Extermann M.
Older Patients, Cognitive Impairment, and Cancer: An Increasingly Frequent Triad. 

J Natl Compr Canc Netw. 2005 Jul;3(4):593-596.PMID: 16038648 [PubMed – as supplied by publisher]

The incidence of both cancer and cognitive impairments from various origins increases with age. Oncologists are increasingly being confronted with cancers occurring in patients with cognitive impairment, yet very few studies have addressed the problem. Cognitive impairment affects a patients’ survival to an extent similar to an average cancer, and this can be an important thing to consider, especially in the adjuvant setting. Cognitive impairment also predisposes patients to delirium in the surgery setting or during hospitalization. Because effective preventive measures exist, careful attention should be paid to identifying patients at risk. Cognitive impairment does not automatically mean inability to consent, but particular precautions should be taken. For outpatient treatments such as chemotherapy, a comprehensive multidisciplinary approach is key for a good outcome. Proper caregiver support should be ensured upfront, and aggressive supportive care should be used. In the setting of an experienced geriatric oncology team, patients with cognitive impairment appear more likely to receive standard oncologic therapies. Cancer patients with cognitive impairment are at high risk of concomitant depression.

bulletFrom the University of South Florida, Senior Adult Oncology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; Correspondence: Martine Extermann, MD, Departments of Oncology and Medicine, University of South Florida, and Senior Adult Oncology Program, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: extermann@moffitt.usf.edu.
Falleti MG, Sanfilippo A, Maruff P, Weih L, Phillips KA.
The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: A meta-analysis of the current literature.

Brain Cogn. 2005 Jun 20; [Epub ahead of print]
PMID: 15975700 [PubMed – as supplied by publisher]

OBJECTIVE: Several studies have identified that adjuvant chemotherapy for breast cancer is associated with cognitive impairment; however, the magnitude of this impairment is unclear. This study assessed the severity and nature of cognitive impairment associated with adjuvant chemotherapy by conducting a meta-analysis of the published literature to date. METHOD: Six studies (five cross-sectional and one prospective) meeting the inclusion criteria provided a total of 208 breast cancer patients who had undergone adjuvant chemotherapy, 122 control participants and 122 effect sizes (Cohen’s d) falling into six cognitive domains. First, the mean of all the effect sizes within each cognitive domain was calculated (separately for cross-sectional and prospective studies); second, a mean effect size was calculated for all of the effect sizes in each cross-sectional study; and third, regression analyses were conducted to determine any relationships between effect size for each study and four different variables. RESULTS: For the cross-sectional studies, each of the cognitive domains assessed (besides attention) showed small to moderate effect sizes (-0.18 to -0.51). The effect sizes for each study were small to moderate (-0.07 to -0.50) and regression analysis detected a significant negative logarithmic relationship (R(2)=.63) between study effect size and the time since last receiving chemotherapy. For the prospective study, effect sizes ranged from small to large (0.11-1.09) and indicated improvements in cognitive function from the beginning of chemotherapy treatment to 3 weeks and even 1 year following treatment. CONCLUSION: This meta-analysis suggests that cognitive impairment occurs reliably in women who have undergone adjuvant chemotherapy for breast cancer but that the magnitude of this impairment depends on the type of design that was used (i.e., cross-sectional or prospective). Thus, more prospective studies are required before definite conclusions about the effects of adjuvant chemotherapy on cognition can be made.

bulletSchool of Psychological Science, LaTrobe University, Level 7, 21 Victoria Street, Melbourne, Vic. 3053, Australia; Peter MacCallum Cancer Center, St. Andrew’s Place, East Melbourne 3002, Australia.
Mills PJ, Parker B, Dimsdale JE, Sadler GR, Ancoli-Israel S.
The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer.


