Robert J Ferguson Raine Riggs Tim Ahles and Andrew J Saykin

1.0. BACKGROUND

Dysfunction in memory and attention associated with cancer treatment has gained increased attention over the past two decades. In 1999 the President's Cancer Panel1 and the National Coalition for Cancer Survivorship2 formally recognized the problem as a quality of life matter that deserved higher priority in clinical research. With nearly 1 million chemotherapy recipients annually in the United States alone, the problem is widespread. Over this same time span, research has clearly documented persistent cognitive deficits following various cancer treatments, especially for the pediatric population, but there has been increasing investigation on the effects ofsys-temic chemotherapy among adult cancer survivors. The nature of these findings will be summarized here to illustrate the rationale for cognitive and behavioral strategies that may help improve management of chemotherapy-related cognitive dysfunction. This chapter will describe a recently developed cognitive-behavioral treatment that is being studied to aid survivors with chemotherapy-related cognitive problems and outline future directions of management.

2.0. COGNITIVE EFFECTS OF CHEMOTHERAPY

Interest in the neuropsychological impact of cancer treatment dates back to the early 1980s when Silberfarb and colleagues observed measurable cognitive decline among patients undergoing cancer treatment.3 However, many of these early studies had methodological shortcomings such as comparing chemotherapy recipients'

neuropsychological performances to published norms and not matched control participants. Also, many studies evaluated chemotherapy recipients immediately following completion of chemotherapy regimes when acute effects of treatment, such as stress, anxiety, and depressive symptoms could adversely influence neuropsychological test performance. Nonetheless, these early results paved the way for more rigorous research that utilized control comparison designs and isolated the effects of anxiety, depression, fatigue, and menopausal status on cognitive performance.

In the mid-1990s Wieneke and Dienst4 evaluated 28 women with a standardized battery an average of 6 months posttreatment with CAF (cyclophosphamide, doxyrubicin and 5-fluorouracil) and/or CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). Seventy-five percent of patients scored greater than two standard deviations below published norms on one or more of the neuropsycholog-ical measures. Measures of working memory and sustained attention were most commonly affected. The pattern of cognitive impairment was unrelated to depression, type of chemotherapy, or time since treatment. van Dam et al.5 then evaluated breast cancer patients an average of 2 years posttreatment who were randomized to high-dose chemotherapy plus tamoxifen or standard-dose therapy (FEC, 5-fluorouracil, epidoxorubicin, and cyclophosphamide) plus tamoxifen. They also included a control group of Stage I patients who were treated with local therapy only (surgery plus local radiotherapy). Patients in the high-dose arm were more likely to demonstrate cognitive impairment (37%). However, a greater number of patients in the standard-dose arm (17%) demonstrated cognitive impairment as compared to the local therapy group (9%). Stated another way, the risk of cognitive impairment was 3.5 times higher (95% CI + 1.0-12.8) standard-dose patients versus local therapy patients. This finding suggested that cognitive changes may be dose dependent.

Schagen et al.6 studied 39 breast cancer patients treated with CMF plus or minus tamoxifen and a control group of 34 age-matched axillary node negative breast cancer patients who received surgery and local radiotherapy but not systemic chemotherapy. Neuropsychological testing was approximately 2 years posttreatment. Results demonstrated patients treated with CMF had significantly more problems with concentration (31% versus 6%) and memory (21% versus 3%). Across all domains, cognitive impairment was seen in 28% of chemotherapy patients and 12% of controls. Comparison of chemotherapy patients who were (N = 20) and were not (N = 19) treated with tamoxifen showed no significant differences. Similar to those results, Brezden et al. compared cognitive functioning in women with breast cancer who were currently receiving adjuvant chemotherapy (CMF or CEF, cyclophosphamide, epirubicin, and 5-fluorouracil) or were greater than 1 year post-chemotherapy (median, 25 months) to that of healthy controls. They found a greater number of patients in both groups had moderate or severe cognitive impairment compared to healthy controls.

