Thomas, Adam C.G.
Improved cancer survival and newer forms of chemotherapy have increased exposure to neurotoxic agents.1 Chemotherapy-induced neurological adverse effects can reduce treatment efficacy because doses are delayed or reduced, and lead to treatment failure (if drugs are contraindicated or refused), surgical intervention, and persistent disability.2–4 The type and degree of this collateral damage depends on the drug, dose-intensity and cumulative dosage.5 It is further affected by the presence of preexisting neurological impairment and baseline neuropathy.6
The impact on activities of daily living (ADLs) is often a critical factor in deciding whether to continue therapy.
Assessing neurological adverse effects
Several toxicity grading systems exist to aid assessment of iatrogenic neurological effects (Table 1), though it is unclear which is best.7–10 National Cancer Institute–Common Toxicity Criteria (NCI-CTC) is used routinely in UK practice, but may not describe the breadth of symptoms.10
Communicating descriptions of neurotoxicity between care providers can be challenging: for example the same toxicity, ‘severe paraesthesia,’ would be recorded as ‘WHO grade 2’ but ‘NCI-CTC grade 3’. Therefore, it is desirable that the tool adopted by a single provider is consistent and suitably referenced. Nerve conduction studies have limited sensitivity; however, nerve excitability studies are shown to predict patients at risk of neuropathy.11
Confounding factors may make it difficult to establish the cause of neurotoxicity. Peripheral neuropathic pain may, for example, be attributed to the effect of a tumour, as well as prior chemotherapy.12 Cumulative neurological damage occurs with successive cycles of therapy. In addition, cancer pain reportedly affects 48% of patients with early disease and 64–75% of patients with advanced disease.12 One meta-analysis (n = 1647) showed that only a fifth (20.3%) of recorded neuropathic pain was caused by the anticancer therapy.12 It is difficult to detect a change from the previous level of damage using subjective questionnaires.10,11
Central nervous system adverse effects
Central nervous system (CNS) adverse effects range from commonly reported headache to encephalopathy, intracranial haemorrhage (ICH), and the entity known as ‘chemobrain’ (also known as chemohead or chemofog). The differential diagnosis includes progressive disease, cerebrospinal fluid (CSF) obstruction, infectious causes and paraneoplastic syndromes (e.g. hyponatraemia).13
Encephalopathy is defined as an alteration in consciousness, neurobehavioural abnormalities, seizures or focal neurological deficits.13,14 Diffuse encephalopathy is associated with high doses of antimetabolites (therapy such as cytarabine and methotrexate), often in older patients (>60 years) and renal impairment.15–17 Its onset may be acute (within hours) or delayed. In a study of primary CNS lymphomas treated solely with such chemotherapy, 14% of long-term survivors suffered encephalopathy as defined by cognitive decline.16 In 10–15% of treated patients,9,14,17 ifosfamide (an alkylating agent used to treat solid tumours) causes an acute diffuse encephalopathy that is reversible with methylthioninium chloride.17
Posterior reversible encephalopathy syndrome (PRES) is characterized by hypertension, headaches, seizures, confusion/altered mental status and visual disturbance.13,14,18 PRES is well described with ciclosporin, cisplatin, fluoropyrimidine, antiangiogenic therapy and high-dose chemotherapy. PRES is precipitated by acute endothelial cell damage causing a microangiopathy, cerebrovascular dysregulation and vasogenic oedema.13,14,18
Novel inhibitors of angiogenesis such as sunitinib, sorafenib, pazopanib and bevacizumab are known to cause iatrogenic intercranial hypertension (ICH). The risks of ICH, ischaemic stroke, venous thromboembolism and haemorrhage are modestly amplified by such agents. There is also an increased risk of cerebral ischaemia with traditional cytotoxic drugs such as mitomycin, gemcitabine, methotrexate and platinum compounds.14 ICH or stroke may be considered a contraindication to further therapy.13,19,20
‘Chemobrain’ is well documented, specifically in relation to adjuvant treatment of breast cancer, affecting 15–50% of patients.13,21,22 It is a late-onset disorder manifest as a widespread subjective deterioration in executive function (processing, multitasking, goal-directed behaviour) with complaints of forgetfulness and inattentiveness. The current aetiological hypotheses include direct neuronal damage, oxidative stress, DNA damage, induced hormone changes, immune dysregulation/cytokine release and CNS embolism.21 By contrast, a study of patients receiving adjuvant treatment with FOLFOX4 (oxaliplatin, 5-fluorouracil, folinate) to treat colorectal cancer showed no evidence of cognitive decline, but rather changes in emotional performance.23
Peripheral neurological adverse effects
Chemotherapy-induced peripheral neuropathy (CIPN) may involve motor, sensory and autonomic neurons. Clinically, it can present with signs of damage, with or without pain.24 Drugs of different classes cause different patterns of damage. Common causative agents include platinum compounds (oxaliplatin, cisplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinorelbine), proteasome inhibitors (bortezomib) and other antineoplastic immunomodulators (ipilimumab, thalidomide and lenalidomide).