Biol Psychol. 2005 Apr;69(1):85-96. Epub 2005 Jan 8.
PMID: 15740827 [PubMed – indexed for MEDLINE]

Chemotherapy for breast cancer leads to increased fatigue, poor mood, and reduced quality of life. Few studies have examined possible changes in inflammation during chemotherapy as potential contributors to this phenomenon. This study examined the relationship among circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) and fatigue, depressed mood, and quality of life before and during anthracycline-based chemotherapy. Twenty-nine women diagnosed with stage I-IIIA breast cancer (mean age 49.5 years, S.D.+/-11) were studied prior to cycle 1 of chemotherapy and 2.5 months later at the start of cycle 4 of chemotherapy. Chemotherapy led to a significant increase in sICAM-1 (P<0.05) and VEGF (P<0.01) levels, as well as increased ratings of fatigue (P<0.01), depressed mood (P<0.03), and poorer quality of life (P<0.01). Multiple regression analyses revealed that elevated VEGF (P<0.01) and sICAM-1 (P<0.02) were related to the increased fatigue and/or poorer quality of life as a result of chemotherapy. Pre-chemotherapy levels of VEGF and pre-chemotherapy ratings of quality of life predicted quality of life in response to chemotherapy (P<0.001). The findings contribute to the literature by showing that both pre-chemotherapy and chemotherapy-induced changes in inflammation are related to changes in fatigue and quality of life in response to chemotherapy.

bulletDepartment of Psychiatry, University of California, San Diego (UCSD), Medical Center, 200 West Arbor Drive, San Diego, CA 92103-0804, USA. pmills@ucsd.edu
Shilling V, Jenkins V, Morris R, Deutsch G, Bloomfield D.
The effects of adjuvant chemotherapy on cognition in women with breast cancer–preliminary results of an observational longitudinal study.


Breast. 2005 Apr;14(2):142-50.
PMID: 15767184 [PubMed – indexed for MEDLINE]

Several studies have reported that chemotherapy-treated patients have impaired cognition function relative to control groups. We are conducting a longitudinal study with cognitive assessments at baseline, 6 and 18 months. A planned preliminary analysis of data from 50 chemotherapy patients and 43 healthy controls at baseline and post-treatment found a significant group by time interaction on three measures of verbal and working memory. Chemotherapy patients were more likely to show cognitive decline than controls (OR 2.25). Patients were significantly more likely to have GHQ(12) scores indicative of possible psychological morbidity and showed significant increases in endocrine symptoms and fatigue post-treatment however neither GHQ(12) nor quality-of-life variables were related to cognitive performance.

bulletCancer Research UK Psychosocial Oncology Group, Brighton and Sussex Medical School, University of Sussex, Falmer, East Sussex BN1 9QG, UK. v.m.shilling@sussex.ac.uk
Jansen CE, Miaskowski C, Dodd M, Dowling G.
Chemotherapy-induced cognitive impairment in women with breast cancer: a critique of the literature.


Oncol Nurs Forum. 2005 Mar 5;32(2):329-42.
PMID: 15759070 [PubMed – in process]

PURPOSE/OBJECTIVES: To review and critique the studies that have investigated chemotherapy-induced impairments in cognitive function in women with breast cancer. DATA SOURCES: Published research articles and textbooks. DATA SYNTHESIS: Although studies of breast cancer survivors have found chemotherapy-induced impairments in multiple domains of cognitive function, they are beset with conceptual and methodologic problems. Findings regarding cognitive deficits in women with breast cancer who currently are receiving chemotherapy are even less clear. CONCLUSIONS: Although data from published studies suggest that chemotherapy-induced impairments in cognitive function do occur in some women with breast cancer, differences in time since treatment, chemotherapy regimen, menopausal status, and neuropsychological tests used limit comparisons among the various studies. Further studies need to be done before definitive conclusions can be made. IMPLICATIONS FOR NURSING: The potential for chemotherapy-induced impairments in cognitive function may influence patients’ ability to give informed consent, identify treatment toxicities, learn self-care measures, and perform self-care behaviors.

bulletDepartment of Physiological Nursing, University of California, San Francisco, CA, USA. catherine.jansen@kp.org
Cimprich B, So H, Ronis DL, Trask C.
Pre-treatment factors related to cognitive functioning in women newly diagnosed with breast cancer.


