University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Drugs Aging. 2024 Feb;41(2):165-176. doi: 10.1007/s40266-023-01084-8. Epub 2023 Dec 20.
While the effectiveness of tyrosine kinase inhibitors (TKIs) seems similar in older patients with gastrointestinal stromal tumors (GIST) compared with younger patients, toxicities in older patients treated with TKIs more often lead to discontinuation of treatment.
To better understand the age-related pharmacology and pharmacodynamic differences in patients with GIST treated with TKIs, the primary aim of this study was to evaluate TKI dosing patterns in older patients with GIST, while the secondary aims were to evaluate differences in imatinib trough plasma concentrations between age groups and to compare the overall survival (OS) in patients with and without dose reductions in all treatment lines in a palliative setting.
Patients (18 years of age or older) with histologically proven GIST diagnosed between January 2009 and June 2021 and treated with one or more lines of TKIs were selected from the Dutch GIST Registry (DGR) database. Age groups were divided into younger patients (age <70 years) and older patients (age ≥70 years). All imatinib trough plasma concentrations of blood withdrawals taken from initiation of imatinib until a maximum of 1 year of treatment with imatinib were collected. Reasons for first adjustment of treatment were classified as adverse event, dose modification, progressive disease and other reasons. The next treatment steps after first adjustment of treatment were defined as dose escalation, dose reduction, dose interruption, or end of treatment. The association of dose reduction and OS was analyzed using the landmark approach.
Overall, 871 patients were included in this study, including 577 younger patients and 294 older patients. Older patients more often had an adverse event as the reason for first adjustment of treatment with both imatinib (45.6%; p < 0.001) and sunitinib (58.6%; p = 0.224) compared with younger patients (19.5% and 42.7%, respectively). Adjustment of imatinib and sunitinib after starting on a standard dose because of an adverse event most often resulted in dose reduction in both age groups. Median trough plasma concentrations of all samples taken within the first year after initiation of imatinib were higher in older patients (1228 ng/mL, interquartile range [IQR] 959-1687) compared with younger patients (1035 ng/mL [IQR 773-1377]; p < 0.001). No significant differences were seen between OS in patients with or without dose reduction in all treatment lines (imatinib: p = 0.270; sunitinib: p = 0.547; and regorafenib: p = 0.784).
Older patients showed higher imatinib trough plasma concentrations compared with younger patients and also had earlier and more often adverse events as the reason for first adjustment of treatment with imatinib followed by dose reduction. However, in a landmark analysis, patients with imatinib dose reductions had no poorer outcomes compared with patients not requiring a dose reduction.
虽然酪氨酸激酶抑制剂（TKI）在老年胃肠道间质瘤（GIST）患者中的疗效似乎与年轻患者相似，但老年患者接受 TKI 治疗时的毒性更常导致治疗中断。
为了更好地了解接受 TKI 治疗的 GIST 患者中与年龄相关的药代动力学和药效动力学差异，本研究的主要目的是评估老年 GIST 患者的 TKI 给药模式，次要目的是评估不同年龄组伊马替尼谷浓度的差异，并比较所有治疗线中剂量减少患者与未剂量减少患者在姑息治疗中的总生存期（OS）。
从荷兰 GIST 登记处（DGR）数据库中选择了 2009 年 1 月至 2021 年 6 月期间经组织学证实的 GIST 诊断且接受一种或多种 TKI 线治疗的患者（年龄≥18 岁）。年龄组分为年轻患者（年龄<70 岁）和老年患者（年龄≥70 岁）。收集了从开始使用伊马替尼到使用伊马替尼治疗最长 1 年期间的所有伊马替尼谷浓度血样。首次调整治疗的原因分为不良反应、剂量调整、疾病进展和其他原因。首次调整治疗后的下一步治疗步骤定义为剂量升级、剂量减少、剂量中断或治疗结束。使用里程碑分析方法分析剂量减少与 OS 的关系。
本研究共纳入 871 例患者，其中 577 例为年轻患者，294 例为老年患者。与年轻患者相比（分别为 19.5%和 42.7%），老年患者因不良反应首次调整治疗的比例更高，伊马替尼（45.6%；p<0.001）和舒尼替尼（58.6%；p=0.224）的比例均更高。由于不良反应开始使用标准剂量后，伊马替尼和舒尼替尼的调整最常导致剂量减少，在两个年龄组中均如此。与年轻患者相比（1035ng/ml [IQR 773-1377]；p<0.001），开始使用伊马替尼后 1 年内所有样本的伊马替尼谷浓度中位数在老年患者中更高（1228ng/ml，四分位距 [IQR] 959-1687）。在所有治疗线中，剂量减少的患者与未剂量减少的患者的 OS 无显著差异（伊马替尼：p=0.270；舒尼替尼：p=0.547；regorafenib：p=0.784）。
与年轻患者相比，老年患者的伊马替尼谷浓度更高，且因不良反应首次调整治疗并随后减少剂量的比例更高。然而，在里程碑分析中，需要伊马替尼剂量减少的患者与不需要剂量减少的患者相比，其结局没有更差。
