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CANCER INVESTIGATION Vol. 21, No. 3, pp. 439–451, 2003
NURSING PERSPECTIVES
Chemotherapy-Induced Peripheral Neuropathy Constance Visovsky, R.N., Ph.D., A.C.N.P.* Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, Ohio, USA
ABSTRACT While cancer remains an important public health concern, novel and enhanced treatment modalities have increased the length of survival of individuals diagnosed with the disease. The treatment of most cancers requires the use of chemotherapeutic agents to affect cure, maintain control of the disease, or provide palliation of symptoms. Although the use of chemotherapeutic agents can serve to prolong life, such agents are associated with significant side effects. Increasing clinical evidence suggests treatment of cancer with neurotoxic agents results in some degree of peripheral neuropathy. Specific drug categories implicated in the development of peripheral neuropathy are the plant alkaloids, interferons, antimitotics, taxanes, and platinum-based compounds. Drug-induced peripheral neuropathy is sensory, dose-related and cumulative and is usually delayed, appearing weeks after initiation of therapy. The number of individuals at risk for the development of chemotherapy-induced neuropathy is expected to increase proportionately with clinical protocols utilizing higher or more frequent dosing. As advanced cancer treatments and clinical trials can result in extending the lives of individuals affected by cancer, long-term functional deficits resulting from life-saving treatments must now be addressed. As such, peripheral neuropathy has emerged as an important consequence of cancer therapy. Key Words:
Peripheral neuropathy; Side-effects; Interventions.
agents implicated in the development of peripheral neuropathy are the plant alkaloids, interferons, antimitotics, taxanes, and platinum-based compounds.[6 – 10] Chemotherapy-induced peripheral neuropathy is primarily sensory, dose-related, and cumulative, appearing
INTRODUCTION Increasing clinical evidence suggests the treatment of cancer with neurotoxic agents results in some degree of peripheral neuropathy.[1 – 6] Specific chemotherapeutic
*Correspondence: Constance Visovsky, R.N., Ph.D., A.C.N.P., Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA; E-mail:
[email protected]. 439 DOI: 10.1081/CNV-120018236 Copyright q 2003 by Marcel Dekker, Inc.
0735-7907 (Print); 1532-4192 (Online) www.dekker.com
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weeks after initiation of therapy.[8,11 – 13] In addition, the number of individuals at risk for the development of chemotherapy-induced neuropathy is expected to increase proportionately with clinical protocols utilizing higher or more frequent dosing. The majority of data related to therapy-induced neuropathy is derived from case studies. These studies are limited by the indirect, retrospective nature of the supporting data and by the lack of correlation of neuropathy with measurable differences in physiologic markers as endpoints of neuronal damage. Until recently there has been little attempt to address the long-term functional deficits that can result from cancer treatments. Individuals receiving neurotoxic agents have not been systematically monitored for long-term effects following the administration of neurotoxic agents, although peripheral neuropathy represents chronic changes in function for which the individual and family are ill prepared. As a result, peripheral neuropathy has emerged as an important consequence of cancer chemotherapy. While treatment-induced peripheral neuropathy is not a new phenomenon, it remains relatively unexplored and the diagnosis and evaluation of peripheral neuropathy remains unstandardized, posing issues for measurement and follow-up of sequelae. This article presents a review of the pathophysiologic processes, incidence, measurement issues, and treatments surrounding drug-induced peripheral neuropathy.
BACKGROUND While a concrete definition of toxic neuropathy has yet to be established, it is believed that a toxin interferes with the metabolic processes of neurons, ultimately resulting in axonal degeneration.[14] Peripheral neuropathy causes a dysfunction of peripheral motor, sensory, and autonomic neurons, resulting in peripheral neuropathic symptoms.[15] While peripheral neuropathy can be of hereditary, metabolic, vascular, or immunologic origin, this review will focus on neuropathy resulting from neurotoxic agents. The ability of toxic chemicals to induce peripheral neuropathy has been examined in animal models using such agents as isoniazid (INH), organophosphate compounds, thallium, vinca alkaloids, and nitrofurans. Research into the understanding of the process involved in nerve fiber changes following injury by toxics resulted in a hypothesized mechanism. The principal changes begin with a silent period ranging from days to months when pathologic alterations begin that vary according to
type and amount of toxin exposure. These changes first begin in the distal regions of the peripheral nervous system (PNS), affecting the sciatic nerve, branches of the tibial nerve supplying the calf musculature, and the ascending and descending spinal cord tracts. Degeneration of myelinated nerve fibers and unmyelinated axons follows. Alterations in the axon are accompanied by changes in the Schwan cells.[16] Earlier studies hypothesized that neurotoxic chemicals cause axons to die-back from nerve terminals by interfering with neuronal soma metabolism.[17,18] More recently, it has been hypothesized that neurotoxic chemicals directly damage nerve fibers by inactivation of components required to maintain the metabolic needs of the axon. The longer and larger distal axons are the first to be affected by this metabolic compromise, resulting in interruptions of axonal transport and precipitating distal nerve fiber degeneration.[14,16] The hypothesis of direct nerve fiber damage is supported in a recent study of platinum-induced peripheral neuropathy in Wistar rats treated with 2 mg/kg cisplatin twice weekly for 9 weeks. Following treatment, the rats were examined for the presence of platinum in dorsal root ganglia deoxyriboneucleic acid (DNA). Immunohistological evidence using polyclonal antibodies detected cisplatin not only in the dorsal root ganglia but in the kidney as well. Evidence suggests that platinum compounds induce a sensory neuropathy evidenced by reduced pain detection and decreased nerve conduction velocity accompanied by morphologic changes in dorsal root neurons.[19] The effects of peripheral neuropathy on the autonomic nervous system are the result of injury to small myelinated and unmyelinated nerve fibers. Postural hypotension results when nerve fibers to the splanchnic vessels are damaged. These nerve vessels are responsible for maintenance of blood pressure through sympathetic nervous system vasoconstriction of the splanchnic and peripheral blood vessels.[20]
