Drug Dose Per Kilogram Lean Body Mass Predicts Hematologic Toxicity From Carboplatin-Doublet Chemotherapy in Advanced Non-Small-Cell Lung Cancer
Drug Dose Per Kilogram Lean Body Mass Predicts Hematologic Toxicity From Carboplatin-Doublet Chemotherapy in Advanced Non-Small-Cell Lung Cancer
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DOI：
10.1016/j.cllc.2016.09.008
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发表时间：
2017-03-01
影响因子：
3.6
通讯作者：
Jordhoy, Marit
中科院分区：
文献类型：
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作者：
Sjoblom, Bjorg;Benth, Jurate Saltyte;Jordhoy, Marit
瘦体重（LBM）的变化被认为是癌症药物毒性的个体间差异。在接受卡铂双联治疗的晚期非小细胞肺癌患者中，按体表面积计算的非铂类药物每千克LBM剂量是3/4级血液学毒性的重要独立预测因子。考虑到身体成分可能会提高剂量个性化的化疗agents.Background：瘦体重（LBM）的变化已被建议解释全身癌症治疗的毒性变化。我们研究了在IIIB/IV期非小细胞肺癌（NSCLC）患者中，每千克LBM的药物剂量是否与严重血液学毒性（HT）相关，这些患者参加了比较一线卡铂双联治疗的随机试验。患者与方法：患者接受卡铂（AUC [血药浓度-时间曲线下面积] = 5）联合培美曲塞500 mg/m2、吉西他滨1000 mg/m2或长春瑞滨60 mg/m2（2）。LBM是根据计算机断层扫描第三腰椎的横截肌肉面积估计的。第一周期第1天的给药剂量重新计算为每千克LBM的药物毫克数。主要结局为第1周期后不良事件通用术语标准3.0版3/4级HT。结果：共分析了424例患者的数据。平均年龄为65岁，57%为男性，78%为IV期疾病。尽管非铂类药物按体表面积进行了剂量个体化，但以mg/kg LBM表示的平均（范围）剂量与3倍范围相似：吉西他滨38.0（22.5-61.7）mg/kg LBM、培美曲塞19.1（8.1-27.9）mg/kg LBM和长春瑞滨2.4（1.4-3.6）mg/kg LBM。对于这些药物，在调整的多变量模型中，每公斤LBM的剂量与HT相关（P = .004）。以每种药物每千克LBM的平均剂量为参考，增加1%（比值比[OR] = 1.03; 95%置信区间[CI]，1.01-1.06）或减少1%（OR = 0.97; 95% CI，0.95-0.99）与3/4级HT风险改变相关。对于高于和低于平均值> 20%的剂量（分别为14%和15%的患者），3/4级HT的风险几乎分别增加一倍（OR = 1.93，95%CI，1.21-3.10）和减半（OR = 0.52; 95%CI，0.32-0.83）。结论：每公斤LBM的剂量变化很大，是HT的独立预测因子。计算机断层扫描定义的LBM可能为更好的剂量个体化提供未来的基础。(C)2016 Elsevier Inc. All rights reserved.
Variations in lean body mass (LBM) are proposed to contribute to interindividual differences in toxicity from cancer drugs. In advanced non-small-cell lung cancer patients receiving carboplatin-doublets, dose per kilogram of LBM of the nonplatinum drug dosed by body surface area was a significant independent predictor of grade 3/4 hematologic toxicity. Taking body composition into account may improve dose individualization of chemotherapeutic agents.Background: Variations in lean body mass (LBM) have been suggested to explain variations in toxicity from systemic cancer treatment. We investigated if drug doses per kilogram of LBM were associated with severe hematologic toxicity (HT) in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) enrolled onto randomized trials comparing first-line carboplatin-doublets. Patients and Methods: Patients received carboplatin (AUC [area under the plasma concentration vs. time curve] = 5) plus either pemetrexed 500 mg/m2, gemcitabine 1000 mg/m2, or vinorelbine 60 mg/m(2). LBM was estimated from the cross-sectional muscle area at the third lumbar vertebra on computed tomographic scans. Administered doses on day 1, first cycle, were recalculated as milligram of drug per kilogram of LBM. Primary outcome was Common Terminology Criteria for Adverse Events version 3.0 grade 3/4 HT after cycle 1. Results: Data from 424 patients were analyzed. Mean age was 65 years, 57% were men, and 78% had stage IV disease. Despite dose individualization by body surface area for the nonplatinum drugs, mean (range) doses expressed as mg/kg LBM showed similar to 3-fold range: gemcitabine 38.0 (22.5-61.7) mg/kg LBM, pemetrexed 19.1 (8.1-27.9) mg/kg LBM, and vinorelbine 2.4 (1.4-3.6) mg/kg LBM. For these drugs, dose per kilogram of LBM was associated with HT in adjusted multivariate models (P = .004). Taking mean dose per kilogram LBM for each drug as reference, a 1% increase (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.01-1.06) or 1% decrease (OR = 0.97; 95% CI, 0.95-0.99) was associated with altered risk of grade 3/4 HT. For doses > 20% above and below mean (14% and 15% of patients, respectively) the risk of grade 3/4 HT was almost doubled (OR = 1.93, 95% CI, 1.21-3.10) and halved (OR = 0.52; 95% CI, 0.32-0.83), respectively. Conclusion: Dose per kilogram of LBM varied considerably and was an independent predictor of HT. Computed tomography-defined LBM may provide a future basis for better dose individualization. (C) 2016 Elsevier Inc. All rights reserved.