With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies.

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Administration of oxaliplatin, a platinum-based chemotherapy used extensively in the treatment of colorectal cancer, is complicated by prominent dose-limiting neurotoxicity. Acute neurotoxicity develops following oxaliplatin infusion and resolves within days, while chronic neuropathy develops progressively with higher cumulative doses. To investigate the pathophysiology of oxaliplatin-induced neurotoxicity and neuropathy, clinical grading scales, nerve conduction studies and a total of 905 axonal excitability studies were undertaken in a cohort of 58 consecutive oxaliplatin-treated patients. Acutely following individual oxaliplatin infusions, significant changes were evident in both sensory and motor axons in recovery cycle parameters (P < 0.05), consistent with the development of a functional channelopathy of axonal sodium channels. Longitudinally across treatment (cumulative oxaliplatin dose 776 +/- 46 mg/m(2)), progressive abnormalities developed in sensory axons (refractoriness P < or = 0.001; superexcitability P < 0.001; hyperpolarizing threshold electrotonus 90-100 ms P < or = 0.001), while motor axonal excitability remained unchanged (P > 0.05), consistent with the purely sensory symptoms of chronic oxaliplatin-induced neuropathy. Sensory abnormalities occurred prior to significant reduction in compound sensory amplitude and the development of neuropathy (P < 0.01). Sensory excitability abnormalities that developed during early treatment cycles (cumulative dose 294 +/- 16 mg/m(2) oxaliplatin; P < 0.05) were able to predict final clinical outcome on an individual patient basis in 80% of patients. As such, sensory axonal excitability techniques may provide a means to identify pre-clinical oxaliplatin-induced nerve dysfunction prior to the onset of chronic neuropathy. Furthermore, patients with severe neurotoxicity at treatment completion demonstrated greater excitability changes (P < 0.05) than those left with mild or moderate neurotoxicity, suggesting that assessment of sensory excitability parameters may provide a sensitive biomarker of severity for oxaliplatin-induced neurotoxicity.

The pathophysiology of oxaliplatin-induced neurotoxicity remains unclear, although in vitro studies suggest involvement of voltage-gated Na+ channels. In the present study, clinical assessment was combined with nerve conduction studies (NCS) and nerve excitability studies in 16 patients after completion of oxaliplatin therapy. Chronic neuropathic symptoms persisted in 50% of patients. NCS confirmed abnormalities in symptomatic patients: sensory potentials were significantly low, whereas motor studies remained essentially normal. At 12-month follow-up of symptomatic patients, positive sensory symptoms improved but NCS abnormalities persisted. Cumulative oxaliplatin dose was a predictor of neuropathy, and long-term effects appeared to be minimized by low single-infusion dosages. Nerve excitability measures in symptomatic patients established that axons were of high threshold. Refractoriness was significantly greater in patients (symptomatic group, 56.3 +/- 24.9%; entire patient group, 46.3 +/- 12.5%; controls, 27.1 +/- 1.9%; P < 0.05). Thus, although positive sensory symptoms of oxaliplatin-induced neuropathy improved, negative sensory symptoms and abnormalities of sensory nerve conduction persisted. Differences in nerve excitability measures, particularly refractoriness, support in vitro studies indicating involvement of voltage-gated transient Na+-channel dysfunction in the development of oxaliplatin-induced neurotoxicity.

