Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana; Department of Medicine, University of Washington, Seattle, Washington.
Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
Int J Radiat Oncol Biol Phys. 2014 Jun 1;89(2):284-91. doi: 10.1016/j.ijrobp.2014.02.024. Epub 2014 Apr 11.
To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer.
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).
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.
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.
定义索拉非尼联合吉西他滨为基础的放化疗（CRT）治疗局部晚期胰腺癌的安全性、疗效、遗传药理学和药效学作用。
患者在 CRT 前接受吉西他滨 1000mg/m2 静脉注射每周 3 次，每个周期 4 周，CRT 后最多进行 4 个周期。在 25 个分次中，每周给予吉西他滨 600mg/m2 静脉注射，同时给予 50Gy 的强度调节放射治疗。索拉非尼口服剂量为每天 2 次，每次 400mg，直到疾病进展，除了在 CRT 期间，剂量从每天 200mg 增加到 400mg，每天 2 次。最大耐受剂量队列扩展到 15 例患者。相关研究包括动态对比增强 MRI 和血管生成基因多态性（VEGF-A 和 VEGF-R2 单核苷酸多态性）。
共纳入 27 例患者。诱导吉西他滨/索拉非尼后联合 CRT 无剂量限制毒性。最常见的 3/4 级毒性是疲劳、血液学和胃肠道毒性。最大耐受剂量为索拉非尼每天 2 次，每次 400mg。25 例可评价患者的中位无进展生存期和总生存期分别为 10.6 个月和 12.6 个月。VEGF-A-2578AA、-1498CC 和-1154AA 与替代基因型相比，患者的中位总生存期为 21.6 个月和 14.7 个月。动态对比增强 MRI 显示，反应患者的基线 K(trans)更高。
在局部不可切除的胰腺癌中，索拉非尼联合 CRT 具有适度的临床活性，但胃肠道毒性增加。特定的 VEGF-A/VEGF-R2 基因型与良好的生存相关。
