Mechanisms and treatment of cancer therapy-induced peripheral and central neurotoxicity

Neurotoxicity is a common and potentially severe adverse effect from conventional and novel cancer therapy. The mechanisms that underlie clinical symptoms of central and peripheral nervous system injury remain incompletely understood. For conventional cytotoxic chemotherapy or radiotherapy, direct toxicities to brain structures and neurovascular damage may result in myelin degradation and impaired neurogenesis, which eventually translates into delayed neurodegeneration accompanied by cognitive symptoms. Chemotherapy-induced peripheral neuropathy is one of the most prevalent adverse events of chemotherapy, seen specifically with platinum- and taxane-based regimens, vinca alkaloids, thalidomide and bortezomib, and is also emerging as a concerning feature of novel targeted therapies and immunotherapies. In patients treated with molecularly targeted compounds or immune-activating agents, on-target but off-tumour effects and systemic inflammation characterize a distinct clinical profile with predominantly acute neurological symptoms with a phenotype defined by the specific antigen target. The development of mechanistically driven treatment strategies for both central and peripheral nervous system injury from cancer therapies is a major unmet medical need. Clinical trials designed to test pharmacotherapeutic interventions (including anti-dementia drugs or cognitive stimulants) for cognitive symptoms after conventional chemotherapy have produced conflicting results. In the case of acute neurotoxic adverse events from immunotherapies, reversal of T cell expansion together with drugs targeting specific pro-inflammatory interleukins have shown beneficial effects in selected patients. Large clinical trials to test novel strategies and pharmacotherapeutic interventions for acute or delayed neurotoxicity are ongoing. Informed by data derived from clinical trials and preclinical models, promising treatment strategies are on the horizon.