Peripheral nerve damage associated with administration of taxanes in patients with cancer

https://doi.org/10.1016/j.critrevonc.2008.01.008Get rights and content

Abstract

Peripheral neuropathy is a well recognized toxicity of taxanes, usually resulting to dose modification and changes in the treatment plan. Taxanes produce a symmetric, axonal predominantly sensory distal neuropathy with less prominent motor involvement. A “dying back” process starting from distal nerve endings followed by effects on Schwann cells, neuronal body or axonal transport changes and a disturbed cytoplasmatic flow in the affected neurons is the most widely accepted mechanism of taxanes neurotoxicity. The incidence of taxanes-induced peripheral neuropathy is related to causal factors, such as single dose per course and cumulative dose and risk factors including treatment schedule, prior or concomitant administration of platinum compounds or vinca alcaloids, age and pre-existing peripheral neuropathy of other causes. The most reliable method to assess taxanes neurotoxicity is by clinical examination combined with electrophysiological evaluation. There is currently no effective symptomatic treatment for paclitaxel-associated pain, myalgias and arthralgias. Tricyclic antidepressants and anticonvulsants have been used as symptomatic treatment of neurotoxicity with some measure of success. Therefore, new approaches for prophylaxis against taxanes-induced peripheral neuropathy are needed. Several neuroprotective agents including, thiols, neurotrophic factors, and antioxidants hold promise for their ability to prevent neurotoxicity resulting from taxanes exposure. However, further confirmatory trials are warranted on this important clinical topic. This review critically looks at the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of taxanes-induced peripheral neuropathy. We also highlight areas of future research.

Introduction

Over the past years, several new antineoplastic agents demonstrated their efficacy against a broad spectrum of solid malignancies. However, the cytotoxic usefulness of these drugs is compromised by a wide range of side effects, with fast-dividing cells of the body to bear the main brunt of these toxicities [1].

Taxanes, including polyoxyethylated castor oil-based paclitaxel, polyoxyethylated castor oil-free paclitaxel (ABI-007) and docetaxel, are the main members of the family of microtubule-stabilizing agents (MTSAs). Taxanes stabilize microtubules, block mitosis in the late G2 mitotic phase of cell cycle by polymerization and induce cell death, thereby demonstrating a broad spectrum of cytotoxic activity against lung, breast and ovarian cancer [2].

Although taxanes in clinical practise prolong remissions and improve survival, they are also associated with significant occurrence of toxicities [3]. Paclitaxel has been isolated from the bark of the Pacific yew tree Taxus brevifolia [4]. Its clinical application was restricted from severe anaphylactic reactions, attributed either to paclitaxel itself or its polyoxyethylated castor oil vehicle, Cremopher EL (CrEL). Therefore, new CrEL-free formulations of paclitaxel, such as ABI-007, were developed to overcome such severe adverse event [5].

Due to scarcity of paclitaxel, extensive research resulted in the formulation of docetaxel, a new semisynthetic taxoid, extracted from the European yew tree. Docetaxel inhibits tubulin depolymerization and has an approved claim for treatment of patients who have undergone anthracycline-based chemotherapy and failed to stop cancer progression or relapsed [6]. Peripheral nerve damage was described as taxanes main non-haematological toxicity soon after both drugs were introduced in clinical practice. Consequences of neurotoxicity include treatment modification and reduction in the quality of life (QOL) of patients with cancer [7].

We critically review and discuss the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of taxanes-induced peripheral neuropathy (TIPN). We also highlight areas of future research.

Section snippets

Search strategy and selection criteria

References were identified by searches of PubMed from 1980 until May 2007 with the terms “microtubule-stabilizing agents”, “taxanes and neurotoxicity”, “paclitaxel-induced peripheral neuropathy”, “docetaxel-induced peripheral neuropathy” and “chemotherapy-induced peripheral neuropathy”. Articles were also identified through searches of the authors’ own files. Only papers published in English were reviewed.

Pathogenesis of peripheral neuropathy

The primary target of TIPN is contraversial [8]. Studies in preclinical models demonstrated that the administration of paclitaxel resulted in accumulation of microtubules in Schwann cells and axons of sciatic nerve [9], [10]. Additionally, Persohn et al. [11] examined the effect of chronic administration of paclitaxel and docetaxel in the Wistar rat using neurophysiological, neuropathological and morphometrical methods. They demonstrated that both drugs induce a significant, equally severe and

Incidence and risk factors

The incidence of TIPN is usually related to risk factors including treatment schedule, single dose per course and cumulative dose [18], [19], [20]. Other risk factors are prior or concomitant administration of platinum compounds or vinca alcaloids, age and pre-existing peripheral neuropathy due to medical conditions, such as hereditary, associated with nutritional agents, paraneoplastic, diabetes mellitus, alcohol abuse, etc. [21].

