 95% CI 0.291-0.841). CONCLUSIONS Early tumor shrinkage was associated with maintained HRQOL in AGC patients on the second-line chemotherapy with taxanes.
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Efficacy and safety of apatinib alone or apatinib plus paclitaxel/docetaxel versus paclitaxel/docetaxel in the treatment of advanced non-small cell lung cancer: A meta-analysis.
Li, Z, Liu, Z, Wu, Y, Li, H, Sun, Z, Han, C, Zhang, X, Zhang, J
Thoracic cancer. 2021;(21):2838-2848
Abstract
BACKGROUND To investigate the efficacy and safety of apatinib alone or apatinib plus paclitaxel/docetaxel versus paclitaxel/docetaxel in the treatment of advanced non-small cell lung cancer (NSCLC) through pooling of open published data. METHODS The electronic databases of Medline (1960-2021.5), Cochrane central register of controlled trials (CENTRAL), EMBASE(1980-2021.5) and Wan fang (1986-2021.5) were systematically searched by two reviewers to identify the relevant clinical trials related to the above subject. The objective response rate (ORR), disease control rate (DCR) and drug relevant adverse reactions were pooled and demonstrated by risk ratio (RR) and 95% confidence interval (95% CI). The statistical heterogeneity across studies was assessed by I-square test. The publication bias was evaluated by Egger's line regression test and demonstrated by Begg's funnel plot. RESULTS Eleven prospective studies were included in the meta-analysis. The pooled results indicated that the ORR (RR = 1.62, 95% CI: 1.32-2.00, p < 0.05) and DCR (RR = 1.29, 95% CI: 1.18-1.41, p < 0.05) of apatinib alone or apatinib plus paclitaxel/docetaxel was significantly higher than that of the paclitaxel/docetaxel group for advanced NSCLC, respectively. The drug-related adverse reaction was not statistically different between apatinib alone or apatinib plus paclitaxel/docetaxel with regard to the hand-foot syndrome, gastrointestinal reaction, thrombocytopenia, anemia and leukocytopenia (pall > 0.05) except for hypertension (RR = 3.60, 95% CI: 1.26-10.31, p < 0.05). Subgroup analysis also indicated that the hypertension and hand-foot syndrome in apatinib + paclitaxel/docetaxel were higher than that of the paclitaxel/docetaxel group with a statistical difference (p < 0.05). CONCLUSIONS Apatinib alone or apatinib plus paclitaxel/docetaxel was superior to paclitaxel/docetaxel for ORR and DCR. However, combined treatment with apatinib appears to increase the risk of a patient developing an adverse reaction, especially hypertension and hand-foot syndrome.
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Causes of death after treatment of small coronary artery disease with paclitaxel-coated balloons.
Jeger, RV, Kaiser, C, Mangner, N, Kleber, FX, Scheller, B, ,
Clinical research in cardiology : official journal of the German Cardiac Society. 2021;(2):307-311
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Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial.
Kunzmann, V, Siveke, JT, Algül, H, Goekkurt, E, Siegler, G, Martens, U, Waldschmidt, D, Pelzer, U, Fuchs, M, Kullmann, F, et al
The lancet. Gastroenterology & hepatology. 2021;(2):128-138
Abstract
BACKGROUND The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer. METHODS In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, fluorouracil 400 mg/m2 by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m2 for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136. FINDINGS Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3-48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7-56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35-1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8-27·6), median overall survival was 18·5 months (95% CI 14·4-21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9-28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55-1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase. INTERPRETATION Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival. FUNDING Celgene.
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Cost-effectiveness analysis of FOLFIRINOX vs gemcitabine with nab-paclitaxel as adjuvant treatment for resected pancreatic cancer in the United States based on PRODIGE-24 and APACT trials.
Kharat, AA, Nelson, R, Au, T, Biskupiak, J
Journal of managed care & specialty pharmacy. 2021;(10):1367-1375
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Abstract
BACKGROUND Pancreatic cancer is associated with low median overall survival. Combination chemotherapy regimens FOLFIRINOX and gemcitabine with nab-paclitaxel (GemNab) are the new adjuvant treatment standards for resectable pancreatic cancer. PRODIGE-24 and APACT trials demonstrated superior clinical outcomes with FOLFIRINOX and GemNab, each vs gemcitabine monotherapy. OBJECTIVE To evaluate the cost-effectiveness of FOLFIRINOX vs GemNab for resectable pancreatic cancer in adults from the U.S. payer perspective, in order to inform decision makers about which of these treatments is optimal. METHODS A Markov model with 3 disease states (relapse free, progressive disease, and death) was developed. Cycle length was 1 month, and time horizon was 10 years. Transition probabilities were derived from PRODIGE-24 and APACT survival data. All cost and utility input parameters were obtained from published literature. Cost-effectiveness analysis was performed to obtain total costs, quality-adjusted life-years (QALYs), life-years (LYs), and incremental cost-effectiveness ratio (ICER). A 3% annual discount rate was applied to costs and outcomes. The effect of uncertainty on model parameters was assessed with 1-way and probabilistic sensitivity analysis (PSA). RESULTS Our analysis estimated that the cost for FOLFIRINOX was $40,831 higher than GemNab ($99,669 vs. $58,837). Despite increased toxicity, FOLFIRINOX was associated with additional 0.18 QALYs and 0.25 LYs compared with GemNab (QALY: 1.65 vs. 1.47; LY: 2.09 vs. 1.84). The ICER for FOLFIRINOX vs GemNab was $226,841 per QALY and $163,325 per LY. FOLFIRINOX was not cost-effective at a willingness-to-pay (WTP) threshold of $200,000 per QALY, and this was confirmed by the PSA. CONCLUSIONS Total monthly cost for FOLFIRINOX was approximately 1.7 times higher than GemNab. If the WTP threshold increases to or above $250,000 per QALY, FOLFIRINOX then becomes a cost-effective treatment option. DISCLOSURES This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors have no conflicts of interest to declare.