Anti-cancer treatment schedule optimization based on tumor dynamics modelling incorporating evolving resistance

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_{TS) 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 TTS 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.}