Chemotherapy and Polyneuropathies Grisold W, Oberndorfer S Windebank AJ European Association of Neurooncology Magazine 2012; 2 (1) 25-36
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Volume 2 (2012) // Issue 1 // e-ISSN 2224-3453 Neurology · Neurosurgery · Medical Oncology · Radiotherapy · Paediatric Neuro- oncology · Neuropathology · Neuroradiology · Neuroimaging · Nursing · Patient Issues Chemotherapy and Polyneuropathies Grisold W, Oberndorfer S Windebank AJ European Association of NeuroOncology Magazine 2012; 2 (1) 25-36 Homepage: www.kup.at/ journals/eano/index.html OnlineOnline DatabaseDatabase FeaturingFeaturing Author,Author, KeyKey WordWord andand Full-TextFull-Text SearchSearch THE EUROPEAN ASSOCIATION OF NEUROONCOLOGY Member of the Chemotherapy and Polyneuropathies Chemotherapy and Polyneuropathies Wolfgang Grisold1, Stefan Oberndorfer2, Anthony J Windebank3 Abstract: Peripheral neuropathies induced by taxanes) immediate effects can appear, caused to be caused by chemotherapy or other mecha- chemotherapy (CIPN) are an increasingly frequent by different mechanisms. The substances that nisms, whether treatment needs to be modified problem. Contrary to haematologic side effects, most frequently cause CIPN are vinca alkaloids, or stopped due to CIPN, and what symptomatic which can be treated with haematopoetic taxanes, platin derivates, bortezomib, and tha- treatment should be recommended. growth factors, neither prophylaxis nor specific lidomide. Little is known about synergistic neu- Possible new approaches for the management treatment is available, and only symptomatic rotoxicity caused by previously given chemo- of CIPN could be genetic susceptibility, as there treatment can be offered. therapies, or concomitant chemotherapies. The are some promising advances with vinca alka- CIPN are predominantly sensory, duration-of- role of pre-existent neuropathies on the develop- loids and taxanes. Eur Assoc Neurooncol Mag treatment-dependent neuropathies, which de- ment of a CIPN is generally assumed, but not 2012; 2 (1): 25–36. velop after a typical cumulative dose. Rarely mo- clear. tor, autonomic, or CNS involvement occurs. Typi- Neurologists are often called in as consult- cally, the appearance of CIPN is dose-dependent ants for cancer patients suffering from CIPN and Key words: chemotherapy, neurotoxicity, cen- although in at least 2 drugs (oxaliplatin and have to assess whether the neuropathy is likely tral nervous system, prevention, therapy Introduction age. Mitochondria in aged persons could also be a factor in distal axonal degeneration. Patients with oncological diseases need to receive the most effective anti-cancer therapy. To achieve this, usually a com- Sensory neurons in the dorsal root ganglia (DRG) seem to be bination of surgery, radiotherapy (RT), and chemotherapy, exposed to several pathologies: also with biologicals with an increased use of targeted thera- – The blood supply of the DRG by fenestrated capillaries that pies, is applied. Like most other side effects of therapy, such allow passage of drugs into the extracellular space around as nausea, haematotoxicity can be managed but the increased DRG neurons (blood-nerve-barrier less well-expressed). use of neurotoxic drugs and the development of CIPN are be- – Platinum binding to nuclear DNA appears to stimulate coming major dose-limiting factors. post-mitotic neurons to enter a state resembling G1 of the cell cycle which might start processes resulting in apop- Although the biological effects of all neurotoxic substance tosis. classes are known, the precise mode of action on the periph- – Cutaneous sensory fibres lose their glial ensheathment as eral nerves is not always clear, and much effort has to be made they approach the epidermis and are less protected contrary to develop strategies of prevention and treatment of CIPN. to motor fibres. The morphologic correlates of CIPN are depicted in Figure 1. This is of particular importance as the number of long-term survivors has increased due to the success of oncologic treat- ments and peripheral neurotoxicity becomes a major dose- limiting factor. Patients can be exposed to dysfunctions im- pairing their quality of life as well as to neuropathic pain. To overcome this challenge several approaches are being made. Several possibilities for common pathways and affected struc- tures of sensory neurons and peripheral nerves are being dis- cussed. The impairment of mitochondrial function (suggested by the loss of mitochondrial mobility in bortezomib, pacli- taxel, and vinca alkaloid neuropathy) could be one of the key factors. Mitochondrial failure could be a mechanism causing axonal injury either by a failure to maintain ionic concentra- tions, or by the fact that impaired mitochondrial motility re- sults in mitochondria being unable to move to areas of high