Moreover, because cancer-targeted therapies frequently are used after or in combination with conventional chemotherapy, the possibility that their use could worsen the toxicity profile of standard neurotoxic chemotherapy drugs also should be considered. Risk factors include extremes of age, dose/ schedule, previous cranial radiotherapy, and renal or hepatic dysfunction.8,9. Mechanisms for this functional decline are not fully understood, but recent work by Han et al.5 on 5-fluorouracil neurotoxicity in mice suggest extensive myelin damage and persistent suppression of both oligodendrocyte and progenitor cell proliferation in the subventricular zone, hippocampus, and corpus callosum. Relationships marked “L” indicate leadership positions. The availability of large registries of patients with cancer who were carefully observed—such as the Patient-Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship (PROFILES) registry—has allowed investigations on the persistence of CIPN-related long-term effects in several cancer types and, therefore, on the relationship existing with different treatments. Although these drugs are generally considered safer and less toxic than conventional chemotherapy, off-target toxicities (e.g., neurotoxicity) may emerge, particularly during prolonged use. Central Neurotoxicity, Memory Loss, and Their Relationship to Chemotherapy Neurotoxicity Includes: Confusion , Cognitive Problems , Memory Problems , and Seizures Advertisers, Journal of Clinical Oncology Autonomic neuropathy can also occur and causes symptoms such as constipation, erectile dysfunction, bladder retention, and orthostatic hypotension. Asparaginase acts to cleave asparagine, an essential amino acid required by rapidly proliferating cells (hence its antimitotic action) and also as a neurotransmitter. Infusions of methylene blue are used prophylatically in patients receiving ifosfamide who have previously developed acute encephalopathy. Expert Testimony: None. The symptoms of brain injury from exposure to hazards like lead paint and toxic chemicals vary widely. Also, the pathogenesis of cancer-targeted drugs effects on the PNS is largely unknown. 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. Overall, the importance of chemotherapy-related toxicity caused by PNS damage is underestimated. Intrathecal chemotherapy is administered either as part of a lumbar puncture procedure or into the ventricles, via an Ommaya reservoir. 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. Methylene blue is used for ifosfamide-induced encephalopathy and infusional calcium with magnesium may lessen the severity of established peripheral neuropathy due to oxaliplatin. In rare instances, neuropathy may be paraneoplastic in origin. 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. Conventional chemotherapy has limitations in its effectiveness, and it is associated with potentially severe side effects as a result of damage to normal tissues, as shown for CIPN. 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. The overall incidence of these toxicities is unknown, but they are becoming more common with the escalations in cytotoxic dose that are now possible with modern hydration regimens, and the use of growth factor support and/or peripheral blood stem cells rescue to prevent myelosuppression. However, cancer survivors deserve and ask for the best possible quality of survival after cancer treatment, particularly over the long term. Leadership Position: None. Where chemotherapy and radiation both can be neurotoxic. CIPN pathogenesis is still unclear for many aspects, and most of the available information relies on the results of preclinical models. 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. But there are ways you and your experts can pinpoint the damage and its cause. Generally, symptoms are self-limiting, but in some patients the symptoms persist. 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. 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). 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. Enter words / phrases / DOI / ISBN / authors / keywords / etc. 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. Paola Marmiroli, Kedrion (I). Behavioral signs include acute psychosis, restlessness, wide mood swings with inappropriate crying and laughing, cortical blindness, visual hallucinations, stupor, and akinetic mutism … 54, 55 Symptoms tend to resolve spontaneously within a few days of treatment cessation although administration of thiamine may be helpful. 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. 54, 55 Symptoms tend to resolve spontaneously within a few days of treatment cessation although administration of thiamine may be helpful. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated. JCO OP DAiS, ASCO eLearning Paola Alberti. The neuropathy tends to be predominantly sensory in nature, with a glove and stocking distribution. Identifying signs and symptoms of cancer treatment-related neurotoxicity is a critical piece of every oncology nurse’s role. Patients with HIV-related malignancies are also at increased risk of cytotoxic-induced neuropathy, since both HIV and the drugs used to treat it (highly active antiretroviral therapy, or HAART) can cause neurological damage independently.34 Distal sensory neuropathy is the commonest form of HIV-associated neuropathy and can be difficult to distinguish from that caused by specific nucleoside antiretrovirals. Cancer patients may experience a wide range of central neurotoxic symptoms, such as cognitive deficits, seizures, cerebellar dysfunction, psychiatric symptoms and extrapyramidal disorders. May 14, 2015. The onset may be acute or insidious, the effects transient or progressive and permanent. In the study, the persistence of CIPN-related symptoms was demonstrated for up to 11 years after treatment. Methylene blue is used for ifosfamide-induced encephalopathy and infusional calcium with magnesium may lessen the severity of established peripheral neuropathy due to oxaliplatin. Several of these targeted drugs are now used routinely. 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. Acta Obstet Gynecol Scand. 