Shift in Concerns. What Effects Survivor Cognition? Short-Term and Late-Term Effects

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1 CANCER AND COGNITION Current Knowledge and a Proposed Intervention What Effects Survivor Cognition? Short-Term and Late-Term Effects Diagnosis of cancer Surgery Anesthesia/Analgesia Pain Medications Chemotherapy HRT and anti-cancer medications Late-term effects of cancer treatment Shift in Concerns Previously, concerns related to classical side effects of chemotherapy Myelosuppression (reduced red and white blood cells and platelets) Risks of infection and bleeding Nausea and vomiting Currently, there is significant concern of the psychosocial impact of chemotherapy and other cancer-treatment related symptoms Chemo-brain Fatigue/sleep deprivation Loss of self, and loss of a sense of mastery

2 Short vs Long-Term Effects For most patients, the problems appear subtle and often improve after ceasing chemotherapy. However, for a sub-set of patients, symptoms continue to impact QOL and cognitive ability. In clinical trials, cognitive dysfunction reports, after chemotherapy, range 15 to 50% of patients; in some studies, this figure is as high as 75%. In most studies, symptoms improve with the passage of time between a few months (acute conditions) and 2 to 10 years (long-term), although cognitive function may not return to pre-treatment levels. The Effects of Chemotherapy These abnormalities are characterized by Slow mental processing with difficulties with Attention Encoding Retrieval of information Psychomotor slowing. The Effects of Chemotherapy Neuropsychologists believe these types of deficits are most consistent with sub-cortical abnormalities.

3 CHALLENGES TO KNOWING Published clinical trials often used different Neuro- Psychological (NP) tests to assess cognitive function. Tests are not necessarily designed specifically for cancer patients. The NP tests typically did not correlate with self-reported cognitive dysfunction by cancer patients. Why? Challenges to Knowing The NP tests did not adequately measure issues of multi-tasking, a major complaint of cancer survivors. They also did not test cognitive function during real-life experiences, post-treatment. The cognitive challenges reported by cancer survivors were multi-factorial, and not easily measured with existing NP tests. New tests need to be created that measure the real-world cognitive challenges of cancer patients, post-treatment. EXAMPLES OF STUDY OUTCOMES WHAT THEY TELL US; WHAT THEY DON T

4 Seminal Studies Wieneke & Dienst performed the first comprehensive NP tests to evaluate cognitive impairment in breast cancer survivors, 3-18 months post-chemotherapy and compared it to normative data. 75% of chemotherapy patients demonstrated cognitive impairment, rating two standard deviations below the norm, on at least 1 of 16 cognitive tests Seminal Studies No association was found between the level of cognitive impairment and chemotherapy regimen, time from completion of treatment, or level of depression. Duration (length) of treatment was associated with worse cognitive impairment. Main cognitive abilities impacted were concentration and memory. Study weaknesses: Cognitive impairment was compared to a norm (not pre-treatment levels) and cognitive impairment was defined as two S.D. below the norm on only one test. Seminal Studies Van Dam et al. compared lymph node-positive breast cancer patients randomized to standard dose chemotherapy (5-fluorouracil, epirubicin and cyclophosphamide [FEC]) + tamoxifen or high-dose chemotherapy (FEC-cyclophosphamide, thiotepa, carboplatin (CTC) with peripheral blood stem cell transplant) + tamoxifen or a control group with stage 1 cancer who received no chemotherapy. Patients were, on average, 2 years postchemotherapy.

5 Seminal Studies Two standard deviations below norm determined impairment. NP testing revealed 32% of high-dose patients still had impairment; 17% of standard-dose were still impaired, and 9% of controls were impaired (local treatment only). (p=0.043) Important: This study demonstrated dosedependent outcome. Follow-up at 4 years showed cognitive improvement in all groups. Seminal Studies Ahles et. al assessed breast cancer/lymphoma survivors 5+ years after receiving treatment and compared cancer patients who received chemotherapy with those who received local treatment only. 39% of cancer patients who had chemotherapy had cognitive impairment; 14% of patients receiving local treatment had cognitive impairment (p<0.002). Although cognitive impairment was global, verbal memory and executive function domains were most affected. Seminal Studies The Tortonto group found a 50% impairment of function with chemotherapy, although cognitive function improved to normal range in most subjects 1-2 years later. CAVEAT: Reviewers observed that improvement in scores may have been due to practice effects of testing.