In one of the more comprehensive studies to date, Ahles and Saykin, et al.8 examined neuropsychological performance of long-term survivors (>5 years postdiagnosis, disease free) of breast cancer and lymphoma, that compared patients treated with systemic chemotherapy to those treated with local therapy. Analysis of the data demonstrated a significant multivariate effect across nine domains of neuropsychological functioning (p < 0.04) with survivors treated with systemic chemotherapy scoring significantly lower than survivors treated with local therapy only. Univariate analyses revealed significant treatment differences in the following domains: verbal memory (p < 0.01), and psychomotor processing speed (p < 0.03).

There was also a trend for spatial ability (p < 0.10) and visual memory (p < 0.12). Survivors who had received systemic chemotherapy scored lower than survivors who had received local therapy only. Using a definition of low neuropsychological performance similar to that used in the studies reported above, 39% of chemotherapy patients compared to 14% of local therapy patients scored within the low performance range (Chi sq. p < 0.002).

Overall these data support the hypothesis that a certain subset of cancer patients experience cognitive decline secondary to treatment with systemic chemotherapy. The functional domains affected generally appear to be verbal memory and psy-chomotor processing speed. However, the bulk of data show two distinct trends. First, not all cancer patients are equally affected. Ahles and Saykin, et al. found 24—50% of chemotherapy recipients had lower neuropsychological performance as compared to only 5-23% of survivors treated with local treatments in various neuropsychological performance domains. The result that not all chemotherapy recipients are found to have cognitive problems after treatment implies that some individuals may be more vulnerable than others to the cognitive effects of chemotherapy. Vulnerability factors, such as genetic predispositions (e.g., apolipoprotein, 4th allele), previous neurological insult, lower IQ, and lower "cognitive reserve" are all factors under investigation.9,10 A second trend in the cognitive dysfunction and chemotherapy literature is neuropsychological performance scores of cancer patients who complain of memory problems after chemotherapy are usually normalrange. To date, there are few published longitudinal data examining pretreatment neuropsychological test performance to post-chemotherapy performance. It may be that those individuals who report problems in cognitive function after completing chemotherapy have had relatively high neuropsychological performance and thus their decline, although subtle, is more noticeable upon full resumption offunctional activity such as employment or taking on full social or familial role responsibilities. In summary, an accurate picture of the etiological causes of cognitive dysfunction following chemotherapy remains elusive. In light of this fact, and given the growing number of patients undergoing chemotherapy and improved rates of long-term survivorship,1,2,11,12 the application of existing nonpharmacological, behavioral, and cognitive compensatory strategies to this problem seems practical.13-15

3.0. OTHER FACTORS CONTRIBUTING TO NEUROPSYCHOLOGICAL PERFORMANCE IN CANCER SURVIVORS

As noted earlier, heightened levels of emotional distress and psychological symptoms can be associated with neuropsychological impairment. In addition, estrogen may play a role in the neuropsychological performance of cancer patients and survivors. Research on these effects is summarized below.

Depression. Numerous studies have shown neuropsychological deficits in depressed populations.16-19 Most of this research has been conducted with participants who were experiencing a major depressive episode. Deficits found in this population include both short- and long-term memory deficits, as well as deficits in psychomotor function, new learning, and naming. For example, King et al.20 found that, compared to age, education, and gender matched control participants who had no history of depression, depressed participants performed significantly worse on several neuropsychological tests, including word generation, verbal memory (both immediate and delayed recall), and visual memory (both immediate and delayed recall).

These findings are important because depressive symptoms are common among women diagnosed with breast cancer.21 Since many of the neuropsychological symptoms of depression overlap with the neuropsychological effects of systemic treatments for breast cancer, it is important to take symptoms of depression into account.

Anxiety. Similarly, numerous studies have demonstrated neuropsychological deficits in individuals with anxiety disorders.22-25 Most of these studies were conducted with participants who had been diagnosed with obsessive compulsive disorder (OCD), not simply people who suffered from anxiety. These studies have shown that individuals with OCD have weaknesses in visuospatial abilities and difficulty switching cognitive set. For example, in one study, patients with intractable OCD completed neuropsychological testing before undergoing psychosurgery and post surgery.24 The participants were found to have deficits in information processing speed and visuospatial performance, as evidenced by performance on subtests of the Wechsler Adult Intelligence Scale-Revised Edition. These deficits were present before and after the surgery.

