E Gabriela Chiorean1, Bryan P Schneider2, Fatih M Akisik3, Susan M Perkins4, Stephen Anderson5, Cynthia S Johnson4, John DeWitt5, Paul Helft2, Romnee Clark2, Erica L Johnston2, A John Spittler2, Jill Deluca6, Guixue Bu3, Safi Shahda2, Patrick J Loehrer2, Kumar Sandrasegaran3, Higinia R Cardenes7. 1. Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana; Department of Medicine, University of Washington, Seattle, Washington. Electronic address: gchiorea@uw.edu. 2. Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. 3. Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana. 4. Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana. 5. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. 6. Department of Radiation Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. 7. Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.
Abstract
PURPOSE: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients received gemcitabine 1000 mg/m(2) intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m(2) intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). RESULTS: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K(trans) in responding patients. CONCLUSIONS: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.
PURPOSE: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients received gemcitabine 1000 mg/m(2) intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m(2) intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). RESULTS: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K(trans) in responding patients. CONCLUSIONS: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.
Authors: Christoforos Kosmidis; Konstantinos Sapalidis; Efstathios Kotidis; Nikolaos Mixalopoulos; Paul Zarogoulidis; Drosos Tsavlis; Sofia Baka; Yan-Gao Man; John Kanellos Journal: Ann Transl Med Date: 2016-05
Authors: Zipeng Lu; Maximilian Weniger; Kuirong Jiang; Stefan Boeck; Kai Zhang; Alexander Bazhin; Yi Miao; Jens Werner; Jan G D'Haese Journal: Target Oncol Date: 2018-08 Impact factor: 4.493
Authors: E Gabriela Chiorean; Susan M Perkins; R Matthew Strother; Anne Younger; Jennifer M Funke; Safi G Shahda; Noah M Hahn; Kumar Sandrasegaran; David R Jones; Todd C Skaar; Bryan P Schneider; Christopher J Sweeney; Daniela E Matei Journal: Mol Cancer Ther Date: 2020-08-26 Impact factor: 6.261