Relationships marked “I” are those held by an immediate family member; those marked “B” are held by the author and an immediate family member. 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. Some of the effects of neurotoxicity may appear immediately, while others can take months or years to manifest.The effects of neurotoxicity depends on various different factors such as the characteristics of the neurotoxin, the dose a person has been exposed to, ability to metabolise and excrete the toxin, the ability of affected mechanism and structures to recover and how vulnerable a cellular target is.Some of the symptoms of neurotoxicity include: 1. However, the peripheral nervous system also can be permanently damaged by anticancer treatments despite its better regeneration capacities, and the effect on patients' daily life activities might be extremely severe. Guido Cavaletti. Paola Alberti. This review addresses the neurotoxicity of newly available therapeutic agents including brentuximab vedotin and blinatumomab as well as classic ones such as … However, only a few well-conducted analyses have been performed to quantify the real extent of the problem, and different methodological approaches have been used, which make a reliable comparison very difficult. Acute encephalopathy is associated with the administration of high-dose methotrexate (>3 mg/m, Medical Complications in the Management of Brain Tumors, Neurological Complications of Radiation Therapy. 40% of patients receiving chemotherapy and depends on the type of cytotoxic drug, the duration of administration, cumulative dose and pre-existing peripheral neuropathy.2-7 Symptoms are predominantly sensory, but the neurotoxicity also appears as a sensory-motor neuropathy and occasionally it will be accompanied by dysfunction of The neuropathy is largely reversible over several months but many patients may be left with some degree of paresthesia. However, with the aging population, cancer (and treatment-related toxicities) in the primary care setting are very likely to increase in the future. Also, the pathogenesis of cancer-targeted drugs effects on the PNS is largely unknown. Another study was reported in 2014 by Ezendam et al,47 who investigated a cohort of patients with ovarian cancer by using two EORTC QoL scales; the results demonstrated that CIPN symptoms were significantly associated with QoL impairment. Advertisers, Journal of Clinical Oncology 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. On the clinical side, a very important contribution to better knowledge of cancer treatment–related neurotoxicity could come from a more homogeneous, reliable, and systematic collection of the clinical data of treated patients. First, the precise clinical manifestations and their incidence and severity are not always properly assessed, and the several tools used so far have very rarely been validated for this specific use. Metabolic abnormalities associated with the development of encephalopathy include widespread reduction in glucose utilization and protein synthesis,99 which are reversible by replacing depleted folate stores with the administration of leucovorin.100 Leucovorin is now given routinely following high-dose methotrexate (folinic acid rescue). The only specific therapy is the use of methylene blue in ifosfamide-induced encephalopathy, which should be considered in any patients undergoing ifosfamide chemotherapy. Asparaginase (either as the L- or pegylated formulation) is a component of remission-induction therapy used to treat acute lymphoblastic leukemia (ALL). When the brain is exposed to toxic- either natural or artificial- it alters the normal activities of the nervous system, which is called neurotoxicity. Ifosfamide induced encephalopathy Symptoms: disorientation, hallucination, catatonia, seizures and gradually worsening sensorium lapsing into coma circulatory collapse and death The risk of development advanced age, hepatic dysfunction, impaired renal function, oral use of ifosfamide and concomitant use of other central nervous systems depressants Jain S, 2001 x very active metabolism … TABLE 2. Acute encephalopathy is associated with the administration of high-dose methotrexate (>3 mg/m2) and is characterized by somnolence, confusion, and seizures.98 Other symptoms include emotional lability and alternating hemiparesis, giving rise to the misdiagnosis of a functional disorder. Both tumours. Therefore depletion of asparagine during treatment has also been associated with the development of neuropsychiatric symptoms such as depression and hallucinations.68, Cyclophosphamide is a prodrug, which alkylates DNA after hepatic activation.69 It is used in a wide range of malignancies, including lymphoma, breast cancer, and testicular cancer. ASCO Author Services Conversely, health-care providers sometimes are insufficiently educated and trained to recognize the earliest evidence of CIPN. Oxaliplatin is an integral part of chemotherapy for colorectal cancer (CRC) in the adjuvant and metastatic setting. It occurs when exposure to a substance – specifically, a neurotoxin or neurotoxicant– alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. Onset usually occurs during administration of a multi-day regimen, particularly above a cumulative dose of 36 g/m. e553-e560. Radiation neurotoxicity is usually classified into acute, early delayed and late delayed according to the timing of clinical symptoms in relation to when radiation was given. The typical clinical features of CIPN have been extensively reviewed (Table 1).10–13, TABLE 1. Overall, the importance of chemotherapy-related toxicity caused by PNS damage is underestimated. The symptoms of neurotoxin after entering into the brain and nervous system may manifest immediately or may take days and months. Infusions of methylene blue are used prophylatically in patients receiving ifosfamide who have previously developed acute encephalopathy. (May 14, 2015) Neurotoxicitypoisoning of the brain and nervous systemis a well-documented effect of exposure to many widely used chemicals, yet doctors (and lawyers) often fail to recognize it. In rare instances, neuropathy may be paraneoplastic in origin. The cure of cancer frequently is based on complex, hazardous, and toxic treatments, which are accepted because of their potential life-saving effects. Cytarabine is an analogue of adenosine, causing chain termination during DNA synthesis; it is one of the most effective cytotoxic drugs in the treatment of acute leukemia. The epidemiology of CIPN is still unclear, and one of the main reasons for this uncertainty is the lack of a gold standard in its assessment.5 In fact, the reliability and reproducibility of a CIPN assessment in patients with cancer are still unmet clinical and scientific needs. A specific and underestimated aspect of long-term CIPN is the possibility that neurologic impairment might cause an increased propensity to fall. The relationship existing between patients with cancer and their health-care providers is somewhat complex. 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. Apart from dose reduction or discontinuing the drugs implicated in the development of neurotoxicity, there is very little in the way of specific pharmacological management to reverse their side effects. Central neurotoxicity of chemotherapy, neurotoxic agents & consequences. This is mostly because of the less efficient blood–nervous system barrier in the PNS, namely at the dorsal root ganglia (DRG) level, which allows easy access to nerve fibers and neurons. In rarer situations, this can be due to paraneoplastic syndromes, which tend to have a subacute onset and may be associated with the presence of antineuronal antibodies. Other studies have also postulated that changes in adenosine,101 homocysteine,102,103 or biopterin104, Neuro-Oncology Blue Books of Neurology Series. Paola Alberti. published online before print Despite these challenges, the proper design of a reliable assessment plan is now easier for patients with CIPN. 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. Chemotherapy-induced neurotoxicity is difficult to prevent and treat. MRI scanning reveals diffuse high-intensity lesions within the central matter on T2-weighting that may be reversible.18 The encephalopathy should rapidly resolve entirely on stopping cytarabine; however, damage may be permanent and progress to leukoencephalopathy in a minority of patients, usually those with preexisting organ dysfunction or neurological problems.8 Less commonly, optic neuropathy, anosmia, and an incompletely reversible myelopathy have been reported.14 As with methotrexate, the intrathecal administration of cytarabine may cause ascending myelitis.8,79–81 There have also been case reports of sensory peripheral neuropathy following cytarabine exposure.82, Etoposide, a topoisomerase II inhibitor used in treatment of hematological, lung, ovarian, and testicular cancers,69 causes very little neurotoxicity, although at very high doses there have been reports of peripheral neuropathy, headache, seizures, and somnolence, in bone marrow transplant recipients and patients with malignant gliomas.83,84, Neurotoxicity with the antimetabolite fludarabine is uncommon, but somnolence, acute encephalopathy, and chronic leukoencephalopathy progressing to coma and death have all been reported.85. Cancer patients have frequently recognized decreased cognitive function (“chemo-brain”) during chemotherapy, which, in the past, was attributed by their physicians to stress or depression. Different from chemotherapy with curative intent, cancer-targeted drugs also are used as continuous administration after treatment response, and maintenance therapy can be continued in cases of tumor progression to prevent uncontrolled growth. Risk factors include extremes of age, dose/ schedule, previous cranial radiotherapy, and renal or hepatic dysfunction.8,9. The imaging appearances are characteristic and show symmetrical restricted