Cognitive Impact of Intensive Treatments for Chronic Illness
J. Aubrey Burhart, Ed.M., Doctoral Student
James P. Donnelly, Ph.D., Assistant Professor
University at Buffalo/SUNY
Counseling Educational School of Psychology
Sally Speed, Office of Medicaid Management Unit Director
Award: 31177
Project: 1037112
Task: 2
Funding for this research project was provided by NYS Office of Children and Family Services, Contract year 2004: Project 1037122, Award 31177, through the Center for Development of Human Services, College Relations Group, Research Foundation of SUNY, Buffalo State College.
INTRODUCTION
Although the 2004 Annual Report to the Nation from the National Cancer Institute reported a decrease in the risk of getting and dying from cancer, it is predicted that the number of new cancer cases to arise in 2004 is upwards of one million. Close to 600,000 people are expected to die from cancer in 2004 (http://seer.cancer.gov/csr/1975_2001/results_single/sect_01_table.01.pdf). Cognitive dysfunction is a frequently observed complication in cancer patients (Pereira, Hanson, & Bruera, 1997; Meyers & Abbruzzese, 1992; Ahles, Tope, Furstenberg, Hann, & Mills, 1996; Andrykowski, Schmitt, Gregg, Brady, & Lamb, 1992; Sjogren, Olsen, Thomsen, & Dalberg, 2000). It is associated with increased distress for both patient and caregivers, and impacts patients’ ability to sufficiently comprehend the information necessary to make informed decisions regarding their healthcare. Intact cognitive functioning is imperative for adhering to treatment regimens and medication compliance (Folstein, Fetting, Lobo, Niaz, & Capozzoli, 1984). Cognitive functioning is also essential for carrying out activities of daily living, intellectual development, success in the workplace, and maintenance of social relationships (Walch, Ahles, & Saykin, 1998). Cognitive impairment can be acute or chronic, subtle or pronounced, temporary or permanent, stable or progressive (Walch, Ahles, & Saykin, 1998). While cognitive dysfunction is common in cases central nervous system (CNS) metastases, involvement of CNS does not have to be present for impairment to occur. A host of factors may be detrimental to cognitive functioning. They can be classified on an etiologic basis as either disease induced or treatment induced factors (Sjogren et al., 2002; Andrykowski et al., 1992). Disease induced factors include brain metastases, infections, nutritional deficiencies, disturbances in the metabolic/endocrinologic systems, and pain. Chemotherapy, radiation, bone marrow transplant, medications and biologic response modifiers are among the treatment induced factors and have been implicated as risk factors for neurocognitive impairment (Walch, Ahles, & Saykin, 1998). Furthermore, total dose of therapeutic agent, time of administration, and volume of tissue affected may impact the severity of neurotoxicity (Walch, Ahles, & Saykin, 1998). Cognitive dysfunction in cancer patients has been noted for many years. The deficits can be attributed to a variety of causes which can be classified as either disease-induced factors, such as infection, metabolic disruptions, brain metastasis, pain, etc., or treatment related factors including various drug, chemotherapy, and radiation therapies. Medical interventions that are employed for cancer can be extremely toxic, thus imposing measurable cognitive deficits in patients (Walch, Ahles, & Saykin, 1998; Garofalo & Baum, 2001). Radiation therapy, although often deemed an integral component of cancer treatment, has been highlighted as a primary cause of compromised cognitive functioning (Walch, Ahles, & Saykin, 1998; Garofalo & Baum, 2001). This type of treatment entails the use of radiation waves to destroy or weaken cancer cells. Although malignant cells are more prone to become the target of radiation waves, the radiation does not entirely distinguish between malignant cells and healthy cells. Therefore, patients are at risk for losing cells from healthy issue as well.
