Aarhus 1 22022018 EPoS Psykooncology Research Unit established - - PDF document

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Robert Zachariae Professor, DMSc.

Aarhus

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EPoS

• Psykooncology Research Unit

established in 2000 at the Dept. Of Oncology, AUH based on a grant from the Danish Cancer Society

• EPoS established in 2011 in

collaboration between AUH, Dept. Of Oncology, BSS, AU, and Dept of Psychology and Behavioural Science

• Current staff: 17 (1 professor, 3 assoc.
• prof. 1 assist prof, 1 senior researcher, 4

post‐docs, 6 PhD’s, 1 adm.) + 8‐10 research assistants.

EPoS

• Mission

– 1) to produce scientific evidence about the psychosocial consequences of disease and treatment and about the role

• f psychosocial factors for the course of illness and health‐

related quality‐of‐life – with special emphasis on cancer – 2) to develop and evaluate approaches and interventions aimed at minimizing the physical, psychological, social, and societal costs associated with illness and treatments – 3) to contribute to the development of an interdisciplinary perspective in health care

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EPoS

• Contractual obligations

– 1) Research: to conduct health psychology and behavioral medicine research at an international level, – 2) Knowledge: to disseminate the knowledge gained through scientific publications, training of researchers, teaching university students, and popular dissemination – 3) Implementation: to promote the practical application of the knowledge gained in the health care system in collaboration with health care professionals.

Zachariae

PSYCHOONCOLOGY

predictors, moderators, mediators, outcomes

Quality of Life

Physical Psychological Social, Spiritual

Survival Recurrence

Expanded from Holland, 1998

Independent var. Mediators/moderators Dependent var.

Cancer Cancer treatment

Bio‐ behavioral Premorbid factors Genetic Sociodemographic Psychosocial Health behaviors

Intervention

Individual differences Sociodemographic Coping Personality traits Social factors Social support Social network Stressors Medical Patient‐clinician‐relationship Compliance/adherence

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Psychooncology

Zachariae

Cancer, Treatments Biopsychosocial consequences

Cancer

Biopsychosocial factors Cancer, Treatments Biopsychosocial consequences

Recurrence Mortality

The cancer survivor Cancer prognosis Cancer risk

Psychooncology

Zachariae

Cancer, Treatments Biopsychosocial consequences

Cancer

Biopsychosocial factors Cancer, Treatments Biopsychosocial consequences

Recurrence Mortality

The cancer survivor Cancer prognosis Cancer risk

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EPoS

• Research projects

– Epidemiological

• The Danish Breast Cancer Cohort (N=4917)
• Side effects, late effects, prognosis

– Behavioral Intervention studies (RCTs):

• Expressive writing intervention
• Mindfulness‐Based Cognitive Therapy (MBCT)
• Emotion Regulation Therapy (cancer caregivers)
• Conquer Fear (Fear of Cancer Recurrence)

– Internet‐delivered behavioral interventions (RCT’s):

• Cognitive training (breast cancer patients with cognitive impairment),
• Cognitive Behavioral Therapy for Insomnia (breast cancer patients

with insomnia) (SHUTi)

• MBCT for distress (breast‐ and prostate cancer)

EPoS

– Evaluating Self‐management programs (RCT’s) for:

• Chronic pain
• Anxiety and depression
• Back‐to‐work after sick leave

– Cancer‐related fatigue

• Systematic Light Exposure
• Sleep intervention

– Cognition and cancer

• Cognitive impairment among cancer patients (“chemo brain”) and possible

genetic, endocrinological, neurological, neuropsychological, and psychosocial mechanisms

– Use, consequences and mechanisms of Complementary and Alternative Medicine (CAM)

• CAM use among women treated for breast cancer
• Acupuncture
• Healing

– Patient‐health professional communication and Health‐Related Quality‐of‐Life

• Exploring the role of physician‐patient and nurse‐patient communication and

developing and validating instruments to measure these aspects

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EPoS

• Research projects (cont.)

– Systematic reviews and meta‐analyses:

– The influence of stress and expectancy

• Stress and upper respiratory infections
• Stress and response to influenza vaccination
• Stress/distress and outcomes of ART
• Expectancy and post‐chemotherapy nausea
• Psychosocial predictors of pain in breast cancer

– The efficacy of psychosocial interventions

• Efficacy of Mindfulness‐Based Therapy for distress in

cancer patients

• Efficacy of Expressive Writing Intervention on

psychological and physical health outcomes in cancer patients

• Effects of psychosocial interventions on pain in breast

cancer patients and survivors

• Efficacy of psychosocial interventions on psychological

and physical health outcomes in chronic obstructive pulmonary disease (COPD)

