Comparison of Two Mitotane Starting Dose Regimens in Patients With Advanced Adrenocortical Carcinoma
Comparison of Two Mitotane Starting Dose Regimens in Patients With Advanced Adrenocortical Carcinoma
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DOI：
10.1210/jc.2013-2281
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发表时间：
2013-12-01
影响因子：
5.8
通讯作者：
Fassnacht, M.
中科院分区：
文献类型：
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作者：
Kerkhofs, T. M.;Baudin, E.;Fassnacht, M.
背景：米托坦是唯一批准用于治疗肾上腺皮质癌的药物。其药代动力学特性尚未完全阐明，不同的给药方案从未进行过头对头比较。目的：本研究的目的是调查米托坦剂量和血浆浓度之间的关系，比较两种给药方案。设计/设置：这是一项前瞻性、开放标签、多中心试验，预定持续时间为12周。患者/干预措施：40例未接受过丝裂霉素治疗的转移性肾上腺皮质癌患者由当地研究者分配至预定的低剂量或高剂量方案。32名患者可以进行详细的评估。主要结果测量：测量两个治疗组之间米托坦血浆浓度中位数的差异。尽管平均累积剂量存在差异（440 +/- 142 g vs 272 +/- 121 g），两组间的中位最大血浆水平无显著差异[高剂量14.3 mg/L（范围6.3-29.7，n = 20）vs 11.3 mg/L（范围5.5-20.0，n = 12），P = .235]。高剂量方案组20例患者中有10例在46天后（范围18-81 d）达到14 mg/L或更高的血药浓度，而低剂量方案组12例患者中有4例在55天后（范围46-74 d，P = 0.286）达到14 mg/L或更高的血药浓度。所有在第12周达到14 mg/L的患者在第33天的水平为4.1 mg/L或更高（100%灵敏度）。不良事件的频率和严重程度无显著差异。在未接受伴随化疗的患者中，高剂量组的米托坦暴露较高：1013 +/- 494 mg/L.d vs 555 +/- 168 mg/L.d（P = .080）。结论：高剂量起始方案既未导致米托坦水平的显著差异，也未导致不良事件发生率的显著差异，但伴随化疗影响这些结果。因此，对于米托坦单药治疗，高剂量方法是有利的，而对于联合治疗，较低剂量似乎是合理的。
Context: Mitotane is the only approved drug for treatment of adrenocortical carcinoma. Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head to head.Objective: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens.Design/Setting: This was a prospective, open-label, multicenter trial of a predefined duration of 12 weeks.Patients/Interventions: Forty mitotane-naive patients with metastatic adrenocortical carcinoma were assigned to a predefined low-or high-dose regimen by the local investigator. Thirty-two patients could be evaluated in detail.Main Outcome Measure: The difference in median mitotane plasma levels between both treatment groups was measured.Results: Despite a difference in mean cumulative dose (440 +/- 142 g vs 272 +/- 121 g), median maximum plasma levels were not significantly different between the two groups [high dose 14.3 mg/L (range 6.3-29.7, n = 20) vs 11.3 mg/L (range 5.5-20.0, n = 12), P = .235]. Ten of 20 patients onthe high-dose regimen reached plasma concentrations of 14 mg/L or greater after 46 days (range 18-81 d) compared with 4 of 12 patients on the low-dose regimen after 55 days (range 46-74 d, P = .286). All patients who reached 14 mg/L at 12 weeks displayed a level of 4.1 mg/L or greater on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013 +/- 494 mg/L.d vs 555 +/- 168 mg/L.d (P = .080).Conclusions: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.