Neurotoxicity associated with chemotherapy is recognized more often today than ever before. It’s estimated that 60% of patients receiving neurotoxic chemotherapeutic agents have some degree of associated neurotoxicity. 1 Historically, with these agents, bone marrow suppression was the dose-limiting toxicity. But new pharmacologic advances have made it possible to support the bone marrow with growth factors during chemotherapy. Now other neurotoxicities are becoming dose-limiting factors in the administration of neurotoxic chemotherapeutic drugs. Neurotoxicity affects the patient not only physically, but also functionally, psychosocially, and spiritually, and in turn can affect the family as well.
Nurses play an important role in the early detection of and intervention for neurotoxicity, the success of treatment, and the patient’s quality of life both during and after treatment. Survival is more common than ever; 60% of people diagnosed with cancer will survive their disease for at least five years. 2 Therefore, nurses also need to consider how the sequelae of treatment may affect the survivor’s quality of life.
The body does have endogenous mechanisms that protect against damage to the nervous system. One such mechanism, the blood–brain barrier, prevents large molecular substances from passing out of the blood and into the interstitial fluid of the brain. This barrier often makes it impossible to achieve effective concentrations of some non-lipid-soluble drugs in the brain parenchyma, thus interfering with treatment of central nervous system cancer. Most chemotherapeutic agents don’t cross the blood–brain barrier if they are administered intravenously and if the barrier is intact. Myelin sheaths, another protective mechanism, serve to protect nerves from damage and assist in the rapid transmission of nerve impulses.
Despite such protective mechanisms, chemotherapy can damage the nervous system. Numerous chemotherapeutic agents have neurotoxic effects. Patients at higher risk for neurotoxicity include those with preexisting neurologic deficits, those on combination regimens that include more than one neurotoxic drug, and those who have previously been treated with neurotoxic drugs.
Damage to the nervous system may result from the direct or indirect effects of neurotoxic chemotherapeutic agents on the central nervous system, peripheral nervous system, cranial nerves, or a combination of these. Neurotoxicities are usually temporary and resolve when the treatment is stopped. But some are permanent and have lifelong implications for a patient’s quality of life.
The central nervous system is comprised of the brain and spinal cord, with neurons and their connections organized according to function. Toxicity to this system primarily affects the cerebellum, the part of the brain that acts as a center for processing sensory information concerning body position, coordination of muscle activities, and maintenance of body posture. Damage to the cerebellum produces ataxia, unsteady gait, altered reflexes, and confusion.
The peripheral nervous system is the network of cranial and spinal nerves that branch out from the brain and spinal cord to all parts of the body. This system contains myelinated and unmyelinated neurons. Myelinated neurons have layers of Schwann cells that form around the nerve cell axons. The myelin acts as an electrical insulator; when it’s damaged, the electrical signals are interrupted, affecting the nerve cell function.
The autonomic nervous system is the part of the peripheral nervous system that functions without conscious effort. It controls the cardiovascular, respiratory, and endocrine systems, among others. Damage to the peripheral nervous system results in loss of motor or sensory function, paralysis, pain, ileus, urinary retention, constipation, and impotence (see Neurotoxicity Assessment and Management, page 18).
NEUROTOXIC CHEMOTHERAPEUTIC AGENTS
It’s important for nurses to know which chemotherapeutic agents cause neurotoxicity. When two or more neurotoxic agents are used in combination therapy, the neurotoxicity is likely to become more profound. Factors that put patients at higher risk for neurotoxicity include high-dose therapy, diabetes mellitus, alcohol abuse, and previous or concurrent use of other neurotoxic drugs. 3 Chemotherapeutic drugs associated with the greatest degrees of neurotoxicity are described below.