INCIDENCE The exact incidence of peripheral neuropathy associated with neurotoxic chemotherapy is largely unquantified. Although specific chemotherapeutic agents have long been associated with neurotoxicity, neurological problems can be the result of malignancy and therefore pose difficulties in determining the exact incidence of drug-induced peripheral neuropathy. Neurological disorders can result from nerve root impingement by the tumor, metastasis of the disease to
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Chemotherapy-Induced Peripheral Neuropathy
the central nervous system, and metabolic or nutritional deficiencies. In addition, varied and unstandardized approaches to the measurement and grading of peripheral neuropathy ultimately impacts incidence rates. Differing neurotoxicity grading criteria are used across studies of chemotherapeutic agents, making comparison of toxicity incidence data difficult. While grading of peripheral neuropathy lacks standardization, oncology health care professionals are familiar with toxicity grading scales. The World Health Organization (WHO) scale, the Eastern Cooperative Oncology Group (ECOG) scale, and the National Cancer Institute of Canada Common Toxicity Criteria (NCIC-CTC) are commonly used in reporting neurotoxicity. In studies of treatment-related peripheral neuropathy conducted by neurologists, toxicities are described in terms of clinical manifestations rather than through the use of any standardized grading scale. In spite of these methodological difficulties, peripheral neuropathy is a reported, dose-limiting toxicity of many chemotherapeutic agents.
SPECIFIC CHEMOTHERAPEUTIC AGENTS AND PERIPHERAL NEUROPATHY Platinum-based compounds such as cis-diamminedichloroplatinum (cisplatin) have long been known to induce peripheral neuropathy. These agents are heavy metals that bind to DNA, forming cross-links between guanines and resulting in a bending of the DNA that may prevent base pairs from lining up with each other and possibly act as a precursor to axonal degeneration. Neurotoxicity as a consequence of cisplatin therapy is primarily manifested as ototoxicity, retinal toxicity, and sensory neuropathy primarily affecting large fiber nerves. Patients undergoing therapy with cisplatin for testicular cancer developed damage to the dorsal root ganglia, resulting in symptoms of peripheral neuropathy manifested as paresthesia, dysesthesia, and impaired vibratory and position sense. In 20 to 60% of patients treated with cisplatin, symptoms of neurotoxicity have persisted beyond treatment.[21] Ototoxicity is a well-documented adverse effect of cisplatin administration in approximately 20 to 40% of patients.[22 – 25] Animal studies indicate that with higher doses of cisplatin there is evidence of loss of outer and inner hair cells of the cochlea accompanied by scarring and degeneration.[26] When patients treated with cisplatin were followed prospectively with highfrequency audiometry, the resulting high-frequency hearing loss and tinnitus were thought to arise from
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damage to the secretory mechanism of the Organ of Corti.[27] Tinnitus appears to be the most commonly reported symptom of cisplatin-induced ototoxicity and may be reversible.[28] However, symptomatic hearing losses substantiated by audiogram may be permanent. In two separate studies in young patients receiving cisplatin who underwent audiometry, 50% of the children ðn ¼ 23Þ receiving 90 mg/m2 every 3 weeks (cumulative dose 270 mg/m2) had increases in hearing threshold and additional high-frequency hearing loss with further dosages.[29] The risk of developing hearing loss and tinnitus may be associated with age, cumulative drug dose, rate of infusion, and preexisting hearing impairment.[25] Despite evidence of ototoxicity, recommendations for audiometry prior to the start of cisplatin vary widely.[9,30] As there appears to be individual variability in the susceptibility and variability in hearing losses associated with cisplatin, some studies suggest systematic audiometric monitoring throughout therapy,[9,24] as some individuals may be at increased risk of permanent hearing impairment. For such individuals, baseline and follow-up audiograms are recommended. Further research using a longitudinal, prospective design could serve to provide standardized, consistent monitoring of patients for cisplatin-induced hearing loss. Opthalmic changes noted following cisplatin administration have been documented in case studies. However, the exact incidence remains unknown, as these studies were retrospective in design.[31 – 33] Thirteen women receiving high-dose cisplatin (200 mg/m2 divided into five daily doses over two to four cycles) for the treatment of ovarian carcinoma developed visual changes. Sixty-two percent of the women experienced blurred vision, 23% developed dysfunctional color perception, and 85% ðn ¼ 11Þ developed retinal toxicity as confirmed by electroretinography. While visual acuity improved when therapy was discontinued, color vision loss persisted for 16 months after treatment ended.[34] Sensory peripheral neuropathy has also been documented to occur in patients receiving cisplatin for a variety of cancers and appears to be doserelated at a cumulative dose of 300 mg/m2.[35] Cisplatin and oxaliplatin both cause sensory neuropathy that can limit the dose employed.[14] Clinical symptoms for both of these agents include sensory ataxia, reduced vibratory sensation, touch, and proprioception with progressive loss of deep tendon reflexes.[35,36] Biologic agents, such as interferon-alpha, have gained popularity in the treatment of cancers unresponsive to traditional therapies, such as malignant melanoma and renal cell carcinoma. These agents are also the