While it is important to note that this literature pertains most directly to individuals diagnosed with an anxiety disorder, most often OCD, less severe symptoms of anxiety may also play a role in neuropsychological performance. As many women with breast cancer suffer with some degree of anxiety,26 it is important to consider the role of anxiety.

Fatigue. Most studies of the neuropsychological effects of fatigue have been conducted on participants diagnosed with chronic fatigue syndrome (CFS).27,28 While some of these studies have identified deficits in attention, concentration, visuospa-tial abilities, and memory, others have found no differences between participants with CFS and normal controls.29,30 Several researchers in this area have begun to differentiate between subjective cognitive effects and objective neuropsychological test performance.31 While individuals diagnosed with CFS often report cognitive deficits, including a general slowing of information processing, they demonstrate relatively few, if any, deficits on neuropsychological tests.

It is important to note that these studies were conducted with participants who suffer from a specific disease, CFS, and not cancer treatment-induced fatigue which may have an etiology that is altogether distinct, such as compromised hemoglobin transport. Clinical intuition suggests fatigue probably does play a role in performance on neuropsychological tests, so it is important to account for it in this population, as many women undergoing treatment for breast cancer experience considerable fatigue throughout the course of their treatment and recovery.32 In addition, episodic fatigue is a common complaint among cancer survivors following treatment. However, we are aware of no current data examining the effects of episodic fatigue on neuropsychological functioning among former chemotherapy recipients or other cancer survivors.

Sleep Disturbance. A recent review of the literature by Savard and colleagues found that between 31 and 54% of recently diagnosed and/or recently treated cancer patients reported sleep difficulties.33 Even more startling was their finding that 23 -44% of cancer survivors continued to report significant symptoms of sleep disturbance up to 5 years posttreatment. In a sample of 300 women who had been treated with radiation therapy for nonmetastatic breast cancer, 51% endorsed some significant insomnia complaint, as determined by a report of current sleep difficulty or current use of sleep medications.34 Overall, 19% of the total sample met the diagnostic criteria for insomnia, which represents almost twice the percentage of people in the general population who would meet these criteria.

Individuals with chronic insomnia often report decreased memory, attention, concentration, and motor performance.35 A recent review of the literature on cognitive impairments in chronic insomnia concluded that, while results and methodology vary, there is objective evidence that chronic insomniacs demonstrate impairments in attention and vigilance.35 Because chronic insomnia is prevalent in cancer patients and survivors, it is possible that sleep disturbance plays a role in their neuropsycho-logical functioning.

Estrogen. In recent years, a great deal of research has been conducted on the effects of hormones, particularly estrogen, on cognition.36-38 Like the neuropsychological research on fatigue, the research on the effects of estrogen provides mixed results, with some researchers finding that estrogen has an enhancing effect on neuropsychological test performance and other researchers finding no effect. However, methodological differences may explain these different findings. For example, researchers have used different estrogen preparations, have administered different neuropsychological tests, and none have measured actual estrogen levels.

Sherwin39 assessed a group of premenopausal women before they underwent a surgical menopause and again 4 months post surgery. Half of the women received estrogen replacement therapy after the surgery, while the other half received a placebo. The women who received estrogen replacement therapy maintained their preoper-ative scores on all of the neuropsychological tests, while the placebo group demonstrated a significant decline in performance on verbal memory tasks. However, in a similar study, Ditkoff et al.40 found no difference between an estrogen replacement group and a placebo control group. At this time, it is unclear what role estrogen plays in neuropsychological functioning following cancer treatment. The majority of breast cancer survivors are postmenopausal but many premenopausal women undergoing chemotherapy for cancer experience a chemically induced menopause. It remains unclear as to which of these women are vulnerable to neuropsychological decline following chemotherapy.

