The application of mathematical modelling to aspects of adjuvant chemotherapy scheduling
The application of mathematical modelling to aspects of adjuvant chemotherapy scheduling
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DOI：
10.1007/s00285-003-0246-2
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发表时间：
2004-04-01
影响因子：
1.9
通讯作者：
Gaffney, EA
中科院分区：
文献类型：
--
作者：
Gaffney, EA
在本文中，简单的模型，肿瘤生长纳入年龄结构的细胞周期动力学被认为是在存在两个非交叉耐药的S期特异性化疗药物。根据Goldie和Coldman的开创性工作，如果不能同时递送两种细胞周期阶段非特异性、非交叉耐药的药物，例如由于毒性，并且两种药物除了耐药性之外是相同的，则应尽可能快地交替递送。人们可能会推测，例如，以T的间隔交替两种药物，其中T是平均细胞周期时间，比以T/2的间隔交替药物更好，因为后一种策略允许细胞周期保护区的可能性。这种推测隐含地要求细胞周期时间的方差足够低，因此不清楚这种推理是否阻止了Goldie和Coldman结果的推广。本文通过详细的建模研究解决了这个问题，为未来的结直肠辅助化疗试验和肝动脉灌注技术的发展提出了建议。结果表明，耐药细胞群体的细胞周期分布受到化疗方案的强烈影响。其后果可能是戏剧性的，并且可能导致在共振化疗时间的化疗失败，特别是对于细胞周期时间的小标准偏差。与文献中的其他模型相比，这种观察的新方面突出显示了在定期化疗方案的时机中表现出共振行为。上述研究还导致本文的主要预测，如果可能的话，将药物交替时间减少到大约几个小时，可以导致预测的化疗结果的实质性改善。关键是，Goldie Coldman模型或文献中的其他化疗计划模型无法预测此类改善。
In this paper simple models for tumour growth incorporating age-structured cell cycle dynamics are considered in the presence of two non-cross-resistant S-phase specific chemotherapeutic drugs. According to the seminal work of Goldie and Coldman, if one cannot deliver two cell cycle phase non-specific, non-cross-resistant drugs simultaneously, for example due to toxicity, and both drugs are identical apart from resistance, one should alternate their delivery as rapidly as possible.However consider S-phase specific drugs. One might speculate that, for example, alternating the two drugs at intervals of T, where T is the mean cell cycle time, is better than alternating the drugs at intervals of T/2, as the latter strategy allows the possibility of a cell cycle sanctuary. Such speculation implicitly requires a sufficiently low variance of the cell cycle time, and hence it is not clear if such reasoning prevents a generalisation of the results of Goldie and Coldman. This question is addressed in this paper via a detailed modelling investigation, as motivated by suggestions for future colorectal adjuvant chemotherapy trials and developments in hepatic arterial infusion technology. It is shown that the cell cycle distribution of the resistant cell populations is strongly influenced by the chemotherapy schedule. The consequences of this can be dramatic, and can lead to chemotherapy failure at resonant chemotherapy timings, especially for a small standard deviation of the cell cycle time. The novel aspects of this observation are highlighted compared to other models in the literature exhibiting resonant behaviour in the timing of a periodic chemotherapy protocol. The above investigation also results in the principal prediction of this paper that reducing the drug alternation time to approximately a few hours, if possible, can result in substantial improvements in predicted chemotherapy outcomes. Critically, such improvements are not predicted by the Goldie Coldman model or other chemotherapy scheduling models in the literature.