chemotherapy-induced cognitive dysfunction: a clearer picture

Clinical Breast Cancer Supplement November 2003 • S89Clinical Breast Cancer Supplement November 2003 • S89

Introduction Increasing evidence suggests that chemotherapy can cause cognitive deficits with regard to memory, concentration, and the ability to remain focused or organized in some adult can-cer survivors.1 Although these changes often are subtle, they can significantly affect patients’ quality of life (QOL). Many questions remain unanswered, including which subsets of pa-tients are most likely to be affected, which chemotherapeutic regimens or other treatment modalities are responsible for ob-served deficits, whether duration on chemotherapy is an impor-tant factor, and whether the effects of cognition are reversible. This article reviews data regarding the effect of adjuvant chemotherapy on cognitive function, the potential relationship between hemoglobin levels during chemotherapy and cognitive function, and the endogenous erythropoietin (EPO)-mediated neuroprotective system and the effects of treatment with re-combinant human EPO (epoetin alfa) on the development of cognitive dysfunction in patients undergoing chemotherapy.

Impact of Chemotherapy on Cognition in Pa-tients with Breast Cancer A number of prospective and observational studies have evaluated the effects of chemotherapy on cognition in patients with breast cancer1-4 (Table 1). van Dam et al assessed the

prevalence of cognitive deficits and the relationship between cognitive deficits and chemotherapy dose in women receiving adjuvant treatment for high-risk breast cancer.2 Two groups of patients with high-risk breast cancer (stages II and III) were randomly assigned to postsurgical treatment with either high-dose chemotherapy (n = 34; 4 cycles of 5-fluorouracil/ epirubicin/cyclophosphamide [FEC], followed by a fifth che-motherapy course of high-dose cyclophosphamide/thiotepa/ carboplatin [CTC]) or standard-dose chemotherapy (n = 36; 4 cycles of FEC only). Both groups of high-risk patients received local radiation therapy and tamoxifen for 2 years. A third group of patients (n = 34) with stage I breast cancer who were not treated with chemotherapy served as controls. The neuropsychological status of all patients was assessed by administering a standard battery of 13 neuropsychological tests covering a broad range of functions (eg, short-term and long-term memory, concentration and speed, psychomotor performance, visual-conceptual and visuomotor tracking, ca-pacity for sustained attention, motor speed, decision-making skills, perceptual-motor performance, accuracy of information processing and mental speed, and verbal ability), along with interviews regarding cognitive problems, health-related QOL (using the European Organization for Research and Treat-ment of Cancer Quality-of-Life Questionnaire [EORTC QLQ]-C30), anxiety, and depression. Because these tests were administered to the 3 separate patient populations only after treatment was received (or no treatment in the control group), baseline (prechemotherapy) cognitive assessment data were not available. Therefore, assessments of cognitive impairment

Chemotherapy-Induced Cognitive Dysfunction: A Clearer PictureJoyce A. O’Shaughnessy

Submitted: Oct 1, 2003; Revised: Oct 29, 2003; Accepted: Oct 30, 2003

Address for correspondence: Joyce A. O’Shaughnessy, MD, Baylor Sammons Cancer Center, US Oncology, 3535 Worth St, Collins Bldg, Fifth Floor, Dallas, TX 75246Fax: 214-370-1850; e-mail: joyce.o’[email protected]

Chemotherapy-associated cognitive dysfunction occurs in a subset of patients treated with adjuvant che-motherapy. Recent data suggest that development of chemotherapy-related anemia predisposes patients to cognitive dysfunction. Endogenous erythropoietin (EPO) is well recognized for its central role in erythropoiesis, and recombinant human EPO (epoetin alfa) is established as a safe and effective treatment for che-motherapy- related anemia. Treatment with epoetin alfa also improves health-related quality of life in anemic cancer patients undergoing chemotherapy, and several controlled studies have documented increases in quality-of-life scores correlated with increases in hemoglobin. Erythropoietin also plays a role in neuroprotection, presumably by activation of antiapoptotic genes. Erythropoietin and its receptor are expressed in neural cells of the human brain, and their expression is upregulated after hypoxic or ischemic injury. In ani-mal models, systemic administration of epoetin alfa protects against such neural injury. Ongoing and future studies will determine whether epoetin alfa can provide neuroprotection with respect to the development of cognitive dysfunction in patients undergoing adjuvant chemotherapy treatment for breast cancer.

