Cheung M, Chan AS, Law SC, Chan JH, Tse VK.
Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis.

Arch Neurol. 2000 Sep;57(9):1347-52.
PMID: 10987903 [PubMed – indexed for MEDLINE]

BACKGROUND: Radiotherapy is the primary treatment for nasopharyngeal carcinoma, and temporal lobe necrosis is observed in about 7% of patients after radiotherapy. Although some studies reported that these patients demonstrated cognitive impairment after radiotherapy, it is still unclear if the cognitive deficits are related to the radiation exposure or the radiation-induced necrosis. OBJECTIVE: To compare the cognitive function of patients with and without temporal lobe necrosis after radiotherapy for nasopharyngeal carcinoma. METHODS: A comprehensive neuropsychological battery was administered to 53 patients with nasopharyngeal carcinoma who had completed their radiotherapy at least 1 year previously. As evidenced by magnetic resonance imaging, 31 patients developed necrosis after treatment. Thirty-one age- and education-matched individuals were recruited as normal control subjects. RESULTS: Whereas the performance of patients without temporal lobe necrosis was similar to that of normal control subjects, patients with temporal lobe necrosis demonstrated significant impairment on tests of verbal (P<.001) and visual memory (range, P<.001 to P =.03), language (range, P<.001 to P =.01), motor ability (P =.02), planning (P =.02), cognitive ability (P =.007), and abstract thinking (range, P =.009 to P =.04). However, the performance of patients with necrosis on tests of general intelligence (range, P =.08 to P =.15), attention (range, P =.06 to P =.55), and visual abilities (range, P =.06 to P =.47) was not significantly different from that of normal control subjects and patients without necrosis. CONCLUSIONS: Radiotherapy for nasopharyngeal carcinoma seemed to have adverse but insignificant effects on the cognitive functions of the patients. However, for patients who developed temporal lobe necrosis after radiotherapy, memory, language, motor ability, and executive functions were significantly impaired, although their general intelligence remained relatively intact.

bulletDepartment of Psychology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China. aschan@psy.cuhk.edu.hk
Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF.
Cognitive function in breast cancer patients receiving adjuvant chemotherapy.

J Clin Oncol. 2000 Jul;18(14):2695-701.
PMID: 10894868 [PubMed – indexed for MEDLINE]

PURPOSE: Breast cancer patients receiving chemotherapy have complained of difficulties in their ability to remember, think, and concentrate. This study assessed whether there are differences in cognitive function between breast cancer patients treated with standard-dose adjuvant chemotherapy compared with healthy controls. PATIENTS AND METHODS: The High Sensitivity Cognitive Screen and the Profile of Mood States (POMS) were used to assess cognitive function and mood in a group of 107 women. The women consisted of 31 breast cancer patients receiving adjuvant chemotherapy (group A), 40 breast cancer patients who had completed adjuvant chemotherapy a median of 2 years earlier (group B), and 36 healthy controls (group C). RESULTS: Univariate analysis showed statistically significant differences (P =.009) in overall cognitive function scores between groups A and C, with poorer function in patients receiving adjuvant chemotherapy. These differences remained significant (P =.046) when controlling for age, education level, and menopausal status. More patients had moderate or severe cognitive impairment in groups A and B than in controls (P </=.002). There were no significant differences in POMS scores between the groups, suggesting that the differences seen in cognitive scores were unlikely to be because of mood disturbance. CONCLUSION: Cognitive differences were observed in breast cancer patients receiving adjuvant chemotherapy compared with healthy controls. These differences did not seem to be caused by significant differences in mood disturbance between the two groups. If confirmed, these results have substantial implications for informed consent, counseling, and psychosocial support of patients receiving adjuvant chemotherapy for breast cancer.

bulletDepartment of Medical Oncology and Hematology, Department of Biostatistics, Department of Psychosocial Oncology, Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
Meyers, CA.
Neurocognitive Dysfunction in Cancer Patients

Oncology. 2000 Jan;14(1)

Many cancer patients experience impairments of neurocognitive function, including memory loss, distractibility, difficulty in performing multiple tasks (multitasking), and a myriad of other symptoms. Patients may also concurrently suffer from mood disturbance and symptoms that compromise their ability to function adequately, including fatigue and pain. The etiologies of these problems are diverse and include the direct effects of cancer within the central nervous system (CNS), indirect effects of certain cancers (eg, paraneoplastic brain disorders), and both diffuse and highly specific effects of cancer treatments on the brain. In addition to these cancer-related causes, patients may have coexisting neurologic or psychiatric disorders that affect their cognition and mood. Careful assessment of patients complaining of neurocognitive or behavioral problems is essential to providing appropriate interventions and maximizing their ability to carry out usual activities. [ONCOLOGY 14(1):75-81, 2000]

Introduction

Cancer patients are vulnerable to neurocognitive dysfunction for a variety of reasons.[1] Impairment of brain function profoundly affects cognition, psychological well-being, and the ability to perform the usual activities of daily living. For example, many cancer patients experience the symptom of “forgetfulness.” Despite the fact that neurocognitive deficits limit patients’ productivity and independence, these problems are underreported by patients and underdiagnosed by health care professionals.

The differential diagnosis of memory dysfunction and other cognitive complaints in cancer patients is quite varied and, thus, multidisciplinary assessment is required. Assessment of the patient’s neurocognitive function, ability to perform daily activities, and quality of life is an indispensable first step toward prescribing appropriate interventions. Such an assessment also provides information for clinical treatment trials.

Direct Effects of Cancer

Primary brain tumors, metastatic brain tumors, and leptomeningeal metastases all directly alter brain functioning at the site of the tumor. Primary brain tumors are increasing in prevalence, and between 20% and 40% of patients with other types of solid tumors develop brain metastases. Thus, patients with primary or metastatic brain lesions constitute a large proportion of patients with primary brain dysfunction.

In addition to the direct effects of brain tumors on brain functioning, treatment of these tumors, particularly radiation therapy, affects subcortical white matter, causing a pattern of deficits similar to those seen in other subcortical diseases of white matter, such as multiple sclerosis and Parkinson’s disease.[2]

Indirect Effects of Cancer

Certain types of cancers indirectly cause brain dysfunction, resulting in paraneoplastic brain disorders. In addition to the florid presentation of limbic encephalitis in patients with small-cell lung cancer, a large proportion of these patients experience subclinical alterations in memory and frontal lobe executive function (ie, the ability to plan and execute activities) prior to the institution of any treatment.[3]

Antineuronal antibodies (particularly anti-Hu) have been found in 16% of patients with small-cell lung cancer in the absence of florid paraneoplastic neurologic disease.[4] However, subtle cognitive or neurologic dysfunction in small-cell lung cancer patients has not yet been correlated with low-titer antibody responses.