calcium concentration in the axon, resulting in axonal dam- Received on September 23, 2011; accepted for publication on October 22, 2011; Pre-Publishing Online on December 15, 2011 From the 1Department of Neurology, Kaiser-Franz-Josef-Spital, Vienna; the 2Depart- Figure 1. Morphologic correlates of CIPN. The DRGs can be the target of cumulative ment of Neurology, Landesklinikum St. Pölten, Austria; the 3Department of Neuro- neurotoxicity as in platinum compounds. Axons, rarely the myelin, can be damaged. At the neuromuscular transmission site (NMT), the acute toxicity of oxaliplatin oc- logy, Mayo Clinic, College of Medicine, Rochester, MN, USA curs. Unmyelinated fibers and terminal nerve arbors are the sites of acute taxane Correspondence to: Wolfgang Grisold, MD, Department of Neurology, Kaiser-Franz- toxicity. An additional spinal mechanism at the alpha-2-delta-Typ1 subunit in neuro- Josef-Spital, A-1110 Vienna, Kundratstraße 3; e-mail: [email protected] pathic pain is assumed. EUR ASSOC NEUROONCOL MAG 2012; 2 (1) 25 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Chemotherapy and Polyneuropathies – Disruption of axonal transport also interferes with retro- Table 1. Muscle symptoms related to chemotherapy grade transport of target-derived trophic factors, recycled membrane, and other vesicular components. In the near fu- Rhabdomyolysis Cytarabine ture, based on databases containing cancer type, type, and Proximal weakness Taxanes dose of chemotherapy, phenotyping of patients with CIPN Radiation recall phenomenon Gemcitabine might become more easily available and provide a basis for Necrotizing myopathy Vincristine Myalgia Taxanes, gemcitabine, several future strategic plans and even individualized therapies. others Distal cramps Vinca alkaloids (as neuropathy) Concerning the severity and expression of neuropathies, as well as the frequency of occurrence, there are major prob- loss of stereotactile recognition of small figures such as coins, lems. The characterization with scales and scores is heteroge- keys etc. neous and is discussed by Cavaletti et al in this issue [1]. The frequency of neuropathy for each drug is even more complex, Motor function is usually not an issue in CIPN, apart from as most series rely on small studies or are the result of larger vinca alkaloids, which can induce monopareses and drop medical oncologic studies which report neuropathies only as foot, and suramin which has a significant motor involvement side effects. Often, these figures provide no information on but is infrequently used. associated diseases, pre-existing neuropathies, previous drug treatments, and the combination of chemotherapies. Websites Autonomic signs are rare but can be seen in vinca alkaloids, recording individually reported side effects reach large num- resulting in intestinal symptoms, even ileus, and have also bers, and by and large they seem to list the distribution of been noted in taxanes and platinum compounds. toxic effects, but are not sufficiently evaluated to determine neurotoxic effects. Several reviews on chemotherapy-induced Motor symptoms can occur as mononeuropathies or cranial neuropathies exist, which rely on the available data [2–6]. nerve lesions in vinca alkaloids. Some drugs cause muscle involvement (Table 1) with myal- Symptoms, Signs, and Investigations gia, muscle cramps, or weakness [3, 7]. This can be a proxi- Clinical Symptoms mal myopathy as seen in taxanes [8, 9] and vincristine [10]. Most chemotherapy-induced neuropathies are sensory. As the Myalgia has been observed in a combination of taxanes and CIPNs are duration-of-treatment-dependent, tingling or gemcitabine [11]. Cramps rarely occur, but when they do, numbness in the feet or fingers is an early sign. Patients also they occur in particular in small foot and hand muscles. The report hypaesthesias, dysaesthesias or paraesthesias and neu- radiation recall syndrome [12] has been described in ropathic pain. Sensory symptoms such as numbness are usu- gemcitabine and carboplatinum. Rhabdomyolysis has been ally irritating. But also a “plus” of symptoms, such as tingling, rarely attributed to chemotherapy [13, 14]. Sarcopenia, which itching, stabbing, or pain, may occur. When symptoms is a common phenomenon in advanced cancer, has also been progress, the sensory zone widens and progresses from the related to drug treatment [15]. In myelomas, muscle amyloi- tips of the extremities to a stocking-glove-like distribution. At dosis occurs as well [16, 17], which is characterized by a com- this stage, patients are usually already disabled: on the upper bination of weakness and pseudohypertrophic muscles. extremities by a loss of dexterity and development of clumsi- ness, on the lower extremities by an addition of instability, Nerve Conduction Velocities (NCV) which leads to disturbed balance and falls.