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Neuropathy is a common complication of end-stage kidney disease (ESKD), typically presenting as a distal symmetrical process with greater lower-limb than upper-limb involvement. The condition is of insidious onset, progressing over months. and has been estimated to be present in 60%-100% of patients on dialysis. Neuropathy generally only develops at glomerular filtration rates of less than 12 ml/min. The most frequent clinical features reflect large-fiber involvement, with paresthesias, reduction in deep tendon reflexes, impaired vibration sense, muscle wasting, and weakness. Nerve conduction studies demonstrate findings consistent with a generalized neuropathy of the axonal type. Patients may also develop autonomic features, with postural hypotension, impaired sweating, diarrhea, constipation, or impotence. The development of uremic neuropathy has been related previously to the retention of neurotoxic molecules in the middle molecular range, although this hypothesis lacked formal proof. Studies utilizing novel axonal excitability techniques have recently shed further light on the pathophysiology of this condition. Nerves of uremic patients have been shown to exist in a chronically depolarized state prior to dialysis, with subsequent improvement and normalization of resting membrane potential after dialysis. The degree of depolarization correlates with serum K(+), suggesting that chronic hyperkalemic depolarization plays an important role in the development of nerve dysfunction in ESKD. These recent findings suggest that maintenance of serum K(+) within normal limits between periods of dialysis, rather than simple avoidance of hyperkalemia, is likely to reduce the incidence and severity of uremic neuropathy.

After completing this course, the reader will be able to:1. Define the symptoms of sensory neurotoxicity in oxaliplatin-treated patients and identify the long-term natural history of nerve dysfunction as a long-lasting complication of treatment that does not necessarily resolve within 6 months.2. Use sensory excitability techniques to predict long-standing changes in sensory nerve function produced by oxaliplatin.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTObjectives. Oxaliplatin-induced neuropathy is a significant and dose-limiting toxicity that adversely affects quality of life. However, the long-term neurological sequelae have not been adequately described. The present study aimed to describe the natural history of oxaliplatin-induced neuropathy, using subjective and objective assessments. The Oncologist CME Program is located online at http://cme.theoncologist.com/. To take the CME activity related to this article, you must be a registered user. Methods. From a population of 108 oxaliplatin-treated Symptom Management and Supportive CareThe Oncologist 2011;16:708 -716 www.TheOncologist.com Results. At follow-up, 79.2% of patients reported residual neuropathic symptoms, with distal loss of pinprick sensibility in 58.3% of patients and loss of vibration sensibility in 83.3% of patients. Symptom severity scores were significantly correlated with cumulative dose. There was no recovery of sensory action potential amplitudes in upper and lower limbs, consistent with persistent axonal sensory neuropathy. Sensory excitability parameters had not returned to baseline levels, suggesting persisting abnormalities in nerve function. The extent of excitability abnormalities during treatment was significantly correlated with clinical outcomes at follow-up.Conclusions. These findings establish the persistence of subjective and objective deficits in oxaliplatin-treated patients post-oxaliplatin, suggesting that sensory neuropathy is a long-term outcome, thereby challenging the literature on the reversibility of oxaliplatin-induced neuropathy. The Oncologist 2011;16:708 -716

Patients with chronic kidney disease (CKD) are frequently afflicted with neurological complications. These complications can potentially affect both the central and peripheral nervous systems. Common neurological complications in CKD include stroke, cognitive dysfunction, encephalopathy, peripheral and autonomic neuropathies. These conditions have significant impact not only on patient morbidity but also on mortality risk through a variety of mechanisms. Understanding the pathophysiological mechanisms of these conditions can provide insights into effective management strategies for neurological complications. This review describes clinical management of neurological complications in CKD with reference to the contributing physiological and pathological derangements. Stroke, cognitive dysfunction and dementia share several pathological mechanisms that may contribute to vascular impairment and neurodegeneration. Cognitive dysfunction and dementia may be differentiated from encephalopathy which has similar contributing factors but presents in an acute and rapidly progressive manner and may be accompanied by tremor and asterixis. Recent evidence suggests that dietary potassium restriction may be a useful preventative measure for peripheral neuropathy. Management of painful neuropathic symptoms can be achieved by pharmacological means with careful dosing and side effect considerations for reduced renal function. Patients with autonomic neuropathy may respond to sildenafil for impotence. Neurological complications often become clinically apparent at end-stage disease, however early detection and management of these conditions in mild CKD may reduce their impact at later stages.