Sensory CIPN commonly follows a distal ‘glove and stocking’ distribution.24–26 Effects may include paraesthesia (with or without pain), dysaesthesia, pruritus and proprioceptive loss.24 Bortezomib is associated with small fibre loss, affecting unmyelinated C-fibres,24 whereas platinum compounds such as cisplatin are associated with damage to large fibres and to ganglia.24,27 Paclitaxel therapy is particularly associated with pruritus.28
Pain is an important neurological adverse reaction that is especially associated with early nociceptor loss.24 Improved survival means that long-term supportive management of neuropathic pain is commonly required.
Motor symptoms, for example foot drop, are commonly detected at late progression.24 Effects in the early stages are minor and barely noticeable; for example there may be transient distal cramp. Occasionally, chemotherapy-induced deafferentation causes spontaneous movement disorders.24
Autonomic neurotoxic effects may in rare patients result in symptomatic urinary bladder or sexual dysfunction, constipation and orthostatic hypotension.13,24
Chemotherapy-induced peripheral neuropathy by drug class
Antimetabolites, especially when prescribed at high doses, are more frequently associated with CNS toxicity than with peripheral neuropathy.13,15–17,24 Examples include methotrexate, cytarabine arabinoside (Ara-C) and the closely related agent fludarabine causing encephalopathy and myelopathy.24 Other antimetabolites such as gemcitabine are not known to cause or exacerbate CIPN in combination therapy with taxanes, platinum agents or vinca alkaloids.24,29 5-fluorouracil30 can cause CIPN,31 and in addition a cerebellar syndrome has been described in 2–5% of treated patients. The prodrug of fluorouracil, capecitabine, is known to cause palmoplantar erythrodysaesthesia (PPE), known as ‘hand-foot syndrome,’ in which distal paraesthesia is accompanied by pruritus,24 perhaps as a result of small nerve fibre damage.24,32
Mitotic spindle inhibitors
Vinca alkaloids cause sensori-motor and autonomic neuropathies. Vincristine and vindesine are more potently neurotoxic than vinblastine and vinorelbine.24 A glove-and-stocking pattern of paraesthesia, pain, muscle weakness and cramp with loss of deep-tendon reflexes is common.33 Vinorelbine can produce more severe neurotoxicty in patients previously given paclitaxel therapy.34 The effect is thought to be additive rather than synergistic,24 supporting arguments of overall treatment neurotoxicity.
Constipation is the principal clinical sign of vinca alkaloid-induced autonomic neuropathy. Paralytic ileus or megacolon,24,35 bladder atony, impotence, orthostatic hypotension and arrhythmia may all occur.24 Late-onset vincristine-induced peripheral neuropathy is associated with nine distinct inherited SNPs in the ATP-binding cassette transporter gene (ABCC1). ABBC1 codes for proteins that transport molecules across cell membranes, enhancing cellular penetration. Vincristine is a known substrate of the ABCC1 transporter.36
Neurological adverse effects of taxanes are classically manifest as sensory CIPN.25 Numbness, tingling ‘pins and needles’, burning, reduced or altered sensation with hypoaesthesia/hyperaesthesia and dysaesthesia are all described as characteristic symptoms.24–26 There is a clear cumulative dose-dependence, and susceptibility is amplified by preexisting neuropathy and comorbidity such as diabetes mellitus.25 Docetaxel, when compared with paclitaxel, produces significantly less frequent severe sensory (11% vs. 30%; P < 0.001) and motor (3% vs. 7%; P < 0.001) neuropathy.25
Podophyllin analogues like etoposide prevent mitotic spindle formation through inhibition of topoisomerase. Agents in this group have not been shown to cause CIPN or augment CIPN caused by other agents.24
Platinum agents show disparate neurotoxic profiles, perhaps because of nucleophile reactivity.37 Ototoxicity (any grade) is reported in 75–100% of patients treated with cisplatin,37 but only 1–2% of patients treated with carboplatin.38 Peripheral neurotoxicity occurs in 15–60% of patients treated with either cisplatin or oxaliplatin, but only 4–6% of patients treated with carboplatin.37,38 Chronic patterns of sensory neuropathy are described in 50% of patients treated with oxaliplatin.37
Platinum compounds are associated with predominantly sensory involvement and damage is linked to the fenestrated capillary blood supply of the sensory neuron.39–42 The concentration of platinum compounds in peripheral nerves is similar to that in tumour tissue,42–45 and causes apoptotic cell death in both.2,38 Delayed onset neuronal damage may be due to ongoing binding of platinum to mitochondrial DNA.46 Sensory neurological adverse effects are dose-limiting and related to total cumulative dosing.27,45,47 Autonomic effects include dizziness, palpitation and impotence.27
