Preventing evolutionary rescue in cancer using two-strike therapy

Abstract

First-line cancer treatment frequently fails due to initially rare therapeutic resistance. An important clinical question is then how to schedule subsequent treatments to maximize the probability of tumor eradication. Here, we provide a theoretical solution to this problem by using mathematical analysis and extensive stochastic simulations within the framework of evolutionary rescue theory to determine how best to exploit the vulnerability of small tumors to stochastic extinction. Whereas standard clinical practice is to wait for evidence of relapse, we confirm a recent hypothesis that the optimal time to switch to a second treatment is when the tumor is close to its minimum size before relapse, when it is likely undetectable. This optimum can lie slightly before or slightly after the nadir, depending on tumor parameters. Given that this exact time point may be difficult to determine in practice, we study windows of high extinction probability that lie around the optimal switching point, showing that switching after the relapse has begun is typically better than switching too early. We further reveal how treatment efficacy and tumor demographic and evolutionary parameters influence the predicted clinical outcome, and we determine how best to schedule drugs of unequal efficacy. Our work establishes a foundation for further experimental and clinical investigation of this evolutionarily-informed multi-strike treatment strategy.