Schmidt Marieke, Vernooij Robin, van Nuland Merel, Smeijsters Erin, Devriese Lot, Mohammad Nadia Haj, Hermens Thom, Stammers Julian, Swart Christina, Egberts Toine, Haitjema Saskia, Lammers Laureen
Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands.
Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
BMC Cancer. 2024 Dec 18;24(1):1553. doi: 10.1186/s12885-024-13330-2.
The anticancer drug paclitaxel is primarily metabolized in the liver. Previous studies have indicated a correlation between impaired liver function and paclitaxel toxicity, which may indicate dose reduction. Since the evidence is limited, the aim of this study was to investigate the effect of impaired liver function on the hematological toxicity of paclitaxel, dose modifications and overall survival (OS).
For this single-center retrospective observational study, patients treated with paclitaxel for breast, esophageal and ovarian cancer at the University Medical Centre Utrecht between 2011 and 2022 were identified from the Utrecht Patient Oriented Database (UPOD). Based on regression analysis, the risk of developing Grade 3/4 hematological toxicity was compared between patients with normal and impaired (based on the NCI criteria for bilirubin and ASAT (aspartate aminotransferase) concentrations) liver function. Additionally, differences in the occurrence of toxicity-related dose modifications and OS were evaluated between the two groups.
A total of 569 patients were included. Breast cancer patients who were receiving advanced treatment and had mildly impaired liver function (ASAT ≤ 2x ULN, bilirubin ≤ ULN) had an increased risk of developing grade 3/4 neutropenia (HR = 4.39, 95% CI 1.20-16.02; p = 0.03). In addition, patients with impaired liver function treated according to the advanced ovarian cancer regimen had an increased risk of developing grade 3/4 leukopenia (HR = 12.64, 95% CI 2.12-75.22, p = 0.01) and dose modification (treatment discontinuation) (HR = 3.91, 95% CI 1.74-8.79, p < 0.01). Impaired liver function was also associated with decreased OS in inoperable esophageal and advanced ovarian cancer patients (HR = 7.65, 95% CI 2.54-23.1, p < 0.01 and HR = 2.98, 95% CI 1.36-6.54, p < 0.01, respectively). The risk of developing grade 3/4 hematological toxicity during lower-dose paclitaxel treatment protocols was not significantly different in patients with impaired liver function.
This study revealed that patients with impaired liver function treated with paclitaxel for breast and ovarian cancer in an advanced setting are at greater risk of developing hematological toxicity than patients with normal liver function at the start of therapy. Furthermore, in patients with ovarian (advanced) or inoperable esophageal cancer, impaired liver function is associated with decreased OS. Within these groups of patients, it is important to weigh the risk of upfront paclitaxel dose modifications versus an adaptive strategy.
抗癌药物紫杉醇主要在肝脏中代谢。先前的研究表明肝功能受损与紫杉醇毒性之间存在关联，这可能表明需要降低剂量。由于证据有限，本研究的目的是调查肝功能受损对紫杉醇血液学毒性、剂量调整和总生存期（OS）的影响。
在这项单中心回顾性观察研究中，从乌得勒支患者导向数据库（UPOD）中识别出2011年至2022年期间在乌得勒支大学医学中心接受紫杉醇治疗乳腺癌、食管癌和卵巢癌的患者。基于回归分析，比较肝功能正常和受损（根据美国国立癌症研究所胆红素和天冬氨酸转氨酶（ASAT）浓度标准）的患者发生3/4级血液学毒性的风险。此外，评估两组之间毒性相关剂量调整和总生存期发生情况的差异。
共纳入569例患者。接受晚期治疗且肝功能轻度受损（ASAT≤2倍正常上限，胆红素≤正常上限）的乳腺癌患者发生3/4级中性粒细胞减少的风险增加（风险比[HR]=4.39，95%置信区间[CI]1.20-16.02；p=0.03）。此外，按照晚期卵巢癌方案治疗的肝功能受损患者发生3/4级白细胞减少的风险增加（HR=12.64，95%CI 2.12-75.22，p= 0.01）以及剂量调整（治疗中断）的风险增加（HR=3.91，95%CI 1.74-8.79，p<0.01）。肝功能受损还与无法手术的食管癌和晚期卵巢癌患者的总生存期缩短相关（HR分别为7.65，95%CI 2.54-23.1，p<0.01和HR=2.98，95%CI 1.36-6.54，p<0.01）。在低剂量紫杉醇治疗方案期间，肝功能受损患者发生3/4级血液学毒性的风险无显著差异。
本研究表明，在晚期情况下接受紫杉醇治疗的肝功能受损的乳腺癌和卵巢癌患者，在治疗开始时发生血液学毒性风险高于肝功能正常的患者。此外，在卵巢（晚期）或无法手术的食管癌患者中，肝功能受损与总生存期缩短相关。在这些患者群体中，权衡预先调整紫杉醇剂量与采用适应性策略的风险很重要。
