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Assessment of Cognitive Function in Patients Receiving Adjuvant Endocrine Therapy
research
brief
in
Assessment of Cognitive Function in Patients Receiving Adjuvant Endocrine Therapy Rationale
• Cognitive dysfunction is a general term that refers to a number of neuropsychologic impairments including impaired verbal and short-term memory, decreased verbal fluency, impaired manual dexterity, and decreased ability to concentrate. It is currently estimated that approximately one third of patients who undergo adjuvant chemotherapy for breast cancer experience some degree of cognitive dysfunction. • There are several factors that can influence cognitive function in patients with cancer. In patients with central nervous system involvement, the tumor itself can impair cognitive development. Moreover, psychologic factors such as anxiety and depression can often result in impaired performance on neuropsychologic tests. Anemia caused by the cancer itself or treatment can significantly influence mental status, not only in patients with cancer, but also in those with chronic renal insufficiency and vascular dementia.1 Moreover, anemia can exacerbate fatigue, which can also impair function. In addition to its effects on red blood cell precursors, erythropoietin has also been shown to prevent apoptosis of neurons subjected to ischemic insult in preclinical models. In a study by O’Shaughnessy et al, patients with breast cancer who are treated with epoetin alfa had significantly higher (P < 0.001) hemoglobin levels compared with placebo-treated patients during adjuvant chemotherapy, and this was accompanied by superior executive function control during chemotherapy as demonstrated by Executive Interview scores.2 • Bioavailable estrogen levels have been shown to relate to better verbal memory and less cognitive decline.3,4 However, in the Women’s Health Initiative, hormone replacement therapy was associated with cognitive decline and increased dementia.5,6 Prepared by: Heather DeGrendele, PhD Reviewed by: Joyce A. O’Shaughnessy, MD
• More than 200,000 women in the United States are diagnosed with breast cancer annually, and the current 5-year survival rate is 86%.7 Some of the improvement in breast cancer survival rates has resulted from adjuvant chemotherapy. Therefore, it is important to better understand whether this treatment causes cognitive dysfunction in women who are expected to be cured of breast cancer. At this time, chemotherapy-related cognitive dysfunction is poorly understood. To date, 5 published studies in patients with earlystage breast cancer have evaluated cognitive function during and after adjuvant chemotherapy using standard neuropsychologic evaluation tests. In each of these studies, < 50 patients treated with chemotherapy were evaluated, and cognitive function was not assessed before initiation of chemotherapy.8-12 The preliminary data from these studies demonstrate that acute and persistent cognitive dysfunction occurs in patients with chemotherapy-treated breast cancer, and that 15%-30% of women show evidence of cognitive dysfunction 2-10 years after completion of chemotherapy. • These early data and the possible impact of cognitive dysfunction on the long-term well being of breast cancer survivors provide the rationale for developing novel objective means of assessing cognitive changes caused by chemotherapy as well as prospective controlled studies with longitudinal follow-up. Recent studies by groups headed by Silverman and Shilling have used novel methodologies to assess cognitive function in patients who had undergone adjuvant chemotherapy or were receiving adjuvant hormonal therapy.13,14
The Use of PET Imaging in Assessing the Pathophysiology of Cognitive Dysfunction
Silverman and colleagues conducted a trial using positron emission tomography (PET) imaging to determine whether adjuvant chemotherapy was associated with
regional brain activity changes in breast cancer survivors.13 In addition, correlation between [18F]fluorodeoxyglucose (FDG) uptake and neuropsychologic testing was examined.
Study Design In order to assess regional brain activity, activation PET data were collected immediately after intravenous (I.V.) administration of 15 mCi oxygen-15–labeled water. During the PET scan, the patient was asked to perform a series of cognitive tasks, including short-term and long-term memory recall tasks. Regional cerebral activity was assessed in 42 separate brain regions in all scans. Metabolic PET data were collected 45 minutes after I.V. injection of 5 mCi FDG to detect any chemotherapy-related changes in brain metabolism.