Paclitaxel stimulates the cellular microtubule assembly, causing neurotoxicity by demyelination of nerve fibers and disruption of microtubules in the neural tissue. 4 Postma and colleagues evaluated the incidence, severity, dose dependency, and reversibility of paclitaxel-induced neuropathy. 5 Three dosage levels were evaluated: low (135 mg/m2), medium (175 mg/m2), and high (250 mg/m2 to 300 mg/m2). Neuropathic signs and symptoms occurred in 50% to 83% of the study participants receiving a low dose, 79% to 86% of those on a medium dose, and 100% of those on high doses. Neurotoxicity was the dose-limiting factor in 21% of the medium-dose group and 71% of the high-dose group. The researchers concluded that dose level and duration of infusion affect the incidence and severity of neurotoxicity. Single doses of paclitaxel exceeding 175 mg/m2 are associated with more profound neurotoxicity. 3
Vinca alkaloids were the first class of drugs to be recognized as neurotoxic. Neurotoxicity is dose-limiting in the use of vincristine, which disrupts the microtubules, causing degeneration and atrophy of axons. Risk factors include doses exceeding 2 mg/m2 and prior neuropathy. Vincristine-related neurotoxicity occurs primarily as peripheral nerve damage and can include loss of deep tendon reflexes; numbness or burning sensations in fingers, toes, hands, and feet; paraparesis (lower extremity weakness); constipation; orthostatic hypotension; urinary retention; loss of pain and temperature sensation; myalgia; and arthralgia. 4
Cisplatin is a heavy metal commonly used in combination with other neurotoxic agents. Neurotoxicity associated with cisplatin administration results from demyelination of nerve cells and damage to large fibers. 4 Cisplatin-related neurotoxicities may be dose-limiting, especially with cumulative dosing. Cisplatin is indicated for use in metastatic testicular and ovarian tumors and advanced bladder cancer. 6 Neurotoxicities, which are most often seen with a cumulative dose of 300 mg/m2 to 500 mg/m2, primarily affect the peripheral nervous system, manifesting in burning sensations and numbness in toes and feet, loss of Achilles tendon reflex (early), loss of deep tendon reflexes (late), loss of ability to sense vibration, and sensory ataxia. 3 Cisplatin also causes ototoxicity, resulting in loss of the hairs in the organ of Corti in the inner ear. 7 The tinnitus caused by cisplatin-related ototoxicity is dose related and irreversible.
Cytarabine, given intravenously or intrathecally, is commonly associated with neurotoxicities that include cerebellar dysfunction (most common), generalized encephalopathy, peripheral neuropathy, and seizures. 3 Risk factors include doses exceeding 1 g/m2, age greater than 50 years, prior cytarabine therapy, and renal dysfunction. Signs and symptoms of cerebellar toxicity are altered mentation, headache, memory loss, somnolence and seizures. Peripheral neuropathies can include paresthesia, but this is rare. Recovery from neurologic sequelae is usually complete within a few days after cessation of treatment. 3
Ifosfamide, a chemotherapeutic agent used in treatment of several malignancies, may cause central nervous system toxicity. Although the mechanism of damage is unclear, one possibility is that the accumulation of chloracetaldehyde (an ifosfamide metabolite) directly damages this system. 3,4,6 Incidence of central nervous system toxicity is reported to be 12%. Signs and symptoms include somnolence, confusion, dizziness, depressive psychosis, hallucinations, cranial nerve dysfunction, seizures, coma, and (rarely) death. Treatment is suspended when toxicities are evident, and recovery usually occurs several days after treatment stops. 3 Risk factors for developing neurologic toxicities include renal insufficiency, low serum albumin, renal toxicity during prior treatment with cisplatin, presence of a central nervous system tumor, and age (children are more susceptible).
Methotrexate administered intravenously, orally, or intramuscularly in standard doses rarely causes neurologic toxicities. But when standard doses are given intrathecally, with or without brain irradiation, central nervous system toxicities often occur. The mechanism of damage most likely involves high methotrexate levels in the central nervous system, which are thought to cause demyelination of nerve fibers. 3,4 Headache, lethargy, nausea and vomiting, nuchal rigidity, paraparesis, cranial nerve dysfunction, and cerebellar dysfunction are common manifestations. In rare cases, repeated doses of intrathecal methotrexate can cause progressive necrotizing leukoencephalopathy. Symptoms include initial memory loss progressing to severe dementia and seizures. Risk factors associated with methotrexate-induced neurotoxicities include the presence of neoplastic cells in the spinal fluid; cranial irradiation; cumulative drug dose; and concomitant use of cytarabine, daunorubicin, salicylates, sulfonamides, or vinca alkaloids.
Excellent nursing assessment and identification of chemotherapy-induced neurotoxicity are paramount to early intervention and positive outcomes for cancer survivors. Other pathologic processes that a patient may be experiencing should be ruled out as causes for the neurologic symptoms. 8 Differential diagnoses include the following.