Psychooncology. 2005 Jan;14(1):70-8.
PMID: 15386786 [PubMed – indexed for MEDLINE]

Women treated for breast cancer have shown cognitive deficits with reduced capacity to focus and concentrate or to direct attention. This study examined the relationship between cognitive function prior to any treatment for breast cancer and individual factors including age, education, menopausal status, chronic health problems, and distress. Women newly diagnosed with breast cancer (N=184), ages 27-86 years, were assessed with standardized attention tests, self-reports of effectiveness in cognitive functioning, and measures of distress at about 18 days before surgery. Measured performance on the cognitive tests was not significantly correlated to self-reports of effectiveness in cognitive functioning. Age, education, presence of a chronic health problem, and menopausal status, but not distress, were associated with performance on the cognitive tests. Only age and education, however, were significant (p<0.001) predictors of overall performance on the cognitive tests, when controlling covariates. In contrast, symptom and mood distress significantly (p<0.001) predicted perceptions of effectiveness in cognitive functioning. Thus, different factors were associated with measured performance versus self-reports of cognitive functioning. Individual factors that predispose to lowered effectiveness in cognitive functioning prior to treatment in women newly diagnosed with breast cancer are discussed. 2004 John Wiley & Sons, Ltd.

bulletSchool of Nursing, University of Michigan, Ann Arbor MI 48109-0428, USA.

Galantino, M, Henderson, A, Michaels, J
Cognitive Challenges for Women Undergoing Adjuvant Chemotherapy for Treatment for Breast Caner:  The Role of Rehabilitation Oncology

Rehabilitation Oncology, 2005

Breast cancer is the most common malignancy and the second leading cause of cancer-related death in women in the United States.1 Adjuvant chemotherapy continues to be the mainstay of treatment for many types of breast cancer, improving the cure rate and prolonging survival. However, chemotherapy has been associated with significant side effects. Adverse effects of anticancer drugs include myelosuppression with consequent risks of infection or bleeding, nausea, vomiting, and hair loss. More subtle chronic adverse effects that have been recognized include fatigue, symptoms associated with early menopause, and cognitive dysfunction.

The goal of adjuvant chemotherapy in treatment of breast cancer is to reduce recurrence and mortality. With respect to quality of life and morbidity, however, such treatments may come at a cost.: Cognitive deficits resulting from chemotherapy, recently referred to Chemotherapy Related Cognitive Dysfunction (CRCD), have posed significant challenges for breast cancer and other cancer patients. Cognitive deficits associated with cancer treatment can have a dramatic effect on a patient’s quality of life and have been recognized by the President’s Cancer Panel and the National Coalition for Cancer Survivorship as a challenge for people with cancer.’

The actual incidence and severity of chemotherapy related cognitive impairment in patients with cancer has not been well documented.4 Deficits in cognitive function that occur as a result of cancer or its treatment are difficult to examine, as they may be subtle or dramatic, temporary or permanent, and stable or progressive. Additionally, there may be treatment factors including the type of chemotherapy and regimen or individual factors such as IQ, education, genetic factors, or estrogen levels that may predispose certain patients to cognitive dysfunction.

Other factors, such as the process of aging and psychological manifestations, such as anxiety or depression, can contribute to cognitive dysfunction, making it hard to directly link chemotherapy as the source of the problem. Bender4 suggests that the effects of adjuvant chemotherapy on estrogen and progesterone levels combined with the natural decline in reproductive hormones that occurs with advancing age may result in more significant cognitive declines than those commonly experienced because of normal cognitive aging. It is difficult to attribute the cognitive decline to depression, chemotherapy, or a combination of the two. In a case review of 2 patients by Paraska et al,1 there were incidences of depression that correlated to the patients’ reported decreased cognitive abilities. In addition, at a period when one of the patients was not depressed, most of her scores on the measures of cognitive function improved from a period when she was depressed. Both women perceived problems with cognitive function before deterioration was detected in their scores on the neuropsychological tests. However, a Danish study published in the Harvard Women’s Health Watch reported that chemotherapy patients performed worse on cognitive tests than women who were treated with radiation and surgery.5 This study also showed levels of depression, anxiety, and fatigue were similar in the two groups, suggesting that such factors were not responsible for the cognitive differences.