Clinical Breast Cancer, Vol. 4, Suppl. 2, S89-S94, November 2003Key words: Anemia, Breast cancer, Epoetin-α, Erythropoietin, Neuroprotection, Quality of life

Abstract

Baylor Sammons Cancer Center, US Oncology, Dallas, TX

S90 • Clinical Breast Cancer Supplement November 2003

were made by patient questionnaires and by comparing the risk of cogni-tive impairment in patients who received cytotoxic therapy with the risk in those who did not (control group), given that the groups were statistically similar in age and pre-morbid intelligence. For all patients, the average time from completion of the last nonhormonal therapy was 2 years. No significant differences existed among the 3 groups with re-gard to age or premorbid intelligence. Cognitive impairment was found in 32%, 17%, and 9% of patients in the high-dose chemotherapy, stan-dard-dose chemotherapy, and con-trol groups, respectively (Table 1).2 The risk of cognitive impairment was significantly higher in patients who received high-dose chemotherapy compared with the risk in the control group (odds ratio [OR], 8.2; 95% CI, 1.8-37.7; P = 0.006). This risk also was elevated in the high-dose group versus the standard-dose group (OR, 3.5; 95% CI, 1.0-12.8; P = 0.056) and in the standard-dose group versus the control group (OR, 2.4; 95% CI, 0.5-11.5; P = 0.287), although these differences did not reach statistical significance.2 On the EORTC QLQ-C30 function scales, the mean scores of the patients who received high-dose chemotherapy were significantly lower (ie, worse function) than those of the control group on the physical function, role function, social function, and global QOL scales (P ≤0.004) and significantly lower than those of the low-dose chemotherapy group on the physical function, role function, cognitive function, and social function scales. Overall, the EORTC QLQ-C30 symptom scales were not significantly different among the 3 groups, except that patients in the high-dose chemotherapy group reported being more fatigued and more depressed than those in the control group (P ≤0.041). Pa-tients in the high-dose chemotherapy group had significantly higher scores on the depression subscale (ie, more depression) compared with the patients in the control group; patients in all 3 groups had comparable scores on the anxiety subscale. Therefore, high-dose chemotherapy seems to impair cognitive functioning more than standard-dose chemotherapy does, and central nervous system (CNS) toxicity might be a dose-limiting factor in high-dose chemotherapy regimens. Limitations of this study include a relatively small sample size, a cross- sectional rather than a longitudinal design, and a lack of control or stratification for differences in meno-pausal status and hormonal therapy. Schagen et al investigated cognitive deficits following

postoperative cyclophosphamide/methotrexate/5-fluorouracil (CMF) chemotherapy in patients with operable primary breast carcinoma and positive axillary lymph nodes (n = 39).3 The control group included 34 patients with node-negative breast cancer who received the same surgical and radiation therapy but no systemic adjuvant treatment. Patients receiving che-motherapy underwent 6 cycles of CMF, and 20 patients sub-sequently received tamoxifen for 3 years. As in the previous study, no baseline cognitive assessment data were available. Patients were interviewed about cognitive problems and the extent to which these problems occurred in their daily lives. To determine whether psychological stress played a role in cognitive problems, these patients also were given a battery of 14 neuropsychological tests that evaluated verbal function, memory, attention, concentration, mental speed, motor func-tion, visual-constructional function, and mental flexibility; a health-related QOL questionnaire; and a symptom checklist. At a mean follow-up of 2 years, patients who received chemotherapy reported significantly more problems with concentration (31% vs. 6%; P = 0.007) and with memory (21% vs. 3%; P = 0.022) than did patients in the control group.3 On the neuropsychological assessments, 28% of patients treated with chemotherapy had impaired cognitive function versus 12% of patients in the control group (OR, 6.4; 95% CI, 1.5-27.6; P = 0.013) (Table 1). Cognitive impairment, as

Study Odds Ratio

value(vs. control)