* vitamin B12 deficiency (diagnosed through a serum B12 greater than 100 pg/mL, a Schilling test, and a neurologic examination)
* Charcot-Marie-Tooth disease, a progressive, hereditary condition present in up to 30% of patients with peripheral neuropathic symptoms (diagnosis is based on clinical and genetic determinations)
* diabetic neuropathy
* atherosclerotic ischemic disease
* paraneoplastic neuropathy
A thorough neurologic assessment during the first visit and subsequent visits will ensure quick identification of chemotherapy-induced neurotoxicities. The clinician should assess for changes in mental status and vision, ability to walk, hallucinations, numbness and tingling in extremities, constipation, urinary retention, hearing loss, myalgia, arthralgia, weakness, hemiparesis, and hemiplegia.
The patient and family need to be educated about possible side effects of chemotherapeutic agents and symptoms of neurotoxicity at the beginning of treatment. By reporting symptoms to their health care providers, patients can assist in the early detection, assessment, and treatment of their conditions.
Nursing interventions include prevention or early identification; enhancing patient communication techniques when necessary (such as when dysarthria or ototoxicity is present); preventing patient injury; and fostering patient mobility. 7 (Immobility can cause numerous complications for an already compromised patient.) These goals can be modified depending on where the damage to the nervous system occurs.
Treatment of neurotoxicity is an interdisciplinary undertaking. Nurses work with occupational therapists, speech therapists, and physical therapists to improve patient function. Holistic care may mean adding social workers, clergy, or psychotherapists to the treatment team. Some of the above-named interventions are discussed in more detail below.
Prevention or early identification. Chemotherapy-induced neurotoxicity is difficult to prevent and treat. However, amifostine, a cytoprotective agent used in conjunction with chemotherapy, has been shown to prevent or reduce neurotoxic damage to normal cells while allowing chemotherapeutic agents to attack malignant cells. 9
Diligent neurologic screening of patients at risk for neurotoxicity is vital to prevention as well as early intervention.
Injury prevention. For the appropriate safety measures to be implemented, it’s necessary to understand the type of neurotoxicity a patient has. Interventions designed to prevent injury and ensure safety are especially important for patients with peripheral neurotoxicity, which can lead to falls, the inability to discriminate hot and cold temperature with hands and feet, impaired pressure sensation, and the inability to ambulate safely. 7,8,10 Skin integrity becomes a concern when protective sensory functioning is impaired.
Occupational therapists can augment the plan of care by suggesting assistive devices and evaluating the home for necessary modifications. Physical therapists can provide ambulation and safety interventions. Nurses can educate patients and families regarding the neurotoxic effects of chemotherapy and their implications for patient safety.
Monitor autonomic dysfunction closely, as this can lead to ileus or urinary retention. Assessment of bowel and bladder functioning is vital; nurses need to educate patients about good bowel hygiene and the use of stool softeners and stimulants. Impotence, another autonomic dysfunction, can significantly affect quality of life. 7 Impotence may be irreversible; the patient and his significant other may need information and guidance regarding penile implants, pharmaceutical interventions, alternative ways to express love physically, and emotional support resources. 10
Pain management. Neuropathic pain is a major morbidity related to neurotoxicity. Damage to peripheral nerves causes pain that needs to be assessed and treated. A multimodal approach is the most effective means of managing neuropathic pain. Adjuvant therapies, such as anticonvulsants, tricyclic antidepressants, topical agents, and zinc sulfate have been found to be effective. 8 The use of opioids has had variable results. While some patients benefit from their use, others receive primary benefit from adjuvant therapy. Finding the most effective combination of drugs to treat each patient’s pain requires patience from all involved (the patient as well as the providers). Chronic neuropathic pain may lead to depression. Conversely, assessment and treatment of depression can have a positive impact on pain relief. Nurses can provide the assessment data and offer patient and family education as needed.
Nonpharmacologic interventions, including acupuncture and acupressure, massage, guided imagery, relaxation techniques, biofeedback, and meditation, are important in the management of neuropathic pain. 7,10 The success of these alternative and complementary therapies may depend largely on the patient and the health care provider’s level of acceptance of them. Many people report that these modalities make a difference. As a patient in a cancer support group said, “Swimming helped my peripheral neuropathy more than anything else I tried.”