Engineering Personalized Cancer Chemotherapy Schedules

1235182/Parker目前，抗癌药物的临床给药时间表是根据以前使用类似有效药物的经验，结合动物研究和第一阶段试验，通过统计驱动的试错过程来制定的，以确定第二阶段试验的最大耐受剂量和起始剂量。随后的第二阶段试验的结果，当成功时，是一个可行的，但不是最优的给“一般”患者的药物方案。但个体是一个与“平均水平”不同的群体。研究人员采用了系统医学的方法，将医疗实践与严格的系统工程工具相结合，努力改善接受癌症化疗的患者的潜在结果(更好的抗肿瘤效果；更少的毒副作用)。他们将构建的疾病数学模型将从机制和生理学中推导出来，并从现有的临床数据中获得信息。随着将这些模型用于设计新的患者定制的化疗方案的兴趣，研究人员将专注于与控制相关的模型，这意味着适当的复杂性将明确用于基于模型的系统工程算法。最后，它们将明确地将临床问题纳入治疗设计问题的制定中，从而使临床治疗目标和约束将对设计算法返回的化疗时间表提供实际限制。为了将这些结果有效地转化为临床实践，研究人员将重点放在两种一线化疗药物上：吉西他滨和多西他赛。

1235182/ ParkerThe clinical schedule of administration for anticancer agents is developed currently through a statistically-driven trial-and-error process based on previous experience with similar effective agents, in combination with animal studies and Phase I trials, to establish maximum tolerated dose (MTD) and starting dose for Phase II trials. The result of the ensuing Phase II trial, when successful, is a feasible, but suboptimal, schedule for a drug administered to an "average" patient. But individuals are a population of differences from the "average". The researchers employ a systems medicine approach, interfacing medical practice with rigorous systems engineering tools in an effort to improve the potential outcomes (better antitumor effect; fewer toxic side effects) for patients receiving chemotherapy for treatment of cancer. The mathematical models of disease that they will construct will be derived from mechanism and physiology and informed from available clinical data. With an interest in using these models for the design of novel patient-tailored chemotherapy treatment schedules, the researchers will focus on models that are control-relevant, meaning of suitable complexity to be used explicitly in model-based systems engineering algorithms. Finally, they will explicitly incorporate clinical concerns in the treatment design problem formulation, such that clinical treatment objectives and constraints will provide practical limits on the chemotherapy schedules returned by the design algorithm. With an eye to translating these results efficiently to clinical practice, the researchers focus on two first-line chemotherapeutics: gemcitabine and docetaxel.