More recently, it has been discovered that patients who have testicular cancer may also be at risk for developing autoimmune paraneoplastic encephalitis.[5]

Proinflammatory cytokines have profound effects on brain function and are known to cause cognitive and mood dysfunction. Interleukin-1 (IL-1) is elevated in patients with certain leukemias.[6] Other elevated cytokines in acute leukemia include interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), both of which are implicated in neurodegenerative diseases.[7,8] It has not yet been determined whether patients with acute leukemia or myelodysplastic syndrome have neurocognitive impairments related to their disease, but clinical trials to ascertain this are being conducted.

Effects of Cancer Treatment

Standard- and high-dose chemotherapy, immunotherapy, novel agents, and hormonal treatments all have potential neurotoxic side effects. Cognitive impairments due to treatment effects have been distinguished from mood disturbances in the clinical trials that have assessed both.[9-13]

Chemotherapy

It is estimated that 18% of cancer patients who have received standard-dose chemotherapy manifest cognitive deficits on post-treatment neuropsychological testing.[14] A recent study assessed the neurocognitive function of women randomized to standard- or high-dose chemotherapy with stem-cell rescue for breast cancer.[9] This study found that 32% of women had cognitive impairments following high-dose adjuvant chemotherapy, compared to 17% of women who received standard doses. These impairments were observed 2 years after treatment was completed.

Although most impairments related to chemotherapy are relatively diffuse and have an impact on tests that require sustained attention and speed of information-processing, some agents have more circumscribed effects on the brain due to their mechanisms of action. For instance, CI-980, a mitotic inhibitor that binds to the colchicine receptor on tubulin, causes a highly specific decline in memory functioning.[11]

Immunotherapy

Immunotherapy also can have profound effects on brain function. In fact, more than half of patients receiving cytokine treatment have documented cognitive impairments.[14]

Cancer patients receiving treatment with such cytokines as interferon-alfa (Intron A, Roferon-A) frequently develop impairments of memory, motor, executive functions, and mood that are suggestive of frontal-subcortical dysfunction.[10] The degree of impairment is related to both dose and length of treatment. Although the symptoms generally improve with a reduction in dose or the cessation of interferon treatment, in some patients, the impairments persist for years.[15,16]

Hormonal Therapy

There is a burgeoning literature on the effects of sex hormones on cognitive functioning. Serum testosterone may be related to spatial ability.[17,18] Women with gynecologic problems who are receiving gonadotropin-releasing hormone agonists that inhibit both tes-tosterone and estrogen release have reported declines in memory functioning and mood.[19,20] These deficits appear to be reversed with estrogen replacement.[21,22]

Thus, hormone ablation therapy for breast and prostate cancers may have deleterious neurocognitive effects. However, formal prospective trials to test this hypothesis have not yet been completed.

Adjuvant Medications

In addition to the neurotoxic effects of primary cancer therapy, adjuvant medications may also cause neurocognitive symptoms, complicating the assessment of patients who receiving multiple medications. Drugs with cognitive and mood effects include steroids, immunosuppressive agents, pain medications, psychotropic medications, and antiemetics.

Coexisting Neurologic Conditions

The elderly comprise the largest percentage of cancer patients. Patients in older age groups not only are at increased risk for developing cancer but also are more vulnerable to age-related neurocognitive disorders unrelated to but coexisting with cancer, such as cerebrovascular disease and Alzheimer’s type dementia.

In addition, cancer patients of any age may have a history of traumatic brain injury, developmental disorder, multiple sclerosis, or other conditions or diseases that affect cognitive functioning. These patients may be more vulnerable to developing neurotoxic side effects from cancer and its treatment and need to be monitored closely.

Sensory Impairment

Elderly patients may have difficulties with hearing or sight, or suffer from general frailty. In addition, many cancer patients, irrespective of age, experience ototoxicity and other sensory problems from chemotherapy.[23] These sensory deficits reduce the amount of information patients are able to process and may lead to complaints of memory dysfunction. Some patients even manifest psychiatric difficulties, such as paranoia, because a relative sensory deprivation impedes their ability to perceive and/or understand what is going on around them.

Functional and Psychiatric Disorders

Stress, anxiety, depression, and other mood disorders can represent acute reactions to the patient’s current situation or can predate the cancer diagnosis. In either case, mood and adjustment disorders negatively affect patients’ ability to focus, concentrate, and organize activities, leading to complaints of forgetfulness and other cognitive problems.

Cancer patients are just as likely as the general population to suffer from major psychiatric disorders, such as bipolar illness, major depression, schizophrenia, and personality disorders. These disorders also have associated cognitive symptoms if they are not well controlled with psychiatric management.

Although rare, there do exist patients with certain psychiatric disorders who may present for cancer treatment without an actual cancer diagnosis. Patients with somatoform disorders may fear that they have cancer or misinterpret other physical symptoms as being due to a malignancy.

Even less common are the factitious disorders. Over 15 years, our group has evaluated three individuals with Munchausen’s syndrome who intentionally feigned or induced symptoms to support a diagnosis of cancer.

Fatigue, Pain, and Anemia

Fatigue is extraordinarily common in cancer patients. The causes of fatigue are myriad and overlap considerably with the etiologies of cognitive disorders (Table 1).[24] Fatigue may be physical, in that the person has very little stamina or energy to perform usual activities.

Fatigue also can be mental. Similar to patients with cognitive dysfunction, patients who suffer from mental fatigue often report that they are easily overwhelmed, have difficulty being organized and efficient in their daily activities, and have problems meeting deadlines or getting tasks done on time. Activities that used to be automatic now require more effort, so that patients become exhausted even when performing routine tasks.

A similar situation exists for patients who experience pain.[25] Patients in pain also suffer from deficits in attention and concentration, multitasking, and speed and efficiency of thinking. They also may be receiving medications that are sedating and contribute to cognitive problems, and are likely to be suffering from fatigue as well.

