Evaluation of synergism in drug combinations and reference models for future orientations in oncology

Current cancer therapy includes a variety of strategies that can comprise only one type of treatment or a combination of multiple treatments. Chemotherapy is still the gold standard for cancer therapy, though sometimes associated with undesired side effects and the development of drug resistance. For this reason, drug combination is an approach that has been proposed to overcome the problems related to monotherapy and several studies have already demonstrated the superiority of combined therapies compared to monotherapy. The main goal when designing and evaluating drug combinations is to achieve synergistic effects by demonstrating that the combined effects are greatly superior to the expected from the additive effects of the single drugs, allowing for dosage reduction and therefore decreasing toxicity. Nevertheless, synergism quantification is not a simple task due to the different definitions of additivity and over the years several reference models have been proposed based on different assumptions and with different mathematical frameworks. In this review, we begin to cover the available treatment options for cancer therapy, with emphasis on the importance of drug combinations in cancer therapy. We next describe the classical reference models that have been proposed for synergism evaluation, usually classified as effect-based and dose-effect based methods, with a brief analysis of the current limitations of these models. We also describe here the novel methods for the accurate quantification of drug interactions in combined treatments. At the end of this manuscript, we covered some of the most recent preclinical and clinical combination studies that reflect the importance of the appropriate, accurate and precise application of the concepts and methodologies here described for the evaluation of synergism.