New Directions in Cancer-Related Cognitive Impairment, Fatigue, and Pain: Symposium

SAN DIEGO, California—A symposium at the Oncology Nursing Society’s 26th Annual Congress addressed the challenges of managing cancer-related cognitive impairment, fatigue, and pain. Each of three speakers gave an overview of one of these problems, including contributing factors and current research, and then discussed new approaches to symptom management.

Cognitive Impairment

Catherine M. Bender, PhD, RN, assistant professor of oncology nursing, University of Pittsburgh School of Nursing, reviewed current knowledge concerning cancer-related cognitive impairment. She described the components of cognitive function—attention, learning and memory, psychomotor speed and manual dexterity, visuospatial ability, and general intelligence.

"These processes are all highly interrelated," Dr. Bender said. "Thus, a problem with one process may also impact the functioning of other processes."

In addition, she said, many of these cognitive processes are multidimensional. "For example," she said, "attention has multiple related capacities that permit you to be receptive to stimuli in the environment so that you can select information, concentrate on that information, inhibit irrelevant information, and thus sustain your attention."

The cognitive processes most often affected in cancer patients are attention, learning and short-term memory, and psychomotor speed and manual dexterity. Problems with these processes have a significant impact on the cancer patient, she said. They can impair decision-making, interfere with the patient’s roles in the family and at work, and erode quality of life.

A long list of direct and indirect factors can contribute to cognitive impairment. Direct factors are primary or metastatic brain lesions. Indirect factors include the effects of cancer therapy—virtually all of which, Dr. Bender said, can affect cognitive function—infections, fevers, nutritional deficiencies, hematologic abnormalities such as anemia, and metabolic and endocrine abnormalities such as a decline in reproductive hormone levels.

Medications, advancing age, depression and anxiety, and sleep disorders also take a toll on cognitive abilities.

"Reports suggest that between 28% and 32% of women receiving adjuvant chemotherapy for breast cancer do experience some cognitive impairment," Dr. Bender said. "This impairment is dose dependent; thus, the higher the dose, the more frequently the problem occurs and the more severe the problem appears to be." Cognitive impairment can last for years after the conclusion of therapy, she added.

Role of Anemia

One potential mechanism of cognitive impairment may be the anemia associated with chemotherapy, she added. Several studies in animal models have shown that recombinant human erythropoietin (epoetin alfa, Procrit^®, Eprex^®,Erypo^®) has a neuroprotective effect when administered systemically within 6 hours of a concussion, seizure, or stroke.

Epoetin alfa crosses the blood-brain barrier and binds with erythropoietin receptors, inhibiting cell death and modulating neuronal excitability. Moreover, cerebral infusion of epoetin alfa has been shown in an animal model to reduce the injury associated with focal ischemic stroke by 50% to 70%.

"Clearly, further studies are needed to clarify the potential role of anemia in cognitive functioning in cancer patients," she said, "and to explore the potential role of recombinant human erythropoietin in managing cognitive impairment associated with chemotherapy."

Another potential mechanism for cognitive impairment in women with breast cancer, she said, is the reduction in estrogen and progesterone levels that occurs as a result of adjuvant therapy. Mounting evidence suggests that estrogen plays an important role in neuronal development, maintenance, and regeneration.

Some clinicians have advocated the use of conventional hormone-replacement therapy in the management of cognitive affects as well as other menopausal symptoms following chemotherapy. However, in most women previously treated for breast cancer, this is not an option.

Alternative approaches include the use of selective estrogen-receptor modulators (SERMs) and cholinesterase inhibitors, such as donepezil hydrochloride (Aricept^®), which has been found to be useful in patients with mild to moderate Alzheimer’s disease.

A number of other agents are being considered for managing cancer-related cognitive impairment, including psychostimulants, such as methylphenidate (Ritalin^®), antidepressants, and opiate antagonists. In addition, a variety of compensatory strategies can help cancer patients organize information and maintain attention.

Fatigue

Patricia Kramer, RN, MSN, an oncology nurse educator and consultant in San Francisco, reviewed new findings about the effects of cancer-related fatigue and discussed various approaches to managing this common and debilitating problem.