Anemia is very common in cancer patients undergoing active treatment. Cognitive deficits have been reported in well-dialyzed patients with end-stage renal disease who are anemic but do not have uremia.[26,27]

Cognitive deficits are also exhibited by patients who have anemia due to iron deficiency.[28-30] The cognitive problems observed on neuropsychological testing include deficits in attention, perceptual-motor speed, memory, and verbal fluency; these cognitive deficits are accompanied by slowed auditory evoked potentials.[31-33] The cognitive deficits and slowed evoked potentials often improve following reversal of anemia with erythropoietin (Epogen, Procrit).[34]

Metabolic Disturbances and Other Medical Complications

Alterations of thyroid functioning are common in cancer patients, and can be associated with cognitive and mood disorders. In addition, cancer patients are at risk for all types of infections, which may result in significant cognitive problems or even delirium.[35] Hepatic and renal dysfunction also can cause cognitive problems in acutely ill patients.

In patients with metabolic disturbances or other medical complications, treatment of the underlying disease will often result in resolution of the cognitive problems as well. However, we have evaluated several patients who developed viral encephalitis following bone marrow transplantation who had permanent amnesia following their recovery from acute infection, suggesting that there may be permanent sequelae to infections that are within the central nervous system (CNS).

Evaluating Cognitive Dysfunction

Determining the specific cause(s) of cognitive dysfunction is critically important to guide interventions, as the type of intervention that is most helpful will differ dramatically, depending on the etiology. The specific intervention plan not only needs to take into account the underlying cause of the complaint but also must be individualized, as the impact of a cognitive problem will vary in different people.

Determining the Impact of Dysfunction

A practical system to evaluate the impact of neurocognitive dysfunction in cancer patients was developed by the World Health Organization. This system classifies the impact of an illness with respect to three domains: impairment, disability, and handicap.[36] All three levels of function (deficit, disability, handicap) need to be assessed for appropriate management of the patient.

Impairment is the deficit in function. In the case of neurocognitive symptoms, the deficit occurs in brain functioning, and is manifested by neurologic, cognitive, and emotional changes. Formal assessment of neurocognitive function can help determine the etiology of the complaints, ascertain the profile of the cognitive changes, and help institute appropriate intervention strategies.

Disability is the impact of the deficit on the patient’s ability to perform usual work and home activities. The degree of disability for an individual patient will be related, at least in part, to age, the type of work performed, and the amount of support that is available. Performance and functional status measures may help define the disability and determine the need for more comprehensive assessments.

Handicap is the impact of the disability on the person’s overall satisfaction and well-being. Handicap is generally what is meant in discussions of quality of life and is often assessed by quality-of-life questionnaires.[27]

Again, what constitutes a handicap varies greatly from individual to individual. One person can be handicapped by a relatively minor disability, whereas another individual suffering from a severe impairment may experience little handicap.

For example, an impairment in multitasking caused by a difficulty with sustained attention is a common problem for cancer patients. This may not be particularly troublesome to a person who is self-employed and can work at his or her own pace at home. However, it might cause a secretary in a busy office, who needs to answer the phone while word-processing, to be fired.

Many patients have difficulty resuming their normal activities following the diagnosis and treatment of cancer. Unfortunately, neurobehavioral functioning often receives the least attention in a medical evaluation unless the patient exhibits very severe behavioral changes. Multidisciplinary assessment of neurocognitive complaints can maximize the patient’s ability to function at the highest level of independence and productivity for the longest period of time.

As cancer treatment becomes more successful, increasing numbers of patients will live longer and will expect to return to their preillness level of functioning. Thus, the risks of treatment and their impact on the patient’s ability to perform daily activities must be addressed more comprehensively.

Intervention Strategies

Many intervention strategies are available to manage neurocognitive complaints. These include pharmacologic management, behavioral strategies, lifestyle alterations, formal rehabilitation, and counseling.

Pharmacologic Strategies

Fatigue and neurobehavioral slowing are ubiquitous in cancer patients. Treatment with stimulants can be very useful in alleviating concentration difficulties, psychomotor slowing, and

fatigue and can also help elevate mood.[12,37] When mood disturbance, pain, or fatigue are affecting patients’ cognitive and neurologic functioning, aggressive treatment of these symptoms also has the potential to improve neurocognitive functioning.

Physical, Occupational, and Speech Therapy

Physical and occupational therapy can be of tremendous benefit in patients who have developed weakness, generalized deconditioning, sensory neuropathy, or other nerve or musculoskeletal impairments from cancer and its treatment. Both of these modalities can improve mobility and general physical stamina.

In patients who have developed impairments of upper extremity function due to peripheral neuropathy from systemic therapy or focal radiation or from central lesions of the spinal cord or brain, occupational therapy may help improve function.[38] Patients who have developed difficulties with swallowing, articulation, or even primary language problems may benefit from speech therapy.

Cognitive and Vocational Rehabilitation

If given the appropriate type of support, many cancer patients who experience neurocognitive impairments can improve their function at home and in vocational and leisure pursuits and enjoy an improved level of independence and quality of life. Since cancer patients generally have fairly mild, limited cognitive problems, they tend to respond very well to focused rehabilitation efforts.

Cognitive rehabilitation is designed to improve independence level, while vocational rehabilitation is designed to improve productivity, which may include volunteer work, performing household activities, going back to school, working at a modified job, or maintaining competitive employment. A preliminary study found that brain tumor patients who underwent cognitive and vocational therapy required shorter length of treatment, needed fewer rehabilitation sessions, and had better overall outcome in terms of independence and productivity, as compared with patients who have traumatic brain injuries.[39]

Education, Counseling, and Support Groups

Primary physicians may not discuss potential neurobehavioral symptoms with cancer patients, in part, because these clinicians are not aware of the impact that even subtle symptoms can have on social and vocational functioning. Patients who experience neurobehavioral symptoms and their families may feel isolated and alone.

Thus, education of the patient and family is extremely important. The more knowledge the patient and family members have about the disease, treatment, and expected problems, the more effectively they can cope. Even simple strategies, such as taking intermittent naps, writing notes, and taking special care to plan and organize activities, may be sufficient to effectively cope with symptoms.

Support groups and counseling can also reassure patients and families that their experiences are not unusual, and can help them deal with the grief, anger, frustration, and other problems that frequently arise over the course of the disease.

Summary

As we develop new treatments for cancer that provide improved survival, it is imperative that we also give some consideration to the long-term sequelae of cancer and its treatment. Cancer survivors should be able to expect to return to a productive, fulfilling life. We need to provide support for this effort, not only to reduce disability and improve patient function and satisfaction but also to decrease the overall burden and cost to society that such disability engenders.

References

1. Meyers CA: Issues of quality of life in neuro-oncology, in Vecht Ch J (ed): Handbook of Clinical Neurology, vol 23, pt I, pp 389-409. Amsterdam, Elsevier, 1997.