4.0. COGNITIVE REMEDIATION OF CHEMOTHERAPY-RELATED MEMORY DYSFUNCTION

Cognitive rehabilitation approaches have been generally shown to improve functioning of patients with subtle to severe cognitive deficits.14,15,41 However, relatively little is known about rehabilitation of cognitive dysfunction among adult cancer survivors treated with systemic chemotherapy. For example, Cimprich13 observed improvement in directed attention among stage I and II localized breast cancer patients who were treated with a brief attention restoration program—but participants in the study were patients who underwent surgery with no other cancer treatment. The cognitive remediation program (CRP) involved instructing patients to schedule daily relaxing activity in the natural environment—a procedure hypothesized to restore directed attention. Results suggested treated patients improved in directed attention performance but it is unknown if Cimprich's intervention would have similar positive results among past chemotherapy recipients. Further, the participants in the Cimprich study enrolled relatively soon after treatment (6 months) when recovery is expected to naturally occur. By contrast, many cancer survivors who report chemotherapy-related memory problems do so years following treatment.

Approaches to nonpharmacological cognitive remediation involve two broad types41: A traditional cognitive-rehabilitation approach that typically involves repetitive practice and drill in cognitive tasks to promote over-learning and aid circuitry repair and cortical reorganization.15,42,43 Another approach is helping patients compensate for cognitive problems through use of behavioral and cognitive techniques (such as self-regulation and metacognitive training) to aid function in the environment.42 This "compensatory strategy" approach is found in the pediatric behavioral medicine and neuropsychology literature. Specific strategies can include social skills training, audio-taping of lectures, teaching participants to make written outlines of reading material, using oral and written forms of tests, self-instructional training (SIT) and applied relaxation training.44 Butler and Copeland42 conducted a preliminary randomized, wait-list control trial with CRP that in essence combines the traditional cognitive rehabilitation and compensatory strategy approaches. Cognitive remediation program consisted of components similar to Attention Process Training (APT)14 a multifaceted approach to enhance cognitive and behavioral function in specific areas of directed attention and distraction reduction. Twenty-one participants (mean age, 11.9 years, SD = 3.7) who were on average 4 years post-cancer treatment-treatment (SD = 3.7) enrolled in the CRP program. Compared to controls (N = 10), the CRP participants made significant gains in scores of sustained vigilance/attention (Continuous Performance Test), p < .04, and sentence memory, p < .05. Cognitive remediation program holds great promise for the population of pediatric cancer survivors. However, participants in the study had a variety of cancer treatments beyond chemotherapy (e.g., irradiation and surgical treatments) and six participants had central nervous system cancer, suggesting this intervention is best suited for developing pediatric cancer survivors who likely require intensive cognitive remediation and less suited for adult chemotherapy recipients. The concern about CRP is that it is a lengthy treatment consisting of up to 50 hours of training sessions. Adult chemotherapy recipients returning to vocational or social roles following treatment recovery may view the time commitment to CRP as too great. From that standpoint, a brief compensatory treatment approach may be helpful for the rehabilitation and readjustment to functional activity following cancer treatment.45 Our group has developed a program with these aspects in mind.

5.0. COGNITIVE BEHAVIORAL MANAGEMENT

Memory and Attention Adaptation Training (MAAT) places an emphasis on learning strategies to compensate for subtle memory problems in daily life. This is a slight departure from a more traditional cognitive rehabilitation approach. Emphasis is placed on maximizing function and adaptation in the natural environment and not necessarily on cognitive restoration as measured by neuropsychological test performance.15 In effect, MAAT presumes that the problem of chemotherapy-related memory dysfunction can be conceptualized from a "diathesis-stress" framework. That is, under times of low demand, such routine times at the workplace or household, cognitive dysfunction may not be a hindrance or cause undue interference. If problems of memory or attention arise, they are readily handled. By contrast, under times of high performance demand such as sales presentations, dispensing

Table 1. Outline of Memory and Attention Adaptation Training. Visit Content

1

Treatment overview & provision of workbook

Education on memory and attention and effects of chemotherapy

Self-monitoring instruction

Relaxation training

Homework

Phone Contact 1

Review Homework, problem solve

2

Homework review

Compensatory strategy(ies) selection, instruction, and rehearsal

Homework

Phone Contact 2

Review Homework, problem solve

3

Homework review

Compensatory strategy selection, instruction, and rehearsal

Activity pacing and scheduling

Homework

Overview

Phone Contact S

Review Homework, problem solve

4

Homework review

Compensatory strategy review

Activity pacing and scheduling review

Plan for relapse prevention

Wrap-up

dangerous medications, or socializing where simultaneous conversations occur, cognitive failures may become a greater hindrance to functional performance.