Beyond doubt, the essential causal factor for TIPN is dose,

Diagnosis

The assessment of TIPN is primarily based on clinical examination and quantitative methods, such as nerve conduction studies [40]. Several comprehensive neurotoxicity grading scales have been used. Commonly used grading systems are the NCI Common Toxicity Criteria [41], the Eastern Cooperative Oncology Group Criteria [42], the Ajani [43] and the WHO criteria [44]. Table 1 outlines the historically available, clinically based scales used in oncologic studies.

Outcome measures for the assessment

Clinical and electrophysiological characteristics

Sensory neuropathy is the most common neurotoxic effect of taxanes treatment, while motor and autonomic neuropathy occurs less frequent. Although, neurotoxicity is cumulative and dose-dependent, sensory symptoms may initially occur within 24–72 h following even the first administration of taxanes at single high doses [54], [55]. Table 3 summarizes the clinical and electrophysiological signs and symptoms of TIPN.

Primary clinical symptoms include paresthesia, numbness and/or pain in the hands and

Symptomatic treatment

For symptomatic management of TIPN, amitriptyline, glutamine, low-dose oral prednisone and gabapentin have been used with some measure of success for reducing pain, myalgia and arthralgia. In a trial assessing the 1-h weekly paclitaxel infusion in breast cancer patients, the tricyclic antidepressant amitriptyline at a dose of 10–50 mg, has been found as capable of demonstrating relief against taxanes-induced neuropathic pain [68]. Gabapentin, at a daily dose ranging from 900–1200 mg, might also

Conclusions and future research perspectives

Peripheral neuropathy is the major non-haematological adverse effect of taxanes-based chemotherapy, obviously deteriorating the QOL of patients with cancer. A widely accepted grading scale of neurotoxicity is lacking and therefore it should be developed and employed in clinical trials, so that data concerning the efficacy of neuroprotective agents can be objectively compared. This grading instrument should demonstrate high sensitivity, reducing interobserver and intraobserver variability. Skin

Reviewers

Koeppen S., Department of Neurology, University of Essen, Hufelandstrasse 55, D-45122 Essen, Germany.

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

Conflicts of interest

The authors have no conflicts of interest. No funding source had a role in the preparation of this paper or in the decision to submit it for publication.

Acknowledgments

Each author contributed equally in the preparation of this review. All authors have seen and approved the final version.

Andreas A. Argyriou is Consultant Neurologist with current primary affiliation at the Neurology Department of “Saint Andrew's” General Hospital of Patras. He is also Senior Research Fellow at the Laboratory of Clinical Oncology of the University Hospital of Patras, Greece. His main research interests include Clinical Neurophysiology, Toxic neuropathies and Neuro-Oncology.

References (93)

  • M. Markman et al.

    Use of low-dose oral prednisone to prevent paclitaxel-induced arthralgias and myalgias

    Gynecol Oncol

    (1999)
  • P.N. Konings et al.

    Reversal by NGF of cytostatic drug-induced reduction of neurite outgrowth in rat dorsal root ganglia in vitro

    Brain Res

    (1994)
  • D. Lorusso et al.

    Multicenter Italian Trials in Ovarian Cancer invesitgators. Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients

    Ann Oncol

    (2003)
  • T.J. Kilpatrick et al.

    Leukaemia inhibitory factor abrogates Paclitaxel-induced axonal atrophy in the Wistar rat

    Brain Res

    (2001)
  • M.D. Stubblefield et al.

    Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study

    Clin Oncol (R Coll Radiol)

    (2005)
  • S.J. Flatters et al.

    Acetyl-l-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy

    Neurosci Lett

    (2006)
  • G. Bianchi et al.

    Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-l-carnitine

    Eur J Cancer

    (2005)
  • A.A. Argyriou et al.

    Preventing paclitaxel-induced peripheral neuropathy: a phase II trial of vitamin E supplementation

    J Pain Symptom Manage

    (2006)
  • A.J. Windebank

    Chemotherapeutic neuropathy

    Curr Opin Neurol

    (1999)
  • E.K. Rowinsky et al.

    Paclitaxel (Taxol)

    N Engl J Med

    (1995)
  • E.K. Rowinsky et al.