She cited results from two national surveys commissioned by the Fatigue Coalition—a multidisciplinary group of health care providers, patient advocates, and researchers that was formed in 1996 to study the prevalence of cancer-related fatigue and its impact on cancer patients, and to develop guidelines for interventions and treatments.

The first survey—Fatigue I—established that symptomatic fatigue is a profound and common problem for cancer patients. The Fatigue II survey sought to extend the earlier findings and to include observations about the physical, social, psychological, and economic effects of cancer-related fatigue and the duration of fatigue.

Results of this survey, conducted among 301 chemotherapy patients, suggest that fatigue is the cancer-related side effect that lasts the longest and has the greatest effect on patients’ everyday lives.

"The survey found that 75% of the employed patients had to change their employment status because of fatigue, which included reducing the number of hours worked, assuming fewer responsibilities, and taking more vacation time or sick days," Ms. Kramer said.

The survey showed that 28% of the patients had to stop work altogether because of fatigue. Men were twice as likely as women to stop work altogether, she said.

Fatigue has a significant economic impact on caregivers as well. "Interestingly," Ms. Kramer said, "patients who continued to work missed approximately 1 day a week from work because of their fatigue, but so did their caregivers, and 20% of patients had to hire help—childcare, help around the house, or help with yard work."

The survey also asked patients about their doctor’s recommendations for managing fatigue: 77% indicated that their physician had made no recommendations concerning fatigue or had recommended rest and relaxation; 11% recommended dietary approaches; 9% prescribed medication; 7% recommended vitamins; and only 5% recommended exercise.

Targeting Treatment

Ms. Kramer reviewed the many factors that potentially contribute to fatigue: physiologic and biochemical changes related to the cancer itself, cancer therapy, anemia, immobility and decreased activity, impaired nutrition, sleep disturbances, psychosocial stress and depression, and polypharmacy.

"Gaining insight into cancer-related fatigue can be a challenge because of its multifactorial nature," Ms. Kramer said. "But I am drawn to the analogy of putting together a jigsaw puzzle. As we identify and assemble factors that are present for a specific patient, the puzzle starts to take form, and we start to get a clearer picture of what is going on."

Treatment can then be targeted to those areas that are amenable to correction or intervention, she said. "Anemia, pain, infection, inactivity, depression—these are areas that we can target because we can do something about them," she noted.

Anemia Is ‘Not a Benign Occurrence’

Ms. Kramer emphasized that anemia is "not a benign occurrence." She said that research involving more than 7,000 anemic cancer patients shows a direct relationship between hemoglobin levels and patient reports of energy, activity, and quality of life.

Teaching patients with fatigue effective self-help strategies is important. These might include exercise, meditation, improving nutrition, learning to conserve energy and delegate tasks, and sharing their feelings of fatigue.

Medical interventions for fatigue include blood transfusions for those with severe anemia and use of epoetin alfa to reduce transfusion requirements and to raise hemoglobin levels in patients with mild to moderate anemia.

Three major community-based studies have shown that epoetin alfa can correct anemia and reduce transfusion use in patients receiving chemo-therapy, Ms. Kramer said. "The greatest incremental improvement in quality of life is observed at a hemoglobin level of 12 g/dL,’’ [range, 11-13 g/dL] she said. "That seems to be the magic number."

She cited a recent study showing that once-a-week administration of epoetin alfa can achieve results similar to those of the three-times-weekly schedule (Gabrilove J et al: J Clin Oncol 19:2875-2882, 2001).

Once-Weekly Epoetin Alfa

This prospective, multicenter, open-label, single-arm, nonrandomized study involved 2,964 assessable patients receiving chemotherapy for a nonmyeloid malignancy and having a baseline hemoglobin level less than 11 g/dL.

Quality of life was assessed at baseline, after 2 months, and at study completion (4 months), using two self-report instruments: the 20-item anemia subscale of the FACT-AN and a 100-mm linear analog scale assessment (LASA) of energy level, ability to perform daily activities, and overall quality of life.

