Division of Medical Oncology, Department of Internal Medicine, Washington University, St. Louis, Missouri.
Section of Hematology/Oncology, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
Clin Cancer Res. 2023 Dec 1;29(23):4733-4739. doi: 10.1158/1078-0432.CCR-23-1405.
Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma.
Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2).
Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.
维生素 D 类似物重塑纤维性基质，并改善临床前胰腺癌模型中化疗的血管生成和疗效。
我们进行了一项试点研究，以评估维生素 D 类似物帕立骨化醇与纳米脂质体伊立替康（Nal-iri）联合 5-氟尿嘧啶/亚叶酸（5-FU/LV）联合治疗在吉西他滨治疗后进展的晚期胰腺癌患者中的安全性和初步疗效。测试了帕立骨化醇的两个剂量水平（DL）：固定剂量每周（75 mcg，DL1）和基于体重的每周（7 mcg/kg，DL2）。主要终点是安全性，次要终点包括总缓解率、无进展生存期（PFS）和总生存期（OS）。相关目标旨在确定反应的分子预测因子和肿瘤基质的变化。
2021 年 3 月至 5 月期间，共招募了 20 名患者（DL1 组和 DL2 组各 10 名）。未观察到与帕立骨化醇相关的 3/4 级不良事件。最常见的毒性反应是恶心、腹泻和疲劳，两个队列中相似。3 名患者在一个周期后停止研究，无法进行影像学评估。在其余 17 名可评估的患者中，2 名患者有部分缓解，12 名患者有稳定疾病。DL1 组可评估患者的中位 PFS 为 4.14 个月，DL2 组为 4.83 个月。DL1 和 DL2 的意向治疗中位 OS 分别为 6.15 个月和 6.66 个月。相关研究表明，接受较高剂量帕立骨化醇（DL2）治疗的患者的肿瘤血管密度增加。
帕立骨化醇每周 7 mcg/kg/周联合 Nal-iri/5-FU/LV 安全耐受，可能增加肿瘤血管生成，值得进一步研究。