Patient Characteristics A total of 28 patients underwent neuropsychologic testing and PET imaging, including a normal FDG-PET reference group of 10 patients. Among the other patients analyzed, 11 had received adjuvant chemotherapy for breast cancer, 6 with tamoxifen. A control population of 7 patients who had not received chemotherapy, 4 of whom had breast cancer, was also assessed.
Results In patients with breast cancer who have undergone adjuvant chemotherapy, a significant decrease in resting metabolism to 9% below the normal mean was observed in the frontal cortex, including the superior frontal gyrus and Broca’s area, along with its contralateral counterpart (P < 0.001; Table 1). Of note, these areas play a critical role in language as well as higher aspects of motor control, the planning and execution of behavior, and other tasks that require the integration of information over time. Patients treated with tamoxifen plus chemotherapy demonstrated significantly decreased FDG metabolism in the lentiform nucleus, compared with a normal reference group (P < 0.001) and patients treated with chemotherapy
Clinical Breast Cancer October 2003 • 241
research in
brief
Table 1. Metabolic and Regional Brain Activity Changes in Patients Undergoing Chemotherapy Brain Region
Decrease in Activity Compared with Control Group
Patient Characteristics
P Value
FDG Metabolism FDG Metabolism Superior frontal gyrus
–9%
< 0.001
Broca’s area
–9%
< 0.001
Broca’s area
NR
< 0.05
Right inferior lateral temporal lobe
NR
< 0.001
NR
0.25
–10.5%
< 0.001
Regional Brain Activity
Lentiform nucleus Chemotherapy only Chemotherapy + tamoxifen
Abbreviations: FDG = [18F]fluorodeoxyglucose; NR = not reported
alone (P < 0.001). Alterations in activity were observed in the Broca’s area in chemotherapy-treated patients during the performance of a short-term visual memory recall task, and this decrease correlated with short-term recall performance (P < 0.05). A decrease in activity in the right inferior lateral temporal lobe was also seen in patients treated with chemotherapy, which also correlated with short-term recall performance (P < 0.001). It was suggested that PET brain imaging may be used in the future to assess basilic metabolic function and to monitor metabolic changes following chemotherapy, similar to the use of cardiac multiple gated acquisition scans to monitor anthracycline cardiac toxicity.
Effect of Adjuvant Hormonal Therapy on Cognition: Preliminary Analysis from the ATAC Trial
Because of its antiestrogenic effects, it has been hypothesized that tamoxifen therapy may contribute to cognitive changes observed in some patients with breast cancer.15 However, data from several trials have found no differences in cognitive function between women treated with tamoxifen and untreated women.9,11,16 With the goal of
242 • Clinical Breast Cancer October 2003
developing a standardized battery of tests to evaluate cognition in a large, randomized trial, Shilling and colleagues conducted a pilot study of the effects of anastrozole and tamoxifen on cognition in postmenopausal patients with cancer.14
Study Design Women enrolled in the Arimidex® (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial, as well as a nonrandomized control group of postmenopausal women without breast cancer, were evaluated to assess the sensitivity, acceptability, and suitability of a battery of cognitive tests. Patients enrolled on the ATAC trial were randomized to receive tamoxifen 20 mg/day, anastrozole 1 mg/day, or a combination of the 2 agents for 5 years. Cognitive assessments included tests for verbal memory (story recall, both immediate and delayed), visual memory (face recognition, both immediate and delayed), working memory (including spatial span, sequencing, and digit span), intelligence quotient (IQ; National Adult Reading Test), and processing speed (Kendrick digit copying task). Self-reported tests included the General Health Questionnaire 12, the Broadbent Cognitive Failures Question-naire, and the Functional Assessment of Cancer Therapy–Endocrine subscale.
A total of 94 patients enrolled on the ATAC trial and 35 control patients, with median ages of 62 and 60 years, respectively, underwent cognitive function testing.14 Median patient IQs were 113 and 117 for the treated and control groups, respectively. Approximately half of the patients in the ATAC group (49%) had previously received hormone replacement therapy, compared with 60% of control patients.