2. Scheibel RS, Meyers CA, Levin VA: Cognitive dysfunction following surgery for intracerebral glioma: Influence of histopathology, lesion location, and treatment. J Neurooncol 30:61-69, 1996.

3. Meyers CA, Byrne KS, Komaki R: Cognitive deficits in patients with small- cell lung cancer before and after chemotherapy. Lung Cancer 12:231-235, 1995.

4. Dalmau J, Graus F, Rosenblum MK, et al: Anti-Hu associated paraneoplastic encephalomyelitis/sensory neuronopathy: A clinical study of 71 patients. Medicine 71:59-72, 1992.

5. Voltz R, Gultekin HG, Rosenfeld MR, et al: A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 340:1788-1795, 1999.

6. Kurzrock R, Wetzler M, Estrov Z, et al: Interleukin-1 and its inhibitors: A biologic and therapeutic model for the role of growth regulatory factors in leukemias. Cytokines Cell Mol Ther 1:177-184, 1995.

7. Sugiyama H, Inoue K, Ogawa H, et al: The expression of IL-6 and its related genes in acute leukemia. Leuk Lymphoma 21:49-52, 1996.

8. Bruserud O, Nesthus I, Buhring HJ, et al: Cytokine modulation of interleukin-1 and tumor necrosis factor-alpha secretion from acute myelogenous leukemia blast cells in vitro. Leuk Res 19:15-22, 1995.

9. 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 vs standard-dose chemotherapy. J Natl Cancer Inst 90:210-218, 1998.

10. Pavol MA, Meyers CA, Rexer JL, et al: Pattern of neurobehavioral deficits associated with interferon-a therapy for leukemia. Neurology 45:947-950, 1995.

11. Meyers CA, Kudelka AP, Conrad CA, et al: Neurotoxicity of CI-980, a novel mitotic inhibitor. Clin Cancer Res 3:419-422, 1997.

12. Meyers CA, Weitzner MA, Valentine AD, et al: Methylphenidate improves cognition, mood, and function of brain tumor patients. J Clin Oncol 16:2522-2527, 1998.

13. Meyers CA, Weitzner M, Byrne K, et al: Evaluation of the neurobehavioral functioning of patients before, during, and after bone marrow transplantation. J Clin Oncol 12:820-826, 1994.

14. Meyers CA, Abbruzzese JL: Cognitive functioning in cancer patients: Effect of previous treatment. Neurology 42:434-436, 1992.

15. Valentine AD, Meyers CA, Kling MA, et al: Mood and cognitive side effects of interferon-a therapy. Semin Oncol 25(suppl 1):39-47, 1998.

16. Meyers CA, Valentine AD: Neurological and psychiatric adverse effects of immunological therapy. CNS Drugs 3:56-68, 1995.

17. Christiansen K, Knussmann R: Sex hormones and cognitive functioning in men. Neuropsychobiology 18:27-36, 1987.

18. Gouchie C, Kimura D: The relationship between testosterone levels and cognitive ability patterns. Psychoneuroendocrinol 16:323-334, 1991.

19. Friedman AJ, Juneau-Norcross M, Rein MS: Adverse effects of leuprolide acetate depot treatment. Fertil Steril 59:448-450, 1993.

20. Newton C, Slota D, Yuzpe AA, et al: Memory complaints associated with the use of gonadotropin-releasing hormone agonists: A preliminary study. Fertil Steril 65:1253-1255, 1996.

21. Sherwin BB, Tulandi T: “Add-back” estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. J Clin Endocrinol Metab 81:2545-2549, 1996.

22. Berman KF, Schmidt PJ, Rubinow DR, et al: Modulation of cognition-specific cortical activity by gonadal steroids: A positron-emission tomography study in women. Neurobiology 94:8836-8841, 1997.

23. Schweitzer VG: Ototoxicity of chemotherapeutic agents. Otolaryngol Clin North Am 26:759-789, 1993.

24. Mendoza TR, Wang XS, Cleeland CL, et al: The rapid assessment of fatigue severity in cancer patients: Use of the Brief Fatigue Inventory. Cancer 85:1186-1196, 1999.

25. Cleeland CS: Pain assessment in cancer, in Osoba D (ed): Effect of Cancer on Quality of Life, pp 293-305. Boca Raton, Florida, CRC Press, 1991.

26. Nissenson AR: Epoetin and cognitive function. Am J Kidney Dis 20(suppl 1):21-24, 1992.

27. Martin-Lester M: Cognitive function in dialysis patients. Anna J 24:359-365, 1997.

28. Walter T: Effect of iron-deficiency anemia on cognitive skills in infancy and childhood. Bailleres Clin Haematol 7:815-827, 1994.

29. Pollitt E: Iron deficiency and cognitive function. Annu Rev Nutr13:521-537, 1993.

30. Lozoff B: Behavioral alterations in iron deficiency. Adv Pediatr 35:331-360, 1988.

31. Temple RM, Deary IJ, Winney RJ: Recombinant erythropoietin improves cognitive function in patients maintained on chronic ambulatory peritoneal dialysis. Nephrol Dial Transplant 10:1733-1738, 1995.

32. Marsh J, Brown WE, Wolcott D, et al: RhuEPO treatment improves brain and cognitive function of anemic dialysis patients. Kidney Int 39:155-163, 1991.

33. Brown WE, Marsh J, Wolcott D, et al: Cognitive function, mood, and P3 latency: Effects of the amelioration of anemia in dialysis patients. Neuropsychologia 29:35-45, 1991.

34. Nissenson AR: Recombinant human erythropoietin: Impact on brain and cognitive function, exercise tolerance, sexual potency, and quality of life. Semin Nephrol 9(suppl 2):25-31, 1989.

35. Olofsson SM, Weitzner MA, Valentine AD, et al: A retrospective study of the psychiatric management and outcome of delirium in the cancer patient. Support Care Cancer 4:351-357, 1996.

36. World Health Organization: International Classification of Impairments, Disabilities, and Handicaps. Geneva, World Health Organization, 1980.

37. Weitzner MA, Meyers CA, Valentine AD: Methylphenidate in the treatment of neurobehavioral slowing associated with cancer and cancer treatment. J Neuropsychiatry Clin Neurosci 7:347-350, 1995.

38. Cook A, Burkhardt A: The effect of cancer diagnosis and treatment on hand function. Am J Occup Ther 48:836-839, 1994.

39. Sherer M, Meyers CA, Bergloff P: Efficacy of post acute brain injury rehabilitation for patients with primary malignant brain tumors. Cancer 80:250-257, 1997.