Specific techniques used in MAAT are drawn from the cognitive-behavior therapy (CBT) and rehabilitation literature related to an array of problem areas. These include: mild traumatic brain injury cerebral damage due to stroke or brain trauma and reading comprehension/attention.15,46-49 Memory and Attention Adaptation Training is organized into four components: (1) education (on chemotherapy-related cognitive problems and other influences on attention and memory such as stress); (2) self-awareness training (self-monitoring to identify "at risk" situations or conditions associated with cognitive failure); (3) compensatory cognitive skills training; and (4) applied relaxation training for arousal reduction. Similar components have been demonstrated to aid patients with chronic symptoms associated with mild traumatic brain injury, stroke, and cancers of the central nervous

The MAAT format could be characterized as falling on a spectrum of "guided self-help" in that the patient uses a workbook in conjunction with visits to the treating clinician. Memory and Attention Adaptation Training consists of four individual visits, once every 2—3 weeks, with three phone contacts (One between each visit) for support and review of procedures. This is a total of seven contacts. Visits are typically 50 minutes each. Participants also complete homework assignments or "applied exercises" between visits and thus telephone contacts serve as a venue to problem solving or address questions (see Table 1).

6.0. EVALUATION OF MAAT

Empirical investigation of MAAT efficacy is underway but far from complete. However, pilot research and preliminary data point to some support. In a single-arm feasibility study, 29 breast cancer survivors who were on average 8.2 years post-chemotherapy (SD = 4.4 years) completed the MAAT program. Principal outcome measures included self-reported cognitive function in daily life as assessed by The Multiple Ability Self-Report Questionnaire (MASQ)50,51; The Quality of Life Cancer Survivors scale, satisfaction ratings and a brief neuropsychological testing battery (the California Verbal Learning Test-II (CVLT-II)52; Logical Memory I and II from the Wechsler Memory Scale, 3rd Edition53; Digit Symbol subtest from the Wechsler Adult Intelligence Scale III54;Trail-making tests A & B55; Stroop Color-Word Interference Test.56 Testing occurred at four time points: baseline, posttreatment, 2-month, and 6-month-follow-up. Participants were excluded if they had any history of neurological problems such as prior traumatic brain injury or central nervous system disease, substance history, epilepsy, or severe psychiatric illness. Results indicated a significant reduction in self-reported daily cognitive complaints as assessed by the MASQ, improved quality of life and high satisfaction ratings. Neuropsychological test score improvements were observed in tests of verbal memory (total score for the CVLT-II, Logical Memory Tests) and in processing speed. These neuropsychological test results, although positive, are interpreted with caution as there was no control group to rule out the effects of practice with repeated testing. Nonetheless, the pilot results did justify further investigation.

In a study being completed at the time of this writing, 26 breast cancer survivors at 18 months posttreatment were enrolled in randomized, wait-list control trial of MAAT. The mean age of participants was 50.7 years (SD = 6.2). The same exclusion criteria were used as in the previous study to rule out neurological or psychiatric influences on cognitive performance. Preliminary results were examined. Those individuals who were randomized to MAAT demonstrated reduced number of daily cognitive complaints relative to wait-list controls at posttreatment with adjustment to baseline differences in MASQ scores. Memory and Attention Adaptation Training participants also demonstrated some improvement in verbal memory as assessed by CVLT-II total score as compared to controls, and also provided high general satisfaction with treatment ratings. None of the results demonstrated statistical significance but the direction of trends suggest the MAAT participants improved in daily cognitive function and the approach continues to be modified to improve its impact, particularly given the absence of alternatives at this time.