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mainstay of treatment for individuals with chronic hepatitis. Three patients who were being treated with interferon (INF)-alpha 2b (Intron-A) 3 MU subcutaneously three times weekly for chronic hepatitis developed optic neuritis. In all three patients, blurred vision was the presenting symptom. Two of the patients involved had resolution of the symptoms within 1 month of discontinuation of therapy. In one case, residual optical impairment and decreased visual acuity remained.[37] Case study evidence suggests an association between treatment with interferon-alpha and axonal neuropathy. In one case study, a 44-year-old male developed a sensory peripheral neuropathy during treatment with interferonalpha for hepatitis C.[38] In a second case study, a 43-yearold male treated with interferon-alpha for chronic hepatitis C developed significant paresthesias in his hands 6 weeks after the initiation of treatment. Although treatment with interferon was discontinued at 9 weeks, he continued to have progression of his symptoms that culminated with inability to clear the walking surface during the swing phase of gait, with complete remission following a course of plasma exchange treatments.[6] A 46-year-old male developed acute onset polyneuropathy with predominantly small fiber involvement following 6 months of treatment with interferon alpha-2a (3 MU three times a week) for hepatitis C. Sensory examination revealed diminished vibration sense and absent sharp/dull discrimination in both feet.[39] Rare cases of inflammatory demyelinating polyneuropathies following treatment with interferon-alpha have also been reported.[40,41] Interference with DNA, RNA synthesis, and protein metabolism of neurons has been suggested as a potential mechanism by which interferon could evoke neuropathy, but there is no evidence to support this claim. While these case studies do not present conclusive evidence of causality, they suggest a need for prospective follow-up of patients for optic nerve complications, especially as the long-term effects of these agents have not been fully explored. The vinca alkaloids induce paresthesias of the hands and feet in approximately 57% of patients and weakness, foot drop, and gait disturbances in 23 – 36%.[42,43] Additionally, vincristine and vinblastine have demonstrated effects on the cranial nerves. Case studies of patients treated with vinca alkaloids who developed vocal cord paralysis, jaw pain, and rare cases of optic neuropathy have been reported. It is believed that these findings may occur in 10% of patients receiving vinca alkaloids.[7] Eighteen patients treated for lymphoma with vincristine were given clinical and electrophysiological examinations at baseline and for 3 months after
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the initiation of therapy. After 2 weeks, impaired ankle jerk was noted and patients complained of paraesthesia by 4– 5 weeks after therapy. At the conclusion of the study, all 18 patients had clinically absent ankle jerk, 75% reported sensory symptoms, and 62.5% had impaired vibratory sense. The only autonomic abnormality reported was constipation, noted in 62.5% of the sample. Electromyography studies revealed denervation in the small muscles of the hand in 46.7%. Nerve conduction studies showed decreased muscle action potentials but unchanged conduction velocity. In this study, the patients treated with vincristine developed a distal, symmetrical, sensorimotor neuropathy of larger nerve fibers in the early phase of treatment.[44] In a study of long-term neurological effects of vinca alkaloid therapy, 40 patients of similar age treated with vincristine from 1980 to 1990 for non-Hodgkin’s lymphoma were evaluated using interview and vibratory and thermal testing 7 to 77 months (median 34 months) after treatment. These patients received a cumulative dose of 12 mg of vincristine over 18 to 24 weeks. Thirteen of 27 patients (48%) reported sensory symptoms that were not disabling at the time of the examination. Normal reflexes were noted in two-thirds of the patients examined. The study suggests that this particular cumulative dose of vincristine and dosing schedule may not cause permanent, irreversible neuropathy.[45] In studies by Hollans et al.[43] and Sandler et al.[42] constipation representing autonomic neuropathy occurred in 30– 46% of patients treated with vinca alkaloids. Although impotence as a toxic effect of vincristine has been documented, the exact incidence is unknown but is thought to be vastly underreported.[46] Antimitotics, such as paclitaxel and docetaxel, induce a wide range of peripheral sensory neuropathy. Clinical manifestations include burning dyesthesias and parasthesias, decreased vibration, and deep tendon reflexes.[14] Doxetaxel is a semisynthetic taxane that induces sensory neuropathy in 50% of treated patients. Sensory loss can be distinguished even after the first dose is administered. With cumulative doses exceeding 600 mg/m2, neuropathic symptoms can be severe.[47] Paclitaxel is a natural product derived from the Pacific yew tree. Early clinical phase I trials indicated that patients who received paclitaxel in amounts equal to or greater than 200 mg/m2 developed neuropathy as substantiated by electrophysiologic data, demonstrating both axonal degeneration and demyelination.[48] In a study of women treated with doses of 200 mg/m2 paclitaxel for advanced breast cancer, 84% were found to have paresthesias.[49,50] prospectively studied 27 patients
