Chapter 4 – Adverse Events

Any medical intervention generates modifications in the homeostasis of the treated organism. The effect in most cases is not apparent at the clinical level; when manifested, it may be inherent to the expected therapeutic action or associate as a side effect expressed in a multiplicity of epiphenomena with different physiognomy and capacity of altering the health status, generally defined as an adverse event. Drugs are a major cause of undesired events, including last generation agents, although much effort is being dedicated in the attempt of reducing their overall undesired consequences. Different definitions and various criteria of classification of such events have been eventually adopted with the aim of defining their characteristics, origin, the potential mechanistic relation with their pharmacological activity, and entity of potential harm to the host, as briefly discussed in this chapter. However, most of these criteria were established before targeted therapies were developed, and therefore a subsequent need to adjust them to new therapeutic formulations and strategies is warranted. Indeed, targeted therapy was expected to substantially reduce the toxicity burden, but expectancies were only in part fulfilled, while new and unexpected reactivities emerged, mostly related to specific structural characteristics of these agents [e.g., the proteic backbone of monoclonal antibodies (mAbs)], and/or their unique capacity of interfering with vital signaling pathways of normal and pathological cell subsets (e.g., mAbs and KIs—kinase inhibitors). The analysis of these safety issues is fundamental for the understanding of the new risk/benefit profiles determined by the introduction of oncotargeted therapy, and the continuous struggle to further improve that ratio in the future. With this respect, experience with the clinically approved KIs that have already been accumulated and directed to a wide spectrum of human tumors is essential.