Results Using these assessment tools, no significant differences were observed in visual or working memory between patients receiving hormonal therapy and the control group. A significant impairment in mean processing speed (P = 0.032) was seen in the hormonal therapy group compared with the control group according to the investigator (Table 2). Additionally, immediate verbal recall was significantly impaired in patients receiving hormonal therapy (P = 0.026); however, no significant difference in delayed verbal recall was seen.
Conclusion
These 2 pilot studies support the hypothesis that adjuvant therapy can diminish cognitive function in breast cancer survivors. An important goal of future research will be to validate cognitive function assessment tools that are simple and practical enough for widespread use in large, randomized clinical trials. Large, prospective longitudinal studies using functional brain imaging methods and standardized cognitive assessment tools are needed to aid physicians in predicting which patients may be at risk for developing cognitive dysfunction, and to incorporate this information into the risk–benefit analysis for adjuvant breast cancer therapy. In the exploratory study reported by Shilling and colleagues, a battery of cognitive tests was found to be acceptable and suitable for use in patients with early-stage breast cancer in treatment trials. These neuropsychologic tests will be used in a cognition subprotocol of the IBIS II chemoprevention trial, an international multicenter study comparing the efficacy of anastrozole to placebo in postmenopausal women at increased risk of breast cancer. This cognitive subprotocol will en-
Table 2. Effects of Hormonal Therapy on Cognitive Assessment Test Results Patient Group
Control Group
P Value
Mean Processing Speed
69.26
63.17
0.032
Immediate Verbal Recall
12.04
13.80
0.026
Delayed Verbal Recall
9.69
10.57
NS
Abbreviation: NS = not significant
roll 350 women in each arm to assess cognitive function at baseline and after 6 months, 2 years, and 5 years of riskreduction therapy.
5.
References 1. O’Shaughnessy JA. Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clin Breast Cancer 2002; 3(suppl 3):S116-S120. 2. O’Shaughnessy J. Impact of epoetin alfa on cognitive function, asthenia, and quality of analysis of 6-month follow-up data. Breast Cancer Res Treat 2002; 76(suppl):S138 (Abstract #550). 3. Yaffe K, Sawaya G, Lieberburg I, et al. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998; 279:688-695. 4. Shaywitz SE, Shaywitz BA, Pugh KR, et al. Ef-
6.
7. 8.
fect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 1999; 281:1197-1202. Rapp SR, Espeland MA, Shumaker SA, et al, for the WHIMS Investigators. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289:2663-2672. Shumaker SA, Legault C, Rapp SR, et al, for the WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289:2651-2662. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003; 53:5-26. van Dam FS, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998;
90:210-218. 9. Schagen SB, van Dam FS, Muller MJ, et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85:640-650. 10. Brezden CB, Phillips KA, Abdolell M, et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000; 18:2695-2701. 11. Ahles TA, Saykin AJ, Furstenberg CT, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 2002; 20:485-493. 12. Wieneke M, Dienst E. Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psychooncology 1995; 4:61-66. 13. Silverman D. Use of functional brain imaging in assessing pathophysiology of cognitive dysfunction. Presented at: Second Annual Future of Breast Cancer: An International Breast Cancer Congress, Banff, Alberta, Canada; July 31-August 3. 14. Shilling V, Jenkins V, Fallowfield L, et al. Does hormone therapy affect cognition? Preliminary results from the ATAC trial & IBIS II design. Presented at: Second Annual Future of Breast Cancer: an International Breast Cancer Congress, Banff, Alberta, Canada; July 31-August 3. 15. Arpels JC. The female brain hypoestrogenic continuum from the premenstrual syndrome to menopause. A hypothesis and review of supporting data. J Reprod Med 1996; 41:633639. 16. Paganini EP. Continuous renal prosthetic therapy in acute renal failure: an overview. Pediatr Clin North Am 1987; 34:165-185.