The Meyers Article Reviewed

Matthew M. Clark, PhD, and Teresa A. Rummans, MD, Mayo Medical School, Rochester, Minnesota

The subspecialty of psycho-oncology has highlighted how important psychosocial issues are to cancer patients.[1] Research demonstrates that psychiatric distress not only diminishes an individual’s quality of life but also contributes to morbidity and mortality.[2]

Both quantity and quality of life are important issues for cancer patients, their caregivers, and their health care providers. Although quality of life in cancer patients has been the focus of some recent empirical study, it remains an often underemphasized and overlooked area in both research and practice. Thus, greater attention to quality-of-life assessment and subsequent interventions should be beneficial to both cancer patients and their families.

Neurocognitive Dysfunction and Quality of Life

Neurocognitive status is a major component of quality of life in all cancer patients. When neurocognitive dysfunction presents initially as a behavioral problem, effort is frequently directed toward correcting the problem. However, when subtle cognitive alterations, eg, mild cognitive impairment or personality changes, occur, too often they are overlooked or ignored.

Ironically, these “less severe” neurocognitive conditions can be the most troublesome and burdensome for family and friends. Thus, neurocognitive dysfunction has a negative impact not only on the patient’s quality of life but also on the family’s quality of life. Improving the quality of life of those afflicted with cancer and those caring for them requires attention to the recognition and diagnosis of neurocognitive dysfunction and the interventions available for maintaining or improving neurocognitive status.

The article by Dr. Meyers explores the impact of neurocognitive function on quality of life in the cancer patient. This is an important area because many cancer patients experience cognitive difficulties. The author describes the various ways in which cancer can affect memory and other cognitive domains. These include direct and indirect effects of cancer on the central nervous system (CNS), as well as effects of cancer treatments on the nervous system.

Many cancer patients have coexisting medical, neurologic, or psychiatric symptoms or conditions that can negatively affect their cognition. Unfortunately, Dr. Meyers does not provide details on the specific types of neurocognitive dysfunction that occur with each of these coexisting conditions—details that would help clinicians identify the source of the problem when it arises. Likewise, the author does not suggest the best way to screen patients for neurocognitive changes, nor does she discuss the optimal approach to evaluating these problems once they have been detected.

Comprehensive Screening Tool Needed

At present, however, there is no brief, comprehensive, validated measure to screen for quality of life, neurocognitive functioning, and psychosocial issues in cancer patients. Existing measures are limited to only one or two domains. For example, some assessment instruments center solely on psychiatric issues, such as anxiety and depression, whereas other measures focus exclusively on social support issues, such as the physician-patient relationship and the individual’s personal social support system.

To be truly useful in cancer patients, a measure needs to evaluate all domains of quality of life. These include mental (cognitive abilities and function), emotional (positive and negative moods), physical (pain level, physical activity, and functional impairment), social (interactions with health care providers and significant others), and spiritual (hope, fighting spirit, and internal peace) domains.

How Neurocognitive Deficits Affect Quality of Life

Once neurocognitive deficits have been recognized and diagnosed, Dr. Meyers describes the ways in which such deficits adversely affect patients’ quality of life. The three affected domains include impairment (deficit in function), disability (deficit in ability to perform work-related activities), and handicap (impact on overall satisfaction and well-being).

Neurocognitive functioning has clearly been shown to have a significant impact on quality of life following participation in cardiac rehabilitation programs. In a sample of 93 participants in such a program, Clark and colleagues found that baseline neurocognitive functioning was related to both baseline quality of life and the degree to which quality of life improved following the intervention.[3]

Given that neurocognitive functioning has been shown to impact quality of life in this medical population, it seems reasonable to assume a similar effect of neurocognitive functioning in the cancer population. This highlights the importance of utilizing the limited interventions that are available to improve cognitive functioning and of developing new interventions to ameliorate cognitive disabilities, when they do occur, or to prevent them from worsening.

References

1. NCCN practice guidelines for the management of psychosocial distress. Oncology 13(5A):113-147, 1999.

2. Holland JC: Societal values of cancer and the emergence of psycho-oncology, in Holland JC (ed): Psycho-Oncology, pp 3-15. New York, Oxford University Press, 1998.

3. Cohen RA, Moser DJ, Clark MM, et al: Neurocognitive functioning and improvement in quality of life following participation in cardiac rehabilitation. Am J Cardiol 83:1374-1378, 1999.

The Meyers Article Reviewed

Andrew J. Saykin, PsyD, ABPP, and Tim AAhles, PhD, Dartmouth Medical School, Hanover, New Hampshire

In addressing neurocognitive impairments in individuals with cancer, including patients undergoing cancer-related treatments, this article by Dr. Christina Meyers reviews a very important area that has not received the degree of research attention that it deserves. Dr. Meyers is a neuropsychologist whose research has focused on the cognitive effects of cancer and its treatments. She provides a concise review of her own findings and the work of others on the direct and indirect neurobehavioral effects of cancer and cancer therapies.

The comprehensive scope of the review conveys the complexities of assessing and treating these neurobehavioral effects by calling attention to the role of coexisting medical, neurologic, and psychiatric conditions. Examples of the myriad relevant factors include pain, fatigue, and anemia, as well as various metabolic, infectious, and toxic conditions. Furthermore, age-related changes are important, given that many cancer patients are in the older age ranges. The article also considers appropriate areas for clinical assessment and types of interventions that can benefit cancer patients.

Neurocognitive Changes Are Common and Treatment-Responsive

Dr. Meyers reviews evidence that neurocognitive and behavioral changes in cancer patients are common, and she persuasively argues that these changes merit careful multidisciplinary assessment. It is clear from the available data that there is considerable heterogeneity in the characterization and etiology of neurocognitive and behavioral changes in cancer patients. Although available data most often implicate relatively diffuse cognitive changes, with impairment in memory processing and complex attention particularly prevalent, there are situations in which cancer patients show more focal or isolated deficits.

Depression, anxiety, and other psychiatric symptoms are also common. Effective pharmacologic, behavioral, and rehabilitative treatments are available for these symptoms and should be offered to patients.

Successful intervention requires an individualized determination of the source of a patient’s impairment. For example, fatigue secondary to anemia is best addressed by the use of medications to normalize hematologic function, whereas fatigue due to depression may best be treated with a combined psychopharmacologic and behavioral approach. Similar considerations apply to complaints regarding memory and concentration, as these important functions can be compromised by numerous factors that are pervasive in patients with cancer.