Treatment Regimen

Number of Patients

Cognitive Impairment

(% of Patients)

Prior systemic chemotherapy ( 5 years

after diagnosis)

Prior local therapy ( 5 years after diagnosis)

No chemotherapy (control)

Standard-dose FEC + tamoxifen‡

High-dose FEC/CTC + tamoxifen§

No chemotherapy

CMF||

Current FEC or CMF**

Completed chemotherapy**

Healthy controls/no chemotherapy

35/36*

35/22*

34

36

34

34

3931

40

36

39%

14%

9%†

17%†

32%†

12%¶

28%¶

48%

50%

11%

–

–

–

2.4

8.2

–

6.4

–

–

< 0.01

–

0.287

0.006

0.013

< 0.002

–

*Study included breast cancer and lymphoma patients: breast cancer (n)/lymphoma (n).†Cognitive impairment defined as 3/13 neuropsychological examinations at 2 SDs below mean of control group.‡5-Fluorouracil 500 mg/m2 I.V., epirubicin 90-120 mg/m2 I.V., and cyclophosphamide 500 mg/m2 I.V. for 4 or 5 cycles, followed by locoregional radiation therapy.§FEC as in standard group for 4 cycles, followed by cyclophosphamide 600 mg/m2 I.V., thiotepa 480 mg/m2, and carboplatin 1600 mg/m2.¶Cognitive impairment determined from overall impairment score based on a battery of 14 neuropsychological tests.||Cyclophosphamide 100 mg/m2 p.o. on days 1-14, methotrexate 40 mg/m2 I.V. on days 1 and 8, and 5-fluorouracil 600 mg/m2 I.V. on days 1 and 8.**The current FEC group received standard-dose adjuvant chemotherapy; the completed chemotherapy group received various regimens.Abbreviations: CMF = cyclophosphamide/methotrexate/5-fluorouracil; CTC = cyclophosphamide/thiotepa/ carboplatin; FEC = 5-fluorouracil/epirubicin/cyclophosphamide; SD = standard deviation

Chemotherapy-Induced Cognitive Dysfunction


assessed by neuropsychological testing after chemotherapy, was noted in a broad domain of functioning; was unaffected by anxiety, depression, fatigue, and time since treatment; and was not related to self-reported cognitive dysfunction. These results suggest that adjuvant chemotherapy for breast cancer is associated with a significantly increased risk of late cognitive impairment and that evaluation of cognitive functioning should involve both patient self-reporting and neuropsychological testing. In a follow-up study at 4 years after therapy, 31 of 39 pa-tients treated with CMF and 27 of 34 patients in the control group were reexamined, along with 22 of 34 patients treated with CTC and 23 of 36 patients treated with FEC.4 Improved performance was noted in all chemotherapy groups, whereas cognitive function was slightly diminished in the control group. Although this study was not randomized and had a small sample size, these results suggest that changes in cog-nitive function following adjuvant chemotherapy in patients with breast cancer are reversible in a subset of patients. Brezden et al compared cognitive function and mood states among 3 groups of women: patients with breast cancer receiv-ing standard-dose adjuvant chemotherapy (n = 31; FEC or CMF), patients with breast cancer who had completed adju-vant chemotherapy a median of 2 years earlier and had no evidence of recurrence (n = 40), and healthy control subjects (n = 36).5 Cognitive impairment was assessed using the High Sensitivity Cognitive Screen, a tool validated for testing 6 cognitive domains (ie, memory, language, visuomotor, spatial, attention/concentration, and self-regulation and planning). The Profile of Mood States test was administered to detect mood disturbances and to assess potentially fluctuating affec-tive states. Age, menopausal status, and education level were included as covariates in the statistical model. Overall cogni-tive function scores showed significantly lower function among patients undergoing adjuvant chemotherapy compared with controls (P = 0.009). These differences remained significant (P = 0.046) after controlling for age, education, and menopaus-al status. Significantly more patients had moderate or severe cognitive impairment in the group receiving chemotherapy (48%) and the group who had completed prior chemotherapy (50%) compared with the control group (11%) (P ≤0.002). Measures of mood states were not significantly differ-ent among groups, suggesting that observed differences in cog-nitive scores were not directly related to mood disturbances. Limitations of this study include a relatively small sample size, a cross-sectional rather than a longitudinal study design, and the use of healthy women without cancer as controls. A study recently published by Ahles et al focused on spe-cific cognitive domains affected by chemotherapy treatment.1 These authors investigated the neuropsychological impact of standard-dose chemotherapy in disease-free long-term survivors of breast cancer or lymphoma who were not receiv-ing cancer treatment (except tamoxifen) 5 years after their diagnosis and treatment. Patients had been treated either with systemic chemotherapy (n = 71) or with local therapy alone (n = 57). Of those who had received che-