Patients received epoetin alfa 40,000 U once a week by subcutaneous injection. This was increased to 60,000 U if hemoglobin levels did not increase by at least 1 g/dL after 4 weeks of therapy. Response was defined as an increase in hemoglobin of at least 2 g/dL or achievement of a hemoglobin level of at least 12 g/dL, with no transfusions within the previous 30 days.

The results showed a significant mean increase in hemoglobin of 1.8 g/dL from baseline (P < .001). The mean final hemoglobin for the group was 11.3 g/dL. These levels were similar to those obtained with the three-times-weekly schedule (2 g/dL and 11.3 g/dL, respectively).

Scores on the FACT-AN anemia subscale improved by 6 points (14%) from baseline (P < .001). On the LASA, percentage changes from baseline in energy level, activity level, and overall quality-of-life scores were 30%, 26%, and 19%, respectively (P < .001 for all changes).

"There was a direct relationship between hemoglobin level and patient reports of improvements in energy, activity, and quality of life in this study," Ms. Kramer said. Patients who had mean increases in hemoglobin of 0 to 2 g/dL, between 2 and 4 g/dL, and greater than 4 g/dL had corresponding significant mean percentage increases on the FACT-AN anemia subscale of 11%, 18%, and 25%, respectively, and increases of 17%, 25%, and 32%, respectively, on LASA overall quality-of-life scores.

Pain Issues

The third symposium speaker, Christine Miaskowski, PhD, RN, professor and chair of the Department of Physiological Nursing, University of California, San Francisco, explored the many issues surrounding treatment of pain in cancer patients.

She began by reviewing prevalence statistics, noting that 50% of patients being actively treated for cancer experience pain. "Every other patient who walks through your door is a person who is potentially experiencing pain," she said.

A corollary point, Dr. Miaskowski remarked, is that cancer is now a chronic disease. "This means that patients who are experiencing pain are going to be living longer with that experience," she said. "We are going to be seeing patients with chronic pain that needs intervention."

In the terminal/palliative stage, she noted, pain prevalence rises to 80% to 90%.

Dr. Miaskowski acknowledged the difficulty of managing pain, noting the effects of symptom clustering and the fact that patients often experience more than one type of pain.

As people are aging and getting cancer later in life, she added, they are going to come to that experience with chronic, non-cancer-related pain such as arthritic pain, diabetic neuropathy, and low back pain. That makes it even more important to identify the mechanisms causing the patient’s problems.

"Probably the toughest group of pain syndromes that we treat are neuropathic-based pain problems," Dr. Miaskowski said. "Those problems that occur in patients at surgical incision sites—typically called postsurgical pain syndromes—are syndromes that we don’t know a whole lot about. Postmastectomy pain is something that many women experience but that has largely been ignored."

Thoracic surgery and nephrectomy produce other sequelae, she said. "Again, it’s important to question patients who have had these procedures—Do they have numbness? Do they have tingling or burning sensations at the site?—and then try to treat those syndromes, usually with a combination of antidepressants and anticonvulsants and then some local therapy."

Postherpetic neuralgia in immunosuppressed patients is another tough problem, Dr. Miaskowski said.

She reviewed the general principles of effective pain management: Perform a comprehensive pain assessment, determine the source of the pain, and develop a comprehensive pain management plan that utilizes both pharmacologic and nonpharmacologic approaches.

She emphasized the importance of a comprehensive education and "coaching" program for patients and their families. "It’s not enough to simply give instructions," she said. Patients and caregivers need more in-depth assistance with pain management issues, such as dosing schedules, handling breakthrough pain, and learning how to anticipate pain.

"Some also may need reassurance that taking a narcotic is not only acceptable but is the best way to manage the patient’s pain," she added.

With drug treatment, she said, it is important to individualize the dosing regimen, titrate to get the maximal effect with the fewest side effects, administer medications around the clock, and use the least invasive route possible.

Practitioners should use appropriate drug combinations based on mechanisms of action and use the simplest regimen possible to avoid polypharmacy.

Finally, she said, it is important to anticipate and treat the side effects of the medications and continually reassess the pain management plan’s effectiveness.