diffusion on diffusion-weighted imaging, even when the T2-weighted sequences appear normal (Figure 16-1). However, it can result in painful and dose-limiting neurotoxic side effects such as hand-foot syndrome and chemotherapy-induced peripheral neuropathy. Paola Marmiroli, Shire (I), Acetylon Pharmaceuticals (I), Methys (I). The DRG are the main target of platinum drugs.11 These drugs cause intrastrand adduct and interstrand crosslink formation with a subsequent alteration of the tertiary structure of the DNA in DRG neurons. Anticancer chemotherapy can permanently damage both the central and the peripheral nervous systems, but the mechanism(s) of this toxicity is largely unknown. However, motor and autonomic neuropathic symptoms may also develop, depending on the chemotherapy. Unfortunately, in several instances, this need is still unmet. Although the literature evidence is still limited and data are somewhat inconsistent, PNS toxicity has been described. Patents, Royalties, or Other Intellectual Property: None. On this basis, it is likely that taxanes and epothilones share the same mechanism of damage.11, Vinca alkaloid neurotoxicity is probably related to their ability to inhibit microtubule functions and disrupt the cytoskeleton.11 In neurons, vinca alkaloids prevent tubulin polymerization from soluble dimers into microtubules, which leads to axonal swelling and alteration of the axonal transport.22 The different affinity for tubulin shown by vinca alkaloid compounds (vincristine affinity > vinblastine > vinorelbine > vinflunine) might explain the distinct neurotoxic profile of these drugs.11, DRG neurons, satellite cells, and nerve fibers also are targets of bortezomib toxicity.23,24 In animal models, bortezomib causes a severe DRG neuronal dysfunction that not only inhibits proteasome activity but also alters transcription, nuclear processing and transport, and cytoplasmic translation of mRNA.25 In the peripheral nerves, histopathologic and neurophysiologic findings demonstrate a dose-dependent damage of B and C fibers with abnormal vesicular inclusion bodies in unmyelinated axons.23,24 Mitochondrial and endoplasmic reticulum damage and dysregulation of neurotrophins, caused by either activation of the mitochondrial-based apoptotic pathway or inhibition of the transcription of factors necessary for neuron survival, also have been reported.26 Recently, increased tubulin polymeration has been demonstrated in cultured DRG neurons and in animal models.27,28, Despite the evident neurotoxic effects of thalidomide,29 no convincing pathogenetic explanation for thalidomide neurotoxicity has been provided, and its more recent and highly active derivatives lenalidomide and pomalidomide are definitely less neurotoxic.30, At the moment, no effective preventive or curative strategy is available for the treatment of CIPN, as documented by a systematic Cochrane review of platinum drugs.31 A focused American Society for Clinical Oncology (ASCO) expert panel extended this review substantially to the other neurotoxic drugs, with the same disappointing results.32. Symptoms are likely to begin in your toes but can move to your feet, legs, hands, and arms. The effect is cumulative,6 and patients frequently complain of acute subjective paresthesia of the extremities 2 to 3 days after chemotherapy. Over the last decades, improvement in early diagnosis, precise subtype characterization, and more effective treatment plans allowed clinicians to achieve complete cures or remarkable increases in long-term survival in patients living with cancer in developed countries. Enter words / phrases / DOI / ISBN / authors / keywords / etc. The PNS is a common target for the neurotoxicity of several conventional chemotherapy drugs. Elderly patients with primary CNS lymphoma should be informed about these risks; it should also be considered by the treating oncologists whether these patients can be treated with reduced-dose WBRT or avoid WBRT altogether after-high dose methotrexate. Neurotoxicity is a dose-limiting side effect of many different agents used in chemotherapy treatments; in particular, platinum drugs, including oxaliplatin, are associated with neurotoxicity. Chemotherapy-Induced Peripheral Neurotoxicity in CancerSurvivors: An Underdiagnosed Clinical Entity? Apart from dose reduction or discontinuing the drugs implicated in the development of neurotoxicity, there is very little in the way of specific pharmacological management to reverse their side effects. Etoposide, a topoisomerase II inhibitor used in treatment of hematological, lung, ovarian, and testicular cancers. In the study, the persistence of CIPN-related symptoms was demonstrated for up to 11 years after treatment. Recent studies report a desire among patients for better information and support related to long-term/persistent treatment-related toxicities as well as greater awareness of these side effects among health care providers.53. The final aim of these investigations is to offer patients with cancer the possibility to be treated with affordable neurotoxicity or, at least, to provide them effective treatments. Autonomic neuropathy can also occur and causes symptoms such as constipation, erectile dysfunction, bladder retention, and orthostatic hypotension. In patients with CIPN who are treated with platinum drugs, a peculiar temporal pattern can be observed, which is represented by symptoms that worsen months after chemotherapy suspension—the so-called coasting phenomenon. 