Neurotoxic complications of chemotherapy in patients with cancer - Clinical signs and optimal management

Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity. Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheral neuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or even coma. In this article we describe the neurological adverse effects of the most commonly used chemotherapeutic agents. The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies such as ovarian and breast cancer, and haematological cancers. Chemotherapy-induced neuropathy is clearly related to cumulative dose or dose-intensities. Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy. Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily known for their central neurotoxic side effects. Central neurotoxicity ranges from acute toxicity such as aseptic meningitis, to delayed toxicities comprising cognitive deficits, hemiparesis, aphasia and progressive dementia. Risk factors are high doses, frequent administration and radiotherapy preceding methotrexate chemotherapy, which appears to be more neurotoxic than methotrexate as single modality. Data on management and neuroprotective agents are discussed. Management mainly consists of cumulative dose-reduction or lower dose-intensities, especially in patients who are at higher risk to develop neurotoxic side effects. None of the neuroprotective agents described in this article can be recommended for standard use in daily practise at this moment, and further studies are needed to confirm some of the beneficial effects described. CNS toxicities such as seizures, drowsiness, cognitive deficits or even coma are observed less frequently. However, these adverse effects should always be taken into account when starting clinical chemotherapeutic trials in which higher doses or shorter intervals between doses are evaluated. Neuroprotective agents ideally should reduce the chemotherapy-induced neurotoxicities without reducing the antitumour effect of the cytostatic agent. Unfortunately, data on neuroprotection in chemotherapy-related peripheral neurotoxicity are still controversial at this time. In our view, no neuroprotective agent can be recommended for standard use in daily clinical practice. Additional studies are needed. Therefore, the management of neurotoxicity mainly consists of the reduction of dose of the cytostatic agent or the use of longer intervals between cycles. Furthermore, patients with diabetes, patients with hereditary neuropathies and patients who have received previous neurotoxic chemotherapy are more likely to develop peripheral neuropathy; therefore, these patients should be evaluated carefully when potentially neurotoxic chemotherapy is administered.