Two other important points regarding the development and evaluation ofMAAT need to be made. First, the approach the MAAT program takes is a practical and efficient delivery of existing methods to help individuals manage and cope with every day cognitive problems that can arise after a life-disrupting diagnostic and treatment process. It may be that self-efficacy in the mastery over cognitive symptoms in daily life is the key variable that MAAT targets and hence coping with, not curing, cognitive problems should be the principal aim of MAAT. Future research on MAAT should include self-efficacy in coping with cognitive problems as a dependent measure. A second point is related to using standardized neuropsychological tests as principal outcome measures. Current neuropsychological testing may not be sensitive to the subtle changes in daily cognitive function that many chemotherapy recipients report. While research cited earlier clearly shows differences in standardized neuropsychological test scores between groups of cancer survivors who do and do not undergo chemotherapy, these results show many cancer survivors who have cognitive complaints score in a normal range. Certainly, development of standardized tests of neuropsychological function in functional domains utilizing advance computer technology may help enhance identification of subtle changes in memory and attention function among affected cancer survivors. Development of such testing will be highly valuable to future cancer survivor research, such as that in the development of MAAT. In the case illustration to follow, these points are evident in the context of a breast cancer survivor who begins the process of adapting to life with cancer and long-term symptoms associated with treatment.

7.0. CASE VIGNETTE

The following case vignette illustrates the application of MAAT: Ms. A. is a 53-year-old university professor who was diagnosed with breast cancer with findings of a 2 cm tumor with 1 of 12 lymph nodes positive. Her tumor was low grade, estrogen and progesterone receptor positive. She had a lumpectomy and subsequently treated with four cycles of doxorubicin cyclophosphamide (AC) followed by radiation therapy to the breast. She then started hormone therapy with daily tamoxifen. She had taken an 8-week leave of absence from summer classes in her recovery from surgery and subsequent chemotherapy. She later resumed her position of instruction and writing at a reduced workload during her course of radiation treatments. While she experienced stress and fatigue during this time period she had no other complaints. Her family and social support network were regarded by her as satisfying and her economic needs were adequately met. After completing treatment she began to resume a full teaching load, committee work, and journal editing tasks that she had regularly completed prior to the onset of breast cancer.

When she began to resume full duties, Ms. A. began to notice she had word-finding difficulty during class lectures. She noticed that in the middle of explaining a technical concept, she would lose a word well-known to her and become frustrated and anxious, making the word-finding problem all the more difficult. She also began missing important meetings that she thought she had scheduled in her day planner and noticed that others would remind her of conversations she recently had for which she had no memory.

Ms. A. had inquired about the problem and was evaluated with a brief neu-ropsychological test battery. As seen in Table 2, her verbal memory performance as evaluated by the CVLT-II was in the normal-high range. She also completed tests of visual motor processing speed with similar findings of average scores. While

Table 2. Baseline and Posttreatment Neuropsychological and Self-Report Test Results of Ms. A.

Pretreatment Posttreatment Normative

Test scores scores comparison scores

Table 2. Baseline and Posttreatment Neuropsychological and Self-Report Test Results of Ms. A.

Pretreatment Posttreatment Normative

Test scores scores comparison scores

MASQTotal Score (higher score, more

120

93

B1.25 (SD = 18.67)

cognitive failures)

CVLT-II Total Score (T-Score)

61

70

Digit Symbol Subtest of the Wechsler Adult

10

13

Intelligence Scale-III (scaled score)

Stroop Color-Word Test (in seconds; lower

56

49.5

scores indicate better performance)

CES-D (Depressive Symptoms; <16 normal

10

6

range)

State Anxiety T-score

47

40

these neuropsychological tests demonstrated normal performance, it may have been slightly lower than expected given her estimated premorbid intellectual functioning (IQ equivalent score of 127). Her responses to the MASQ indicated the total score was 2.1 standard deviations above the mean of a sample of healthy women of comparable age (higher scores denote more cognitive complaints). Ms. A. did not report depressive or anxiety symptoms on standardized self-report measures that were in a clinical range, suggesting that depression or anxiety was not solely accountable for cognitive complaints.