Mechanistic Research on Cognitive Factors Is Essential

We are clearly at an early stage in our understanding of the fundamental mechanisms of cognitive dysfunction in cancer patients. Dr. Meyers provides a useful clinical framework by differentiating among primary, secondary, treatment-related, and combined causes.

Examples of primary changes include the direct effects of brain tumors that disrupt function based on location. Secondary effects include such factors as neurotoxic secretions by tumors and inflammatory cytokines. Treatment-related effects on cognitive function have been studied in children undergoing chemotherapy and radiation therapy, but these effects have been investigated to a much lesser extent in adult cancer patients.

Early work by Dr. Meyers and colleagues, and by several other groups, has attempted to isolate mechanisms of cognitive dysfunction. However, most available data are descriptive; ie, cognitive deficits are observed, but the underlying causes cannot be separated given the study designs.

Controlled trials are clearly needed to elucidate the mechanisms of cognitive dysfunction in cancer patients. Such trials should include measures of the range of relevant factors necessary to ascertain the individual and combined cognitive and emotional changes associated with primary, secondary, and treatment-related causes. Furthermore, the specific roles of constitutional symptoms, fatigue, and pain in producing cognitive changes are relatively unknown but are very likely to be important.

In addition, clinical trials need to control for the presence of comorbid conditions that may be preexisting or emerge during treatment. Examples of relevant psychiatric, neurologic, and medical conditions include abuse of alcohol and other drugs, cerebrovascular disorders, Alzheimer’s or other dementia, mild cognitive impairment, and

traumatic brain injury, as well as developmental disorders, such as attention deficit disorder and learning disability, which can persist throughout life. Attention to these issues is also clearly important for clinical assessment and treatment planning.

Neurocognitive Changes After Chemotherapy

Neuropsychological studies indicate that a substantial percentage of patients undergoing chemotherapy exhibit cognitive deficits. Although most studies are not prospective or double blind in design, the available data consistently show that about 20% of patients exhibit some measurable degree of therapy-related impairment.[1-3]

New unpublished data from our program on long-term survivors of breast cancer and lymphoma are consistent with these reports. We administered a detailed neuropsychological battery to examine cognitive function after systemic chemotherapy compared to local treatment and found an increased frequency of neurocognitive impairment in the chemotherapy group.

In general, the characteristics of cognitive changes after chemotherapy are poorly understood. Available data suggest that the pattern is diffuse, but that some neurocognitive functions are more vulnerable than others. For example, working memory appears to be particularly vulnerable. [4,5]

A critical current issue is the need for studies that examine the specific changes caused by different chemotherapeutic agents. Powerful cytotoxic, antibiotic, mitotic, steroidal, and hormonal agents are likely to have different effects on the central nervous system (CNS) and to exert these effects through differing biological pathways and time frames. For example, the cognitive concomitants of hormonal therapy for breast, ovarian, and prostate cancer are largely unknown, and yet there is increasing evidence of hormonal effects on cognition, particularly during early development and later life (eg, in postmenopausal women).[6] Cognitive effects of steroids, immunomodulators, and nonsteroidal anti-inflammatory drugs (NSAIDs) and other pain medications also require evaluation.

The effects of drug delivery route, dose, regimen, and duration on cognitive changes are largely unknown. Furthermore, drug interactions and combination therapies require special attention, as they are difficult to “tease out.” It is important that future studies attempt to separate single, combined, and interactive effects.

The problem of differentiating among the effects of specific agents, given a database of patients who have been treated with many different regimens, is of particular interest to our group. In addition to the optimal situation of controlled trials, it may be possible to analyze large observational databases to gain insights into the cognitive effects of treatment regimens. These methodologically challenging analyses, which require large samples and specialized statistical models, may provide another tool to help differentiate the effects of specific agents. The latter strategy seems well suited to multicenter, collaborative projects.

Viewing Neurocognitive Deficits in Context

It is important that neurocognitive deficits be seen in context. A biopsychosocial perspective not only incorporates cognitive changes identified on neuropsychological testing and cognitive complaints elicited on patient interviews but also encompasses activities of daily living and quality of life—issues now recognized as important in evaluating the outcome of any cancer therapy.

This global perspective has obvious implications for a patient’s assessment of the risks and benefits of therapy. Of particular importance, such an approach has the potential to help clinicians and patients choose the least neurotoxic regimen among equally efficacious treatment options.

Next Step: Role of Advanced Brain Imaging Technologies

Initial progress has been made in clinical care and the mechanistic understanding of neurocognitive dysfunction in cancer patients, as reflected in Dr. Meyers’ review. She contributes to this progress by bringing neurocognitive changes in cancer patients to the attention of the broader clinical oncology community. There remains an urgent need for more systematic research in this area. There is also a need for focused, well-articulated hypotheses to drive this research.

Fortunately, new tools to examine the neural substrates of cognitive dysfunction are becoming available. Advances in neuroimaging technologies and their increased availability will undoubtedly accelerate progress in directly assessing the effects of cancer and cancer therapies.

Magnetic resonance imaging (MRI)–based three-dimensional morphology can accurately measure changes in gray and white matter associated with the atrophic effects of therapy. Magnetic imaging spectroscopy can assess markers of neuronal integrity and metabolic pathology, which can be correlated with cognition.

A particularly exciting development is functional MRI (fMRI)—a noninvasive, repeatable method that permits direct observation of brain activity during neurocognitive assessment. A recently completed, as yet unpublished pilot study from our laboratory suggests that fMRI is sensitive to the long-term effects of chemotherapy. These new methods can reveal the structural, metabolic, and functional consequences of cancer and cancer therapy and ultimately inform clinical decision-making.

References

1. Walch SE, Ahles TA, Saykin AJ: Neuro-psychological impact of cancer and cancer treatments in adults, in Holland J et al (eds): Textbook for Psycho-Oncology. New York, Oxford University Press, 1998.

2. Schagen SB, van Dam FSAM, Muller MJ, et al: Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 85(3):640-650, 1999.

3. van Dam FSAM, Schagen SB, Muller MJ, et al: Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: High-dose vs standard dose chemotherapy. J Natl Cancer Inst 90(3):210-218, 1998.

4. Komaki R, Meyers CA, Shin DM, et al: Evaluation of cognitive function in patients with limited small-cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 33:179-182, 1995.