6 Seminal Studies Welfal et al. combined data from 3 studies (N=84) after patients received either surgery or coreneedle biopsy but before receiving any chemotherapy. They reported that 35% of patients had cognitive impairment. However, There was no control group and Impairment was defined as low score on 1 of 14 tests. Main areas of impairment were verbal learning (18%) and memory (25%) Seminal Studies Welfal also undertook a prospective longitudinal study of 18 breast cancer patients. Prior to chemotherapy, 33% of patients already had some levels of cognitive impairment; 6 months after chemotherapy, 61% declined from their pre-chemotherapy baseline on at least one tested domain. Seminal Studies At 18 months, 50% of those who had declined had improved; but 50% remained stable (that is, they had not improved on any measure). Areas affected included: Attention, Learning speed, and Information processing speed. No correlation was found between cognitive function, depression, anxiety, age, education, menopausal status, radiotherapy, HRT history, or tumor stage.

7 IMPORTANT FINDING Important findings from Welfal studies: There may be a higher cognitive impairment rate prechemotherapy than previously reported. Reasons: Stress, A pre-existing cognitive condition, Impact of surgery, radiation, or anesthesia, Medication(s) Need to evaluate changes before any treatment begins (do a baseline before surgery, anesthesia, chemotherapy, or any medication). Stress-Related Findings Cimprich, So, Ronis & Trask found that after diagnosis, but before surgery, cognitive ability was not impaired in breast cancer patients. This suggests that issues related to the cancer treatments, not just the stress of a cancer diagnosis, may impair cognition. This was the only study located that assessed patients before any treatments (surgical, core biopsy, radiation, chemotherapy, etc). We need more prospective longitudinal studies that control for cognitive function prior to any treatment. Research Challenges: What is Cognitive Impairment? The problem with current research is clearly defining what we mean by cognitive impairment. There is little consistency in definition in the cancer studies, or in neuropsychology literature. Typically, a battery of NP tests is performed, and compared to a norm or a control group. Cut off-points are different (one, or two S.D. below the normative mean) Outcomes may not reflect the lived experience of survivors. What matters to the survivor, and what determines QOL, is how he/she performs cognitively, as compared to before treatment. The issue of norms is problematic. High performing patients, pre-treatment, may be impaired, but not register as impaired in NP tests. Even baseline at diagnosis may have its limitations, because of the shock of a diagnosis.

8 What the Survivor Experiences There are no significant associations between what survivors self-report and what objective NP tests of cognitive function find. The survivor selfreports are significantly worse than what is detected by cognitive performance tests. Why? In a critical review, Vardy & Tannock suggest the cognitive tests do not evaluate function under relevant (real-world) conditions. Survivor problems are experienced most strongly during multi-tasking functions not well tested by NPs. High functioning people may still be impaired but fall within normal range for other individuals. Emotional stress and anxiety, which exaberate existing dysfunction, are more apparent in realworld events; again, the tests don t tell the tale. Summary of Findings Chemo-brain and its consequences are underestimated by the medical and psychological community. Overview of studies suggest that cognitive deficits are diffuse, spotty across domains, and most frequently involve domains of attention, concentration, verbal and visual memory, and processing speed. What Accurately Demonstrates A Cognitive Effect? The Evidence How does one establish a causal relationship between chemotherapy and cognitive impairment? Vardy & Tannock suggest causation be evaluated based upon: Appropriate timing between the exposure and effect of chemotherapy or other treatments Strength of association A dose-response relationship Consistency Biological plausibility Specificity of association

