SYMPTOM SCIENCE IN CANCER SURVIVORS: ADVANCES IN BIOLOGY AND MANAGEMENT

Transcription

1 SYMPTOM SCIENCE IN CANCER SURVIVORS: ADVANCES IN BIOLOGY AND MANAGEMENT Patricia A. Ganz, MD Jonsson Comprehensive Cancer Center UCLA Schools of Medicine & Public Health Society of Integrative Oncology Meeting-Keynote 2 Lecture October 28, 2018

2 Disclosures I have no financial relationships to disclose. I will not discuss off label use and/or investigational use in my presentation.

3 Why study symptoms in cancer survivors? More than 40 million cancer survivors worldwide In the USA, there are more than 15 million cancer survivors; > 5% of the population More the 66% of cancer patients will be long term survivors; most over 65 yrs of age Ongoing need for medical care, increased comorbidity The number of cancer survivors will increase sharply during the next 25 yrs with aging of the population

4 18 Million U.S. Cancer Survivors Projected in 2022

5 Definitions Long-term effect: a symptom or problem that begins during cancer treatment and persists when treatment ends e.g., fatigue, cognitive complaints, pain Late effect: a symptom or problem that occurs months to years after treatment ends, e.g. a second cancer, congestive heart failure, lymphedema Some symptoms or problems can either be long-term or late effects---confusing!

6 Comparison of cancer survivors and age-matched individuals from the National Health Interview Survey (NHIS) in 2000 Multiple measures of burden embedded within the survey JNCI 96:1322, 2004

7 Health Status is Significantly Poorer in Cancer Survivors Cancer Survivors (N=1817) Noncancer Controls (N=5465) Excellent Very Good Good Fair Poor 31% Fair & Poor 18% Fair & Poor Yabroff, JNCI 2004 P <.001

8 Number of Comorbid Conditions Burden of Illness is Greater in Cancer Survivors % Ca Surv Noncancer P< >= 3 Yabroff et al. JNCI 2004

9 Cancer Survivors Need More Help with Activities of Daily Living (ADLs) Cancer survivors N=1817 Noncancer controls N=5465 Needs help with instrumental ADLs 11.4% 6.5% Any limitation in any way 36.2% 23.8% Needs help with ADLs 4.9% 3.0% P <.001 P <.001 P=.003 Yabroff et al. JNCI 2004

10 Comorbid Conditions Causing Limitation in Cancer Survivors Condition causing limitation, % CA Survivor Control P-value Arthritis/rheumatism Back/neck problem Fracture/bone/joint injury Heart problem Stroke Hypertension Diabetes Lung/breath problem Depression/anxiety/emotional problem Weight problem Musculoskeletal problem Yabroff et al. JNCI 2004

11 Common Survivorship Concerns Pain Fatigue Depression Insomnia Physical limitations Cognitive changes Lymphedema Sexual dysfunction Neuropathy Menopause-related symptoms Body image changes

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13 Not just tired During cancer therapy I always felt the exhaustion of physical exercise without any of the positive attributes.my limbs felt heavy. The quality of my sleep was changed. The mere act of sleeping itself seemed like work sometimes. My brain felt tired and so did my spirits. I seemed to have lost my zest for life. (Poulson, 2001)

14 Inflammation Body s response to infection or injury Mediated by proinflammatory cytokines IL-1β, IL-6, TNF-α Local and systemic effects, including effects on CNS

15 Tissue Trauma, Inflammation, CNS Response Cancer treatments Sickness Behavior

16 Cancer-related Fatigue Fatigue is the most common side effect of cancer and its treatment Occurs in 60 96% of patients during treatment (Wagner & Cella, 2004) Fatigue may persist for months or years after successful treatment completion 30% of breast cancer survivors report fatigue 1-5 years postdiagnosis (Bower et al., 2000) 63% of fatigued survivors continue to report fatigue 5-10 years post-diagnosis (Bower et al., 2006)

17 Description of Cancer-related Fatigue Different than normal fatigue due to lack of sleep or over-exertion More pervasive, debilitating, longer-lasting Involves physical, mental, emotional components Not relieved by adequate sleep or rest

18 Fatigue occurs across different types of cancer and different types of cancer treatment Mechanisms underlying cancerrelated fatigue have not been determined

19 Why is it important to understand biological mechanisms of symptoms? Identification of underlying biology provides support/validity for complaints Leads to possible interventions (pharmacological or behavioral) Potential for prevention, if at-risk individuals identified Possible relationship to tumor biology and progression

