Rigshospitalet, Copenhagen University Hospital, and Department of Oncology 5073, University of Copenhagen, 9 Blegdamsvej, Copenhagen, DK-2100, Denmark.
J Clin Oncol. 2010 Dec 20;28(36):5280-6. doi: 10.1200/JCO.2009.27.3953. Epub 2010 Nov 15.
Fluorouracil (FU) is a cornerstone of colorectal cancer treatment; however, it has clinical and subclinical influence on the heart. This study aimed to clarify the pathophysiology, risk factors, and long-term effects of FU cardiotoxicity.
The study prospectively accrued colorectal cancer patients (n=106) completely resected and adjuvantly treated with FU and oxaliplatin according to the FOLFOX4 regimen (infusional FU, folinic acid, and oxaliplatin). Serial measurements were made of systolic and diastolic features of the left ventricle by radionuclide ventriculography, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), lactic acid, and ECG before chemotherapy, immediately after a treatment infusion, and at follow-up 2 weeks after cessation of the intended 12 treatment courses and were further evaluated by multivariate regression analysis that included cardiovascular history and its risk factors.
In the entire cohort, NT-proBNP significantly increased from baseline 14.5±3.2 pmol/L (mean±standard error) to 28.3±5.3 pmol/L during FU therapy (P<.001). Nine patients (8.5%) with cardiotoxicity had significantly higher NT-proBNP of 55.3±40.8 pmol/L compared with 25.4±4.1 pmol/L in those without (P<.001). In multivariate analysis, the FU-induced rise of NT-proBNP was significantly higher in females (P<.001). Plasma lactic acid significantly increased from baseline (1.3±0.1 mmol/L to 1.8±0.1 mmol/L) during FU therapy (P<.001). Left ventricular ejection fraction at baseline of 0.66±0.01 remained unchanged at 0.65±0.01 during FU therapy and 0.66±0.01 at follow-up (P=.4).
FU therapy generally induces myocardial neuroendocrine changes with increasing plasma NT-proBNP and lactic acid but without long-term dysfunction of the left ventricle. The usability of NT-proBNP as a predictive marker for FU cardiotoxicity remains to be clarified.
氟尿嘧啶（FU）是结直肠癌治疗的基石，但它对心脏具有临床和亚临床影响。本研究旨在阐明 FU 心脏毒性的病理生理学、危险因素和长期影响。
本研究前瞻性纳入了 106 例完全切除并接受 FU 和奥沙利铂辅助治疗的结直肠癌患者，采用 FOLFOX4 方案（静脉输注 FU、亚叶酸和奥沙利铂）。通过放射性核素心室造影术连续测量左心室收缩和舒张功能，在化疗前、治疗输注后即刻以及在停止预期的 12 个疗程治疗后 2 周进行血浆 N 末端脑利钠肽前体（NT-proBNP）、乳酸和心电图测量，并通过包括心血管病史及其危险因素的多变量回归分析进行进一步评估。
在整个队列中，NT-proBNP 从基线时的 14.5±3.2 pmol/L（平均值±标准误差）显著增加到 FU 治疗期间的 28.3±5.3 pmol/L（P<.001）。9 例（8.5%）出现心脏毒性的患者的 NT-proBNP 明显更高，为 55.3±40.8 pmol/L，而无心脏毒性的患者为 25.4±4.1 pmol/L（P<.001）。多变量分析显示，FU 引起的 NT-proBNP 升高在女性中显著更高（P<.001）。血浆乳酸从基线（1.3±0.1 mmol/L）显著增加至 1.8±0.1 mmol/L（P<.001）。FU 治疗期间左心室射血分数从基线时的 0.66±0.01 保持不变，在 FU 治疗期间为 0.65±0.01，在随访时为 0.66±0.01（P=.4）。
FU 治疗通常会引起心肌神经内分泌变化，导致血浆 NT-proBNP 和乳酸升高，但左心室无长期功能障碍。NT-proBNP 作为 FU 心脏毒性预测标志物的可用性仍需进一步阐明。
