Chemotherapy-induced neuropathy: A comprehensive survey

doi:10.1016/j.ctrv.2014.04.004

Cancer Treatment Reviews

Volume 40, Issue 7, August 2014, Pages 872-882

https://doi.org/10.1016/j.ctrv.2014.04.004 Get rights and content

Abstract

Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose limiting side effect of commonly used chemotherapeutic agents like taxanes, vinca-alkaloids, platinum compounds, bortezomib and thalidomide.

Supposed pathogenetic mechanisms of CIPN are axonopathy through dying back axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved. The exact pathophysiology however is not clear and different underlying mechanisms have been proposed for different classes of anti-cancer drugs.

Sensory symptoms, like pain, numbness and tingling are most common, but motor weakness, autonomic dysfunction and even cranial nerve involvement may occur. CIPN can be painful and/or disabling, causing significant loss of functional abilities and decreasing quality of life. This can lead to dose reductions, discontinuation of treatment and may thus, ultimately, affect survival.

Risk factors for CIPN include dose per cycle, cumulative dose, treatment schedule, duration of infusion, administration of other chemotherapeutics, comorbidity and pre-existing peripheral neuropathy.

The exploration of polymorphisms in genes associated with incidence or severity of neuropathy might result in identifying individuals being at higher risk of neurotoxicity. An update on genes possibly associated with CIPN is given.

CIPN may be reversible or be more or less permanent. Many preventive and treatment strategies have been explored, without significant efficacy up till now.

In this review we describe the different drug-related characteristics of CIPN, pharmacogenomic studies, neurophysiological findings, treatment and outcome, and neuroprotective strategies.

Introduction

Chemotherapy induced peripheral neuropathy (CIPN) is a common and potentially debilitating side-effect of cancer treatment. Because of better treatment options like new anti-emetics and hematopoietic colony stimulating factors for other serious side-effects CIPN becomes more often a dose limiting factor. Despite its clinical relevance and common occurrence, the pathophysiology of CIPN in the different groups of chemotherapy is still largely unknown. Mechanisms of CIPN are axonopathy through axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved. The primary axon damage starts at the most vulnerable part of the nerve, i.e. the end of the longest nerves, after which it spreads centrally (dying back neuropathy). The exact pathophysiology however is not elucidated and different underlying mechanisms have been proposed for the different classes of anti-cancer drugs.

Symptoms are predominantly sensory, like pain, numbness and tingling. Sometimes there are motor symptoms like weakness, autonomic neuropathy and incidentally cranial nerve involvement. CIPN can be painful and/or disabling, causing significant loss of functional abilities and decreasing quality of life. This can lead to dose reductions, discontinuation of treatment, and may thus, ultimately, affect overall survival. In routine practice CIPN is evaluated using clinical parameters. Usually objective assessment of neuropathic signs is performed with bedside clinical examinations, sometimes with additional electrophysiological studies. There are several scales to evaluate CIPN; commonly used are the common toxicity criteria of the national cancer institute (NCI-CTC) and the total neuropathy score (TNS). TNSc, mISS, NCI-CTC and the EORTC QLQ-C30 questionnaire with its CIPN20 module are the most reliable tools for accurately grading CIPN [1].

Electromyography and nerve conduction studies have only limited usefulness in the clinical setting. Compared to clinical examination nerve conduction studies in patients treated with cisplatin showed no diagnostic advantage [2]. Semi-quantitative assessment of sensory threshold or of muscle strength has been advocated, but standardization of the instruments and of the methods have never been achieved.

In this review we summarize the characteristics and management of CIPN caused by different chemotherapeutic agents.

Section snippets

Taxanes

Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere). These chemotherapeutic agents inhibit the disassembly of microtubules by binding to the beta-tubulin subunit in the microtubules. The principal function of microtubules is the formation of the mitotic spindle during cell division. Consequently, microtubules become extraordinarily stable and dysfunctional, leading to death of the cell by disrupting the normal tubule dynamics required for cell division and vital interphase processes [3].

Vinca-alkaloids

Antitubulin vinca alkaloids prevent tubulin polymerization from soluble dimers into microtubules. The affinity for tubulin differs among vinca-alkaloid compounds (decreasing in order vincristine, vinblastine, vinorelbine), which might explain the distinct neurotoxic profiles of these drugs [37]. Vincristine is the most neurotoxic one, vinblastine, and vinorelbine are less neurotoxic. Vincristine is used in the treatment of hematologic tumors and for pediatric sarcomas. Vincristine has low bone

Ixabepilone

Epothilones constitute a novel class of microtubule targeting agents. Ixabepilone is an epothilone derivate and a macrolide antibiotic. It is used in the treatment of breast cancer. Similar to the taxanes, ixabepilone binds to tubulin and enhances microtubule stability, inducing G2–M cell-cycle arrest and apoptosis. However, ixabepilone has a distinct tubulin binding site and therefore has activity in taxane-resistant disease. Main toxicities are neuropathy and neutropenia.

