Chemotherapy-induced peripheral neurotoxicity (CIPN): An update

doi:10.1016/j.critrevonc.2011.04.012

Critical Reviews in Oncology/Hematology

Volume 82, Issue 1, April 2012, Pages 51-77

https://doi.org/10.1016/j.critrevonc.2011.04.012 Get rights and content

Abstract

The peripheral nervous system can be vulnerable to the toxic action of several drugs since it is not protected as effectively as the central nervous system from noxious exogenous agents. Drug-induced neurotoxicity can affect the nerve fibers or the neuronal bodies (generally the dorsal root ganglia of the primary sensory neurons). Among the neurotoxic drugs antineoplastic agents represent a major clinical problem, given their widespread use and the potential severity of their toxicity. In fact, the peripheral neurotoxicity of antineoplastic agents frequently represents one of their dose-limiting side effects. Moreover, even when antineoplastic agents’ peripheral neurotoxicity is not dose-limiting, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. Among the anticancer chemotherapy drugs, platinum derivates, antitubulins, thalidomide and bortezomib can induce the most severe effects on the peripheral nervous system of the treated patients. Therefore, we will review the features of chemotherapy-induced peripheral neurotoxicity (CIPN) resulting from the administration of these drugs with a focus on new classes of promising antineoplastic agents, such as epothilones and proteasome inhibitors.

Highlights

► We revise the current knowledge in chemotherapy-induced peripheral neurotoxicity. ► Several effective antineoplastic drugs are harmful to peripheral nerves. ► Incidence of the damage is poorly known. ► Chemotherapy-induced peripheral neurotoxicity can be dose-limiting. ► No treatment is available.

Introduction

The peripheral nervous system can be vulnerable to the toxic action of several drugs since it is not protected as effectively as the central nervous system from noxious exogenous agents. Drug-induced neurotoxicity can affect the nerve fibers or the neuronal bodies (generally the dorsal root ganglia (DRG) of the primary sensory neurons). The clinical features of such neurotoxicity are dependent on the type of agent involved and the site of action – ranging from motor, to sensory-motor or almost exclusively sensory neuropathies, with or without autonomic impairment. Among the neurotoxic drugs antineoplastic agents represent a major clinical problem, given their widespread use and the potential severity of their toxicity. In fact, the peripheral neurotoxicity (PN) of antineoplastic agents frequently represents one of their dose-limiting side effects. Moreover, even when antineoplastic agents’ peripheral neurotoxicity is not dose-limiting, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort.

The methods of assessment of the severity of CIPN in clinical trials are not homogeneous, but among the most commonly used scales the National Cancer Institute – Common Toxicity Criteria (NCI-CTC) and to the Total Neuropathy Score (TNS), a composite scale designed to assess the severity of distal polyneuropathies, deserve to be mentioned (Table 1).

We will review the features of chemotherapy-induced PN resulting from the administration of the most widely used and better investigated compounds, such as platinum drugs, taxanes, vinca alkaloids and thalidomide, with a focus on new classes of promising antineoplastic agents, such as epothilones and proteasome inhibitors (Fig. 1).

Section snippets

Platinum drugs

Since platinum compounds were identified as antineoplastic agents (cisplatin has been used since 1970), their use has been increasingly adopted in routine oncological clinical practice. While the toxicity profile differs among the different drugs, platinum-induced PN is a common feature.

Vinca alkaloids

This group of chemotherapeutic agents includes both natural alkaloids, such as vincristine and vinblastine, and semi-synthetic compounds, such as vindesine, vinorelbine and vinflunine. These drugs have a broad spectrum of indications in the treatment of haematologic and lymphatic malignancies as well as of solid tumours such as breast, ovarian, testicular, brain and non-small cell lung tumours and sarcomas. Vinca alkaloids have a different toxicity profile; vincristine being the most neurotoxic

Taxanes

Taxanes (paclitaxel and docetaxel) belong to the family of chemotherapy agents classified as microtubule-stabilizing agents (MTSAs) and they are effective in treating various types of solid tumours. PN is considered as being the main non-haematological toxicity of taxanes, usually resulting in dose modification due to its severity [108].

Epotilones

It was only in 1995 that a second class of MTSAs was discovered [135], [136]. These macrolides were secondary metabolites produced by mycobacteria and they were called “epothilones” to reflect their basic structural features, which include an epoxide moiety, a thiazole-containing side chain and a single ketone function. Two major fermentation products were reported in the myxobacterium Sorangium cellulosum Soce 90, epothilone A and epothilone B (also known as patupilone) [137], [138].