Late effects of adjuvant treatment on perceived health and quality of life in premenopausal and postmenopausal breast cancer patients, free from recurrence 2 to 10 years after primary therapy, were assessed through a survey by Berglund et al.1* Women were randomized to postoperative radiotherapy or adjuvant chemotherapy as adjuncts to primary surgery. The differences between the two treatments were generally small. However, the radiotherapy patients had significantly greater problems with decreased stamina, symptoms related to the operation scar and anxiety. The chemotherapy patients had significantly more problems with smell aversion. Activity level inside and outside the home, anxiousness, and depressive symptoms were similar in both groups.

In a review by Weineke and Dienst,” a study conducted by Van Dam et al of the Netherlands Cancer Institute in Amsterdam had examined whether receiving standard or high-dose chemotherapy had more of an effect or the same effect on memory and concentration. These women were at high risk for recurrence because they had cancer in 4 or more lymph nodes and they were examined 2 years after receiving chemotherapy. There were 3 groups: one received standard dose, another high dose, and another served as a control. They were all randomly assigned and interviewed about depression, anxiety, and their quality of life prior to the study. Investigators found that the higher dose increased the likelihood of memory and concentration problems and cognitive impairment was prevalent among 32% of the women given the high dose.7 Cognitive impairment was found among 17% of those treated with a standard dose and 9% within the control group. The results of this study make it evident that cognitive function can be linked with chemotherapy. Additionally, studies that have used standardized neuropyschological assessments during or shortly after treatment (within 6 months) have documented cognitive dysfunction in 48% to 95% of patients undergoing high-dose and standard-dose chemotherapy.1′

Schagnen et al7 examined 2 groups of women with breast cancer in which one group of women had axillary lymph node involvement and the other group of women did not have axillary lymph node involvement. These women were then given chemotherapy versus no chemotherapy, respectively. They were examined 2 years after receiving chemotherapy. Cognitive impairment was observed in 28% of women in the first group and 12% of women in the second group. Women in first group consistently reported lower on outcome measures of the study, such as the cognitive and physical functioning subscales. There also was no relationship found between cognitive impairment and depression, anxiety, fatigue, or the amount of time since completion of adjuvant therapy. This finding was unique to this study, as it had separated out these factors that have been debated as to whether they predispose one to cognitive dysfunction or perhaps influence it. The studies listed above also have used a control group, which strengthens their evidence for cognitive dysfunction as a result of chemotherapy.

From this brief literature review, it appears that most of the studies of CRCD have included cross-sectional, posttreatment only designs.’1 Many have included control groups for age. gender, education, and psychological factors, but have not been randomized. However, perhaps the most glaring deficit in the literature is that no study has used baseline data to track individual neurocognitive changes across treatment phases after its completion.2 To better examine CRCD, changes need to be assessed over time in large-scale longitudinal RCT studies that include pre- and posttest assessments with control groups. This type of study would improve efficacy and monitor changes in cognitive function over time.

Chemotherapy-induced cognitive dysfunction has become a significant issue for breast cancer survivors (among other survivors), and is becoming a target for symptom management in the health care community/ Most health care professionals are familiar with the physical deficits that occur after chemotherapy, but few have been informed of the cognitive deficits. Early identification of cognitive dysfunction is critical because of the potential impact of this problem on the ability of women to maintain usual family, career, and community responsibilities.4 It is also important to be aware of risks, assessment, and management in order to discuss these issues with patients and caregivers. Concurrently, assessing an individual’s perceived level of cognitive dysfunction to determine how CRCD impacts their life will individualize a treatment protocol for each patient.

POTENTIAL STRATEGIES FOR IMPROVING COGNITION

Cognitive rehabilitation is a functionally oriented service of therapeutic activities directed to achieve functional changes. This is accomplished through reinforcement, strengthening, or reestablishing previously learned patterns of cognitive activity or mechanisms to compensate for impaired neurological systems.1″ Appropriate measurements of cognitive deficits are important to capture before embarking on a program. Table 1 provides a compilation of the assessment tools for quantifying cognitive abilities. Quantifying changes over time are an important aspect of determining the benefits of various strategies to improve CRCD.