motherapy, 85% received only 1 type of chemotherapy regimen, and the median number of chemotherapy cycles administered was 6. Patients completed a battery of standard-ized neuropsychological tests and self-reporting measures of cognitive and psychological function. Those who had received systemic chemotherapy scored significantly lower on neuro-psychological tests (P < 0.04), particularly in the domains of verbal memory (P < 0.01) and psychomotor functioning (P < 0.03), compared with those who had received local therapy only. Patients who received systemic treatment also were more likely to score in the lower quartile on the Neuropsychological Performance Index (P < 0.01) and to self-report greater problems with working memory (P < 0.02). A significant negative correlation was seen between the number of chemotherapy cycles and the mean of the neuropsychologi-cal domain scores. However, no significant association was ob-served between time since treatment and neuropsychological testing scores. These data suggest that a subgroup of patients receiving standard-dose chemotherapy might be expected to experience related long-term cognitive deficits. The authors commented that the observed deficits tended to be fairly subtle and concluded that the survival benefits of chemo-therapy outweigh the potential risks to cognitive functioning for most patients. Limitations of this study include the lack of pretreatment cognitive function assessment, a cross-sectional rather than a longitudinal design, and the lack of a formal as-sessment of the effects of menopause. Recently, Tannock et al assessed fatigue and cognitive changes in women who had completed > 3 courses of chemo-therapy for breast cancer compared with age-matched con-trols who were not receiving treatment for cancer.6 The most commonly administered chemotherapeutic regimen was FEC (66%). First-year results for 93 pairs of patients and control subjects revealed that patients experienced more fatigue than control subjects (P < 0.0001) and had higher rates of moder-ate-to-severe cognitive dysfunction (16% vs. 4%, respectively; P = 0.0001), which was independent of fatigue and meno-pausal symptoms.

Relationship Between Anemia and Cognitive Function The aforementioned studies indicate that cognitive dysfunc-tion occurs in a subset of patients treated with chemotherapy, although specific characteristics of that subset have not been clearly identified. Existing clinical evidence suggests a potential relationship between anemia and cognitive decline outside of the oncology setting. Beard et al reported an almost 2-fold increase in the occurrence of Alzheimers disease among elderly patients with anemia,7 and Milward et al reported a significant association between anemia and the development of vascular dementia in elderly subjects8; however, a causal relationship between anemia and these conditions has not been determined. There is increasing evidence in the oncology setting to sug-gest that patients who experience significant decreases in he-

Joyce A. O’Shaughnessy


moglobin levels during chemotherapy are at an increased risk of cognitive dysfunction. Jacobsen et al investigated the rela-tionship between decline in hemoglobin levels and cognitive functioning and fatigue during chemotherapy.9 In this trial, the most commonly administered chemotherapeutic agents were carboplatin (58% of the patients) and paclitaxel (53% of the patients). Thirty-nine patients completed self-reported measures of fatigue and cognitive problems and underwent cognitive function tests before the start of chemotherapy and following the third treatment cycle. The mean decline in hemoglobin levels after 3 chemotherapy cycles was 1.8 g/dL (range, 0.1-5.7 g/dL). Patients with greater declines in hemoglobin levels reported greater increases in fatigue that af-fected QOL (P = 0.05) and more cognitive problems (P = 0.02). In addition, declines in hemoglobin levels were associated with greater decreases in performance on measures of complex executive cognitive ability (P = 0.04). Although the data are preliminary, these studies suggest a potential relationship between chronic fatigue and cognitive dysfunction that might have relevance in the treatment of patients undergoing chemotherapy.