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Chemotherapy-Induced Peripheral Neuropathy
treated with paclitaxel as a single agent at 135 mg/m2 ðn ¼ 6Þ; 175 mg/m2 ðn ¼ 14Þ; and 250 – 300 mg/m2 ðn ¼ 7Þ for incidence, severity, dose-dependency, and reversibility of neuropathy. Patients were examined at baseline, following every other cycle, and after discontinuation of treatment for self-reported symptoms, vibration perception, and grip strength. Fifty percent, 79%, and 100% of those treated with paclitaxel 135 mg/m2, 175 mg/m2, and 250– 300 mg/m2, respectively, developed neuropathic symptoms. Neuropathic signs were present in 83 –100% of patients. At 250 – 300 mg/m2, neurotoxicity became a dose-limiting factor. Follow-up data available on 12 of the patients revealed the neuropathy to be partially reversible. Additionally, case report evidence has associated paclitaxel with adverse effects on autonomic cardiovascular mechanisms, specifically sympathetic control of blood pressure. Postural hypotension is the result of degeneration of sympathetic neurons supplying vascular areas in the body, the heart, and afferent fibers from baroreceptors.[51] In a study by Elkholm et al.,[52] 18 women with ovarian or breast cancer treated with paclitaxel alone ðn ¼ 14Þ; paclitaxel and cyclophosphamide ðn ¼ 1Þ; and paclitaxel and cisplatin ðn ¼ 3Þ were examined using autonomic cardiovascular function tests at baseline and following the second course of paclitaxel. Autonomic cardiac function tests consisted of both orthostatic and Valsalva testing. The women received paclitaxel in doses ranging from 90 – 200 mg/m2 (median ¼ 170 mg/m2). Heart rate and blood pressure changes and responses to the tests were measured. While heart rate variability remained unchanged, paclitaxel appeared to alter sympathetic control of blood pressure and baroreflex function. In another study, Jerian et al.[53] found administration of paclitaxel (Taxol) was associated with the development of orthostatic hypotension in two patients. Both patients developed severe orthostatic hypotension following a 24-hour infusion of 170 to 250 mg/m2 of taxol. Both patients were treated with fludrocortisone and the hypotension resolved. One patient underwent noninvasive autonomic testing including a tilt-test, Valsalva ratio, heart rate variation with respiration, and change in diastolic blood pressure with hand grip. All autonomic tests resulted in abnormal findings. Objective and subjective autonomic parameters such as orthostatic blood pressure, sensations of dizziness or syncope, constipation, or urinary incontinence are not currently part of routine patient monitoring. A newer agent currently in clinical trials in the United States for the treatment following acute
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promyelocytic leukemia is arsenic trioxide. Arsenic trioxide is now commercially available for the treatment of acute promyelocytic leukemia (APL). In China, patients with APL who received arsenic trioxide for remission induction experienced adverse effects including numbness.[54] Among common dose-related effects of arsenic trioxide is peripheral neuropathy. The maximal presentation of neuropathy seen with arsenic trioxide may not be evidenced until after the drug has been discontinued.[55] While the neuropathy associated with arsenic trioxide is thought to be reversible, it can take months to improve. More severe reactions have included quadriparesis.[56] While the incidence of peripheral neuropathy resulting from single agents is already significant, newer multimodal therapies using combination chemotherapy regimens have become standard, having demonstrated enhanced efficacy in treating cancer. Thus, the need to study the effects of neurotoxic chemotherapy becomes more urgent as agents with particular efficacy against certain tumors share toxicity profiles. The administration of two neurotoxic agents is not uncommon, resulting in higher grades of neurotoxicity.[15] The combination of cisplatin and paclitaxel is used frequently, as regimens containing both agents have resulted in improved survival in individuals with ovarian cancer and non-small cell lung cancer.[8] Neutropenia and peripheral neuropathy are the principal toxicities associated with paclitaxel and cisplatin administration. Neutropenia has been able to be controlled with the concomitant administration of hematopoietic growth factors, such as granulocyte-colony stimulating factor (G-CSF). At relatively high doses, neurotoxicity has now become the predominant dose-limiting toxicity. Chauddry et al.[57] prospectively followed 21 patients receiving paclitaxel (135 – 350 mg/m2) and cisplatin (75 –100 mg/m2) every 3 weeks as combination chemotherapy. Ninety-five percent ðn ¼ 20Þ of patients developed a symmetrical, sensory-motor neuropathy 1 – 21 weeks after the initiation of treatment that became progressive with each course of chemotherapy. Neurological impairment appeared to be more pronounced in patients who received higher doses of paclitaxel. In a similar study by Berger et al.,[8] neurological monitoring by clinical examination and motor nerve conduction studies was performed on 14 patients who received cumulative doses of paclitaxel and cisplatin of 175 – 1225 mg/m2 and 100– 700 mg/m2 every 3 weeks, respectively. Symptoms of neurotoxicity were noted following the second treatment cycle, with 12 patients developing the onset of sensory symptoms, 13 with impaired vibration sense, and 8 patients with leg muscle
