Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, PCAM-2 West, 3400 Civic Center Blvd., Philadelphia, PA, 19104, USA.
Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA, USA.
Cancer Chemother Pharmacol. 2018 Mar;81(3):609-614. doi: 10.1007/s00280-018-3519-6. Epub 2018 Jan 23.
Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma.
We performed a phase 1 study using a 3 + 3 dose escalation strategy to determine the safety and tolerability of dose-escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with two cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy.
Nine patients received nab-paclitaxel at a dose level of either 100 mg/m (n = 3) or 125 mg/m (n = 6). There were no observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%) and neutropenia (11%). No grade 4 toxicities were observed. Following chemoradiotherapy, four patients (borderline resectable, n = 2 and unresectable, n = 2) underwent surgical resection, all with negative margins and with significant treatment effect with limited tumor viability.
The combination of fractionated radiation and weekly full dose nab-paclitaxel was safe and well-tolerated.
局部晚期胰腺癌患者的预后通常较差，中位生存期约为 16 个月。需要新的方法来改善治疗效果。白蛋白结合型紫杉醇（Abraxane）在胰腺癌中显示出疗效，并且已被 FDA 批准与吉西他滨联合用于转移性疾病。基于实验室研究，白蛋白结合型紫杉醇也是一种很有前途的放射增敏剂，但从未在局部晚期胰腺癌的根治性放疗中进行过临床测试。
我们进行了一项 1 期研究，采用 3+3 剂量递增策略，以确定不可切除或边缘可切除胰腺癌患者接受递增剂量的nab-紫杉醇联合分割放疗的安全性和耐受性。在接受两个周期的nab-紫杉醇和吉西他滨诱导化疗后，患者接受每周一次的nab-紫杉醇和每日放疗，总剂量为 52.5Gy，共 25 次。在放疗开始后第 65 天确定最终剂量限制毒性（DLT）。
9 名患者接受了nab-紫杉醇剂量为 100mg/m（n=3）或 125mg/m（n=6）。未观察到 3 级胃肠道毒性。1 名接受 125mg/m nab-紫杉醇的患者发生 1 例 DLT（3 级神经病变）。其他 3 级毒性包括疲劳（11%）、贫血（11%）和中性粒细胞减少症（11%）。未观察到 4 级毒性。放化疗后，4 名患者（边缘可切除，n=2 和不可切除，n=2）接受了手术切除，所有患者均切缘阴性，且肿瘤活性有限，治疗效果显著。
分割放疗联合每周全剂量nab-紫杉醇联合治疗安全且耐受良好。
