Castro Michael P, Quinn Jameson, Wasserman Asher, Awawda Alaa, Cole Zachariah D, Shapiro Mark A, Stuhlmiller Timothy J, Kesari Santosh
Beverly Hills Cancer Center, Beverly Hills, California, USA.
xCures Inc., Oakland, California, USA.
Neurooncol Pract. 2024 May 8;11(6):713-722. doi: 10.1093/nop/npae044. eCollection 2024 Dec.
Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity during glioblastoma (GBM) treatment, but were recently identified as strong inducers of aldehyde dehydrogenase-1A1 (ALDH1A1). ALDH1A1 is a primary metabolic enzyme impacting the outcome of chemotherapy, including temozolomide. High expression of ALDH1A1 is associated with poor prognosis in multiple cancers, suggesting PPIs may have a negative impact on survival.
Real-world data on GBM patients was annotated from electronic medical records (EMR) according to the prospective observational study, XCELSIOR (NCT03793088). Patients with known mutations were excluded. Causal effects on survival were analyzed using a multivariate, time-varying Cox Proportional Hazard (CPH) model with stratifications including methylation status, age, sex, duration of corticosteroid use, extent of resection, starting standard-of-care, and PPI use.
EMR data from 554 GBM patients across 225 cancer centers was collected, with 72% of patients receiving care from academic medical centers. Patients treated with PPIs (51%) had numerically lower median overall survival (mOS) and 2-year OS rates in the total population and across most strata, with the greatest difference for MGMT-methylated patients (mOS 29.2 vs. 40.1 months). In a time-varying multivariate CPH analysis of the above strata, PPIs caused an adverse effect on survival (HR 1.67 [95% CI: 1.15-2.44], = .007).
Evidence from a nationwide cancer registry has suggested PPIs have a negative impact on OS for GBM patients, particularly those with promoter methylation. This suggests PPIs should be avoided for prophylactic management of gastrointestinal toxicity in patients with GBM receiving chemoradiotherapy.
在胶质母细胞瘤（GBM）治疗期间，质子泵抑制剂（PPI）常被用于处理皮质类固醇引起的胃肠道毒性，但最近被确定为醛脱氢酶-1A1（ALDH1A1）的强效诱导剂。ALDH1A1是一种主要的代谢酶，会影响包括替莫唑胺在内的化疗结果。ALDH1A1的高表达与多种癌症的预后不良相关，这表明PPI可能对生存率产生负面影响。
根据前瞻性观察研究XCELSIOR（NCT03793088），从电子病历（EMR）中注释GBM患者的真实世界数据。排除已知突变的患者。使用多变量、时变Cox比例风险（CPH）模型分析对生存的因果效应，分层因素包括甲基化状态、年龄、性别、皮质类固醇使用时长、切除范围、开始标准治疗以及PPI使用情况。
收集了来自225个癌症中心的554例GBM患者的EMR数据，其中72%的患者在学术医疗中心接受治疗。接受PPI治疗的患者（51%）在总体人群以及大多数分层中，其总生存期（mOS）中位数和2年总生存率在数值上较低，对于MGMT甲基化患者差异最大（mOS分别为29.2个月和40.1个月）。在对上述分层进行的时变多变量CPH分析中，PPI对生存产生了不利影响（风险比1.67 [95%置信区间：1.15 - 2.44]，P = 0.007）。
来自全国癌症登记处的证据表明，PPI对GBM患者的总生存期有负面影响，尤其是那些具有启动子甲基化的患者。这表明在接受放化疗的GBM患者中，应避免使用PPI进行胃肠道毒性的预防性处理。
