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