Standard chemotherapy treatment also appears to put cancer patients at risk for cognitive impairment, however drawing conclusions about its neurotoxic effects is challenging due to the great number of chemotherapy drugs used on various schedules and dosages (Walch, Ahles, & Saykin, 1998; Garofalo & Baum, 2001). Advances in the medical field have led to combination therapy treatment in which both chemotherapy and radiation therapy are administered. While this could prove to be more efficacious in conquering the disease, increased exposure to these toxic agents subjects patients to greater risk for neuropsychological impairments. Bone marrow transplantation (BMT) is yet another therapy that is increasingly used in the treatment of cancer. The presence of cognitive dysfunction in BMT patients is not surprising considering the pre-transplant treatment regimen that they must undergo. Patients are treated with high-dose chemotherapy involving various toxic agents, often coupled with total body irradiation (TBI; et al, 1992). This conditioning regimen is then followed by the BMT itself, which involves reinfusement of bone marrow or peripheral stem cells. BMT can be characterized as autologous or allogeneic with the former referring to a procedure by which the patient’s bone marrow is harvested and then reinfused; the latter type employs an unrelated, but matched, donor’s bone marrow. Both types of BMT pose risks for recipients, however there is evidence that allogeneic transplants impose greater neurologic complications due to the potential for graft-versus-host disease and severe immunosuppression (Ahles et al., 1996). Bone marrow transplantation (BMT) is an aggressive cancer treatment often implemented when patients with hematologic or solid malignancies do not respond to typical treatment modalities (Ahles, Tope, Furstenberg, Hann, & Mills, 1996). The BMT procedure makes patients potentially susceptible to many risk factors including infections related to a compromised immune system, graft versus host disease, and neurotoxic effects of immunosuppressive therapy (Harder et al., 2002). The multiple risk factors involved for patients treated with BMT makes BMT a unique treatment modality for cancer compared with other treatments that potentially induce neurotoxic effects. Cognitive deficits have been reported in the literature as one of many potential devastating consequences following BMT (Meyers, Weitzner, Byrne, Valentine, Champlin & Przepiorka, 1994; Ahles et al., 1996; Andrykowski, Schmitt, Gregg, Brady, Lamb, & Henslee-Downey, 1992). Unfortunately, the studies that have examined neuropsychological functioning of these particular patients have been, most often, retrospective and lack a quantitative, systematic protocol (Meyers et al., 1994; Padovan, Yousry, Schleuning, Holler, Kolb, & Straube, 1998). Few studies have systematically assessed changes in patients cognitive functioning with standardized tests across various points in time. An abundance of research has documented the effects of BMT on children, but the nature of cognitive impairment in adults is unclear. Potential bone marrow transplant recipients must be able to adequately comprehend, process, and remember substantial amounts of disease and treatment-related information in order to make informed decisions regarding their health care. BMT patients must exercise precise self-care behaviors during and following bone marrow transplantation. Thus, it is imperative that these patients retain the capacity to understand their necessary self-care regimen (Andrykowski et al., 1992).
Greater understanding of the potential cognitive effects that these aforementioned treatments can have on patients is warranted. As the number of people diagnosed with cancer increases, more and more patients will suffer with cognitive deficits. Cognitive deficiencies can affect patients’ abilities to make informed treatment decisions. Furthermore, the educational and employment opportunities for cancer survivors may be limited by the presence of cognitive dysfunction. By researching the impact that cancer treatment modalities can have on patients cognitively, interventions that have proven efficacious in other types of patients with cognitive deficits could be employed in this population with hopes of similar success. Finally, the quality of patients’ lives following treatment should not be dismissed. Attempting to maintain a previous standard for quality of life can become quite challenging and frustrating for the patient that is suffering cognitively. Quantifying the cognitive effects that chemotherapy, radiation therapy, and bone marrow transplantation have on some patients could lead physicians to modifying treatment regimens. Research in children regarding this topic has resulted in such treatment modifications that illustrated maintenance of treatment efficacy while simultaneously reducing the negative cognitive side effects (Ahles, Saykin, Furstenberg, Cole, Mott, et al., 2002). Literature that has documented the effects of various treatment modalities for cancer on cognitive functioning will now be reviewed.
Literature Review
Chemotherapy
Tannock, Ahles, Ganz, and van Dam (2004) reported the results of a workshop that was held to review literature regarding cognitive effects of chemotherapy, construct hypotheses to be tested as to what the underlying mechanisms are for cognitive impairment, and establish priorities for future research. The clinicians present at this workshop reviewed the literature that had evaluated cognitive functioning in adult cancer patients treated with cytotoxic agents. Some patients experienced cognitive dysfunction as late as ten years, and for those whose cognitive function was determined to be within normal limits, there was an association between low-normal functioning and previous chemotherapy treatment. It was determined that the most appropriate method for assessing cognitive function depends on the question being asked and the context of the study. When seeking to evaluate which cognitive domains are affected by chemotherapy, a traditional, comprehensive neuropsychological battery was deemed necessary. However, if the goal is to simply evaluate whether patients suffer from cognitive deficits, then a brief, validated assessment battery is permissible.
Ahles and colleagues (2003) compared the neuropsychological performance of long term breast cancer and lymphoma survivors treated with standard dose chemotherapy who carried the apolipoprotein E e4 (APOE e4) allele to those whom had other APOE alleles present. The presence of the APOE e4 allele has been associated with greater risk for Alzheimer’s disease, neuropsychological deficits following cardiac bypass surgery, and traumatic brain injury (Ahles et al., 2003).