9 The Evidence An animal study by Wenocur suggests some chemo regimens have greater neurotoxicity than others, e.g., mice were cognitively impaired (spatial, nonspatial memory, rule learning) as compared to saline-injected mice, when receiving 5-fluorouracil. Tannock et al reported that a single high dose of chemotherapy, administered per the Koolhaas model, demonstrated spatial learning and memory retention problems in mice. However, a second mouse model by Lee did not support a causal relationship between chemotherapy and cognition. The Evidence Brain imaging MRIs and PET scans support a causal relationship for chemotherapy and cognitive impairment. Compared to healthy controls, chemotherapy-treated survivors demonstrate reductions in grey matter and locally decreased white matter. Chemotherapy-treated survivors activate (light up) different parts of the brain, in response to a memory task, than nonchemotherapy treated controls. Women who received chemotherapy + tamoxifen had decreased metabolism in basal ganglia, compared to women who received chemotherapy only, or no chemotherapy. The Evidence Neurophysiological studies There are differences between cancer patients who receive high-dose chemotherapy, standard dose chemotherapy, and no chemotherapy. Event related potential (ERP) and electroencephalograms (EEG) found asymmetry of alpha rhythms (> 0.5 Hz) significant enough to be considered pathological in 42% of high dose chemo patients and 12.5% of standard dose, and none in the patients receiving only local treatment.

10 The Evidence No correlation was found between NP tests and EEG results another indicator that existing NP tests do not provide the level of assessment needed for cancer survivors. Reduced amplitude in P3 component was also found in chemotherapy patients, as compared to no chemotherapy. Note: (P3 is thought to be related to decreased activity in the norepinephrine system). Chemotherapy Studies Study by van Dam et al. found the risk of cognitive impairment to be 8.2 times greater for high dose chemotherapy than for local treatment alone and 3.5 times greater for standard chemotherapy. (p=0.006; p=0.06) This presents compelling evidence that chemotherapy may cause cognitive impairment and that it is dose related. In contrast, recent study by Scherwath et al found no statistical difference between high and low dose chemotherapy and cognitive impairment five years after treatment. The Big Picture Vandy & Tannock s critical review (38 studies) led them to conclude it is probable that the chemotherapy regimen used, and the dose and duration of chemotherapy influence the incidence and severity of cognitive dysfunction. Large longitudinal studies, with control groups not receiving chemotherapy, are currently underway and will shed more light on this issue in the future.

11 Duration of Cognitive Impairment Duration of cognitive impairment after anti-cancer treatment is uncertain; Schagen et al found impairment in patients at a median of 1.9 years after chemotherapy, but no difference between groups at 4 years posttreatment. These outcomes may be effected by practice effect rather than true improvement in cognitive function. Potential Confounders Cancer fatigue (i.e., fatigue resulting in tiredness and weakness despite adequate rest or sleep) % of patients suffer from chemo-induced fatigue which, in some patients, lasts well beyond the treatment period. Fatigue is the most common and disabling symptom of chemotherapy, impacting QOL. As assessed by Fact-F, Mar Fan et al. found that fatigue gradually improved during 2 years post-treatment, but remained significantly worse than in healthy controls at 1 and 2 years. At 1 and 2 years, fatigue was no longer associated with chemo regimen or duration, or with cognitive impairment, but associated with overall QOL and menopausal symptoms. A series of other studies have not shown a significant association between fatigue and objective NP tests a potential indicator of testing failure. Potential Confounders Anxiety, Depression and Stress Strongest predictor of depression in survivors was ongoing cancer treatment-related symptoms. Many studies found a strong association between perceived cognitive impairment and anxiety and/or depression.

12 Potential Confounders Hormonal Agents Approximately 60% of women with breast cancer have estrogen receptor positive disease, and most receive 5+ years of hormonal treatment after completing other treatments. Estrogen receptors are located throughout the brain and CNS. HRT and other anti-cancer hormone treatments may effect cognitive function. Studies found patients given tamoxifen after chemotherapy had worse cognitive functioning and that patients taking aromatase inhibitors (Arimidex, tamoxifen) had specific impairments on tasks evaluating verbal memory and information processing speed, as compared to health controls. Hormonal therapies may have confounded cognitive studies of patients who had chemotherapy and women with cancer in control groups of other studies who did not have chemotherapy, but took these agents. Cognitive Programs Various cognitive rehabilitation approaches have been reported as somewhat effective in treating groups with similar forms of cognitive impairment. The ideal intervention would combine all of the effective components to create a targeted cancer treatment intervention. Some interventions focused on restoring specific cognitive function. Others focused on memory and compensatory strategy training. Since stress, anxiety and depression can also affect cognitive function, some emphasized stress reduction. Others targeted improved sense of self-mastery. Psychosocial support was found to strengthen coping with cognitive dysfunction and improve sense of well-being. Education about cognitive challenges and how to manage them improved psychosocial functioning Follow-up phone sessions between training were found to be helpful. Envision the Rhythms Of Life (ERL) Proposed Alaskan Clinical Program for Breast Cancer Survivors

