一种随机对照试验，评估药理性维生素C联合吉西他滨和纳米紫杉醇治疗转移性胰腺癌的疗效

A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer

Redox Biology

影响因子:11.9

分区:生物学1区 Top / 生化与分子生物学1区

发表日期:2024 Nov

作者: Kellie L Bodeker, Brian J Smith, Daniel J Berg, Chandrikha Chandrasekharan, Saima Sharif, Naomi Fei, Sandy Vollstedt, Heather Brown, Meghan Chandler, Amanda Lorack, Stacy McMichael, Jared Wulfekuhle, Brett A Wagner, Garry R Buettner, Bryan G Allen, Joseph M Caster, Barbara Dion, Mandana Kamgar, John M Buatti, Joseph J Cullen

DOI: 10.1016/j.redox.2024.103375

摘要

转移性胰腺导管腺癌（PDAC）患者的5年生存率较低。药理性维生素C（P-AscH-，高剂量静脉注射，维生素C）作为化疗的辅助疗法显示出潜力。我们假设在吉西他滨和纳米紫杉醇基础上加入P-AscH-，可以提高转移性胰腺癌患者的生存率。诊断为IV期胰腺癌的患者随机分为两组：一组接受仅吉西他滨与纳米紫杉醇（标准治疗，控制组），另一组在标准治疗基础上同时接受每周三次、每次75 g的P-AscH-（研究组）。主要观察指标为总生存期，次要指标包括无进展生存期和不良事件发生率。作为探索性目标，收集生活质量和患者报告的常见肿瘤相关症状。共36名参与者被随机分配，实际接受治疗的为34名。所有分析基于2023年12月11日冻结的数据。静脉注射P-AscH-显著提升血清维生素C水平，从微摩尔级升至毫摩尔级。加入P-AscH-的治疗组（ASC）总生存期中位数为16个月，而控制组（SOC）为8.3个月（风险比HR=0.46；90%置信区间CI 0.23-0.92；p=0.030）。无进展生存期中位数为6.2（ASC）对比3.9（SOC）个月（HR=0.43；90% CI 0.20-0.92；p=0.029）。加入P-AscH-未对生活质量产生负面影响，也未增加不良事件的频率或严重程度。每周三次、每次75 g的P-AscH-在转移性胰腺癌患者中延长了总生存期和无进展生存期，且未影响生活质量或增加毒性（临床试验注册号NCT02905578）。

Abstract

Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC.Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH-, 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023.Intravenous P-AscH- increased serum ascorbate levels from micromolar to millimolar levels. P-AscH- added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH- did not negatively impact quality of life or increase the frequency or severity of adverse events.P-AscH- infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578).