Successful memory training and rehabilitation programs have been reported in patients with traumatic brain injury, stroke, encephalitis, and degenerative conditions.” Although there are studies that use various tools to measure CRCD (summarized in Table 2), there are currently no reports of cognitive rehabilitation approaches with CRCD patients in the literature. This is uncharted territory in the postchemotherapy rehabilitation realm, and demands research to establish a protocol that will address deficits through cognitive rehabilitation. There are important implications for designing strategic interventions, such as cognitive rehabilitation approaches or particular exercise protocols, which may be extremely beneficial treatment for those who currently suffer from CRCD.

A study by Hartman et al found that up to 3 years postprimary inpatient rehabilitation, the health-related quality of life was noticeably reduced in breast cancer patients. The researchers found that by an intensive therapy with psychooncologic measures and activating physiotherapy, the quality of life was improved, yet it was not concluded whether this improvement would lead to a long-term effect.12 Many other approaches, such as erythropoietin therapy that has been shown to enhance QOL and cognitive function, are also currently being investigated to determine long-term effects.”

Complimentary alternative medicine is also being explored to determine if it may be able to affect psychological morbidity. These approaches consist of body awareness and movement, artwork, or spiritual exploration. Most conventional approaches have consisted of psychotherapy groups, ‘supportive-expressive’ groups, and cognitive behavioral techniques. Targ et al found evidence demonstrating an equivalence between traditional psychotherapy and complimentary alternative medicine on psychological outcome measures.14

This topic raises many research and clinical questions. What is the underlying mechanism by which chemotherapy affects the brain? What is the etiology of CRCD? Is there a certain time frame for neurological healing after chemotherapy or can the cognitive deficits be addressed immediately? How effective are cognitive rehabilitation approaches for postchemotherapy patients? What are the best tools to measure cognitive dysfunction in the rehabilitation setting? What are potential nonpharmacological treatments for cognitive dysfunction? Could a specified exercise program be the solution to some of the neurological deficits this population faces? What impact, for example, will yoga, tai chi, or other alternative treatments have on concentration and cognition? These questions, as well as many others, need to be addressed in the future of the investigation of chemotherapy-related cognitive deficits.

As more evidence becomes available, it is essential that women surviving breast cancer have cognitive assessments and potential treatment included into their rehabilitation. The CRCD is an area in oncology rehabilitation that requires clinical trials to ascertain the epidemiology and impact on daily activities. Future research will offer much hope and promise in addressing an individual’s quality of life throughout treatment for breast cancer.

REFERENCES

1. Paraska KK, Bender CM. Cognitive dysfunction following adjuvant chemotherapy for breast cancer: two case studies. Oncol Nurs Forum. 2003;30:3, 473-478.

2. Freeman JR, Broshek DK. Assessing cognitive dysfunction in breast cancer: what are the tools? Clin Breast Cancer. 2002; 3:S91-S99.

3. President’s Cancer Panel. Cancer issues in the United States: quality of care, quality of life. NCI. 1999.

4. Bender CM. Paraska KK. Cognitive function and reproductive hormones in adjuvant therapy for breast cancer: a critical review. J Pain Symptom Manage. 2001;21(5):407-424.

5. Harvard Women’s Health Watch. Cognitive problems after chemotherapy for breast cancer. 2002; 10:2, 5-7.

6. Weineke MH, Dienst ER. Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psycho-Oncology. 1995;4:1457-1462.

7. Schagnen SB, Van Dam FS. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer. 1999:85:640-650.

8. Barton D, Loprinzi C. Novel approaches to preventing chemotherapy- induced cognitive dysfunction in breast cancer: the art of the possible. Clin Breast Cancer. 2002;3: S121-S127.

9. Ahles TA, Saykin HA. Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer. 2002;3:S84-S90.

17. Rugo HS. Ahles T. The impact of adjuvant therapy for breast cancer on cognitive function: current evidence and directions for research. Semin Oncol. 2003;30(6):749-762.

18. Berglund G, Bolund C, Fornander T, Rutqvist LE, Sjoden PO. Late effects of adjuvant chemotherapy and postoperative radiotherapy on quality of life among breast cancer patients. Eur J Cancer. 1991;27(9): 1075-1081.

bulletMary Lou Galantino, PT, MS, PhD; Allison Henderson, SPT; Jacqueline Michaels, SPT Physical Therapy Program, Richard Stockton College of New Jersey, Pomona, NJ