    Taxol: a novel investigational antimicrotubule agent

    J Natl Cancer Inst

    (1990)
  • N.K. Ibrahim et al.

    Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel

    Clin Cancer Res

    (2002)
  • K.A. Lyseng-Williamson et al.

    Docetaxel: a review of its use in metastatic breast cancer

    Drugs

    (2005)
  • S. Quasthoff et al.

    Chemotherapy-induced peripheral neuropathy

    J Neurol

    (2002)
  • M. Roytta et al.

    Taxol-induced neuropathy: short-term effects of local injection

    J Neurocytol

    (1984)
  • G. Cavaletti et al.

    Effect on the peripheral nervous system of the short-term intravenous administration of paclitaxel in the rat

    Neurotoxicology

    (1997)
  • J. Kimura

    Electrodiagnosis in diseases of nerve and muscle, principles and practice

    Polyneuropathies

    (2001)
  • Z. Sahenk et al.

    Taxol neuropathy. Electrodiagnostic and sural nerve biopsy findings

    Arch Neurol

    (1994)
  • J. Kimura

    Electrodiagnosis in diseases of nerve and muscle, principles and practice

    Principles and variations of nerve conduction studies

    (2001)
  • P. Dustin

    Microtubules

    Sci Am

    (1980)
  • J.M. Nabholtz et al.

    Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer

    J Clin Oncol

    (1996)
  • R.E. Smith et al.

    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

    (1999)
  • V. Chaudhry et al.

    Toxic neuropathy in patients with pre-existing neuropathy

    Neurology

    (2003)
  • A.C. Peltier et al.

    Advances in understanding drug-induced neuropathies

    Drug Saf

    (2006)
  • J.J. Lee et al.

    Peripheral neuropathy induced by microtubule-stabilizing agents

    J Clin Oncol

    (2006)
  • E.P. Winer et al.

    Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342

    J Clin Oncol

    (2004)
  • S. Chan et al.

    Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer

    J Clin Oncol

    (1999)
  • R.F. DeVore et al.

    Paclitaxel by either 1-hour or 24-hour infusion in combination with carboplatin in advanced non-small cell lung cancer: preliminary results comparing sequential phase II trials

    Semin Oncol

    (1997)
  • A.D. Seidman et al.

    CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion versus standard (s) 3 h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC

    J Clin Oncol

    (2004)
  • A. du Bois et al.

    Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer

    J Natl Cancer Inst

    (2003)
  • V. Chaudhry et al.

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

    Ann Neurol

    (1994)
  • S.M. Jamieson et al.

    Paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons in vivo reducing oxaliplatin toxicity

    Br J Cancer

    (2003)
  • A.A. Argyriou et al.

    Paclitaxel plus carboplatin-induced peripheral neuropathy. A prospective clinical and electrophysiological study in patients suffering from solid malignancies

    J Neurol

    (2005)
  • A.A. Argyriou et al.

    Clinical and electrophysiological features of peripheral neuropathy induced by administration of cisplatin plus paclitaxel-based chemotherapy

    Eur J Cancer Care

    (2007)
  • D.H. Johnson et al.

    Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer

    J Clin Oncol

    (2004)
  • N. Robert et al.

    Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer

    J Clin Oncol

    (2006)
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    Andreas A. Argyriou is Consultant Neurologist with current primary affiliation at the Neurology Department of “Saint Andrew's” General Hospital of Patras. He is also Senior Research Fellow at the Laboratory of Clinical Oncology of the University Hospital of Patras, Greece. His main research interests include Clinical Neurophysiology, Toxic neuropathies and Neuro-Oncology.

    Martin Koltzenburg is Chair of the Department of Clinical Neurophysiology at the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. He specializes in Clinical Neurophysiology, imaging of peripheral nerves and muscle and clinical assessment and treatment of neuropathic pain.

    Panagiotis Polychronopoulos is Assistant Professor of Neurology at the Neurology Department of the University Hospital of Patras, Greece. His main research interests include Epilepsy, Clinical Neurophysiology and Toxic neuropathies.

    Spiridon Papapetropoulos is Assistant Professor of Neurology at the Neurology Department of the University of Miami, School of Medicine, Miami, FL, USA. His main research interests include Movement Disorders and Clinical Neurophysiology.

    Haralabos P. Kalofonos is Associate Professor of Medical Oncology and Chair of the Division of Clinical Oncology of the University Hospital of Patras, Greece. He specializes in the molecular treatment of solid tumors, in Neuro-Oncology and in the assessment of neurocognitive function in patients with cancer.

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