Platinum derivatives

Cisplatin was the first member of a class of platinum-containing anti-cancer drugs, which now also includes carboplatin and oxaliplatin. These compounds contain platinum complexes that inhibit DNA synthesis by forming cross linking of DNA molecules. Cisplatin is used to treat lung, ovary, bladder, head and neck, cervical and testicular cancer. Main toxicities of cisplatin are nephrotoxicity, severe nausea, vomiting, neuropathy and ototoxicity. Peripheral neurotoxicity is the most common

Bortezomib

Bortezomib is a proteasome inhibitor blocking the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. It is used in the treatment of myeloma. Peripheral neuropathy is the main dose-limiting toxicity associated with bortezomib therapy [45].

Thalidomide and lenalidomide

Thalidomide is a glutamic acid derivative that induces production of interferon-γ and interleukin 2, inhibits tumor necrosis factor-α production and angiogenesis. It is used in the treatment of multiple myeloma.

Lenalidomide is a thalidomide analog, used for multiple myeloma and myelodysplastic syndrome. It carries a higher risk of myelosuppression than thalidomide, but peripheral neuropathy is exceptional and mild [92].

Eribulin

Eribulin mesilate is a non-taxane inhibitor of microtubule dynamics. Eribulin inhibits the microtubule growth phase without affecting the shortening phase and causing tubulin sequestration into non-productive aggregates [101].

Eribulin is a new drug for breast cancer. In a recent RCT peripheral neuropathy developed in 35% of the 508 patients who were randomly assigned to eribulin; it was severe (grade 3/4) in 8%. Peripheral neuropathy was the most common adverse event leading to discontinuation

Conclusion

Many chemotherapeutic drugs, extensively used to treat common malignancies including lung-, breast-, colorectal- and ovarian cancer can cause peripheral neuropathy that may limit the use of higher effective doses of the drug. Chemotherapy induced peripheral neuropathy (CIPN) affects the quality of life in the early stage of treatment, but with increasing survival also results in more long lasting morbidity. There is yet no established effective treatment for CIPN, so knowledge of preventive

Conflict of interest

All authors are aware of and agree to the submission of this article and they have both contributed to the work described sufficiently to be named as authors. There are no competing financial interests or other conflicts of interest.

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Complications of TreatmentChemotherapy-induced neuropathy: A comprehensive survey

Abstract

Introduction

Section snippets

Taxanes

Vinca-alkaloids

Ixabepilone

Platinum derivatives

Bortezomib

Thalidomide and lenalidomide

Eribulin

Conclusion

Conflict of interest

Ann Oncol

Neuroscience

Pain

Ann Oncol

Eur J Cancer

Cancer Treat Rev

Ann Oncol

Ann Oncol

Lancet Oncol

Eur J Cancer

Ann Oncol

Gynecol Oncol

J Pain Symptom Manage

Clin Oncol (R Coll Radiol)

Lancet Oncol

Cancer Treat Rev

Eur J Cancer

Eur J Cancer Clin Oncol

Pain

Ann Oncol

Lancet Oncol

Eur J Cancer

Exp Neurol

Clin Neurophysiol

Blood

Lancet Oncol

Eur J Cancer

Lung Cancer

Lancet Oncol

Cisplatin induced neuropathy: central, peripheral and autonomic nerve involvement

J Neurooncol

Paclitaxel (taxol)

N Engl J Med

Microtubules, axonal transport, and neuropathy

N Engl J Med

Peripheral neuropathy induced by paclitaxel: recent insights and future perspectives

Curr Neuropharmacol

Taxol impairs anterograde axonal transport of microinjected horseradish peroxidase in dorsal root ganglia neurons in vitro

Cell Tissue Res

Pathophysiology and animal models of cancer-related painful peripheral neuropathy

Oncologist

Chemotherapy-induced peripheral neuropathies: from clinical relevance to preclinical evidence

Expert Opin Drug Saf

Peripheral neuropathy induced by microtubule-stabilizing agents

J Clin Oncol

Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: national surgical adjuvant breast and bowel project protocol B-26

J Clin Oncol

Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of cancer and leukemia Group B protocol 9840

J Clin Oncol

Motor neuropathy due to docetaxel and paclitaxel

Neurology

Lhermitte’s sign following chemotherapy with docetaxel

Neurology

Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies

Ann Neurol

Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221)

Breast Cancer Res Treat

Taxane-induced peripheral neuropathy has good long-term prognosis: a 1- to 13-year evaluation

J Neurol

Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3

Cancer

Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial

JAMA

Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy

J Clin Oncol

Neurophysiological study of peripheral neuropathy after high-dose paclitaxel: lack of neuroprotective effect of amifostine

Clin Cancer Res

Complications of Treatment
Chemotherapy-induced neuropathy: A comprehensive survey