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weakness. Thirteen patients demonstrated slowing of conduction velocities and 10 patients had prolonged distal latencies denoting axonal degeneration. Neurological symptoms increased with cumulative paclitaxel/cisplatin doses. Cavaletti and others[58] found mild sensory impairment after only three courses of therapy in 51 patients with ovarian cancer treated with either cisplatin (75 mg/m2) and cyclophosphamide (750 mg/m2) ðn ¼ 22Þ every 3 weeks or cisplatin plus paclitaxel (175 mg/m2) ðn ¼ 24Þ over 3 hours. Neurologic and ototoxicities were more pronounced at the end of treatment. Docetaxel and cisplatin were administered in a doseescalating study to 63 patients. These patients were followed prospectively and graded for neurotoxicity using the NCIC-CTC grading scale and vibration perception threshold (VPT) testing. This combination chemotherapy regimen induced a sensory neuropathy in 53% ðn ¼ 29Þ of 55 patients. When cumulative doses of both drugs approached 200 mg, 15 patients had a mild neuropathy, the neuropathy of 10 patients was classified as moderate, and 1 patient developed severe neuropathy. There were significant correlations between the cumulative dose and posttreatment neuropathy and VPT scores.[59] Postma et al.[60] found similar results in a doseescalation study of 22 patients with ovarian cancer treated with combination chemotherapy consisting of paclitaxel (escalating doses of 100, 135, 150, 165 mg/m2), cisplatin (50 mg/m2), and epirubicin (75 mg/m2). Ten of the patients had prior treatment for cancer, and these patients were also given a pancytoprotectant, amifostine 740 mg/m2, to prevent further neurological damage from occurring. Patients were evaluated at baseline and after three and six chemotherapy cycles. Peripheral neuropathy was graded using the NCIC-CTC scale. In patients with prior chemotherapy exposure, NCIC-CTC peripheral neurotoxocity criteria showed that neuropathy developed or progressed in 21 of 22 patients. A grade 3 (severe) neurotoxicity developed after six cycles in those patients who were chemo-naı¨ve and received either 150 mg or 165 mg/m2 of paclitaxel. In these patients, neuropathic symptoms (paresthesia, numbness, fine motor difficulties, and gait disturbances) interfered with daily life. Eighteen of 22 patients developed new neuropathic symptoms, the most common being paresthesia in the hands or feet, hand dysfunction (problems with buttoning, writing, etc.), and gait disturbances. The co-administration of amifostine did not prevent the development of new neurotoxicities in any of the 10 pretreated patients. New neuropathic signs were present in all 22 patients as compared to baseline. The ankle reflex was lost in 14 of 16
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patients. One patient developed motor weakness, while 16 of 19 patients had decreased vibration sensation. Ten of 20 patients had decreased pinprick in the feet. At the highest paclitaxel dose, all ðn ¼ 4Þ patients developed all of these signs. The VPT in the hand showed mild changes from baseline, but became worse in the feet in all patients during therapy. Evidence from these studies suggests that combination therapy with cisplatin and paclitaxel induces a sensory neuropathy that worsens with cumulative doses of cisplatin and at higher doses of paclitaxel. As these and other combination therapies become the standard, more intensive efforts aimed at monitoring and evaluating subsequent neurological effects is required. Combination chemotherapy consisting of carboplatin (AUC 5-6) and paclitaxel (175 mg/m2) is widely used in the treatment of ovarian cancer. Even so, little data is available addressing the neurotoxic potential of this regimen. A retrospective study by Markman and coworkers[80] found the overall incidence of peripheral neuropathy in 87 treated patients to be 25%, with 13% experiencing $ grade 2 severity of neuropathy using the Gynecologic Oncology Group toxicity scale. Case study evidence suggests that underlying neurological disease may increase the incidence of severe neurological toxicity resulting from neurotoxic chemotherapy. A particular predisposition for severe neurotoxicity has been noted in cases of individuals with hereditary neuropathies. In a case study by Hildebrandt et al.,[61] a 52-year-old female with preexisting CharcotMarie Tooth Disease Type IA was treated with a total of 4 mg of vincristine as part of a standard chemotherapy regimen (cyclophosphamide, vincristine, adriamycin, and prednisone) for the treatment of high-grade nonHodgkin’s lymphoma. The patient developed dysphagia, dysarthria, upper and lower muscle weakness, areflexia, and sensory impairment of the fingertips and lower extremities. These symptoms progressed over time until the patient became wheelchair bound. The patient’s symptoms slowly recovered within 6 months of discontinuation of vincristine. In another study, a 44-year-old male with CharcotMarie Tooth Disease Type 1A who was diagnosed with non-Hodgkin’s lymphoma was treated with a combination chemotherapy regimen that included vincristine. He developed a rapid onset of muscle weakness that progressed to quadriplegia. Lastly, Graf and colleagues[62] used a retrospective case review to examine the relationship of the DNA arrangement of individuals with Charcot-Marie Tooth Disease Type 1A (CMT1A) and susceptibility to vincristine-induced neurotoxicity. Three families with autosomal-dominant CMT1A with a member who underwent treatment with
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Chemotherapy-Induced Peripheral Neuropathy
vincristine for treatment of malignancy were identified. In each case, the affected family member suffered rapidly progressive severe neuropathy following vincristine therapy. The researchers of all the above case studies conclude that CMT1A hereditary neuropathy predisposes the individual to severe neurotoxicity and, thus, should be avoided. As in the case of recessive familial hearing loss in males, these findings, although not conclusive, suggest the necessity of obtaining a detailed family history from patients for whom treatment with neurotoxic agents is planned in order to screen for hereditary neuropathies. These cases support the hypothesis that severe axonal degeneration following vincristine administration may be more likely to occur in individuals with an underlying neuropathic disease.[63]
PATTERN/PROGNOSIS In describing peripheral neuropathies, distinguishing between motor, sensory, and autonomic symptoms becomes important. Most peripheral neuropathies demonstrate a mixture of motor and sensory signs.
