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Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group.
Ettrich, TJ, Berger, AW, Perkhofer, L, Daum, S, König, A, Dickhut, A, Wittel, U, Wille, K, Geissler, M, Algül, H, et al
BMC cancer. 2018;(1):1298
Abstract
BACKGROUND Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION ClinicalTrials.gov : NCT02047513, 08/13/2014.
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Harnessing the Immune System in Pancreatic Cancer.
Das, S, Berlin, J, Cardin, D
Current treatment options in oncology. 2018;(10):48
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Abstract
Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.
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A randomized phase II multicenter trial to explore efficacy of weekly intraperitoneal in comparison with intravenous paclitaxel administered immediately after gastrectomy to the patients with high risk of peritoneal recurrence: final results of the INPACT trial.
Takahashi, N, Kanda, M, Yoshikawa, T, Takiguchi, N, Fujitani, K, Miyamoto, K, Ito, Y, Takayama, O, Imano, M, Mitsumori, N, et al
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2018;(6):1014-1023
Abstract
BACKGROUND Intraperitoneal administration of paclitaxel had been considered a promising option to treat peritoneal metastasis, the most frequent pattern of recurrence in gastric cancer after D2 gastrectomy, but its safety and efficacy after gastrectomy had not been fully explored. METHODS A phase II randomized comparison of postoperative intraperitoneal (IP) vs. intravenous (IV) paclitaxel was conducted. Patients with resectable gastric linitis plastica, cancer with minimal amount of peritoneal deposits (P1), or cancer positive for the peritoneal washing cytology (CY1) were eligible. After intraoperative confirmation of the above disease status and of resectability, patients were randomized to be treated either by the IP therapy (paclitaxel 60 mg/m2 delivered intraperitoneally on days 0, 14, 21, 28, 42, 49, and 56) or the IV therapy (80 mg/m2 administered intravenously using the identical schedule) before receiving further treatments with evidence-based systemic chemotherapy. The primary endpoint was 2-year survival rate. RESULTS Of the 86 patients who were randomized intraoperatively, 83 who actually started the protocol treatment were eligible for analysis (n = 39, IP group; n = 44, IV group). The 2-year survival rate of the IP and IV groups was 64.1% (95% CI 47.9-76.9) and 72.3% (95% CI 56.3-83.2%), respectively (p = 0.5731). The IP treatment did not confer significant overall or progression-free survival benefits, and was associated with particularly poor performance in patients with residual disease, including the CY1 P0 population. CONCLUSIONS We were unable to prove superiority of the IP paclitaxel over IV paclitaxel delivered after surgery to control advanced gastric cancer with high risk of peritoneal recurrence.
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Prognostic and predictive factors for angiosarcoma patients receiving paclitaxel once weekly plus or minus bevacizumab: an ancillary study derived from a randomized clinical trial.
Lebellec, L, Bertucci, F, Tresch-Bruneel, E, Ray-Coquard, I, Le Cesne, A, Bompas, E, Blay, JY, Italiano, A, Mir, O, Ryckewaert, T, et al
BMC cancer. 2018;(1):963
Abstract
BACKGROUND We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel. METHODS Circulating pro/anti-angiogenic factors were assessed on day 1 (D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables. RESULTS Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome. CONCLUSIONS De novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS. TRIAL REGISTRATION Retrospectively registered on EudraCT N° 2009-017020-59 and NCT01303497 (February 24, 2011).
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Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02).
Tahara, M, Kiyota, N, Yokota, T, Hasegawa, Y, Muro, K, Takahashi, S, Onoe, T, Homma, A, Taguchi, J, Suzuki, M, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2018;(4):1004-1009
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BACKGROUND The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN. PATIENTS AND METHODS Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients. RESULTS Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia. CONCLUSIONS The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population. REGISTERED CLINICAL TRIAL NUMBER UMIN000010507.
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Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy.
Kang, YK, Ryu, MH, Park, SH, Kim, JG, Kim, JW, Cho, SH, Park, YI, Park, SR, Rha, SY, Kang, MJ, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2018;(5):1220-1226
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BACKGROUND Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. METHODS AND MATERIALS Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. RESULTS Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). CONCLUSIONS DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. CLINICALTRIALS.GOV: NCT01839773.
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Meta-analysis of the effects of oral and intravenous dexamethasone premedication in the prevention of paclitaxel-induced allergic reactions.