Erythropoietin: Hemoglobin and Central Ner-vous System Effects Erythropoietin is recognized for its central role in erythro-poiesis, and the efficacy and safety of epoetin alfa in treating chemotherapy-induced anemia is well established. A number of investigations have reported that treatment with epoetin alfa can improve the QOL in patients with cancer who are undergoing chemotherapy.10-14 In several large clinical trials, patients with chemotherapy-induced anemia treated with epo-etin alfa for 16-28 weeks experienced significant increases in hemoglobin levels (1.8-2.8 g/dL) and reductions in transfusion requirements.10-14 Quality of life scores, including increases in energy and activity, were significantly increased following epoetin alfa treatment. In several studies, improvements in QOL measures correlated with the magnitude of hemoglobin increase (Table 2).10-12,15

Erythropoietin and its receptor are recognized as primary mediators of the normal physiologic response to hypoxia in the periphery, and they also play a role in the CNS. Within

the CNS, EPO is inducible by hypoxia and other metabolic disturbances, and considerable evidence suggests that it also plays a role in neuroprotection by way of activation of the hypoxia- inducible factor-1 pathway.16 Erythropoietin might exert its erythropoietic, neuroprotective, and neurotrophic effects by way of activation of antiapoptotic genes, promoting survival and raising the threshold for apoptosis. Epoetin alfa has been shown to actively cross the blood-brain barrier16,17 and to exert important neuroprotective effects in preclinical animal models of stroke, trauma, status epilepticus, ischemic spinal cord injury, and subarachnoid hemorrhage.16,18-20

Brines et al demonstrated that the EPO receptor is abun-dantly expressed at brain capillaries and that systemically administered epoetin alfa can protect against experimental brain injury.16 Using a rodent model, these investigators showed that systemic administration of epoetin alfa (5000 U/kg body weight) before or up to 6 hours after focal brain ischemia reduced injury by 50%-75% (Figure 1). In addition, systemically administered epoetin alfa ameliorated the extent

Studies Increase in LASA Energy†

Increase in LASA Overall QOL†

Increase in LASA Activity†

Number of Evaluable

Patients

Dosing and Duration

Mean Increase in Hb (g/dL)*†

2019

2237

2869

1.8

2.0

1.8

43%

34%

32%

35%

34%

29%

26%

26%

23%

Abbreviations: Hb = hemoglobin; LASA = Linear Analogue Scale Assessment; QOL = quality of life; t.i.w. = three times weekly*From baseline to final measurement

0.001 vs. baseline

t.i.w. for 16 weeks

t.i.w. for 16 weeks

Once weekly for 16 weeks

P < 0.01P< 0.05

Adapted with permission from Brines ML, et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 2000; 97:10526-10531.

0

40

80

120

160

Saline(9)

-24 h (8)

0 h(9)

9 h(7)

6 h(8)

3 h(8)



