Electrocardiograms (ECGs) in phase I anticancer drug development: the MD Anderson Cancer Center experience with 8518 ECGs
Electrocardiograms (ECGs) in phase I anticancer drug development: the MD Anderson Cancer Center experience with 8518 ECGs
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DOI：
10.1093/annonc/mds130
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发表时间：
2012-11-01
影响因子：
50.5
通讯作者：
Kurzrock, R.
中科院分区：
文献类型：
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作者：
Naing, A.;Veasey-Rodrigues, H.;Kurzrock, R.
肿瘤药物的心脏后遗症是早期癌症药物开发的重要内容。非心脏类药物的校正QT间期（QTc）延长是美国食品和药物管理局（fda）导致药物开发延迟、不批准和上市后撤回的最常见原因。从2006年1月1日开始，我们分析了525名连续癌症患者的8518张心电图（ecg），这些患者参加了22项行业资助的I期临床试验。74例基线时QTc正常的患者[14%，95%可信区间（CI） 11% ~ 17%]在治疗开始后QTc间隔高于正常上限；33例（6%,95% CI 4% ~ 9%）患者在基线时QTc间隔延长，只有1例（3%,95% CI 0% ~ 16%）患者在给药后病情恶化。33例基线QTc延长的患者中有7例（21%，95% CI 9%至39%）在给药后QTc间隔正常化。所有QTc延长均无临床意义；研究药物继续顺利进行。525例患者中有2例（0.4%,95% CI 0% - 1%）出现心脏严重不良事件（心肌梗死可能与药物相关，不稳定心房扑动与转移性疾病相关）。两种心脏事件均通过临床评估而非监测心电图检测。在525例早期试验患者中，频繁的心电图监测没有提供有临床意义的信息。
Cardiac sequelae from oncologic drugs are important in early cancer drug development. Prolongation of the corrected QT interval (QTc) by noncardiac drugs is the most common cause of drug development delays, nonapprovals and postmarketing withdrawals by the US Food and Drug Administration.We analyzed 8518 electrocardiograms (ECGs) in 525 consecutive cancer patients enrolled in 22 industry-sponsored phase I clinical trials, starting 1 January 2006.Seventy-four patients [14%, 95% confidence interval (CI) 11% to 17%] with normal QTc at baseline had QTc intervals above upper limit of normal after treatment initiation; 33 (6%, 95% CI 4% to 9%) had prolonged QTc intervals at baseline, and only one (3%, 95% CI 0% to 16%) worsened after dosing. Seven of 33 patients (21%, 95% CI 9% to 39%) with prolonged baseline QTc had normalization of QTc intervals after dosing. All QTc prolongations were clinically insignificant; study drugs were continued uneventfully. Two of 525 patients (0.4%, 95% CI 0% to 1%) experienced cardiac serious adverse events (myocardial infarction possibly related to drug and unstable atrial flutter related to metastatic disease). Both cardiac events were detected by clinical assessment, not surveillance ECGs.Frequent ECG monitoring provided no clinically significant information in 525 patients in early phase trials.