20 What causes fatigue? Associated risk factors. Comorbid medical conditions Cardiovascular disease BMI Comorbid symptoms Pain Menopausal sx Sleep disturbance Biological factors Anemia Inflammation Fatigue Health behaviors Physical activity Demographic factors Age Income Marital status Psychosocial factors Depression Catastrophizing coping style

21 What is driving persistent inflammation in long term survivors? Alterations in cellular immune system* *Earlier studies in breast cancer survivors >5 years after diagnosis, comparison of fatigued and non-fatigued

22 Focus on HPA axis Glucocorticoids have potent anti-inflammatory effects HPA axis dysregulation linked to inflammatory disease (e.g., Jafarian-Tehrani & Sternberg, 1999) Fatigued breast cancer survivors show lower levels of morning serum cortisol (Bower et al., 2002)

23 Response to Psychological Stress TSST: Speech + mental arithmetic Subject prepares speech on personal strengths and weaknesses and delivers it to an evaluative panel Performs mental arithmetic with harassment 0 min 15 min 30 min 45 min 60 min 75 min TSST=Trier Social Stress Test

24 Response to Psychological Stress TSST: Speech + mental arithmetic 0 min 15 min 30 min 45 min 60 min 75 min Saliva LPS-stimulated cytokine production

25 Cortisol Response to Stress In Long-Term Breast Cancer Survivors Fatigued Non-fatigued * * Salivary cortisol (ug/dl) TSST * * Baseline 15 min 30 min 45 min 60 min 75 min Time Bower et al., Psychosom Med, 2005 Group x Time interaction: F = 4.5, p =.001

26 Stress-induced Changes in Cytokine Production Elevated cytokine production in fatigued BCS Significant effects for IL-6 and IL-1β; marginal for TNF-α IL-6 (pg/ml) / monocytes (log 10) Fatigued Baseline 30 minute recovery Non-fatigued Bower et al., Brain Behav Immun, 2007

27 Cortisol Response and IL-6 Production Stress-induced changes in cortisol are negatively correlated with stress-induced changes in IL-6 production Bower et al., 2007

28 Design of the UCLA Mind Body Study Longitudinal Cohort Study Ganz, et al., JNCI 2013

29 No Chemotherapy Chemotherapy Increased levels of TNF are associated with greater fatigue severity in patients treated with chemotherapy

30 Associations between three individual SNPs in the promoter regions of these cytokine genes and severity of fatigue and cognitive complaints at baseline (n=171) Bower et al., JCO, 2013

31 Additive Genetic Risk Score for These SNPS Bower et al., JCO, 2013 Patients with more high expression alleles have more severe fatigue and cognitive complaints Genetic risk index is significantly associated with greater fatigue and cognitive changes

32 stnf-rii (pg/ml) stnf-rii Change over 1 year by Chemotherapy Treatment Status (n=93) p<0.01 Chemotherapy No Chemotherapy p=0.02 p= T1 T2 T3 Ganz et al., Brain Behav Immun, 2012

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34 Change in Left Broca s Metabolism As TNF declines, there is improved prefrontal activity Chemotherapy Subject with High stnf-rii Baseline stnf-rii: 4051pg/ml r=0.73, p=0.01 r=0.73, p=0.01 Chemotherapytreated subjects (n=11) 0.01 Baseline 1-year followup Chemotherapy Subject with Low stnf-rii Baseline stnf-rii: 1605pg/ml Baseline stnf-rii Levels (ng/ml) Baseline 1-year followup Ganz et al., Brain Behav Immun, 2012 Anterior GFi* Posterior GFi* (including Broca s Area) *GFi= inferior frontal gyrus

35 Fatigue Trajectories in MBS Still High Fatigue Bower et al., Health Psychology, in press

36 Exposures and Fatigue Trajectories Women who received chemotherapy were more likely to be in High and Recovery groups Women who received endocrine therapy were more likely to be in the High vs. Recovery Women who had greater depressive symptoms at baseline were more likely to be in the High and Recovery groups No factor distinguished Low-Very Low from Late group Bower et al., Health Psychology, in press

37 How can we treat cancer-related fatigue? If possible, identify and treat underlying factors Depression Physical symptoms (sleep disturbance, pain) Anemia Medical conditions

38 Non-specific Interventions Pharmacologic Antidepressants Psychostimulants Behavioral/Psychological Psychosocial Exercise Complementary and alternative medicine