of concussive brain injury, immune damage in experimental autoimmune encephalomyelitis, and the toxicity of kainate. Therefore, this study provided evidence that systemically administered epoetin alfa can exert neuroprotective effects in the CNS of rodents. Preliminary data in human brain tissue also suggest a neuroprotective role of EPO. Sirén et al expanded on studies of EPO and the EPO receptor in cell culture and in rodent neural injury models.21 These investigators used immunohis-tochemistry to compare the temporal and cellular patterns of EPO and EPO receptor expression in human brains that were neuropathologically normal with those that had isch-emic infarcts or general hypoxic damage. Specimens were obtained from routine autopsy cases that reflected normal controls and brains with fresh infarcts, older infarcts, or acute hypoxic damage due to cardiorespiratory problems. In normal brains, only weak EPO and EPO receptor immunoreactivity were found in neuronal regions. In tissue from fresh infarcts, strong expression of EPO immunoreactivity was seen in the vascular endothelium, while EPO receptor reactivity was found in microvessels and neuronal fibers. In tissue from older infarcts, immunoreactivity was expressed primar-ily in reactive astrocytes. These findings show that EPO and its receptor are expressed in neural cells of normal and ischemic/hypoxic human brain and further illustrate differen-tial temporal and cellular modulation of the neuroprotective EPO/EPO receptor system by hypoxia and ischemia in human brain. This pronounced upregulation of EPO and the EPO receptor in damaged brain tissues suggests that the molecule and its receptor play a part in an endogenous neuroprotective system. Various investigators have established the molecular path-way of EPO-mediated neuroprotection. Sirén et al demon-strated that EPO prevents neuronal apoptosis induced by kainate exposure or by oxygen, nutrient, or growth factor deprivation by way of activation of extracellular signal–regu-lated kinases and phosphatidylinositol 3-kinase.22 The results of these investigators suggest that inhibition of neuronal apoptosis underlies short-latency protective effects of EPO after brain injury. In addition, neurotrophic actions of EPO were demonstrated in mixed neuron/glia cells and purified motor neurons. The basal survival of these cells following EPO exposure was significantly better than that of controls, and cellular differentiation seemed to be better in EPO-exposed cells. The neurotrophic effects of EPO might offer long-term neuroprotection from acute injury. The mechanism by which EPO prevents the death of nerve cells following brain injury might involve cross-talk between 2 signaling pathways.23 The classic nuclear factor (NF)-κB pathway, induced by stress or inflammation, involves the acti-vation of the inhibitor of NF-κB, IκB, and the release of NF-κB, which upregulates the transcription of inhibitor-of-apoptosis proteins, including XIAP and c-IAP2.23,24 The other pathway, activated by hormones and growth or regulatory factors including EPO, targets the Stat family of transcription factors. On binding of EPO to its receptor, the enzyme Janus kinase-2

(Jak2) is activated, leading to recruitment of the transcription factor Stat5, which dimerizes and moves to the nucleus.23 It is postulated that cross-talk between these 2 pathways occurs in neurons, leading to activation of IκB kinases, as well as phosphorylation of IκBα. Therefore, the neuroprotective ef-fects of EPO are an expanding area of research that has some potentially provocative clinical implications. In a recent randomized double-blind study of 40 patients who had an ischemic middle cerebral artery stroke,25 epoetin alfa 33,333 U or placebo was administered intravenously with-in 8 hours after the onset of symptoms and 24 and 48 hours later (total of 3 doses). In patients who received epoetin alfa, cerebrospinal fluid levels of EPO increased to 60-100 times those of patients who received placebo. Results of serial mag-netic resonance imaging studies indicated a strong trend for reduction in infarct size in patients who received epoetin alfa therapy compared with those who received placebo, with the greatest differences observed at day 18. The levels of a serum marker of infarct damage, S100β, were similar in the 2 groups at baseline; however, by day 30, serum S100β levels of the epo-etin alfa group had normalized, whereas those of the placebo group remained elevated. In addition, epoetin alfa therapy was associated with an improved clinical outcome compared with placebo at day 30, as assessed by the Barthel Index (P < 0.05) and Modified Rankin Scale (P < 0.07). The results of this study are consistent with those observed in animal models of brain injury and provide the basis for further evaluation of epoetin alfa therapy in patients with ischemic stroke.

Effects of Epoetin Alfa on Cognitive Function in Breast Cancer: A Pilot Study The aforementioned in vitro and in vivo studies clearly suggest that epoetin alfa has clinical potential in provid-ing neuroprotection.21 To further investigate the effects of EPO as a neuroprotective agent, a pilot clinical study was conducted to evaluate the effects of once-weekly epoetin alfa therapy on cognitive function, asthenia, and QOL in patients with stage I-III breast cancer.26 Patients were receiving 4 cycles of anthracycline-based adjuvant or neoadjuvant chemotherapy for 3 months and were randomized to receive epoetin alfa (n = 47) or placebo (n = 47). Cognitive function was evaluated using the Executive Interview (EXIT 25), asthenia by the Functional Assessment of Cancer Thera-py–Anemia subscale, and QOL by the Linear Analogue Scale Assessment. Measurements were obtained at baseline, prior to cycle 4 of chemotherapy, and 6 months after the completion of chemotherapy. Preliminary data were reported at the 38th Annual Meeting of the American Society of Clinical Oncology in 2002 and in a previous supplement.27,28 Final results of the pilot study, including the 6-month follow-up data, are forthcoming, and a larger study is under way to further investigate the effects of epoetin alfa on cognitive function and the relationship between hemoglobin levels and cognition. The use of epoetin alfa to prevent chemotherapy-induced cogni-tive dysfunction is still under investigation and should only be

Joyce A. O’Shaughnessy


considered in the setting of a controlled clinical trial.