Oxaliplatin is also associated with distal cold-induced paraesthesia with or without cramp and laryngopharyngeal dysaethesia. Neurological toxicity (at any grade) occurs in 95% of patients treated.48 The latter may be reduced by prolonged (6 h) infusion protocols.48 One small study (n = 76) demonstrates that repeat oxaliplatin exposure desensitizes the transient receptor potential melastatin-8 (TRPM8), which reduces the cold-sensation detection threshold (CDT), in turn leading to cold-induced oxaliplatin peripheral neurotoxicity.49 These phenomena have been shown to be consistent with cumulative-dose-related functional changes in the dorsal root ganglion.42 Oxaliplatin-induced neurotoxicity may be an axonal neuropathy linked to voltage-gated sodium channels, without significant alteration of the axonal membrane potential or Na+/K+ pump function.42,50,51
Carboplatin is an analogue of cisplatin, which, although less neurotoxic than the other platinum compounds,38 in high doses has a similar profile to cisplatin.52,53 The International Collaborative Ovarian Neoplasm 3 trial showed carboplatin combined with paclitaxel produced moderate-to-severe sensory neuropathy in 20% of patients.54 Another much smaller study (n = 51) demonstrated 85.3% incidence of severe peripheral neuropathy using the same combination in gynaecological malignancy.55
Pharmacogentic studies have shown positive correlations between gene expression, DNA repair and neurotoxicity. The glutathione S-transferase pi-1 gene (GSTP1) codes for enzymes that catalyse conjugation of hydrophobic compounds. A mutation in GSTP1 is associated with increased neurotoxicity from oxaliplatin. The sodium channel, voltage-gated, type 1, alpha subunit gene (SCN1A) codes for proteins in sodium channels that are critical for the cell's ability to transmit electrical signals. The presence of SCN1A is associated with decreased prevalence of neurotoxicity in colorectal cancer treatments.37
Bortezomib is a proteasome inhibitor used to treat multiple myeloma. Case reports suggesting autonomic neuropathy and cardiovascular, gastrointestinal and neuroendocrine dysfunctions have been described.56 Pre-existing CIPN increases the risk of moderate-to-severe bortezomib-induced peripheral neurotoxicity.57 Subcutaneous, rather than intravenous, bortezomib injection reduces the incidence of peripheral neuropathy (all grades) somewhat from 53% to 38% (P = 0.044).58
Additive neuropathy is particularly important in multiple myeloma treatment, as each standard line of therapy carries a prominent risk of CIPN and 15–20% of patients have neuropathy at diagnosis.36 Studies investigating genetic profiles of early-onset and late-onset bortezomib-induced neuropathy describe genes that are associated with drug absorption, distribution, metabolism and excretion are also involved in CIPN.36 Inherited SNPs predict susceptibility to both thalidomide-induced and bortezomib-induced peripheral neuropathy.36
The monoclonal antibody ipilimumab potentiates T-cell activation in the treatment of malignant melanoma. In the pivotal phase-III ‘MDX010–20’ trial (n = 676), one case of fatal Guillain–Barré syndrome is recorded. The product licence identifies severe and life-threatening sensori-motor neuropathies occur in 0.1–1% of treated patients.59 These may include cerebral oedema, cranial neuropathy, peripheral neuropathy, syncope and Guillain–Barré syndrome.59 Case reports describe autonomic neuropathy and an ‘inflammatory enteric neuropathy’.60
Overall treatment neurotoxicity
Each treatment regimen will include the active systemic anticancer therapy (SACT) component and the requisite supportive therapy. Supportive pharmacotherapy is essential in permitting the safe administration of modern dose-intense SACT regimens. It includes premedication (e.g. high-dose corticosteroids), antiemetic, antidiarrhoeal, anti-infective, anticoagulant and antiepileptic treatments. Patients may also be using opioid analgesics to control cancer pain. Some supportive therapy may cause neurological adverse effects or augment the effects of anticancer chemotherapy. CNS toxicity related to supportive therapy, for example corticosteroid-related depression, paranoia and psychosis, can be treatment-limiting.
Aggressive treatment plans involving brain-directed surgery, adjuvant/neoadjuvant cranio-spinal irradiation and prophylactic cranial irradiation after chemotherapy lead to more deleterious consequences.13
Many cancer chemotherapeutic agents can cause serious neurological adverse effects. Serial lines of therapy and multiple treatment modalities expose the patient to greater degrees of neurotoxicity. The overall impact of treatment is important, and should be considered when providing patient information.
Better understanding of genetic susceptibilities, and better tests for monitoring nerve function, could in future help to predict patients at increased risk of CIPN.
Conflicts of interest
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