Motor Signs Motor signs include muscle weakness and atrophy as motor neurons become affected by neuropathy. Muscle weakness tends to begin in the distal limbs, proceeding proximally as it progresses. Hypotonia, a decrease or loss of muscle tone, can follow as a result of lower peripheral motor neuron and muscle involvement. Hyporeflexia or areflexia is also a common feature of motor neuron involvement and can result from disturbances in conduction along afferent or efferent fibers.[64]
Sensory Signs Sensory signs can be divided into positive and negative symptoms. Individuals who experience sensations in the absence of normal stimulation are said to have positive symptoms, while negative symptoms are directly related to sensory loss. Individuals with neuropathy often experience a combination of positive and negative sensory signs. Positive signs include burning pain, known as causalgia, that occurs as a result of partial nerve injury. Paraesthesias and dysaesthesias are the most common positive signs associated with peripheral neuropathy. Paraesthesias are feelings of warmth, cold, numbness, or tingling that are felt without
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any specific stimulation or cause. Dysaesthesias are painful, electric sensations felt following tactile stimulation. Negative sensory signs resulting from peripheral nerve injury include loss of proprioception, ataxia, loss of balance, and a decrease in vibration sensation.
Autonomic Dysfunction Autonomic neuropathy results from damage by neurotoxic drugs to unmyelinated nerve fibers. The primary manifestations of autonomic neuropathy include hypotension, cardiac conduction irregularities, impotence, and bowel and bladder dysfunction. Of all autonomic effects, postural hypotension is the most common cardiovascular manifestation of peripheral neuropathy. Autonomic neuropathy may also be evidenced by the development of constipation, paralytic ileus, and urinary retention.[65]
EVALUATION In attempting to quantify the signs and symptoms experienced by individuals with peripheral neuropathy, many difficulties emerge. Grading scales are imprecise and inconsistently employed. The diagnostic approaches taken to determine the presence of neuropathy and the manner in which diagnostic tests are interpreted differ across studies. Lastly, few studies are longitudinal and prospective in design, impeding the ability to determine incidence and prevalence rates and causality.
Measurement Issues/Questions A variety of grading scales have been developed to detect and monitor chemotherapy-induced peripheral neuropathy. However, there is a decided lack of consensus concerning grading of neuropathy. Additionally, guidelines for the implementation of grading scales have not been developed, encouraging an unstandardized approach to detection and evaluation of neuropathy. Many grading scales employ a combination of objective and subjective items in grading neurotoxicity. The assignment of a “grade” to toxicity effects refers to the severity of the toxicity. The majority of grading scales range in severity from grade 0 (none) to grade 4 (very severe). Grading scales are useful in distinguishing between grade 1 and grade 4 toxicity, but more subtle differences, such as between grades 2 and 3, are difficult
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to delineate.[66] Overall, the current system for grading chemotherapy-induced peripheral neuropathy lacks a mechanism to adequately follow changes in peripheral nerve function from baseline. Two frequently encountered scales used in oncology practices for the grading of chemotherapy-induced neurotoxicity are the World Health Organization (WHO) scale and the Eastern Cooperative Oncology Group (ECOG) scale. The WHO scale grades peripheral neuropathy from grade 0 (none) to grade 4 (paralysis). This scale follows the progression of paresthesia (sensory function) and motor function, but deep tendon reflexes (DTR) are not assessed beyond grade 1. Moreover, the meaning of terms used to grade neurotoxicity is obscure. The WHO scale includes terms such as “mild weakness” or “marked motor loss” which lack specific grading criteria, thus, results could be inconsistent. The ECOG scale offers a more complete assessment of neuropathy by including motor component (DTR), sensory component (paresthesia), and an autonomic component (constipation). However, this scale is limited by its single-item approach to denoting the presence or absence of neuropathy. In addition, this scale suffers from the same deficit encountered in the WHO scale, as it contains unspecified terms such as “disabling sensory loss.” Both scales are lacking in the ability to determine the impact of neurological changes on the individual. A study by Postma et al.[67] compared several different chemotherapy-toxicity grading systems. The researchers concluded that physicians interpreted the severity of neuropathy differently, depending on the scale used. The Neuropathy Symptom Profile, Neurological Symptom Score, and Neurological Disability Score have been developed to describe neurological changes associated with diabetes, and therefore have not been tested in diagnosing and monitoring of peripheral neuropathy of differing etiology. Such existing scales fail to account for changes from baseline or neurotoxicity that becomes chronic in nature. An additional concern in grading the clinical manifestations of neuropathy, such as deep tendon reflexes, sensation, and motor function, is that these measures are to some degree dependent upon the cooperation of the patient. There is an inherent intra-subject variability in response and intra/inter-rater variability in the estimation of these responses that must be controlled.[15] Quantitative tests characterizing peripheral nerve function are available to diagnose and monitor neuropathy. Quantitative sensory testing (QST) is a noninvasive measure of sensory function and has been used
