Find the path of least resistance: Adaptive therapy to delay treatment failure and improve outcomes

Cytotoxic chemotherapy and targeted therapies help people with advanced cancers, but for most, treatment fails. Cancer heterogeneity is one cause of treatment failure, but also suggests an opportunity to improve outcomes; reconceptualising cancer therapy as an ecological problem offers the strategy of adaptive therapy. If an agent is active against a patient's cancer, instead of traditional continuous dosing at the maximum tolerated dose until treatment failure, the patient and their oncologist may instead choose to pause treatment as soon as the cancer responds. When tumour burden increases, the cancer is rechallenged with the same agent in hope of delivering another response, ideally before symptoms occur or quality-of-life is impacted. These 'loops' of 'pause/restart' allows an active treatment to be used strategically, to delay the development of evolutionary selection within the cancer, delaying the onset of treatment resistance, controlling the cancer for longer. Modelling predicts patients can navigate several 'loops', potentially increasing the utility of an active treatment by multiples, and early trials suggest at least doubling of progression-free survival. In this narrative review we confront how cancer heterogeneity limits treatment effectiveness, re-examine cancer as an ecological problem, review the data supporting adaptive therapy and outline the challenges and opportunities faced in clinical practice to implement this evolutionary concept. In an era where multiple novel active anti-neoplastic agents are being used with ancient inflexibile maximum tolerated dose for maximum duration approaches, adaptive dosing offers a personalised, n = 1 approach to cancer therapy selection.