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

Nature Reviews Cancer (2025)Cite this article

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Abstract

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.

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Fig. 1: Mechanisms of delayed central nervous system neurotoxicity from conventional cancer treatment.
Fig. 2: Mechanisms of acute central nervous system neurotoxicity from immune-activating biologic agents.
Fig. 3: Mechanisms of peripheral neurotoxicity from cancer therapy.

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Author notes

  1. These authors contributed equally: Philipp Karschnia, Thomas A. Nelson.

Authors and Affiliations

  1. Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    Philipp Karschnia & Jorg Dietrich

  2. Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander-University, Erlangen-Nuernberg, Germany

    Philipp Karschnia

  3. Division of Neuro-Oncology, Department of Neurosurgery, University of California, San Francisco, CA, USA

    Thomas A. Nelson

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  1. Philipp Karschnia
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  2. Thomas A. Nelson
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  3. Jorg Dietrich
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The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Jorg Dietrich.

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Competing interests

J.D. is a consultant for and on the Advisory Board of: Amgen, Novartis, Janssen. He also receives research support from Ono Therapeutics and Novartis, and royalties from Wolters Kluwer. P.K. and T.A.N. declare no competing interests.

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Glossary

Acute inflammatory demyelinating polyradiculoneuropathy

(AIDP). Autoimmune disorder with rapid onset of weakness and sensory loss due to inflammatory damage to the myelin sheaths of peripheral nerves.

Allodynia

A condition that causes pain in response to normally non-painful stimuli (cold allodynia: pain in response to normally non-painful cold temperatures). Mechanical allodynia is a specific type of allodynia prompted by mechanical stimuli such as light touch.

Aphasia

Disruption of language function due to injury to the brain. Expressive aphasia specifically is the loss of the ability to produce language while comprehension generally remains intact.

Corticospinal tracts

Large pathways of axons that control voluntary movement-related information from the cerebral cortex in the brain to the spinal cord (also known as pyramidal tracts).

Dendritic spine

Specialized protrusion on neuron dendrites that often receives a single excitatory input.

Dysaesthesia

Abnormal sense of touch.

Dysautonomia

Malfunction of the autonomic nervous system.

Dysgeusia

Distortion of the sense of taste.

Dysgraphia

Impaired writing by hand.

Electroencephalogram

(EEG). An electrophysiological study that measures brain activity.

Ex vacuo hydrocephalus

Compensatory enlargement of the cerebrospinal fluid spaces caused by brain volume loss.

Executive function

The ability to regulate goal-directed thoughts and behaviours.

Fibre tracking techniques

MRI technique to estimate the axonal (white matter) organization of the brain.

Guillain–Barré syndrome

Autoimmune polyneuropathy with numbness and muscle weakness.

Hyperalgesia

Exaggerated response to normally painful stimulus.

Hypoaesthesia

Decreased sensation, synonymous with ‘numbness’.

Hypophysitis

Inflammation of the pituitary gland.

Myalgias

Painful sensations evolving from muscle tissue.

Myasthenia gravis

Autoimmune disorder characterized by antibodies that block receptors at the neuromuscular junction.

Neurodegeneration

Progressive loss of structure or function of neurons.

Neuronopathy

A broad term that encompasses neuron damage or degeneration.

Neurovascular unit

Multicellular unit composed of neurons, glia cells, endothelial cells, perivascular cells and smooth muscle cells, with structural and functional relevance for blood flow regulation, the blood–brain barrier, metabolism and regeneration.

Nociceptor

Specialized sensory nerve ending that acts as a receptor for painful or potentially noxious stimuli.

Orthostatic hypotension

Drop in blood pressure when standing up from a sitting or lying position.

Paraneoplastic ganglionopathy

Cancer-associated autoimmune disorder with antibodies directed against neurons in peripheral ganglia, mainly dorsal root ganglia neurons.

Periaqueductal grey matter

A region of the midbrain that integrates autonomic and behavioural responses.

Peripheral neuropathy

Damage to peripheral nerves involved in sensory, motor or autonomic function.

Polyneuropathy

Pathology in which multiple peripheral nerves are injured.

Processing speed

Ability to identify, discriminate, integrate and respond to information.

Robin–Virchow spaces

Perivascular fluid-filled cavities that surround perforating vessels in the brain parenchyma.

Scrambler therapy

Non-invasive pain-modifying technique that uses transcutaneous electrical stimulation of pain fibres with the intention of reorganizing maladaptive signalling pathways.

Sensory ataxia

Loss of coordination caused by lack of sensory input.

Somnolence

State of drowsiness with strong desire to fall asleep.

Sural nerve

A cutaneous sensory nerve serving the posterior lower leg. The dorsal sural nerve in particular is the terminal branch of the sensory sural nerve serving the lateral foot and little toe.

Wallerian degeneration

Distal nerve fibre degeneration due to proximal nerve injury that results in disintegration of the axon and its myelin sheath.

White matter

Subcortical brain and spinal cord tissue, composed of nerve fibres, their myelin sheaths and glial cells.

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Karschnia, P., Nelson, T.A. & Dietrich, J. Mechanisms and treatment of cancer therapy-induced peripheral and central neurotoxicity. Nat Rev Cancer (2025). https://doi.org/10.1038/s41568-025-00863-2

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