Metronomic reloaded: Theoretical models bringing chemotherapy into the era of precision medicine.

Oncology has benefited from an increasingly growing number of groundbreaking innovations over the last decade. Targeted therapies, biotherapies, and the most recent immunotherapies all contribute to increase the number of therapeutic options for cancer patients. Consequently, substantial improvements in clinical outcomes for some disease with dismal prognosis such as lung carcinoma or melanoma have been achieved. Of note, the latest innovations in targeted therapies or biotherapies do not preclude the use of standard cytotoxic agents, mostly used in combination. Importantly, and despite the rise of bioguided (a.k.a. precision) medicine, the administration of chemotherapeutic agents still relies on the maximum tolerated drug (MTD) paradigm, a concept inherited from theories conceptualized nearly half a century ago. Alternative dosing schedules such as metronomic regimens, based upon the repeated and regular administration of low doses of chemotherapeutic drugs, and adaptive therapy (i.e. modulating the dose and frequency of cytotoxics administration to control disease progression rather than eradicate it at all cost) have emerged as possible strategies to improve response rates while reducing toxicities. The recent changes in paradigm in the way we theorize cancer biology and evolution, metastatic spreading and tumor ecology, alongside the recent advances in the field of immunotherapy, have considerably strengthened the interest for these alternative approaches. This paper aims at reviewing the recent evolutions in the field of theoretical biology of cancer and computational oncology, with a focus on the consequences these changes have on the way we administer chemotherapy. Here, we advocate for the development of model-guided strategies to refine doses and schedules of chemotherapy administration in order to achieve precision medicine in oncology.