5. Wieneke MH, Dienst ER: Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psycho-Oncol 4:61-66, 1995.

6. Sherwin BB: Estrogen and cognitive functioning in women. Proc Soc Exper Biol Med 217:17-22, 1998.

 

The Meyers Article Reviewed

Matthew M. Clark, PhD, and Teresa A. Rummans, MD, Mayo Medical School, Rochester, Minnesota

The subspecialty of psycho-oncology has highlighted how important psychosocial issues are to cancer patients.[1] Research demonstrates that psychiatric distress not only diminishes an individual’s quality of life but also contributes to morbidity and mortality.[2]

Both quantity and quality of life are important issues for cancer patients, their caregivers, and their health care providers. Although quality of life in cancer patients has been the focus of some recent empirical study, it remains an often underemphasized and overlooked area in both research and practice. Thus, greater attention to quality-of-life assessment and subsequent interventions should be beneficial to both cancer patients and their families.

Neurocognitive Dysfunction and Quality of Life

Neurocognitive status is a major component of quality of life in all cancer patients. When neurocognitive dysfunction presents initially as a behavioral problem, effort is frequently directed toward correcting the problem. However, when subtle cognitive alterations, eg, mild cognitive impairment or personality changes, occur, too often they are overlooked or ignored.

Ironically, these “less severe” neurocognitive conditions can be the most troublesome and burdensome for family and friends. Thus, neurocognitive dysfunction has a negative impact not only on the patient’s quality of life but also on the family’s quality of life. Improving the quality of life of those afflicted with cancer and those caring for them requires attention to the recognition and diagnosis of neurocognitive dysfunction and the interventions available for maintaining or improving neurocognitive status.

The article by Dr. Meyers explores the impact of neurocognitive function on quality of life in the cancer patient. This is an important area because many cancer patients experience cognitive difficulties. The author describes the various ways in which cancer can affect memory and other cognitive domains. These include direct and indirect effects of cancer on the central nervous system (CNS), as well as effects of cancer treatments on the nervous system.

Many cancer patients have coexisting medical, neurologic, or psychiatric symptoms or conditions that can negatively affect their cognition. Unfortunately, Dr. Meyers does not provide details on the specific types of neurocognitive dysfunction that occur with each of these coexisting conditions—details that would help clinicians identify the source of the problem when it arises. Likewise, the author does not suggest the best way to screen patients for neurocognitive changes, nor does she discuss the optimal approach to evaluating these problems once they have been detected.

Comprehensive Screening Tool Needed

At present, however, there is no brief, comprehensive, validated measure to screen for quality of life, neurocognitive functioning, and psychosocial issues in cancer patients. Existing measures are limited to only one or two domains. For example, some assessment instruments center solely on psychiatric issues, such as anxiety and depression, whereas other measures focus exclusively on social support issues, such as the physician-patient relationship and the individual’s personal social support system.

To be truly useful in cancer patients, a measure needs to evaluate all domains of quality of life. These include mental (cognitive abilities and function), emotional (positive and negative moods), physical (pain level, physical activity, and functional impairment), social (interactions with health care providers and significant others), and spiritual (hope, fighting spirit, and internal peace) domains.

How Neurocognitive Deficits Affect Quality of Life

Once neurocognitive deficits have been recognized and diagnosed, Dr. Meyers describes the ways in which such deficits adversely affect patients’ quality of life. The three affected domains include impairment (deficit in function), disability (deficit in ability to perform work-related activities), and handicap (impact on overall satisfaction and well-being).

Neurocognitive functioning has clearly been shown to have a significant impact on quality of life following participation in cardiac rehabilitation programs. In a sample of 93 participants in such a program, Clark and colleagues found that baseline neurocognitive functioning was related to both baseline quality of life and the degree to which quality of life improved following the intervention.[3]

Given that neurocognitive functioning has been shown to impact quality of life in this medical population, it seems reasonable to assume a similar effect of neurocognitive functioning in the cancer population. This highlights the importance of utilizing the limited interventions that are available to improve cognitive functioning and of developing new interventions to ameliorate cognitive disabilities, when they do occur, or to prevent them from worsening.

References

1. NCCN practice guidelines for the management of psychosocial distress. Oncology 13(5A):113-147, 1999.

2. Holland JC: Societal values of cancer and the emergence of psycho-oncology, in Holland JC (ed): Psycho-Oncology, pp 3-15. New York, Oxford University Press, 1998.

3. Cohen RA, Moser DJ, Clark MM, et al: Neurocognitive functioning and improvement in quality of life following participation in cardiac rehabilitation. Am J Cardiol 83:1374-1378, 1999.

The Meyers Article Reviewed

Andrew J. Saykin, PsyD, ABPP, and Tim AAhles, PhD, Dartmouth Medical School, Hanover, New Hampshire

In addressing neurocognitive impairments in individuals with cancer, including patients undergoing cancer-related treatments, this article by Dr. Christina Meyers reviews a very important area that has not received the degree of research attention that it deserves. Dr. Meyers is a neuropsychologist whose research has focused on the cognitive effects of cancer and its treatments. She provides a concise review of her own findings and the work of others on the direct and indirect neurobehavioral effects of cancer and cancer therapies.

The comprehensive scope of the review conveys the complexities of assessing and treating these neurobehavioral effects by calling attention to the role of coexisting medical, neurologic, and psychiatric conditions. Examples of the myriad relevant factors include pain, fatigue, and anemia, as well as various metabolic, infectious, and toxic conditions. Furthermore, age-related changes are important, given that many cancer patients are in the older age ranges. The article also considers appropriate areas for clinical assessment and types of interventions that can benefit cancer patients.

Neurocognitive Changes Are Common and Treatment-Responsive

Dr. Meyers reviews evidence that neurocognitive and behavioral changes in cancer patients are common, and she persuasively argues that these changes merit careful multidisciplinary assessment. It is clear from the available data that there is considerable heterogeneity in the characterization and etiology of neurocognitive and behavioral changes in cancer patients. Although available data most often implicate relatively diffuse cognitive changes, with impairment in memory processing and complex attention particularly prevalent, there are situations in which cancer patients show more focal or isolated deficits.

Depression, anxiety, and other psychiatric symptoms are also common. Effective pharmacologic, behavioral, and rehabilitative treatments are available for these symptoms and should be offered to patients.

Successful intervention requires an individualized determination of the source of a patient’s impairment. For example, fatigue secondary to anemia is best addressed by the use of medications to normalize hematologic function, whereas fatigue due to depression may best be treated with a combined psychopharmacologic and behavioral approach. Similar considerations apply to complaints regarding memory and concentration, as these important functions can be compromised by numerous factors that are pervasive in patients with cancer.