13 Definition The ERL program provides an ongoing educational, interactive, and practice-based experience of selfexploration that is motivating and that activates all five senses for the creation of health-promoting imagery. ERL specifically targets the late-term effects of breast cancer treatments (cognitive impairment, sleep deprivation, loss of sense of self-mastery). It emphasizes imagery modification (from stressful and unhealthy to healthy) and practice-based skill building. The ERL Program is based on IOM recommendations and the most current research. It also incorporates recommended changes from WomenListen and local survivors who took part in the Phase I study. Definition The educational component, explaining how what we imagine and feel modifies physiology and health outcomes, motivates patients to practice imagery. The interaction of full group and triad (three-person) work strengthens social support systems and improves communications skills. Practice outside of class builds skill in coping with short and long-term stressors. The imagery program structure is created to support selfexploration, self-empowerment, and meaningmaking, based on exploration, evaluation, and restructuring of one s unique imagery responses. Phase II Components Cognitive support for chemo-brain Emphasis on 60 second practices during the day, with automated reminders (screen savers, memory dots, textured memory objects, desk reminders), check sheets, and convenient reporting mechanisms. Fatigue and sleep deprivation support All recorded imagery scripts (on DVD) are now practiced at bedtime, with restorative sleep suggestions embedded at the end. Imagery dreaming homework is reported the next day. The DVDs can also be used in the daytime, when restorative rest is a goal. Multiple and different DVDs for practice To the keep practice fresh, different relaxation forms are available to plugin at the beginning of the DVDs. There are now specialized DVDs (for sleep, lymphadema, and other related late-term effects).

14 Phase II Components Visually engaging multi-media DVD options will be available. Professional animations (e.g., neuropeptides, cortisol rhythm, immune function, brain function) will be part of the targeted imagery training sessions. All training materials will be available on a specialized website. An additional research component has been added 15 minute bio- and neuro-feedback data will be gathered, preand post-4 month training/practice protocol. MOST IMPORTANT: The ERL program will be the only clinically tested, quality controlled imagery program, based on the specific needs of breast cancer survivors, as identified by the Institute of Medicine. The modular basis of the program make it adaptable to other forms of cancer. Summary Literature has consistently found that subsets of cancer survivors have cognitive challenges that persist after cancer treatment, and that appear to be sub-cortical in nature. Most evidence suggests chemotherapy is associated with cognitive dysfunction, although other treatmentassociated factors also contribute (it is multi-factoral). Clinically tested, and quality controlled programs need to be developed to support cancer populations. The ERL program is being developed and tested to meet that need. References Ahles TA, Saykin A. (2001). Cognitive effects of standard-dose chemotherapy in patients with cancer. Cancer Investigation, 19 (8), Ahles TA, Saykin AJ, Furstenberg CT, et al. (2002). Neuropsychologic impact of standard-dose systemic dose chemotherapy in long-term survivors of breast cancer and lymphoma. Journal of Clinical Oncology, 20 (2), Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF. (2000). Cognitive function in breast cancer patients receiving adjuvant chemotherapy. Journal of Clinical Oncology, 18, (14), Cimprich B, So H, Ronis DL, Trask C. (2005). Pre-treatment factors related to cognitive functioning in women newly diagnosed with breast cancer. Psycho-Oncology,14, (1), Deimling GT, Kahana B, Bowman KF, Schaefer ML. (2002). Cancer survivorship and psychological distress in later life. Psycho-Oncology, 11 (6), Downie FP et al (2003). Cognitive impairment, fatigue, and menopausal symptoms in breast cancer patients receiving adjuvant chemotherapy: a comparison between formal assessments and interviews with patients. In: 6 th World Congress of Psycho-oncology. Banff. Griffin AM, Butow PN, Coates AS, et al., (1996). On the receiving end: V: patient perceptions of the side effects of cancer chemotherapy in Annals of Oncology, 7 (2),

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