Faculty of Mathematics and Computer Science, University of Warmia and Mazury in Olsztyn, Sloneczna 54, 10-710, Olsztyn, Poland.
Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Banacha 2, 02-097, Warsaw, Poland.
J Cancer Res Clin Oncol. 2021 Aug;147(8):2281-2299. doi: 10.1007/s00432-021-03657-9. Epub 2021 May 29.
Chemotherapy remains a widely used cancer treatment. Acquired drug resistance may greatly reduce the efficacy of treatment and means to overcome it are a topic of active discussion among researchers. One of the proposed solutions is to shift the therapeutic paradigm from complete eradication of cancer to maintenance, i.e., to treat it as a chronic disease. A concept of metronomic therapy (low chemotherapy doses applied continuously) emerged in early 2000s and was henceforth shown to offer a number of benefits, including targeting endothelial cells and reducing acquired drug resistance. Using mathematical modeling and optimal control techniques, we investigate the hypothesis that lower doses of chemotherapy are beneficial for patients. Our analysis of a mathematical model of tumor growth under angiogenic signaling proposed by Hahnfeldt et al. adapted to heterogeneous tumors treated by combined anti-angiogenic agent and chemotherapy offers insights into the effects of metronomic therapy. Firstly, assuming constant long-term drug delivery, the model suggests that the longest survival time is achieved for intermediate drug doses. Secondly, by formalizing the notion of the therapeutic target being maintenance rather than eradication, we show that in the short term, optimal chemotherapy scheduling consists mainly of a drug applied at a low dose. In conclusion, we suggest that metronomic therapy is an attractive alternative to maximum tolerated dose therapies to be investigated in experimental settings and clinical trials.
化疗仍然是一种广泛使用的癌症治疗方法。获得性药物耐药性可能会大大降低治疗效果，克服这种耐药性的方法是研究人员积极讨论的话题。其中一种解决方案是将治疗范式从癌症的完全根除转变为维持治疗，即将其视为一种慢性疾病。节拍化疗（持续应用低剂量化疗药物）的概念在 21 世纪初出现，此后被证明具有多种益处，包括靶向内皮细胞和降低获得性药物耐药性。我们使用数学建模和最优控制技术，研究了低剂量化疗对患者有益的假设。我们对 Hahnfeldt 等人提出的针对血管生成信号的肿瘤生长的数学模型进行了分析，并将其应用于联合抗血管生成药物和化疗治疗的异质性肿瘤，为节拍化疗的作用提供了深入的见解。首先，假设长期持续药物输送，模型表明中等药物剂量可实现最长的生存时间。其次，通过形式化将治疗目标定义为维持而非根除的概念，我们表明在短期内，最佳化疗方案主要包括低剂量药物的应用。总之，我们建议在实验和临床试验中研究将节拍化疗作为最大耐受剂量疗法的替代方法。