Mechanistic Research on Cognitive Factors Is Essential

We are clearly at an early stage in our understanding of the fundamental mechanisms of cognitive dysfunction in cancer patients. Dr. Meyers provides a useful clinical framework by differentiating among primary, secondary, treatment-related, and combined causes.

Examples of primary changes include the direct effects of brain tumors that disrupt function based on location. Secondary effects include such factors as neurotoxic secretions by tumors and inflammatory cytokines. Treatment-related effects on cognitive function have been studied in children undergoing chemotherapy and radiation therapy, but these effects have been investigated to a much lesser extent in adult cancer patients.

Early work by Dr. Meyers and colleagues, and by several other groups, has attempted to isolate mechanisms of cognitive dysfunction. However, most available data are descriptive; ie, cognitive deficits are observed, but the underlying causes cannot be separated given the study designs.

Controlled trials are clearly needed to elucidate the mechanisms of cognitive dysfunction in cancer patients. Such trials should include measures of the range of relevant factors necessary to ascertain the individual and combined cognitive and emotional changes associated with primary, secondary, and treatment-related causes. Furthermore, the specific roles of constitutional symptoms, fatigue, and pain in producing cognitive changes are relatively unknown but are very likely to be important.

In addition, clinical trials need to control for the presence of comorbid conditions that may be preexisting or emerge during treatment. Examples of relevant psychiatric, neurologic, and medical conditions include abuse of alcohol and other drugs, cerebrovascular disorders, Alzheimer’s or other dementia, mild cognitive impairment, and

traumatic brain injury, as well as developmental disorders, such as attention deficit disorder and learning disability, which can persist throughout life. Attention to these issues is also clearly important for clinical assessment and treatment planning.

Neurocognitive Changes After Chemotherapy

Neuropsychological studies indicate that a substantial percentage of patients undergoing chemotherapy exhibit cognitive deficits. Although most studies are not prospective or double blind in design, the available data consistently show that about 20% of patients exhibit some measurable degree of therapy-related impairment.[1-3]

New unpublished data from our program on long-term survivors of breast cancer and lymphoma are consistent with these reports. We administered a detailed neuropsychological battery to examine cognitive function after systemic chemotherapy compared to local treatment and found an increased frequency of neurocognitive impairment in the chemotherapy group.

In general, the characteristics of cognitive changes after chemotherapy are poorly understood. Available data suggest that the pattern is diffuse, but that some neurocognitive functions are more vulnerable than others. For example, working memory appears to be particularly vulnerable. [4,5]

A critical current issue is the need for studies that examine the specific changes caused by different chemotherapeutic agents. Powerful cytotoxic, antibiotic, mitotic, steroidal, and hormonal agents are likely to have different effects on the central nervous system (CNS) and to exert these effects through differing biological pathways and time frames. For example, the cognitive concomitants of hormonal therapy for breast, ovarian, and prostate cancer are largely unknown, and yet there is increasing evidence of hormonal effects on cognition, particularly during early development and later life (eg, in postmenopausal women).[6] Cognitive effects of steroids, immunomodulators, and nonsteroidal anti-inflammatory drugs (NSAIDs) and other pain medications also require evaluation.

The effects of drug delivery route, dose, regimen, and duration on cognitive changes are largely unknown. Furthermore, drug interactions and combination therapies require special attention, as they are difficult to “tease out.” It is important that future studies attempt to separate single, combined, and interactive effects.

The problem of differentiating among the effects of specific agents, given a database of patients who have been treated with many different regimens, is of particular interest to our group. In addition to the optimal situation of controlled trials, it may be possible to analyze large observational databases to gain insights into the cognitive effects of treatment regimens. These methodologically challenging analyses, which require large samples and specialized statistical models, may provide another tool to help differentiate the effects of specific agents. The latter strategy seems well suited to multicenter, collaborative projects.

Viewing Neurocognitive Deficits in Context

It is important that neurocognitive deficits be seen in context. A biopsychosocial perspective not only incorporates cognitive changes identified on neuropsychological testing and cognitive complaints elicited on patient interviews but also encompasses activities of daily living and quality of life—issues now recognized as important in evaluating the outcome of any cancer therapy.

This global perspective has obvious implications for a patient’s assessment of the risks and benefits of therapy. Of particular importance, such an approach has the potential to help clinicians and patients choose the least neurotoxic regimen among equally efficacious treatment options.

Next Step: Role of Advanced Brain Imaging Technologies

Initial progress has been made in clinical care and the mechanistic understanding of neurocognitive dysfunction in cancer patients, as reflected in Dr. Meyers’ review. She contributes to this progress by bringing neurocognitive changes in cancer patients to the attention of the broader clinical oncology community. There remains an urgent need for more systematic research in this area. There is also a need for focused, well-articulated hypotheses to drive this research.

Fortunately, new tools to examine the neural substrates of cognitive dysfunction are becoming available. Advances in neuroimaging technologies and their increased availability will undoubtedly accelerate progress in directly assessing the effects of cancer and cancer therapies.

Magnetic resonance imaging (MRI)–based three-dimensional morphology can accurately measure changes in gray and white matter associated with the atrophic effects of therapy. Magnetic imaging spectroscopy can assess markers of neuronal integrity and metabolic pathology, which can be correlated with cognition.

A particularly exciting development is functional MRI (fMRI)—a noninvasive, repeatable method that permits direct observation of brain activity during neurocognitive assessment. A recently completed, as yet unpublished pilot study from our laboratory suggests that fMRI is sensitive to the long-term effects of chemotherapy. These new methods can reveal the structural, metabolic, and functional consequences of cancer and cancer therapy and ultimately inform clinical decision-making.

References

1. Walch SE, Ahles TA, Saykin AJ: Neuro-psychological impact of cancer and cancer treatments in adults, in Holland J et al (eds): Textbook for Psycho-Oncology. New York, Oxford University Press, 1998.

2. Schagen SB, van Dam FSAM, Muller MJ, et al: Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 85(3):640-650, 1999.

3. van Dam FSAM, Schagen SB, Muller MJ, et al: Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: High-dose vs standard dose chemotherapy. J Natl Cancer Inst 90(3):210-218, 1998.

4. Komaki R, Meyers CA, Shin DM, et al: Evaluation of cognitive function in patients with limited small-cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 33:179-182, 1995.

5. Wieneke MH, Dienst ER: Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psycho-Oncol 4:61-66, 1995.

6. Sherwin BB: Estrogen and cognitive functioning in women. Proc Soc Exper Biol Med 217:17-22, 1998.