Clinical Breast Cancer October 2003 • 243
brief
in
Assessment of Cognitive Function in Patients Receiving Adjuvant Endocrine Therapy Rationale
• Cognitive dysfunction is a general term that refers to a number of neuropsychologic impairments including impaired verbal and short-term memory, decreased verbal fluency, impaired manual dexterity, and decreased ability to concentrate. It is currently estimated that approximately one third of patients who undergo adjuvant chemotherapy for breast cancer experience some degree of cognitive dysfunction. • There are several factors that can influence cognitive function in patients with cancer. In patients with central nervous system involvement, the tumor itself can impair cognitive development. Moreover, psychologic factors such as anxiety and depression can often result in impaired performance on neuropsychologic tests. Anemia caused by the cancer itself or treatment can significantly influence mental status, not only in patients with cancer, but also in those with chronic renal insufficiency and vascular dementia.1 Moreover, anemia can exacerbate fatigue, which can also impair function. In addition to its effects on red blood cell precursors, erythropoietin has also been shown to prevent apoptosis of neurons subjected to ischemic insult in preclinical models. In a study by O’Shaughnessy et al, patients with breast cancer who are treated with epoetin alfa had significantly higher (P < 0.001) hemoglobin levels compared with placebo-treated patients during adjuvant chemotherapy, and this was accompanied by superior executive function control during chemotherapy as demonstrated by Executive Interview scores.2 • Bioavailable estrogen levels have been shown to relate to better verbal memory and less cognitive decline.3,4 However, in the Women’s Health Initiative, hormone replacement therapy was associated with cognitive decline and increased dementia.5,6 Prepared by: Heather DeGrendele, PhD Reviewed by: Joyce A. O’Shaughnessy, MD
• More than 200,000 women in the United States are diagnosed with breast cancer annually, and the current 5-year survival rate is 86%.7 Some of the improvement in breast cancer survival rates has resulted from adjuvant chemotherapy. Therefore, it is important to better understand whether this treatment causes cognitive dysfunction in women who are expected to be cured of breast cancer. At this time, chemotherapy-related cognitive dysfunction is poorly understood. To date, 5 published studies in patients with earlystage breast cancer have evaluated cognitive function during and after adjuvant chemotherapy using standard neuropsychologic evaluation tests. In each of these studies, < 50 patients treated with chemotherapy were evaluated, and cognitive function was not assessed before initiation of chemotherapy.8-12 The preliminary data from these studies demonstrate that acute and persistent cognitive dysfunction occurs in patients with chemotherapy-treated breast cancer, and that 15%-30% of women show evidence of cognitive dysfunction 2-10 years after completion of chemotherapy. • These early data and the possible impact of cognitive dysfunction on the long-term well being of breast cancer survivors provide the rationale for developing novel objective means of assessing cognitive changes caused by chemotherapy as well as prospective controlled studies with longitudinal follow-up. Recent studies by groups headed by Silverman and Shilling have used novel methodologies to assess cognitive function in patients who had undergone adjuvant chemotherapy or were receiving adjuvant hormonal therapy.13,14
The Use of PET Imaging in Assessing the Pathophysiology of Cognitive Dysfunction
Silverman and colleagues conducted a trial using positron emission tomography (PET) imaging to determine whether adjuvant chemotherapy was associated with
regional brain activity changes in breast cancer survivors.13 In addition, correlation between [18F]fluorodeoxyglucose (FDG) uptake and neuropsychologic testing was examined.
Study Design In order to assess regional brain activity, activation PET data were collected immediately after intravenous (I.V.) administration of 15 mCi oxygen-15–labeled water. During the PET scan, the patient was asked to perform a series of cognitive tasks, including short-term and long-term memory recall tasks. Regional cerebral activity was assessed in 42 separate brain regions in all scans. Metabolic PET data were collected 45 minutes after I.V. injection of 5 mCi FDG to detect any chemotherapy-related changes in brain metabolism.