MMAAT Visit 1. Ms. A. began the MAAT program. In the first visit she was provided with a patient workbook and the background and educational highlights of cognitive effects of chemotherapy. An important point made during this time is showing patients data from the healthy control participants in previous research.57 Essentially, everyday cognitive failures such as forgetting people's names, phone numbers, or where they placed belongings such as house keys are relatively common among healthy individuals. Interestingly, reported cognitive failures in these samples are similar in type to those reported by individuals following chemotherapy. The intent of pointing this out to affected cancer survivors is not to minimize or invalidate memory and attention problems following chemotherapy. Rather, the intent is to help cancer survivors recognize cognitive failures in daily life are common to all people and not every cognitive failure is attributable to chemotherapy. Other factors contributing to cognitive failure of daily life include stress, fatigue, environmental distractions, hunger, etc.—factors that are readily manageable and understood. While the effects of chemotherapy may be poorly understood, at least common factors that contribute to attention and memory failures can be addressed with behavioral strategies with relative ease. This is an important step in MAAT as it lays a therapeutic expectation of management of daily cognitive failures and not elimination of the problem—an impossible goal, given healthy control self-report data cited previously. This step also helps the participant in MAAT reduce distress-inducing attributions that could lay the cause of memory problems to factors that cannot be changed and thus spawn more feelings of helplessness. Therefore, a goal of MAAT is to prevent this helpless cycle and improve coping and self-management.

In the remainder of visit one, Ms. A. was instructed to self-monitor memory problems. She was instructed to fill out forms that identify environmental (e.g., noise), internal (e.g., fatigue, hunger), and affective (e.g., anxiety, stress) factors associated with memory failures that were judged by her as interfering. She was asked to complete forms on four to six experiences that exemplified problematic cognitive failures (journaling all cognitive failures would be impractical). Finally, Ms. A. was provided instruction in progressive muscle relaxation (PMR). The intent of PMR is to provide an arousal self-regulation strategy to help manage stress that can interfere with memory processes of recall and directed attention. Ms. A. completed the session with rehearsal of a 17-minute PMR exercise and was provided a CD for daily practice at home.

MMAATPhone Contact 1. Between visits 1 and 2 a scheduled 5-minute phone contact revealed a pattern where Ms. A. was experiencing anticipatory anxiety about word retrieval during class lectures. She also indicated difficulty following conversations at faculty meetings or when socializing with small groups of friends. A factor contributing to this was difficulty ignoring unimportant verbal content when several conversations co-occurred. She reported gradually avoiding these situations and was disappointed that she was withdrawing from valued relationships both at work and her social life. These situations were to be reviewed in visit 2.

MÁAAT Visit 2. In visit 2, time was spent reviewing PMR and self-monitoring of situations described above. With respect to PMR, an important question to ask is whether the participant has increased awareness or "mindfulness" of muscle tension in daily life. While daily rehearsal of PMR is important, the intent of the practice is to increase awareness and self-reduction of muscle tension in daily activity. Increased arousal and muscle tension is hypothesized to adversely affect cognitive processing such as recall or focused attention. Ms. A. reported that she got deeply relaxed during practice sessions and that she noticed her shoulders were tense during work hours. She was then coached in "quick relaxation" which is a method designed to help reduce muscle tension quickly to promote application of relaxation skills to everyday life. After this, Ms. A. again identified problems with following conversation in small groups. She noticed that she avoided going out with friends at regular gatherings. When she did socialize with her group of friends, she was withdrawn and quiet. She rated this as more important than her word-finding problems in class and out of concern it would adversely affect her friendships. Given this, a brief review of compensatory strategies in the MAAT manual was reviewed. It was decided that verbal rehearsal would be used in the form of attentive listening to one speaker, and clarifying what was said in an assertive but natural way—akin to an interviewer using reflection and clarification techniques to assure mutual understanding of what the interviewee is communicating. This was modeled and role-played in the visit with the clinician modeling the technique, then acting as the speaker. Ms. A. then left with the assignment of using the strategy in daily conversations as a means of practicing the strategy.

