Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Leiden Network for Personalized Therapeutics, Leiden University Medical Center, Leiden, The Netherlands.
Sci Rep. 2022 Mar 10;12(1):4206. doi: 10.1038/s41598-022-08012-7.
Quantitative characterization of evolving tumor resistance under targeted treatment could help identify novel treatment schedules, which may improve the outcome of anti-cancer treatment. In this study, a mathematical model which considers various clonal populations and evolving treatment resistance was developed. With parameter values fitted to the data or informed by literature data, the model could capture previously reported tumor burden dynamics and mutant KRAS levels in circulating tumor DNA (ctDNA) of patients with metastatic colorectal cancer treated with panitumumab. Treatment schedules, including a continuous schedule, intermittent schedules incorporating treatment holidays, and adaptive schedules guided by ctDNA measurements were evaluated using simulations. Compared with the continuous regimen, the simulated intermittent regimen which consisted of 8-week treatment and 4-week suspension prolonged median progression-free survival (PFS) of the simulated population from 36 to 44 weeks. The median time period in which the tumor size stayed below the baseline level (T) was prolonged from 52 to 60 weeks. Extending the treatment holiday resulted in inferior outcomes. The simulated adaptive regimens showed to further prolong median PFS to 56-64 weeks and T to 114-132 weeks under different treatment designs. A prospective clinical study is required to validate the results and to confirm the added value of the suggested schedules.
定量描述靶向治疗下肿瘤耐药的演变有助于发现新的治疗方案，从而可能改善癌症治疗的效果。在这项研究中，开发了一种考虑各种克隆群体和不断演变的治疗耐药性的数学模型。通过拟合数据或参考文献数据来确定参数值，该模型可以捕捉到先前报道的转移性结直肠癌患者接受帕尼单抗治疗时的肿瘤负担动态和循环肿瘤 DNA（ctDNA）中突变 KRAS 水平。通过模拟评估了包括连续方案、包含治疗假期的间歇方案以及基于 ctDNA 测量的适应性方案。与连续方案相比，由 8 周治疗和 4 周暂停组成的模拟间歇方案将模拟人群的中位无进展生存期（PFS）从 36 周延长至 44 周。肿瘤大小保持在基线以下的中位时间（T）从 52 周延长至 60 周。延长治疗假期会导致结果恶化。根据不同的治疗设计，模拟适应性方案显示可进一步将中位 PFS 延长至 56-64 周，将 T 延长至 114-132 周。需要前瞻性临床研究来验证结果并确认所建议方案的附加价值。