Conclusion Cognitive dysfunction develops in a subset of patients who undergo chemotherapy, although specific characteristics of that vulnerable subset have not been identified. Studies sug-gest that the neurotoxic effects of chemotherapy are exacer-bated by or associated with chemotherapy-induced anemia and that chronic fatigue seen after adjuvant chemotherapy is related to cognitive dysfunction. Epoetin alfa safely and effectively improves chemotherapy-induced anemia and might improve fatigue and QOL. Erythropoietin also might play a role as an endogenous neuroprotective agent that crosses the blood-brain barrier, and it has been hypothesized that epoetin alfa therapy might provide neuroprotection in patients under-going chemotherapy. Clinical studies are ongoing to determine the effects of epoetin alfa on cognitive function and QOL in patients with breast cancer who are undergoing adjuvant che-motherapy.

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standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 2002; 20:485-493.

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10. Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies dur-ing cancer chemotherapy in community oncology practice. J Clin Oncol 1997; 15:1218-1234.

11. Demetri GD, Kris M, Wade J, et al. Quality-of-life benefit in chemother-apy patients treated with epoetin alfa is independent of disease response

or tumor type: results from a prospective community oncology study. J Clin Oncol 1998; 16:3412-3425.

12. Gabrilove JL, Cleeland CS, Livingston RB, et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improve-ments in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001; 19:2875-2882.

13. Littlewood TJ, Bajetta E, Nortier JWR, et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, pla-cebo-controlled trial. J Clin Oncol 2001; 19:2865-2874.

14. Quirt I, Robeson C, Lau CY, et al. Epoetin alfa therapy increases hemo-globin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J Clin Oncol 2001; 19:4126-4134.

15. Demetri GD, Gabrilove JL, Blasi MV, et al. Benefits for epoetin alfa in anemic breast cancer patients receiving chemotherapy. Clin Breast Cancer 2002; 3:45-51.

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17. Xenocostas A, Cheung WK, Farrell FX, et al. Recombinant human eryth-ropoietin crosses the blood brain barrier: the pharmacokinetics of rhEPO in the cerebrospinal fluid after intravenous administration. Proc Am Soc Clin Oncol 2003; 22:230 (Abstract #922).

18. Buemi M, Cavallaro E, Floccari F, et al. Erythropoietin and the brain: from neurodevelopment to neuroprotection. Clin Sci 2002; 103:275-282.

19. Cerami A, Brines ML, Ghezzi P, et al. Effects of epoetin alfa on the central nervous system. Semin Oncol 2001; 28 (suppl 8):66-70.

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21. Sirén A-L, Knerlich F, Poser W, et al. Erythropoietin and erythropoi-etin receptor in human ischemic/hypoxic brain. Acta Neuropathol 2001; 101:271-276.

22. Sirén A-L, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 2001; 98:4044-4049.

23. Siebenlist U. Barriers come down. Nature 2001; 412:601-602.24. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection

involves cross-talk between Jak2 and NF-κB signaling cascades. Nature 2001; 412:641-647.

25. Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Molecular Med 2002; 8:495-505.

26. O’Shaughnessy J, Vukelja S, Savin M, et al. Impact of epoetin alfa on cog-nitive function, asthenia, and quality of life in women with breast cancer receiving adjuvant or neoadjuvant chemotherapy: analysis of 6-month follow-up data. Breast Cancer Res Treat 2002; 76 (suppl 1):S138 (Abstract #550).

27. 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.

28. O’Shaughnessy J, Vukelja S, Savin M, et al. Effects of epoetin alfa (Procrit®) on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant or neoadjuvant chemo-therapy: a double-blind, randomized, placebo-controlled trial. Proc Am Soc Clin Oncol 2002; 21:363a (Abstract #1449).


chemotherapy-induced cognitive dysfunction: a clearer picture

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