MÁAAT Phone Contact 2. In the second phone contact, Ms. A. noted that quick relaxation was a practical and efficient way for her to apply relaxation skills to everyday life. She noted she was less tense in daily conversation with others and in the classroom. She also indicated it helped her recall of words during lectures. This was surprising to her. Finally, she related that using verbal rehearsal and clarifying her communication with others lead her feel more at ease and she was enjoying her time socializing again. She attributed this to "going with the problem, not stopping it."

MÁAAT Visit 3. The third office visit of MAAT consisted of reviewing strategies to date and selecting another compensatory strategy. Ms. A. indicated that not only was she following conversations with ease she reported less difficulty with verbal recall in the classroom. Further, when she did happen to be "stuck" without a word mid-sentence, she reported she began to ask the class for the term or phrase she was struggling with in a "Socratic, academic fashion." In this way, she was increasing class participation at the same time she was managing her problems with word recall. The visit ended with a review of SIT,58 which is a method to improve task attention and procedural memory. It involves "self-talk" or making overt the inner verbal dialogue one uses in completing tasks such as writing or any task involving discreet steps. She was also briefly instructed in activity scheduling, which was another stress management strategy drawn from both the Cimprich13 study and depression treatment literature.59 It simply involves scheduling a brief, pleasant activity each day to build in a positively reinforcing daily event that reduces the impact of tension and negative affect. The rationale for activity scheduling in MAAT is to provide another strategy that optimizes stress management and minimizes the effects of stress or negative affect on cognitive function.

MÁAAT Phone Contact 3 and Visit 4. In the last phone contact and final visit of MAAT, all strategies were reviewed. The phone contact focused on review of SIT and its application at the workplace. At visit 4 a maintenance plan was reviewed in detail

Table 3. Proposed Directions for Future Research

1. Longitudinal research (e.g., assessment of neuropsychological function before, during, and after cancer treatment) to determine the relative effects of chemotherapy on attention and memory performance.

2. Development of functional neuropsychological measures of memory and attention in daily tasks; perhaps making use of virtual reality technology to simulate "real world" memory and attention tasks. This may tap into subtle memory and attention failure that becomes more salient under conditions of increased demand for cancer survivors.

3. The role of APOE and other genetic markers in the long-term effects of chemotherapy on memory and attention function.

4. Continued evaluation of MAAT and other cognitive rehabilitation strategies for cancer survivors who have undergone chemotherapy or other cancer treatments.

5. Research on possible pharmacological or combined pharmacological and cognitive-behavioral strategies for management of cognitive dysfunction after chemotherapy.

6. The development and evaluation of possible "chemo-protective" agents to prevent chemotherapy-related cognitive problems.

as a means of helping Ms. A. maintain use of the strategies she has used to date, and to at least once per month review the manual to assure she is applying the strategies as planned. The maintenance plan was also explained as a way to build on skills learned and that the end of the brief treatment was only the "end of the beginning." In the future, new tasks or changes in social or vocational roles may require more or different memory functions and thus reviewing the manual on a regular basis was a means of always being prepared for new cognitive challenges that may arise. She was encouraged to call the clinic with questions.

8.0. SUMMARY

While much research remains to be completed on the cognitive effects of chemotherapy, it is hoped that this chapter has summarized knowledge to date and some future directions for treatment. To be sure, pharmacological interventions and chemo-protective agents may hold promise in preventing this widespread problem given the increasing numbers of individuals who undergo chemotherapy annually. More research on genetic and hormonal influences and their interaction with fatigue, anxiety, and depression are needed to discern their collective influence on function (see Table 3). Continued development and refinement of the MAAT program and similar strategies on many outcomes of importance to survivors (e.g., self-efficacy in self-management of daily cognitive problems, coping, vocational adjustment) is urged. It is hoped that this research will offer cancer patients and their families useful and practical methods to manage this is all too common problem that while subtle, can have significant impact on the survivor's function and overall quality of life.

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