Patient Characteristics A total of 28 patients underwent neuropsychologic testing and PET imaging, including a normal FDG-PET reference group of 10 patients. Among the other patients analyzed, 11 had received adjuvant chemotherapy for breast cancer, 6 with tamoxifen. A control population of 7 patients who had not received chemotherapy, 4 of whom had breast cancer, was also assessed.
Results In patients with breast cancer who have undergone adjuvant chemotherapy, a significant decrease in resting metabolism to 9% below the normal mean was observed in the frontal cortex, including the superior frontal gyrus and Broca’s area, along with its contralateral counterpart (P < 0.001; Table 1). Of note, these areas play a critical role in language as well as higher aspects of motor control, the planning and execution of behavior, and other tasks that require the integration of information over time. Patients treated with tamoxifen plus chemotherapy demonstrated significantly decreased FDG metabolism in the lentiform nucleus, compared with a normal reference group (P < 0.001) and patients treated with chemotherapy
Clinical Breast Cancer October 2003 • 241
research in
brief
Table 1. Metabolic and Regional Brain Activity Changes in Patients Undergoing Chemotherapy Brain Region
Decrease in Activity Compared with Control Group
Patient Characteristics
P Value
FDG Metabolism FDG Metabolism Superior frontal gyrus
–9%
< 0.001
Broca’s area
–9%
< 0.001
Broca’s area
NR
< 0.05
Right inferior lateral temporal lobe
NR
< 0.001
NR
0.25
–10.5%
< 0.001
Regional Brain Activity
Lentiform nucleus Chemotherapy only Chemotherapy + tamoxifen
Abbreviations: FDG = [18F]fluorodeoxyglucose; NR = not reported
alone (P < 0.001). Alterations in activity were observed in the Broca’s area in chemotherapy-treated patients during the performance of a short-term visual memory recall task, and this decrease correlated with short-term recall performance (P < 0.05). A decrease in activity in the right inferior lateral temporal lobe was also seen in patients treated with chemotherapy, which also correlated with short-term recall performance (P < 0.001). It was suggested that PET brain imaging may be used in the future to assess basilic metabolic function and to monitor metabolic changes following chemotherapy, similar to the use of cardiac multiple gated acquisition scans to monitor anthracycline cardiac toxicity.
Effect of Adjuvant Hormonal Therapy on Cognition: Preliminary Analysis from the ATAC Trial
Because of its antiestrogenic effects, it has been hypothesized that tamoxifen therapy may contribute to cognitive changes observed in some patients with breast cancer.15 However, data from several trials have found no differences in cognitive function between women treated with tamoxifen and untreated women.9,11,16 With the goal of
242 • Clinical Breast Cancer October 2003
developing a standardized battery of tests to evaluate cognition in a large, randomized trial, Shilling and colleagues conducted a pilot study of the effects of anastrozole and tamoxifen on cognition in postmenopausal patients with cancer.14
Study Design Women enrolled in the Arimidex® (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial, as well as a nonrandomized control group of postmenopausal women without breast cancer, were evaluated to assess the sensitivity, acceptability, and suitability of a battery of cognitive tests. Patients enrolled on the ATAC trial were randomized to receive tamoxifen 20 mg/day, anastrozole 1 mg/day, or a combination of the 2 agents for 5 years. Cognitive assessments included tests for verbal memory (story recall, both immediate and delayed), visual memory (face recognition, both immediate and delayed), working memory (including spatial span, sequencing, and digit span), intelligence quotient (IQ; National Adult Reading Test), and processing speed (Kendrick digit copying task). Self-reported tests included the General Health Questionnaire 12, the Broadbent Cognitive Failures Question-naire, and the Functional Assessment of Cancer Therapy–Endocrine subscale.
A total of 94 patients enrolled on the ATAC trial and 35 control patients, with median ages of 62 and 60 years, respectively, underwent cognitive function testing.14 Median patient IQs were 113 and 117 for the treated and control groups, respectively. Approximately half of the patients in the ATAC group (49%) had previously received hormone replacement therapy, compared with 60% of control patients.
