Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies

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 apply anti-proliferative drug treatments to varying ratios of sensitive and resistant cells. We compare a continuous maximum tolerated dose schedule with an adaptive schedule aimed at tumor control through competition between sensitive and resistant cells. We find that continuous treatment cures mostly sensitive tumors, but with any resistant cells, recurrence is inevitable. We identify 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.