• Efficacy of psychological interventions on outcomes of

ART treatments

• Efficacy of CBTs for distress in cancer caregivers
• Efficacy of Internet‐delivered CBT for insomnia

Danish Cancer Society national center for breast cancer survivorship

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Late effects of cancer and cancer treatment

The cancer survivor

• Every third Dane will be diagnosed with cancer
• Increased cancer incidence and improved treatment leads to

a growing number of people living with cancer (Denmark: 267.496, Nordic Cancer Registries, 2014)

Zachariae

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Cancer and cancer treatment challenges Quality of Life (QoL)

Zachariae

Mental: Depression, post‐ traumatic stress, anxiety, cognitive impairment, etc. Physical: Pain, sensory disturbances, physical changes, fatigue, disturbed sleep, etc. Spiritual: Meaning, living with uncertainty, maintaining hope, etc. Social: Family issues, problems with partner, work problems, social roles and function, etc.

QoL

(1) World Health Organization. The first ten years. The health organization. Geneva: World Health Organization; 1958. (2) WHOQOL SRPB Group. A cross‐cultural study of spirituality, religion, and personal beliefs as components of quality of life. Soc Sci Med 2006 Mar;62(6):1486‐97.

Psychosocial sequelae

Zachariae

Problem Prevalence Depression 0 – 55% Post‐Traumatic Stress (PTSD) 0 – 35% Fear of Cancer Recurrence 0 – 87% Fatigue 35 – 80% Pain 21 – 88% Sexual problems 30 – 65% Body image 30 – 70% Cognitive complaints (”chemo brain”) 0 – 45% Impaired sleep 1 – 30%

Brandao et al. 2016; Horneber et al. 2012; Saligan et al. 2015; Otte et al. 2016; van den Beuken‐van Everdingen et al. 2007; Simard et al. 2013; Zachariae & Mehlsen, 2011; Moore et al. 2014.

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Symptom clusters

Zachariae

Pain Fatigue

Depression

Anxiety

Sleep disturbance

Inflammation

Correlated processes!

Lee et al. 2004; Irwin et al. 2013; Carlotto et al. 2013; Dong et al. 2014

Sickness behavior

• Proinflammatory cytokines (IL‐1B, IL‐6,

TNF, a.o.) released by activated immune cells induce:

– Fatigue – Muscle pain – Reduced appetite – Fever – Depressed mood

Zachariae Hart, 1988; Cirulli et al. 1998; Dantzer et al. 2008

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Sickness behavior

Zachariae

Peripheral cytokines IMMUNE COMPETENCE Anorexia Cachexia Anhedonia Cognitive changes Fatigue Depressed mood Sleep disorder Pain SICKNESS BEHAVIOR Cortisol Brain cytokines

Immune system‐induced motivational states enable flexible responses to select appropriate strategies under varying external and internal threats – all bio‐behavioral processes involve trade‐offs

Hart, 1988; Cirulli et al. 1998; Dantzer et al. 2008 Zachariae

Pathogen‐associated Molecular patterns

Pathogens Cancer Cancer treatments Stress External threats

Symptom cluster

Zachariae

Pain Fatigue

Depression

Anxiety

Sleep

Inflammation

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Symptom cluster

Zachariae

Pain Fatigue

Depression

Anxiety

Sleep

Inflammation

Intervention

Cancer‐related distress

DEPRESSION POST‐TRAUMATIC STRESS FEAR OF CANCER RECURRENCE CARE‐GIVERS

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Pre‐diagnosis Risk of cancer Fear of cancer Surveillance Prevention

Sources of distress across the cancer trajectory

Diagnosis Testing Waiting Fear of cancer Treatment Surgery

• Adjuv. treatm.

Testing Side‐efects Body‐image Survival Fear of recurrence Disability Post‐traumatic stress Social stressors: stigmatization, discrimination, social isolation Premorbid riskfactors: Lack of socio‐economic ressources, comorbidity, psychiatric history

Danish Psychosocial Breast Cancer Cohort

• 2001‐2004: 4917 women treated for primary

breast cancer

• Clinical and sociodemographic data from

DBCG and other national registries

• 3 mo. Baseline questionnaire
• 15 mo. Followup questionnaire
• 7‐9 year followup questionnaire

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Danish Psychosocial Breast Cancer Cohort

• Questionnaire data (at various time points)

– Emotional control/repression – Alexithymia – Social support – Comorbidity – Depressive symptoms (BDI) – Cancer‐related distress (IES, post‐traumatic stress) – Physical function/activity – Health behaviors – Sleep impairment – Pain – Use of complementary and alternative medicine (CAM) – Religious faith – Self‐reported cognitive failures – Concerns about cancer recurrence

Depression and post‐traumatic stress

• 4917 women

– 3343, 68% at 3 mo.; 94% of these at 15 mo.

