Cancer-associated thrombosis (CAT) is the second leading cause of death in cancer patients after tumor progression. The treatment of CAT is challenging because of a high risk of VTE recurrence, a high risk of bleeding, common presence of comorbidities, poly-medication, and potential drug-drug interactions (DDI).

Since 2018, direct oral anticoagulants (DOACs) represent a promising therapeutic alternative and have been recently included into the 2019 update of the International Initiative on Thrombosis and Cancer (ITAC-CME) clinical practice guidelines for management of CAT. However, pharmacokinetic studies suggest that concomitant treatment with P-gp or CYP3A4 inhibitors will result in an increased exposure to rivaroxaban and apixaban, but the clinical relevance of these studies is unknown. In addition, there is an important inter-individual variability in drug absorption, distribution, metabolism and elimination, even more in cancer patients. Overall, the risk of pharmacokinetic DDI should be estimated based on several individual (patient age, renal and liver function, number of comedications) and diseases-related factors, including inflammation, sarcopenia, and low body weight. In this context, DDI with clinical implications could be expected with anti-neoplastic agents or supportive care treatments, especially with drugs known to be moderate or strong inhibitors/inducers of CYP3A4 and P-gp. Consequently, in the presence of potential DDIs through CYP3A4, and/or P-gp, LMWHs remain the first-line anticoagulant of choice for the long-term treatment of CAT. Multidisciplinary consultation meetings and therapeutic patient education should be emphasized in the complex management of CAT.