39 Complementary and Alternative Medicine (CAM) Interventions Many cancer patients and survivors use CAM therapies Acupuncture Tai Chi, Qigong Energy therapies Yoga

40 Yoga for Cancer-related Fatigue Yoga incorporates active components of interventions with beneficial effects on fatigue Exercise Stress management/relaxation Adaptable for fatigued patients who may not be able to participate in standard exercise programs

41 Cancer weeks, two 90-minute classes per week Based on teachings of B.K.S. Iyengar Focus on poses thought to be effective for reducing fatigue Passive backbends Passive inversions Specific sequencing of poses, moving from easier to more challenging

42 Iyengar yoga significantly improves vigor and reduces severity of fatigue in breast cancer survivors. Bower, Cancer 2012

43 The yoga intervention reduced stnfr2 in comparison to health education and decreased activity of NF-κB and increase activity of glucocorticoid receptor (GR) in a gene expression array evaluation.

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45 Cognitive changes: Scope of the problem 45-60% of survivors in recent surveys endorsed experiencing cognitive difficulty Cross-sectional studies show 17-75% of breast cancer survivors showed cognitive deficits 6 mos to 20 years after exposure to chemotherapy Longitudinal studies showed subgroup of 15-25% vulnerable to lasting cognitive problems Not just chemotherapy: Radiation Endocrine therapy Deficits BEFORE treatment Ahles, et al. (2012). JCO Stouten-Kemperman, et al. Brain Imaging and Behavior (2015) 9: 275. Phillips et al. (2012). Cancer, 118: doi: /cncr Castellon, et al. (2004). J Clin Exp Neuropsychol, 26(7): Ganz, et al Journal of the National Cancer Institute, djt073. Ahles et al. Breast Cancer Res Treat. 2008;110: Schmidt, et al. J Cancer Surviv. 2016;10(2): Buchanan, et al. Am J Prev Med. 2015;49(6):S498-S508

46 Survivors Complaints I m still able to function. It s just the fine degree of memory or the speed at which I d be able to recall information. So when I leave at the end of the day, I am spent, when before I was energetic. And it s not a physical spent; it is a mental spent that I didn t used to have. I m just not as sharp as I was I used to be able to think on my feet really well and that edge is just totally gone now. Boykoff, N., Moieni, M., & Subramanian, S. K. (2009). Journal of Cancer Survivorship, 3(4),

47 Candidate Mechanisms Ahles and Saykin Nature Reviews Cancer 7, (March 2007) doi: /nrc2073

48 Multi-factorial Etiology Anxiety and depression Pre-existing genetic factors Changes in estrogen levels Toxic effects of chemotherapy Proinflammatory cytokines influence on brain function High functioning individuals may be more likely to notice subtle changes

49 Recent Commentaries

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51 Cognition over the Lifespan Adapted from Park & Bischof, 2013

52 White Matter Integrity Inflammation is associated with reduced white matter integrity in aging over the lifespan In breast cancer survivors, reduced white matter integrity noted post-chemotherapy in corona radiata, corpus collosum, and superior longitudinal fasiculus

53 What are the consequences? During a memory task, older individuals need to recruit more areas of the brain than younger individuals to perform similarly a compensatory response We see a similar effect in cancer survivors post treatment

54 Reduced Efficiency in Cancer Survivorship Chemotherapy No Chemotherapy Ferguson, R. J., McDonald, B. C., Saykin, A. J., & Ahles, T. A. (2007). Journal of Clinical Oncology, 25(25),

55 PET SCAN ACTIVATION DURING A MEMORY TASK Chemotherapy No Chemotherapy Study in Long-term (> 5 yrs) Breast Cancer Survivors, Silverman et al Chemotherapy exposed brains may have to work harder and engage different or more regions to compensate for damage to neural networks. Frontal areas seem most affected.

56 Cognition Takes More Energy May have the experience of cognitive inefficiency but performance is actually OK Cancer survivor: Consistent with correlation with mental fatigue and reports in qualitative literature of feeling more exhausted at the end of the day O Farrell et al. Current Oncol Rep (2013) 15: de Ruiter, M. B., & Schagen, S. B. (2013). Brain imaging and behavior, 7(4), Ferguson, R. J., McDonald, B. C., Saykin, A. J., & Ahles, T. A. (2007). Journal of Clinical Oncology, 25(25), Ganz, P A., et al. Journal of the National Cancer Institute (2013): djt073.