Bortezomib

Bortezomib, a modified dipeptidyl boronic acid, is one of the first-line treatments in multiple myeloma (MM) patients. Bortezomib inhibits the 20S proteasome complex and acts by disruption of various cell signaling pathways. However, its use is frequently associated with the development of significant neurotoxic effects. Bortezomib-induced PN is, in most cases, painful and when it occurs it can potentially lead to dose modification and severe disability, thereby compromising the outcome of

Thalidomide

Thalidomide was first introduced into European markets in the 1950s as a sleep aid and antiemetic drug for pregnant women. It was withdrawn from the market soon after when its teratogenic effects were discovered. It has re-emerged recently as an effective treatment for several dermatological, gastrointestinal, and oncological conditions. In May 2006 the US Food and Drug Administration (FDA) granted approval to thalidomide for use in combination with dexamethasone in newly diagnosed MM patients.

Conclusion

From this review it appears that CIPN understanding still represents an unmet clinical need in the modern approach to cancer patients. Its importance has become even clearer in view of the better results obtained with more effective schedules of treatment allowing longer survival and cancer cure, thus making the occurrence of a disabling and long-lasting peripheral neurotoxicity even less tolerable.

To give some relief to CIPN patients, several palliative care attempts have been suggested, but

Reviewers

Professor David Cornblath, Johns Hopkins University, Department of Neurology, Baltimore, MD, United States.

Professor Paolo Bidoli, Chief of Medical Oncology, S. Gerardo Hospital, Department of Medical Oncology, Monza, Italy.

Professor Wolfgang Grisold, Kaiser-Franz-Josef-Spital, Department of Neurology, Kundratstrasse 3, A-1100 Vienna, Austria.

Andreas A. Argyriou is Consultant Neurologist at the Department of Neurology, “Saint Andrew's” General Hospital of Patras and researcher at the Division of Clinical Oncology-Department of Medicine of the University Hospital of Patras, Greece

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Jordi Bruna is a specialist of the Unit of Neuro-Oncology, Department of Neurology, Bellvitge University Hospital, Hospitalet del Llobregat and Group of Neuroplasticity and Regeneration, Department of Cell Biology, Physiology and Immunology, Universitat Autonoma of Barcelona.CIBERNED. Spain

Paola Marmiroli is a Neurologist and assistant professor at University of Milan-Bicocca, Monza, Italy Department of Neuroscience and Biomedical Technologies.

Guido Cavaletti is the head of the Experimental Neurology Unit at University of Milan-Bicocca, Department of Neuroscience and Biomedical Technologies and Senior Consultant Neurologist at the Department of Neurology of the S. Gerardo Hospital in Monza, Italy.

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Chemotherapy-induced peripheral neurotoxicity (CIPN): An update

Abstract

Highlights

Introduction

Section snippets

Platinum drugs

Vinca alkaloids

Taxanes

Epotilones

Bortezomib

Thalidomide

Conclusion

Reviewers

Eur J Cancer

Ann Oncol

Neurotoxicology

Neurobiol Dis

Neurobiol Dis

Neurotoxicology

Eur J Pharmacol

Ann Oncol

Ann Oncol

Cancer Treat Rev

Ann Oncol

Ann Oncol

Eur J Cancer

Cancer Treat Rev

Pain.

Cancer Epidemiol

Eur J Cancer

Ann Oncol

Eur J Cancer

Clin Colorectal Cancer

J Pain Symptom Manage

Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies

Cancer

Histology and platinum content of sensory ganglia and sural nerves in patients treated with cisplatin and carboplatin: an autopsy study

Neuropathol Appl Neurobiol

Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity

J Clin Oncol

Cisplatin-induced DNA-platination in experimental dorsal root ganglia neuronopathy

Neurotoxicology

Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy

J Neurosci

Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle

J Clin Invest

Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells

Carcinogenesis

Implications of apurinic/apyrimidinic endonuclease in reactive oxygen signaling response after cisplatin treatment of dorsal root ganglion neurons

Cancer Res

Oxaliplatin-induced neurotoxicity and the development of neuropathy

Muscle Nerve

A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels

J Neurophysiol

Lhermitte's sign as a complication of cisplatin-containing chemotherapy for testicular cancer

Cancer Treat Rep

Acute oxaliplatin-induced peripheral nerve hyperexcitability

J Clin Oncol

Oxaliplatin-induced lhermitte's phenomenon as a manifestation of severe generalized neurotoxicity

Oncology

Electrophysiological study of the peripheral and central neurotoxic effect of cis-platin

Acta Neurol Scand

Cisplatin-induced peripheral neurotoxicity is dependent on total-dose intensity and single-dose intensity

Cancer

The usefulness of nerve conduction studies in objectively assessing oxaliplatin-induced peripheral neuropathy

Oncologist

Incidence and characteristics of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer

Acta Oncol

Cisplatin induced neuropathy: central, peripheral and autonomic nerve involvement

J Neurooncol

Long-term neurotoxicity of chemotherapy in adolescents and young adults treated for bone and soft tissue sarcomas

Sarcoma

Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy

Muscle Nerve

Erythropoietin and cisplatin-induced neuropathies in cancer patients

Clin Ter

Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer

Cancer

Persistence of high-dose oxaliplatin-induced neuropathy at long-term follow-up

Eur Neurol