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as a screening tool for neuropathy for patients with cancer. One study that evaluated the use of QST in determining the presence or absence of peripheral neuropathy in patients with cancer by testing the vibration threshold (VT) of the index finger of the nondominant hand. Findings suggested that QST was able to detect subclinical neuropathy. However, VT screening is unable to assess the functioning of small, unmyelinated or lightly myelinated nerve fibers, resulting in an underestimation of neuropathy.[68] Thermal threshold testing in conjunction with VT allows for estimation of the function of small nerve fibers and the spino-thalamic pathway.[69] Tests such as nerve conduction studies, electromyograms, and sural nerve biopsy are uncomfortable and expensive procedures for the individual. Quantitative tests frequently coincide with clinical presentation, and thus little is gained through such extensive testing. More importantly, quantitative nerve function assessments and clinical severity of the impairment do not always coincide. In reviewing current chemotherapy-induced neuropathy grading systems, Postma and Heimans[15] call for a more accurate and comprehensive grading method that would include a combination of standardized measures for grading neurological signs, symptoms, and assessment of the impact of neuropathy on quality of life. There are few studies that have evaluated peripheral neuropathy grading scales.[15,66] Without consensus and specific guidelines as to the use of the scale selected, it becomes difficult to compare results of toxicity reports across pharmacological studies.
GAPS IN THE LITERATURE There is a decided lack of systematic, longitudinal studies that correlate measures of peripheral nerve damage with clinical manifestations. There has been no attempt to synthesize what is known and unknown about peripheral neuropathy resulting from any etiology. Cancer therapies can contain combinations of neurotoxic agents, resulting in additive neurotoxic effects, yet there are no long-term studies completed that have delineated and evaluated the long-term complications of such treatments.[14] There is little evidence of the impact of functional status changes induced by neuropathy on the individual. The majority of studies are retrospective in design or are case study reports. While it appears evident that patients with hereditary neuropathies, such as Charcot Marie Tooth Disease Type IA, are at risk of more severe neuropathies, it is not clear if this predisposition extends to other populations with
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Chemotherapy-Induced Peripheral Neuropathy
preexistent neuropathy, such as those with diabetes mellitus. To date there is no effective means of measuring the incidence of peripheral neuropathy, and prevalence rates are largely unreported. In addition, there is a dearth of literature evaluating the different measures or grading of peripheral neuropathy and guidelines in using available grading tools are lacking.
Evaluating Sequelae Although the evaluation and monitoring of objective clinical sequelae of chemotherapy-induced peripheral neuropathy is important, reliance on these measures alone fails to capture the impact of peripheral neuropathy on the individual. The inclusion of the patient’s perception of the degree to which peripheral neuropathy impairs physical functioning is necessary to understand its full impact. Quality-of-life outcomes are becoming more commonplace as a component of evaluating medical treatment. While evaluations of medical outcomes such as linking disease regression to shrinkage of the primary tumor or a decrease in tumor markers, the measurement of the patient experience during and after treatment for cancer is not so obvious. Quality of life can be perceived in many different ways, and as a consequence any measure of this phenomena becomes a challenge. While not life threatening, peripheral neuropathy has the potential to greatly impact quality of life. In a descriptive study by Ostchega et al.,[70] the development of neuropathy was associated with increased fatigue, malaise, and psychological distress. Individuals with peripheral neuropathy reported a decrease in life satisfaction related to a decline in physical independence.
INTERVENTION Interventions for peripheral neuropathy are few and primarily aimed at pharmacological measures to reduce the toxicity profile of chemotheraputic agents. For the purposes of this review, interventions for peripheral neuropathy will be categorized as pharmacologic interventions, exercise therapy and occupational therapy, and educational interventions.
