Searching for Goldilocks: How evolution and ecology can help uncover more effective patient-specific chemotherapies

Deaths from cancer are mostly due to metastatic disease that becomes resistant to therapy. A mainstay treatment for many cancers is chemotherapy for which the dosing strategy is primarily limited by patient toxicity. While this Maximum Tolerated Dose (MTD) approach builds upon the intuitively appealing principle that maximum therapeutic benefit is achieved by killing the largest possible number of cancer cells, there is increasing evidence that moderation might allow host-specific features to contribute to success. We believe that a 'Goldilocks Window' of sub-maximal chemotherapy will yield improved overall outcomes. This window combines the complex interplay of cancer cell death, immune activity, emergence of chemoresistance, and metastatic dissemination. These multiple activities driven by chemotherapy have tradeoffs that depend on the specific agents used as well as their dosing levels and schedule. Here we present evidence supporting the idea that MTD may not always be the best approach and offer suggestions towards a more personalized treatment regime which integrates insights into patient-specific eco-evolutionary dynamics.