LOW-INTENSITY COMBINATION CHEMOTHERAPY MAXIMIZES HOST SURVIVAL-TIME FOR TUMORS CONTAINING DRUG-RESISTANT CELLS
LOW-INTENSITY COMBINATION CHEMOTHERAPY MAXIMIZES HOST SURVIVAL-TIME FOR TUMORS CONTAINING DRUG-RESISTANT CELLS
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DOI：
10.1016/0025-5564(92)90039-y
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发表时间：
1992-07-01
影响因子：
4.3
通讯作者：
TEO, KL
中科院分区：
文献类型：
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作者：
MARTIN, RB;FISHER, ME;TEO, KL
最近的临床试验表明，对于某些癌症，与非交替疗法相比，高强度交替化疗并不能显著改善生存时间或反应率。目前的研究使用最佳控制来确定治疗含有不能被破坏的耐药细胞的肿瘤的最佳方法。两种非交叉耐药化疗剂的递送受到药物浓度和剂量强度的限制。这确保了药物毒性保持在可耐受的范围内。该疗法的目的是最大限度地延长宿主存活时间，其定义为肿瘤负荷可以保持在固定范围以下的时间。该模型是作为一个自由的终端时间，最优参数选择问题，其中的约束条件是连续参数化的时间和治疗的疗程数是自由变化的。新的理论开发，使最优参数选择问题可以解决作为一个序列的固定终端时间的问题，使用现有的最优控制软件。Gompertz肿瘤生长的数值模拟显示，在积极治疗下，维持高肿瘤负荷的治疗随着生存时间增加一倍，有时增加两倍。当使用指数和逻辑肿瘤生长模型重复这些模拟时，治疗期间的肿瘤负荷对生存时间几乎没有影响。在所有模拟中，通过同时递送抗癌药物而不是错开治疗组，生存时间没有延长。
Recent clinical trials have shown that for some cancers, high-intensity alternating chemotherapy does not significantly improve either survival times or response rates compared with nonalternating therapy. The current study uses optimal control to determine the best way to treat a tumor that contains drug-resistant cells that cannot be destroyed. The delivery of two non-cross-resistant chemotherapeutic agents is limited by bounds on the drug concentration and the dose intensity. This ensures that the drug toxicity stays within a tolerable range. The aim of the therapy is to maximize the host survival time, defined as the time over which the tumor burden can be kept below a fixed bound. The model is posed as a free terminal time, optimal parameter selection problem in which the constraints are continuously parametrized by time and the number of courses of therapy is free to vary. New theory is developed so that the optimal parameter selection problem can be solved as a sequence of fixed terminal time problems using existing optimal control software. Numerical simulations of Gompertz tumor growth showed that a treatment maintaining a high tumor burden doubled and sometimes tripled with survival time under aggressive therapy. When these simulations were repeated using exponential and logistic tumor growth models, the tumor burden during treatment had little influence upon survival time. In all simulations, survival time was not extended by delivering the anticancer drugs concurrently instead of staggering the treatment arms.