Chen, FC, Wang, LH, Zheng, XY, Zhang, XM, Zhang, J, Li, LJ
Oncotarget. 2017;(12):19236-19243
Abstract
BACKGROUND Dexamethasone premedication is required to prevent paclitaxel-related hypersensitivity reactions (HSRs). Oral dexamethasone (PO-D) has been considered the standard premedication regimen. However, whether intravenous dexamethasone (IV-D) is feasible for preventing paclitaxel-related HSRs is still unclear. We conducted a meta-analysis to compare these two regimens. METHODS We performed a systematic search in the PubMed, China National Knowledge Infrastructure, and Web of Science databases for relevant articles published before June 2016. Outcomes included HSRs and severe HSRs. Statistical analyses were performed using RevMan 5.2 software. RESULT Six studies comprising 1347 patients were included in the meta-analysis. The PO-D premedication regimen showed a significantly decreased incidence of severe HSRs compared with the IV-D regimen with an OR of 0.53 (95% CI 0.28-0.99, p = 0.05). However, there was no difference in the overall paclitaxel-related HSR rates between the two premedication regimens (OR 0.76, 95% CI 0.55-1.06, p = 0.11). Subgroup analyses according to study type and country of origin showed similar statistical results between the two premedication regimens. CONCLUSION Our meta-analysis showed that the PO-D premedication regimen is superior to the IV-D regimen in preventing paclitaxel-related HSRs. Additional randomized controlled trials are needed to confirm our findings.
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Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.
Kubota, K, Yoshioka, H, Oshita, F, Hida, T, Yoh, K, Hayashi, H, Kato, T, Kaneda, H, Yamada, K, Tanaka, H, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;(32):3662-3670
Abstract
Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. Patients and Methods Patients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m2 IV and carboplatin area under the concentration-time curve 6 mg/mL ⋅ min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months ( P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% ( P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade ≥ 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer.
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Long-Term Results from the MAJESTIC Trial of the Eluvia Paclitaxel-Eluting Stent for Femoropopliteal Treatment: 3-Year Follow-up.
Müller-Hülsbeck, S, Keirse, K, Zeller, T, Schroë, H, Diaz-Cartelle, J
Cardiovascular and interventional radiology. 2017;(12):1832-1838
Abstract
PURPOSE To report the 3-year results of the MAJESTIC first-in-human study of the Eluvia Drug-Eluting Vascular Stent System for treating femoropopliteal artery lesions. METHODS The prospective, single-arm, multicenter clinical trial enrolled 57 patients with symptomatic lower limb ischemia (Rutherford category 2, 3, or 4) and lesions in the superficial femoral artery or proximal popliteal artery. Mean lesion length was 70.8 ± 28.1 mm, and 46% of lesions were occluded. Efficacy measures at 2 years included primary patency, defined as duplex ultrasound peak systolic velocity ratio of ≤2.5 and the absence of target lesion revascularization (TLR) or bypass. Safety monitoring through 3 years included adverse events and TLR. RESULTS Primary patency was estimated as 83.5% (Kaplan-Meier analysis) at 24 months, and 90.6% (48/53) of patients maintained an improvement in Rutherford class. At 36 months, the Kaplan-Meier estimate of freedom from TLR was 85.3%. No stent fractures were identified, and no major target limb amputations occurred. CONCLUSION MAJESTIC results demonstrated long-term treatment durability among patients whose femoropopliteal arteries were treated with the paclitaxel-eluting Eluvia stent. LEVEL OF EVIDENCE Level 2b, cohort study.
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A Comparison of Peri-Procedural Myocardial Infarction between Paclitaxel-Coated Balloon and Drug-Eluting Stent on De Novo Coronary Lesions.
Her, AY, Cho, KI, Singh, GB, Garg, S, Kim, YH, Koo, BK, Shin, ES
Yonsei medical journal. 2017;(1):99-104
Abstract
PURPOSE This study compared the impact of paclitaxel-coated balloons (PCB) or drug eluting stents (DES) on peri-procedural myocardial infarction (PMI) on de novo coronary lesion in stable patients. MATERIALS AND METHODS In this observational study, we compared the incidence of PMI amongst patients with single vessel de novo coronary lesions who underwent treatment with a PCB or DES. Propensity score-matching analysis was used to assemble a cohort of patients with similar baseline characteristics. PMI was classified as myocardial infarction occurring within 48 hours after percutaneous coronary intervention with a threshold of 5 x the 99th percentile upper reference limit of normal for creatine kinase-myocardial band (CK-MB) or troponin T (TnT). RESULTS One hundred four patients (52 receiving PCB and 52 receiving DES) were enrolled in this study. The peak mean values of CK-MB and TnT were significantly higher in the DES group. There was a significantly higher rate of PMI in the DES group (23.1% vs. 1.9%, p=0.002). Total occlusion of the side-branch occurred in two patients treated with DES, while no patients treated with PCB. In multivariable analysis, DES was the only independent predictor of PMI compared with PCB (odds ratio 42.85, 95% confidence interval: 3.44-533.87, p=0.004). CONCLUSION Treatment with a PCB on de novo coronary lesion might be associated with a significant reduction in the risk of PMI compared to DES.