Pharmacologic Interventions Cytoprotective agents are drugs that can be coadministered with chemotherapy to prevent or minimize specific toxic side effects associated with certain chemotherapeutic agents. Cytoprotective agents are
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currently being investigated for their potential use in altering drug-induced toxicity at the cellular level by interacting with toxicity targets. Amifostine (Ethyol) has been approved by the U.S. Food and Drug Administration (FDA) for use in reducing renal toxicity associated with cisplatin administration. In addition, amifostine has shown to have hematologic and neurologic protective capabilities. Amifostine works by scavenging oxygen-free radicals and by hydrogen donation to repair damaged DNA.[71] While the use of amifostine does not eliminate neurotoxicity associated with neurotoxic chemotherapy regimens, it can reduce the incidence and severity of the neurotoxicity experienced.[72] Ongoing trials are continuing to investigate the role of amifostine as a neuroprotectant.[21] Glutamate, an amino acid, has been proposed as a neuroprotective agent in cisplatin, paclitaxel, and vincristine therapy.[73,74] In a rat model of drug-induced neuropathy, both sensory and motor disturbances were noted in animals treated with combination therapy consisting of cisplatin and paclitaxel 2– 8 weeks after the onset of treatment. In animals supplemented with glutamate administered 24 hours prior to chemotherapy, there was a significant delay in the onset of gait disturbance, and higher doses of the drug could be tolerated.[74] An earlier animal model study by the same researchers had similar findings using glutamate as a neuroprotectant in vincristine therapy.[73] The manner in which glutamate offers neuroprotection is not yet known and further trials are in progress. Neurotrophic factors may play a role in the development of peripheral neuropathy. Neurotrophic factors are proteins that support the survival of neurons.[75] In particular, one neurotrophic factor, recombinant nerve growth factor (rhNGF), has received some attention as a possible treatment of drug-induced peripheral neuropathy. It is hypothesized that nerve growth factor (NGF) levels decrease with chemotherapy treatment. In a study of 23 cancer patients, NGF levels were measured before and after chemotherapy treatment. Circulating levels of NGF declined or disappeared completely with chemotherapy.[76] Currently, trials are underway to explore the role of rhNGF in both diabetic and HIV-induced peripheral neuropathy. In current clinical trials of both these patient groups, rhNGF has been found to be well tolerated, with pain at the injection site reported as the most frequent adverse event. The function of small-fiber sensory nerves was improved by rhNGF in the diabetic group and neuropathic pain intensity improved in the HIV group.[77] While these factors are currently in phase II and III clinical trials, preliminary reports suggest they
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Visovsky
have variable success, and more data will be needed before recommendations about use can be made.
pesticides, and herbicides must be avoided. The occupational therapist also assesses the patient’s capability to perform self-care activities and can recommend assistive devices as needed.
Exercise Therapy Few studies address the value of exercise for individuals with peripheral neuropathy. However, there is some evidence that exercise may be beneficial. Passive range of motion has been demonstrated to enhance reinnervation in denervated muscle and appears to have therapeutic value.[78] The patient is progressed to active muscle contraction prior to beginning more strenuous exercise. Exercises against heavy resistance using weights helps to develop strength. Strengthening exercises typically use three sets consisting of 15 –30 repetitions. The weights used are increased weekly and the muscle responds accordingly by becoming stronger. The patient is considered to reach maximal muscle strength when the weight lifted remains the same over 1 month. Once this occurs, the patient should be instructed to continue the exercise program at slightly reduced levels of frequency and weights to prevent loss of strength. A physical therapist can make recommendations for orthotic braces or a splint to assist with lower extremity alignment and balance. In a review of exercise therapies used in peripheral neuropathy, Herbison et al.[79] conclude that while stretching is helpful in maintaining range of motion, it does not increase muscle strength. However, brief isometric or progressive resistance exercise programs performed four to six times per day increases muscle strength. In addition, individuals with peripheral neuropathy should be taught compensatory mechanisms to localize muscle contraction, prevent disuse, and build muscle strength. Sensory retraining should be instituted, as appropriate.
Occupational Therapy As the effects of chronic peripheral neuropathy may impact social and functional roles, occupational therapy to evaluate vocational factors may be helpful. The individual with peripheral neuropathy may lack the sensory-motor skills necessary to operate machinery. A cane or walker may be needed and the individual with an occupation requiring fast-paced mobility may require vocational counseling. Patients must be taught to avoid exposure to neurotoxic substances to prevent further nerve fiber deterioration. Exposure to industrial solvents,
Educational Interventions Peripheral neuropathy places the individual at risk of thermal and ischemic injury. Educational efforts need to address personal safety issues such as using visual input to compensate for loss of lower extremity sensation in navigating changing terrain. Education concerning monitoring and coping strategies for symptoms of autonomic dysfunction (postural hypotension, constipation, urinary retention) should be initiated. For example, bowel function can be maintained through the use of a high-fiber diet, adequate fluid intake, and exercise.
CONCLUSION As new applications of neurotoxic agents demonstrate efficacy in eradicating or controlling cancer, the survival time of affected individuals is prolonged. Thus, associated peripheral neuropathy represents chronic, long-term changes in function for which patients and families are ill prepared. Therefore, research using baseline and follow-up assessments to monitor the neurotoxic effects associated with chemotherapeutic agents is a necessary step to assist individuals in making necessary life-style adjustments following the onset of neuropathy. Individuals most at risk of debilitating neuropathies need to be identified and closely monitored. The current clinical practice using the standard neurological evaluation may fail to detect diminutive declines in peripheral nerve function. Consistent, comprehensive monitoring of progressive neuropathy will generate data useful in designing intervention studies and patient/family education materials aimed at reducing the impact of peripheral neuropathy on safety, activities of daily living, occupational and social roles, and quality of life.
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