Results Using these assessment tools, no significant differences were observed in visual or working memory between patients receiving hormonal therapy and the control group. A significant impairment in mean processing speed (P = 0.032) was seen in the hormonal therapy group compared with the control group according to the investigator (Table 2). Additionally, immediate verbal recall was significantly impaired in patients receiving hormonal therapy (P = 0.026); however, no significant difference in delayed verbal recall was seen.
Conclusion
These 2 pilot studies support the hypothesis that adjuvant therapy can diminish cognitive function in breast cancer survivors. An important goal of future research will be to validate cognitive function assessment tools that are simple and practical enough for widespread use in large, randomized clinical trials. Large, prospective longitudinal studies using functional brain imaging methods and standardized cognitive assessment tools are needed to aid physicians in predicting which patients may be at risk for developing cognitive dysfunction, and to incorporate this information into the risk–benefit analysis for adjuvant breast cancer therapy. In the exploratory study reported by Shilling and colleagues, a battery of cognitive tests was found to be acceptable and suitable for use in patients with early-stage breast cancer in treatment trials. These neuropsychologic tests will be used in a cognition subprotocol of the IBIS II chemoprevention trial, an international multicenter study comparing the efficacy of anastrozole to placebo in postmenopausal women at increased risk of breast cancer. This cognitive subprotocol will en-
Table 2. Effects of Hormonal Therapy on Cognitive Assessment Test Results Patient Group
Control Group
P Value
Mean Processing Speed
69.26
63.17
0.032
Immediate Verbal Recall
12.04
13.80
0.026
Delayed Verbal Recall
9.69
10.57
NS
Abbreviation: NS = not significant
roll 350 women in each arm to assess cognitive function at baseline and after 6 months, 2 years, and 5 years of riskreduction therapy.
5.
References 1. O’Shaughnessy JA. Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clin Breast Cancer 2002; 3(suppl 3):S116-S120. 2. O’Shaughnessy J. Impact of epoetin alfa on cognitive function, asthenia, and quality of analysis of 6-month follow-up data. Breast Cancer Res Treat 2002; 76(suppl):S138 (Abstract #550). 3. Yaffe K, Sawaya G, Lieberburg I, et al. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998; 279:688-695. 4. Shaywitz SE, Shaywitz BA, Pugh KR, et al. Ef-
6.
7. 8.
fect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 1999; 281:1197-1202. Rapp SR, Espeland MA, Shumaker SA, et al, for the WHIMS Investigators. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289:2663-2672. Shumaker SA, Legault C, Rapp SR, et al, for the WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289:2651-2662. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003; 53:5-26. van Dam FS, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998;
90:210-218. 9. Schagen SB, van Dam FS, Muller MJ, et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85:640-650. 10. Brezden CB, Phillips KA, Abdolell M, et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000; 18:2695-2701. 11. Ahles TA, Saykin AJ, Furstenberg CT, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 2002; 20:485-493. 12. Wieneke M, Dienst E. Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psychooncology 1995; 4:61-66. 13. Silverman D. Use of functional brain imaging in assessing pathophysiology of cognitive dysfunction. Presented at: Second Annual Future of Breast Cancer: An International Breast Cancer Congress, Banff, Alberta, Canada; July 31-August 3. 14. Shilling V, Jenkins V, Fallowfield L, et al. Does hormone therapy affect cognition? Preliminary results from the ATAC trial & IBIS II design. Presented at: Second Annual Future of Breast Cancer: an International Breast Cancer Congress, Banff, Alberta, Canada; July 31-August 3. 15. Arpels JC. The female brain hypoestrogenic continuum from the premenstrual syndrome to menopause. A hypothesis and review of supporting data. J Reprod Med 1996; 41:633639. 16. Paganini EP. Continuous renal prosthetic therapy in acute renal failure: an overview. Pediatr Clin North Am 1987; 34:165-185.
Clinical Breast Cancer October 2003 • 243