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. Neurotoxicity with the antimetabolite fludarabine is uncommon, but somnolence, acute encephalopathy, and chronic leukoencephalopathy progressing to coma and death have all been reported. Cerebellar signs in an oncology patient are usually due to direct spread of cancer, particularly if it is asymmetric. The patients most at risk are those receiving a high cumulative dose or intensive schedule, particularly if there is a preexisting condition such as diabetes mellitus, hereditary neuropathy, or multiple sclerosis.31 Previous radiotherapy may also increase the risk of developing neurotoxicity if patients are subsequently treated with cisplatin or methotrexate.32,33. Buy Membership for Hematology, Oncology and Palliative Medicine Category to continue reading. In the axons, microtubule disruption can lead to interference in axonal transport, which eventually affects the integrity of sensory neurons. Neurotoxicity is rare, but may include acute cerebellar dysfunction in 3% to 7% of patients, causing gait ataxia, nystagmus, and scanning speech. In Table 2, examples regarding the possible peripheral neurotoxic effect of cancer-targeted drugs are reported. Chemotherapy-induced neurotoxicity is a serious consequence of cancer treatment, which occurs with some of the most commonly used chemotherapies 1,2.Chemotherapy-induced peripheral neuropathy produces symptoms of numbness and paraesthesia in the limbs and may progress to difficulties with fine motor skills and walking, leading to functional impairment. About In addition to the immune-mediated effect on the PNS, clinical pictures compatible with classical CIPN also have been described with cancer-targeted drugs. Consulting or Advisory Role: Guido Cavaletti, Shire Pharmaceuticals. 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. Filed under Hematology, Oncology and Palliative Medicine. Paola Marmiroli. Moreover, the markedly different perception of CIPN severity using physician-assessed measures (e.g., the widely used National Cancer Institute Common Toxicity Criteria [NCI-CTC] adverse events scale and the more comprehensive Total Neuropathy Score, clinical version) or patient-reported outcome measures (e.g., the European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and CIPN20 modules) is emerging very clearly. The frequency, severity, and time course of CIPN can be very variable. The only specific therapy is the use of methylene blue in ifosfamide-induced encephalopathy, which should be considered in any patients undergoing ifosfamide chemotherapy. 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). Some of the more common symptoms are: tingling or … When given in high doses, it may lead to inappropriate secretion of ADH (SIADH), and hence a secondary metabolic encephalopathy may occur, with confusion, seizures, or coma.70–72 There have been a few case reports of cyclophosphamide also being associated with blurred vision, dizziness, and confusion in the absence of SIADH.73,74, 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 conventional drugs associated with CIPN are platinum compounds, taxanes, vinca alkaloids, epothilones, proteasome inhibitors, and thalidomide. Long-term neurotoxicity and Raynaud's phenomenon in patients treated with cisplatin-based chemotherapy for malignant ovarian germ cell tumor. Paola Marmiroli, Shire (I), Acetylon Pharmaceuticals (I), Methys (I). Honoraria: None. 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. Patients most at risk are those with impaired renal function, low serum albumin, pelvic tumors, and previous exposure to cisplatin.88 The risk of encephalopathy varies with route of administration. Mols et al performed a systematic review of the available literature and found 11 studies that assessed the relationship that exists between CIPN and QoL.45 Eight of these studies reported an association, whereas three failed to observe any association between CIPN and QoL. Anticancer chemotherapy can permanently damage both the central and the peripheral nervous systems, but the mechanism(s) of this toxicity is largely unknown. 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. Central nervous system toxicity occurs in approximately 10% to 20% of patients receiving ifosfamide, who present with personality changes, confusion, hallucinations, stupor, and coma. EEG tends to show severe slowing with delta wave activity with or without seizure activity. 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. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6). However, only recently, the paradigms of peripheral neurotoxicity reversibility have been scientifically challenged, and studies have been performed to capture the patients' perspectives on this issue and to measure the effect of peripheral neurotoxicity on their daily life activities. In fact, physicians should be trained not only at the use of treatments but also at the recognition and proper assessment of the first signs of neurotoxicity, and patients should be made aware of it to report early symptoms with the common goal of preventing irreversible damage. Patients present with cognitive deficits, which may progress to dementia, coma, and death.10–14 MRI imaging shows widespread changes throughout the white matter,15–18 and histologically, there is axonal swelling, demyelination, and neuronal death.19 Those most at risk are patients treated with methotrexate or cytarabine, particularly if given intrathecally or if cranial radiotherapy preceded cytotoxic administration.9 Elderly patients with primary central nervous system lymphoma undergoing treatment with high-dose methotrexate and whole-brain radiotherapy (WBRT) are at particularly high risk of developing this complication.20 There is no specific therapy that can halt the progressive decline, and overall the prognosis is poor. Reviewers This concern was raised originally by Tofthagen et al in 2012 in a small series of patients with cancer and CIPN; 20% of them had fallen recently.48 An increased incidence of falls had already been reported in patients with cancer and in older populations.49 Gewandter et al investigated a cohort of 471 patients with CIPN; 27% of participants reported functional impairment (e.g., difficulty in shopping or in doing common tasks necessary to live in their home independently), whereas 12% had a fall in the 3-month period preceding enrollment on the study.50 When these results were analyzed in relation to the type of CIPN, motor neuropathy was significantly associated with falls, which suggests that, in the study cohort, taxanes used as breast cancer treatment were responsible for these events.50. Third, the available pharmacologic and nonpharmacologic strategies designed to limit the incidence and severity of chemotherapy-induced neurotoxicity are not particularly effective in most instances. However, motor and autonomic neuropathic symptoms may also develop, depending on the chemotherapy. Both tumours. No effective treatments are available for alleviating persistent symptoms of chemotherapy-induced peripheral neurotoxicity. A survey fielded in 2009 and recently published revealed that long-term CIPN induced by paclitaxel was recognized by only 27% of primary care physician and the percentage was even lower (22%) for oxaliplatin-treated cancer survivors.52 These results are not surprising, because no specific education and training are provided outside the oncology and neurology fields to recognize CIPN. 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