A total of 80 survivors (Breast cancer N=51; Lymphoma N=29) with no evidence of disease and at least five years post-diagnosis consented to the study. None of the sample was receiving cancer treatment throughout the duration of the investigation. A neuropsychological test battery was administered by superior technicians under the supervision of a board certified neuropsychologist. Survivors’ treatment history and APOE status was not known to neuropsychology technicians. The test battery measured several neuropsychological domains. Verbal ability was measured using the Vocabulary subtest from the Wechsler Adult Intelligence Scale-III (WAIS-III), the Reading subtest of the Wide Range Achievement Test-III (WRAT-III), Boston Naming Test, and the Controlled Oral Word Association Test. Block Design, another subtest from the WAIS-III, was employed to assess spatial ability. Indices of the California Verbal Learning Test (CVLT) were used to assess verbal learning. Verbal memory was measured using Logical Memory I, Stories A and B and Logical Memory Multiple Choice Story B (30’ delay) from the Wechsler Memory Scale-Revised (WMS-R). The Visual Reproduction I and Visual Reproduction II (30’ delay) subtests were also used from the WMS-R to assess visual memory. Psychomotor function was measured by the Digit Symbol subtest of the WAIS-III and Trails A & B. Finger Tapping and Thumb-Finger Sequencing were employed to measure motor functioning. Vigilance and Distractibility subtests from the Continuous Performance Test (CPT) were used to measure two dimensions of attention, accuracy and reaction time. The CES-D, Spielberger State-Trait Anxiety Inventory, and Fatigue Symptom Inventory were also administered as measures of depression, anxiety, and fatigue, respectively (Ahles et al., 2003). Z-scores from a sample of cancer survivors that completed the same neuropsychological assessment battery were used as a reference to calculate nine domain scores. Ten milliliters of blood was drawn for APOE testing. As expected according to the population distribution, 21% of the survivors carried at least one e4 allele, and this group performed significantly lower than those without this gene on visual memory (p<.03) and spatial ability (p<.05) tasks. Compared to the reference normative data, however, performance across domains was within normal limits, regardless of APOE status (Ahles et al., 2003). This study provides evidence to support the hypothesis that carriers of the e4 allele are more susceptible to chemotherapy-induced cognitive deficits. This conclusion should be considered in light of the fact that the investigation lacked pretreatment neuropsychological assessment (Ahles et al., 2003). Brezden et al., (2000) examined the effects of chemotherapy on cognitive functioning across three treatment groups. Group A (n=31) consisted of breast cancer patients currently undergoing adjuvant chemotherapy (at testing, median number of cycles completed was three); Group B (n=40) was comprised of breast cancer patients who completed chemotherapy at least one year prior (median time since chemotherapy was 25 months) and had no evidence of relapse; Group C (n=36) contained healthy controls with no history of major illnesses. The entire sample was female. Individuals in Groups A and B had a diagnosis of early-stage breast cancer with no previous major medical history.
To assess neuropsychological functioning, the High Sensitivity Cognitive Screen (HSCS) was employed. This measure tests six cognitive domains including memory, language, visual-motor, spatial, attention and concentration, and self-regulation and planning. It is reported to have 93% accuracy when distinguishing between normal and abnormal results of a neuropsychological exam (Brezden et al., 2000). By totaling the scores across the six domains, the authors yielded an overall cognition score for each subject on the HSCS. Higher scores were indicative of greater deficits. In addition, the Profile of Mood States (POMS) was administered to each subject. This self-administered questionnaire detects fluctuating mood patterns and is capable of detecting mood disorders (Brezden et al., 2000). Six dimensions measure various derivatives of anxiety and depression, and, when totaled, yield a total score. Higher scores represent greater mood disturbance. Both of the aforementioned assessment tools were administered under the supervision of the primary investigator of the study.
The age of individuals in Group C was significantly younger than those in other groups and significantly more patients in Groups A and B were postmenopausal than in the control group. The results should be considered in light of these findings. Overall scores on the HSCS were significantly lower in Group A than in Group C, above and beyond age, education, and menopausal status (p=.046). The HSCS allows for classification of individuals by degree of impairment as mild, moderate, severe, based on their total score. Treatment groups A and B consisted of significantly more individuals with moderate or severe cognitive impairment (15 out of 31 patients and 20 out of 40, respectively) than in the control group (four out of 36). In terms of specific neuropsychological domains, patients in group A had significantly different scores on memory and language domains than those in group C. Furthermore, analysis of scores in the language and visual-motor skills domains yielded significant differences between groups B and C. Analyses of the POMS scores resulted in no significant differences between groups, suggesting that mood disturbance cannot explain the observed differences in cognitive functioning. This study contributes to the body of literature that illustrates significant effects of chemotherapy on cognitive functioning (Brezden, 2000).