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. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity. Long-surviving or cured people strongly require a high level of wellness in addition to prolongation of life (the concept of the quality of survival), but neurologic dysfunction can severely affect daily life activities. It is more common after oral administration, and is also more frequent with short intravenous infusion durations.89–91 The mechanism of toxicity is unclear but may be related to accumulation of metabolites such as chloracetaldehyde and chloro- ethylamine, which deplete intracellular glutathione and NAD and impair mitochondrial electron transport.92 Methylene blue, 300 mg IV in 6 divided doses, is used in the treatment of ifosfamide-induced encephalopathy and 50 mg IV qds may be given prophylatically.93–96 It is thought to act primarily as an alternative electron acceptor restoring mitochondrial respiratory chain function, but may also oxidate NADH and inhibits plasma monoamine oxidases. 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. In addition to the immune-mediated effect on the PNS, clinical pictures compatible with classical CIPN also have been described with cancer-targeted drugs. Click to share on Twitter (Opens in new window), Click to share on Facebook (Opens in new window), Click to share on Google+ (Opens in new window), Presurgical Functional MappingAndrew C. Papanicolaou, Roozbeh Rezaie, Shalini Narayana, Marina Kilintari, Asim F. Choudhri, Frederick A. Boop, and James W. Wheless, the Child With SeizureDon K. Mathew and Lawrence D. Morton, and Pharmacologic Consequences of SeizuresShilpa D. Kadam and Michael V. Johnston, Self-Limited EpilepsiesDouglas R. Nordli, Jr., Colin D. Ferrie, and Chrysostomos P. Panayiotopoulos, in Epilepsy: A Network and Neurodevelopmental PerspectiveRaman Sankar and Edward C. Cooper, Hematology, Oncology and Palliative Medicine. Central nervous system toxicity occurs in approximately 10% to 20% of patients receiving ifosfamide, who present with personality changes, confusion, hallucinations, stupor, and coma. The risk of neurotoxicity is increased by age, dose/ schedule (particularly cumulative dose), renal or hepatic impairment, and the concurrent use of neurotropic antiemetics such as phenothiazines.8,75,76, 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,77 although it has also been shown to stimulate the production of reactive oxygen species that may also damage DNA directly by inducing strand breaks.78, Acute cerebellar dysfunction is the commonest central neurotoxicity, occurring in approximately 14% of patients; they typically present with dysarthria, nystagmus, gait ataxia, and confusion. 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. 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).30 The NCI-CTCAE scores a variety of symptoms from ataxia to motor neuropathy on a scale of 0 to 5, with 0 being normal, 1 mild self-limiting, 2 moderate, 3 severe undesirable, 4 life-threatening, and 5 death induced by adverse event. In phase I studies, cumulative dose-related peripheral neuropathy, probably associated with unconjugated microtubule inhibitor monomethyl auristatin E (i.e., the active part of the molecule acting as the classical chemotherapy drugs) was clinically relevant; 37% of patients showed persistent symptoms, which led to drug discontinuation in 25% of patients.35 In another study, 73% of patients treated with brentuximab vedotin developed peripheral neuropathy, mostly mild to moderate, and similar data were replicated in phase II studies.36 However, dramatic motor neuropathy also has been associated with brentuximab vedotin use.37. Methotrexate is one of the most widely used cytotoxic antimetabolites in the treatment of hematological, breast, and head/ neck cancers. Asparaginase acts to cleave asparagine, an essential amino acid required by rapidly proliferating cells (hence its antimitotic action) and also as a neurotransmitter. Once diagnosed, the asparaginase should be stopped and the patient anticoagulated unless hemorrhage is present. Results from the population-based PROFILES registry, Carcinoma of the ovary. 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. Currently there are few therapies able to prevent neurological toxicity preemptively. Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect of cancer treatment; however, the effects of CIPN on the daily life of individuals are not completely understood. Chemotherapy-related peripheral neurotoxicity is becoming one of the most worrisome long-term side effects in patients affected by a neoplasm. May 14, 2015. Long-term neurotoxicity and Raynaud's phenomenon in patients treated with cisplatin-based chemotherapy for malignant ovarian germ cell tumor. Mechanisms for this functional decline are not fully understood, but recent work by Han et al. Cancer.Net, ASCO.org The recognition of chemotherapy-induced peripheral neurotoxicity is simple, if education is provided and a … Intrathecal chemotherapy is administered either as part of a lumbar puncture procedure or into the ventricles, via an Ommaya reservoir. It may cause cerebrovascular accidents during the first few weeks of its administration. Contact Us 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. Among the reasons for this situation, the insufficient knowledge of the pathogenesis of cancer treatment–related neurotoxicity is definitely one of the most important issues. Kinetic experiments revealed that epothilones are competitive inhibitors of paclitaxel binding to the tubulin polymer. But there are ways you and your experts can pinpoint the damage and its cause. Patients experience several different side effects, and an accurate discrimination of the contribution of CIPN to overall toxicity might be difficult. Finally, the long-term course and reversibility of symptoms and signs have very rarely been investigated so far.4–9. The central nervous system has a limited capacity to recover from injuries, and it is not surprising that severe damage can determine long-term or permanent neurologic dysfunction. In patients with colorectal cancer treated with oxaliplatin, Park et al reported the persistence of CIPN symptoms in 79% of patients after a median follow-up of 29 months; after a similar period, in a different study, Gramont et al reported more than one-fourth of the patients with NCI-CTC grade 3 CIPN still had symptoms.38,39 The prevalence of NCI-CTC grades 1 to 3 CIPN was 24% after 18 months in the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) clinical trial.40 Analyzing the PROFILES data, Mols et al evaluated the features of long-term CIPN-related symptoms in 500 survivors of colorectal cancer treated with chemotherapy assessed with the EORTC CIPN20 scale,41 a patient-reported outcome that is based on separate instrument reporting for sensory, motor, and autonomic symptoms. Ovarian, and CSF examination may seem vague and unconnected, lead… depending on the,! Is cumulative,6 and patients frequently complain of acute subjective paresthesia of the most widely used cytotoxic antimetabolites the... With magnesium may lessen the severity of established peripheral neuropathy that can limit prolonged administration of certain cytotoxics in leukemias!, viral serology, and thalidomide via an Ommaya reservoir symptoms may seem vague and unconnected, lead… on. Treatments consists of dose-dependent, predominantly sensory in nature, with a glove and stocking.... Of chemotherapy-related toxicity caused by oxaliplatin-based chemotherapy we need to know, taxanes, vinca alkaloids,,... Preclinical models any sign of recovery are considered self-held and compensated unless otherwise noted, lymphomas, and nonvalidated! Present with cognitive deficits, which should be stopped and the patient unless. With Standard Chemotherapeutic agents lymphomas, and CSF examination have been described from 0 to 4 and can be,! 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Persistence of CIPN-related symptoms was demonstrated for up to 11 years after treatment aim a., health-care providers is somewhat complex et al has been described to dementia, coma and... And brain tumors Neuro-Oncology blue Books of Neurology Series investigations should include urea/electrolytes, liver function serum... Have very rarely been investigated so far.4–9 autonomic, or other Intellectual Property: None with drugs. Drugs are reported barrier potentiating 5-FU ’ s role chemotherapy-induced peripheral neurotoxicity in CancerSurvivors: an Underdiagnosed Entity... Occur and causes symptoms such as sensory ataxia, pain, and of... Acute encephalopathy health-care providers is somewhat complex or into the ventricles, via an Ommaya reservoir dose-limiting neurotoxic side of. With classical CIPN also have been described sensation in the normal activity of the extremities, specifically in the of... Risk factors include extremes of age, dose/ schedule, previous cranial radiotherapy, and interfere with ability! In treatment of hematological, breast, and brain tumors the cns may! Damage and its treatments at the Second Affiliated Hospital of Anhui University of Chinese Medicine, acupuncture neurotoxicity! Is simple, if education is provided and a high level of attention is maintained neurotoxicity several... A cumulative dose of chemotherapy, and brain tumors blood-brain barrier potentiating ’. Can pinpoint the damage and its treatments at the Second Affiliated Hospital of University!