Clinical Tests Can Assess Chemotherapy-Induced Neuropathy

An estimated 1,368,000 new cases of invasive cancer were diagnosed and 563,700 cancer-related deaths occurred in the United States in 2004.1 Chemotherapy-based cancer treatment continues to evolve as new agents and more dose-intensive treatment schedules are used, thus increasing survival times of persons in whom the disease is diagnosed. The treatment of most cancers requires use of chemotherapeutic agents to cure, control, or palliate symptoms. While chemotherapy can prolong life, such drugs are associated with significant side effects, and certain chemotherapeutic drugs are associated with peripheral neuropathy.2-7 Peripheral neuropathy results from impairment of peripheral, motor, sensory, and autonomic neurons that causes motor and sensory deficits. Motor neuron involvement results in lower extremity muscle wasting accompanied by weakness. It begins in the distal lower extremities and spreads in a proximal fashion. Sensory neuron dysfunction produces the classic "stocking and glove" distribution of loss of touch sensation in the extremities. In early studies, it was hypothesized that neurotoxic chemicals caused axons to die back from nerve terminals by interfering with neuronal soma metabolism.8 More recently, it has been hypothesized that neurotoxic chemicals directly damage nerve fibers by deactivating components required to maintain the metabolic needs of the axon. The longer and larger distal axons are affected first, and the result is interruptions of axonal transport and degeneration of myelinated nerve fibers and unmyelinated axons.9 Symptoms such as numbness, tingling, and/or pain in the extremities, as well as declines in cutaneous sensation, vibration sensation, and muscle strength, are experienced. Treatment-associated changes in muscles also result in a reduced ability of the muscle to generate force, causing muscle weakness and a decline in functional performance.10 Autonomic dysfunction is causedby damage to unmyelinated nerve fibers that occurs secondary to neurotoxic chemotherapy. Clinical manifestations of autonomic neuropathy include hypotension, cardiac conduction irregularities, impotence, and bowel and bladder dysfunction. Postural hypotension is the most common cardiovascular manifestation of peripheral neuropathy. IMPLICATED AGENTS Platinum-based compounds such as cisplatin are known to induce peripheral neuropathy. These heavy metals bind to DNA and possibly act as precursors to axonal degeneration. Cisplatin therapy is associated with ototoxicity, retinal toxicity, and sensory neuropathy. Large-fiber nerves are primarily affected. Vinca alkaloids, such as vincristine and vinblastine, induce paresthesias of the hands and feet in approximately 57% of patients, and weakness, footdrop, and gait disturbances in 23% to 36 %.11,12 Antimitotics, such as paclitaxel and docetaxel, are associated with a decrease in or loss of deep tendon reflexes (DTRs).13 Docetaxel is a semisynthetic taxane that induces sensory neuropathy in 50% of treated patients. Sensory loss can be distinguished even after the first dose is administered. Many chemotherapeutic regimens require the administration of 2 neurotoxic agents, resulting in higher grades of neurotoxicity.14 For example, the combination of carboplatin and paclitaxel is used frequently; regimens containing both agents have resulted in improved survival in persons being treated for ovarian cancer and nonsmall-cell lung cancer.15 A variety of toxicity grading scales have been used to detect and monitor chemotherapy-induced peripheral neuropathy (CIPN). The 2 most commonly used CIPN grading scales are the Eastern Cooperative Oncology Group (ECOG) scale16 and the World Health Organization (WHO) scale. The ECOG scale contains a motor component (to assess DTRs), a sensory component (to assess paresthesias), and an autonomic component (to assess such symptoms as constipation). However, this scale is limited by the use of a single item as the determinant of the presence or absence of neuropathy. In addition, this scale contains undefined terms such as "mild weakness" and "disabling