Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Int J Radiat Oncol Biol Phys. 2014 Jul 15;89(4):830-8. doi: 10.1016/j.ijrobp.2014.03.034. Epub 2014 May 24.
To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients.
Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood.
The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05).
This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.
在一项 1/2 期研究中，评估短程质子束放疗和卡培他滨在可切除、经活检证实的胰腺导管腺癌（PDAC）患者中的安全性、疗效和生物标志物。
对影像学可切除、经活检证实的 PDAC 患者进行新辅助短程（2 周）质子基放疗联合卡培他滨，然后进行手术和辅助 gemcitabine 治疗。主要目标是证明毒性≥3 级的发生率<20%。使用手术标本组织和外周血进行了探索性生物标志物研究。
2 期剂量确定为 5 天 5GyE。共入组 50 例患者，其中 35 例进入 2 期部分。无 4 或 5 级毒性，仅 2 例患者（4.1%）出现 3 级毒性事件（胸壁痛 1 级，结肠炎 1 级）。48 例可分析患者中，37 例接受了胰十二指肠切除术。37 例中有 30 例（81%）有阳性淋巴结。37 例切除患者中有 6 例（16.2%）发生局部区域复发，48 例患者中有 35 例（72.9%）发生远处复发。中位随访 38 个月，全组中位无进展生存期为 10 个月，总生存期为 17 个月。生物标志物研究表明，生存结果较差与 KRAS 点突变从甘氨酸变为天冬氨酸 12 位、基质 CXCR7 表达以及循环生物标志物 CEA、CA19-9 和 HGF 均显著相关（均 P<.05）。
本研究通过显示新辅助短程质子基放化疗的 3 级毒性发生率为 4.1%，达到了主要终点。治疗与良好的局部控制相关。在探索性分析中，KRAS(G12D)状态、高 CXCR7 表达以及循环 CEA、CA19-9 和 HGF 水平与不良生存相关。
