Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies

TLDR

Advanced cancer treatment has improved with new agents, yet resistance mechanisms still cause therapeutic failure. The study proposes that evolutionary dynamics govern resistant cell survival and that integrating evolutionary strategies with conventional therapy can delay or prevent resistance. An agent‑based model of spatial competition between sensitive and resistant cells was used to compare continuous maximum‑tolerated dose and adaptive schedules that exploit competition to control tumors. Continuous dosing cured sensitive tumors but led to inevitable recurrence when resistant cells were present, whereas two adaptive strategies—dose modulation and a vacation‑oriented schedule—controlled heterogeneous tumors with less drug or better managed invasive disease, suggesting regimen modifications could improve outcomes and reduce resistance.

Abstract

Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells. Therefore, evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we applied antiproliferative drug treatments to varying ratios of sensitive and resistant cells. We compared a continuous maximum-tolerated dose schedule with an adaptive schedule aimed at tumor control via competition between sensitive and resistant cells. Continuous treatment cured mostly sensitive tumors, but with any resistant cells, recurrence was inevitable. We identified two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors. These findings offer potential modifications to treatment regimens that may improve outcomes and reduce resistance and recurrence.