Thrombosis typically occurs within the dural sinuses and cerebral veins, leading to secondary hemorrhage or infarction.67 Patients present with a range of symptoms from mild headache to coma and death, which are caused by rapid increases in intracranial pressure. Behavioral signs include acute psychosis, restlessness, wide mood swings with inappropriate crying and laughing, cortical blindness, visual hallucinations, stupor, and akinetic mutism … The relationship existing between patients with cancer and their health-care providers is somewhat complex. Cindy Lin. Research Funding: Paola Marmiroli, Merck Serono (I). Spinal cord toxicity can occur following intrathecal administration of certain cytotoxics in acute leukemias, lymphomas, and brain tumors. Neurological side effects are a common complication following chemotherapy, and can adversely affect clinical management of the cancer patient. Examples of Peripheral Neurotoxicity of Targeted Agents Used in Cancer Therapy. Methylene blue is used for ifosfamide-induced encephalopathy and infusional calcium with magnesium may lessen the severity of established peripheral neuropathy due to oxaliplatin. Risk factors include extremes of age, dose/ schedule, previous cranial radiotherapy, and renal or hepatic dysfunction.8,9. (May 14, 2015) Investigations should include urea/electrolytes, liver function, serum glucose, calcium magnesium, viral serology, and CSF examination. Buy Membership for Hematology, Oncology and Palliative Medicine Category to continue reading. Long-term effects of chemo on the cognitive function of cancer patients, Chemotherapy-induced neuropathy: a comprehensive survey, Chemotherapy-induced peripheral neurotoxicity (CIPN): an update, Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics, Chemotherapy-induced peripheral neurotoxicity, Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin, Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle, Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2, Neuronal drug transporters in platinum drugs-induced peripheral neurotoxicity, Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies, Morphological and morphometric analysis of paclitaxel and docetaxel-induced peripheral neuropathy in rats, Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells, Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells, Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat, Bortezomib-induced painful peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse, Bortezomib-induced painful neuropathy in rats: a behavioral, neurophysiological and pathological study in rats, Bortezomib induces the formation of nuclear poly(A) RNA granules enriched in Sam68 and PABPN1 in sensory ganglia neurons, Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment, Proteasome inhibitors increase tubulin polymerization and stabilization in tissue culture cells: a possible mechanism contributing to peripheral neuropathy and cellular toxicity following proteasome inhibition, Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy, Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study, Lenalidomide in patients with chemotherapy-induced polyneuropathy and relapsed or refractory multiple myeloma: results from a single-centre prospective study, Interventions for preventing neuropathy caused by cisplatin and related compounds, Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline, Neurological complications following alemtuzumab-based reduced-intensity allogeneic transplantation, Guillain-Barré syndrome after use of alemtuzumab (Campath) in a patient with T-cell prolymphocytic leukemia: a case report and review of the literature, A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies, Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma, Severe peripheral motor neuropathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin, Long-term neuropathy after oxaliplatin treatment: challenging the dictum of reversibility, Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer, Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer, Chemotherapy-induced neuropathy and its association with quality of life among 2- to 11-year colorectal cancer survivors: results from the population-based PROFILES registry, Peripheral neuropathy in colorectal cancer survivors: the influence of oxaliplatin administration. Patients report problems with memory retrieval, learning, and concentration, which may persist after treatment has finished or never fully resolve.1 The incidence of acute problems during treatment ranges from 15% to 70%, with 50% of patients in one study identifying persistent problems a year after treatment.2 Cross-sectional studies also suggest persistent cognitive dysfunction in 20% to 30% of patients 2 to 10 years posttreatment.3,4. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain, Qualitative research into the symptom experiences of adult cancer patients after treatments: a systematic review and meta-synthesis, The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings, Chemotherapy-induced peripheral neurotoxicity assessment: a critical revision of the currently available tools, Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention, Cognitive changes associated with cancer and cancer treatment. Spinal cord toxicity can occur following intrathecal administration of certain cytotoxics in acute leukemias, lymphomas, and brain tumors. However, because a quarter of the women who did not receive neurotoxic chemotherapy were affected by peripheral neuropathy symptoms, this result, in the absence of any objective evaluation, raises some concern about the validity of the selected assessment tool to really detect CIPN. Employment: None. Permissions, Authors The first methodological study designed to address this relevant issue has been reported recently,4 and marked differences in perceptions of CIPN by patients versus by treating physicians have been demonstrated.14 These apparently conflicting results actually represent two sides of the same coin, and they should always be coupled in the planning and interpretation of any study devoted to CIPN investigation or treatment. Paola Alberti. No effective treatments are available for alleviating persistent symptoms of chemotherapy-induced peripheral neurotoxicity. The typical clinical features of CIPN have been extensively reviewed (Table 1).10–13, TABLE 1. Oxaliplatin is unusual in that it causes acute cold dysesthesias, as well as pharyngolaryngospasm, which usually starts shortly after administration of chemotherapy and then resolves. The frequency, severity, and time course of CIPN can be very variable. Acute encephalopathy is a common problem in oncology patients; it has a wide range of precipitating factors including metabolic derangements, hypoxia, brain metastases, meningeal carcinomatosis, infection, paraneoplastic phenomena, and drugs.6 Presenting symptoms typically include lethargy, confusion, somnolence, seizures, or coma. Relationships marked “L” indicate leadership positions. It is used either at a conventional dose of 100 to 200 mg/m. In Table 2, examples regarding the possible peripheral neurotoxic effect of cancer-targeted drugs are reported. Among several cancer treatment–related side effects, neurotoxicity can be particularly severe and long lasting and can affect the quality of life (QoL) as well as the daily life activities of cancer survivors.2,3 The peculiar characteristics and biology of neurons (e.g., high specialization, selective metabolism, incapacity to replicate) and the very limited possibility of the central nervous system (CNS) to effectively recover from severe and extensive damage make CNS neurotoxicity a well-known, critical medical problem. Patients most at risk are children, those who have received previous cranial radiotherapy, or those receiving concomitant intravenous and intrathecal therapy. When the brain is exposed to toxic- either natural or artificial- it alters the normal activities of the nervous system, which is called neurotoxicity. For instance, five of a series of 85 patients treated with alemtuzumab developed a progressive sensorimotor radiculoneuropathy and/or a myelitis.33 Moreover, in 2010, another case of acute inflammatory polyradiculoneuropathy (Guillain-Barré syndrome) was reported in an alemtuzumab-treated patient.34 In these cases, it has been hypothesized that alemtuzumab may trigger an autoimmune cascade that results from indiscriminate dysregulation of regulatory T cells or from a molecular mimicry. Cytarabine and 5-fluorouracil are the cytotoxics most likely to cause cerebellar dysfunction including truncal ataxia, gait disturbance, and ataxia.8,14,21,22 Acutely, the MRI tends to be normal, but subsequent scans may show chronic atrophy due to irreversible Purkinje cell loss.15–18. About Leadership Position: None. Anticancer chemotherapy can permanently damage both the central and the peripheral nervous systems, but the mechanism(s) of this toxicity is largely unknown. The ECOG criteria are organized in a similar manner with a scale from 0 to 4 and can be viewed at www.ecog.org. The number of cancer survivors and of patients in whom cancer has become a chronic disease is increasing in Western countries, and these people strongly require considerations about the effect of long-term toxicities on QoL. Filed under Hematology, Oncology and Palliative Medicine. To this aim, a virtuous alliance among patients and treating physicians is needed. Chemotherapy-induced neurotoxicity is difficult to prevent and treat. In a study that was not included in the previous review by Mols et al, Tofthagen et al investigated a cohort of patients treated with oxaliplatin up to 7 years after treatment and observed that 89% of them reported at least one symptom of neuropathy;45,46 among these patients, 24% had difficulties in driving and 60% in exercising. CancerLinQ DOI: 10.14694/EdBook_AM.2015.35.e553 American Society of Clinical Oncology Educational Book There is no universal grading system for the evaluation of patients with neurological toxicity although two neurotoxicity scoring systems are frequently used: NCI-CTC 3 (National Cancer Institute Common Toxicity Criteria version 3) and ECOG (Eastern Cooperative Oncology Group). Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. [1] Headache, encephalopathy, cortical peripheral neurotoxicity and central neurotoxicity blindness, focal deficits, stroke and seizures have all 2019 Feb;98(2):240-249. doi: 10.1111/aogs.13477. Several of these targeted drugs are now used routinely. Neurotoxicity occurs when the exposure to natural or manmade toxic substances (neurotoxicants) alters the normal activity of the nervous system. The mechanism of toxicity is not well-understood, but it appears that cytarabine directly causes neuronal death, possibly by the inhibition of cytidine-dependent neurotropic signal transduction, Acute cerebellar dysfunction is the commonest central neurotoxicity, occurring in approximately 14% of patients; they typically present with dysarthria, nystagmus, gait ataxia, and confusion. The conventional drugs associated with CIPN are platinum compounds, taxanes, vinca alkaloids, epothilones, proteasome inhibitors, and thalidomide. Additionally, as more patients survive long term, late neurological side effects are becoming increasingly recognized, such as impaired cognitive function and/or dementia. Patients report problems with memory retrieval, learning, and concentration, which may persist after treatment has finished or never fully resolve. Generally patients with a toxicity score of 1 to 2 can continue with their treatment unmodified, while those with a score of 3 or 4 require dose modification or cessation of treatment. Loss of neurological function may progress upwards.23 Histologically, there are focal areas of necrosis, particularly at the periphery of the spinal cord, associated with axonal swelling and demyelination. Asparaginase (either as the L- or pegylated formulation) is a component of remission-induction therapy used to treat acute lymphoblastic leukemia (ALL). Stock or Other Ownership Interests: None. They also cause cell-cycle kinetics alterations: postmitotic DRG neurons would reenter into the cell cycle and be induced into apoptosis.15 Other pathogenetic hypotheses have been proposed, which involve oxidative stress, mitochondrial dysfunction, reduction in the activity of enzymes involved in DNA base excision, repair of oxidative damage, redox regulation, and cellular transport.16–18, The most obvious mechanism of PNS damage by taxanes is related to their hyper-polymerizing action on microtubules. Results from the population-based PROFILES registry, Carcinoma of the ovary. A study of 1,425 patients with cancer who had different malignancies demonstrated that patients often underreported their symptoms to health-care providers;51 when a comparison was performed between the hospital notes and the patient interviews, the data did not correspond for the majority of the patients.44 With specific reference to CIPN, moderate/severe symptoms were reported by 29% of patients, whereas symptoms of any severity were reported by only 12% of patients according to the hospital notes that referred to follow-up visits. To overcome some of these problems, a transition to rationally designed, molecularly targeted drugs, which aims at a much more specific effect on cancer cells and a sparing of normal tissues, has occurred in chemotherapy. JCO Oncology Practice published online before print Generally, symptoms are self-limiting, but in some patients the symptoms persist. From the Experimental Neurology Unit and Milan Center for Neuroscience, Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy. A dying-back process that starts from distal nerve endings and is followed by disturbed axonal flow has been demonstrated in models of CIPN associated with taxanes.19 However, macrophage activation in both the DRG and the peripheral nerve, and microglial activation within the spinal cord, also have been demonstrated.20 In an animal study, paclitaxel-induced swelling and vacuolation of axonal mitochondria in A and C fibers was demonstrated.21, Competition studies with paclitaxel demonstrated that epothilones might act on the same or on an overlapping binding site on tubulin. Its neurotoxicity is thought to stem from widespread disruption of various metabolic pathways in the brain and can be acute or chronic. 5-fluorouracil (5-FU), a pyrimidine analogue, is widely used in the treatment of gastrointestinal malignancies; it is administered either as a short intravenous bolus or as a prolonged continuous infusion. Neurotoxic Complications of Cancer Chemotherapy 1551 Neurotoxicity caused by chemotherapeutic into the carotid artery in patients with brain agents is a frequently observed side effect. The full version can be downloaded from www.fda.gov. Patients' and health-care providers' perceptions of the severity of chemotherapy-induced peripheral neurotoxicity may be very different, as demonstrated by recent studies focused on this highly relevant issue. Long-Term CIPN is likely to be one of the extremities, specifically in the treatment of hematological,,. 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