57 P=.02 P=.007

58 Carroll, et al., Cognitive Performance in Breast Cancer Survivors and Markers of Biological Aging, Cancer in press Mean neuropsychological test score by domain in cancer survivors categorized by low DNA damage and high DNA damage Learning Memory Attention Visuospatial Executive Function Processing Speed Memory and Executive function, p< Low DNA Damage High DNA Damage

59 Neuropsychological Test Scores Scatterplot executive function and psychomotor scores as a function of telomerase enzymatic activity (deciles) in breast cancer survivors. Lower scores indicate worse cognitive performance Carroll, et al., Cancer in press -3-4 Telomerase Enzymatic Activity (TPG per 10,000 cells) Attention Executive Function Processing Speed Linear (Attention) Linear (Executive Function) Linear (Processing Speed) P<.05

60 What can be done to help with cognitive changes? First, address untreated depression, pain, and anxiety Ensure adequate sleep Focus on management of fatigue If complaints persist, obtain consultation from a trained neuropsychologist familiar with cancer treatment Role of pharmacological agents uncertain

61 Cognitive Training Strategies Results in pediatric cancer survivors suggest benefits from individualized cognitive rehabilitation Few studies in adults, but some early results suggest benefit Computerized training strategies Cognitive behavioral therapy Memory training Speed processing training.

62 Potential Treatments Anti-inflammatory agents, and drugs that affect cytokines have theoretical promise-not yet studied Cognitive-Behavioral therapy promising for stress reduction, sleep disturbance, but very few studies target cognition Exercise not studied in cancer survivors although exercise is beneficial for cognitive changes related to aging, mild cognitive impairment Cognitive rehabilitation strategies

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64 Study Results/Conclusions Both interventions showed improvements in symptoms, selfreported cognitive complaints, and NP test results Domain specific efficacy was noted Acceptability and feasibility Need to be tested in larger samples and beyond breast cancer patients

65 48 breast cancer survivors with moderate to severe cognitive dysfunction interfering with everyday activities 32 randomized to intervention and 16 to a waitlist control 5 week group-based cognitive rehabilitation intervention adapted for breast cancer survivors Pre and post-intervention, and 3 month follow-up questionnaires, neurocognitive assessments and quantitative EEG (qeeg) assessments, with additional assessments

66 Intervention Content 5-week intervention, 2-hours per week Education Cognition in general Possible causes of or contributors to chemobrain Exercises in class targeting specific cognitive domains/abilities Homework Goal setting Short- and long-term goals E.g. send greeting card, exercise on treadmill, plan a trip or party, organize a room or garage Ercoli et al. Brain imaging and behavior, 2013

67 Exercise Examples Alternating Attention and Working Memory

68 RCT Study Results

69 Comparison of qeeg Results qeeg maps of delta power comparing intervention and control group Cognitive rehabilitation group showed large decreases in delta slow wave power across the whole head with largest decreases shown in blue

70 Cancer Care Trajectory Start Here Treatment With Intent to Cure Cancer-Free Survival Managed Chronic or Intermittent Disease Recurrence/ Second Cancer Diagnosis and Staging Treatment Failure Survivorship Care Palliative Treatment Death IOM, 2005

71 Survivorship Health Care Delivery The Three P s of Survivor Care Palliation Prevention Health Promotion Ganz, P A. (2011). The 'three Ps' of cancer survivorship care. BMC medicine, 9,

72 Symptom Management/Palliative Care: An Integral Part of Survivorship Care Definition of Palliative Care: Medical care or treatment that concentrates on reducing the severity of disease symptoms (particularly if there is not a curative medical treatment) Goal is to prevent and relieve suffering and to improve QOL for people facing complex illness Focus on the most severe and prolonged symptoms

73 Why is it important to understand biological mechanisms of symptoms? Identification of underlying biology provides support/validity for complaints Leads to possible interventions (pharmacological or behavioral) Potential for prevention, if at-risk individuals identified Possible relationship to tumor biology and progression

74 Cancer Care Trajectory Cancer-Free Survival Start Here Recurrence/ Second Cancer Treatment With Intent to Cure Medical Outcomes and Quality of Life Diagnosis and Staging Safer therapies Survivor health care delivery: Palliation, Prevention and Health Promotion Risk assessment and intervention at diagnosis

75 P. Ganz, M. Irwin, S. Cole, J. Bower Many thanks to my collaborators, the patients who volunteered for our research, AND funding from the Jonsson Cancer Center Foundation, the Komen Foundation, NCI, NIH, and the Breast Cancer Research Foundation.