• Depressive symptoms, 3 months

– 13.7% had depressive symptoms indicating MD – Predictors: Low SES, comorbidity and psychiatric history. Nodal status only clinical cancer predictor.

• Cancer‐related post‐traumatic stress, 3

and 15 months – IES scores suggesting severe PTSD (IES>35): – 3 months: 20.1% – 15 months: 14.3% – Predictors at 15 mo. (adjusted for baseline): Low SES, previous physical and mental illness, nodal status, physical function at 3 mo.

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Depression and prognosis

• 4917 women

– 3343, 68% at 3 mo.; 94% of these at 15 mo. – Followed for up to 13 years – Data obtained from national registries

• Mortality

– BDI ≥ 17 (Major depression) at 15 months: 27.1% – BDI < 17: 19.6% – RR: 1.54 (95%CI: 1.23‐1.92) – BDI depressive symptom scores (RR per point on the BDI):

• All cause mortality: 1.015
• Cancer mortality: 1.019
• Breast cancer mortality: 1.018

– Depression at 3 mo. not associated with mortality

* Adjusted for tumor variables, treatment, comorbidity, BMI, and health behaviours

1 1.5 2 3 Hazard ratio 5 10 15 20 25 30 35 BDI Total score 15 mth postsurgery

HR Linear pred HR Spline HR (95% CI)

Overall Survival (age-adjusted)

1 1.5 2 3 Hazard ratio 5 10 15 20 25 30 35 BDI Total score 15 mth postsurgery

HR Linear pred HR Spline HR (95% CI)

Overall Survival (age-adjusted)

POSSIBLE MECHANISMS

STRESS – DEPRESSION – SLEEP DISTURBANCE Sympathetic nervous system, CRH (Corticotropin Releasing Hormone), HPA (Hypothalamic-Pituitary-Adrenal Axis) Moderating factors: age, nutrition, BMI, physical activity, sleep, etc.

Zachariae

ACTIVATION/ INFLAMMATION Pro-inflammatory cytokines Acute phase proteines Cardio-vascular disease Auto-immune dieseases Inflammatory diseases Cancer Sickness behavior/depression IMMUNOSUPPRESSION Altered leukocyte distribution T-cell-responses, memory cells Infectious disease:

• Viral infections
• Bacterial infections

Cancer

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Written emotional disclosure

• Willingness, ability, and opportunity

to express cancer‐related concerns and emotions influence cancer patients’ adjust‐ment to the stressors associated with cancer and cancer treatment

• Pennebaker paradigm:

– 3‐4 sessions of 20 min writing emotionally about traumatic experience, compared to neutral writing

• Meta‐analyses:

– Expressive Writing Intervention on psychological and physical health

• utcomes

– Healthy participants (d=0.47) – Clinical samples (d=0.19)

Stabton et al. 2000; Hack & Degner, 2004; Smyth 1998; Frisina et al. 2004; Pennebaker & Beall, 1986

Intervention: cancer, distress, EWI

• Individual study

– Three 20‐min weekly sessions of home‐ based writing – Nationwide sample of 507 women treated for primary breast cancer – No main group x time effect on depression

• r cancer‐related post‐traumatic stress

symptoms (Impact of Event Scale) – Moderators: alexithymia, choice of writing topic

• Meta‐analysis

– No main effects of EWI in 16 RCT’s with cancer patients on psychological (g=0.04; p= 0.42) or physical health outcomes (g=0.08; p=0.22). – Social constraints a possible moderator.

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MBT for anxiety and depression among cancer patients and survivors

• Mindfulness‐based therapy

– MBSR: Mindfulness‐Based Stress‐ Reduction – MBCT: Mindfulness‐Based Cognitive Therapy

• Learning new ways of responding to

physical and emotional symptoms with higher degree of accept and

• penness
• Meta‐analysis of 22 RCTs of

manualized 8‐week interventions

• Medium effects on anxiety and

depression (Hedges’s g=0.37 og 0.44)

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Coping with anxiety and depression

• Trans‐diagnostic peer‐to‐peer psycho‐educational program

developed by the Danish Board of Health

• 7 weekly 2½ hour group sessions

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10 15 20 25 30 Linear Prediction, Fixed Portion BDI score Baseline Post kursus 3 mdr post Intervention Group Control Group

BDI Adjusted Predictions of time#group (95% CI)

35 40 45 50 55 60 Linear Prediction, Fixed Portion STAI Score Baseline Post-kursus 3 mdr. post-kursus Intervention Group Control Group

STAI Adjusted Predictions of time#group (95% CI)

849 citizens with anxiety and depression – 39 with cancer Mediating mechanism: improved self‐efficacy

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Fear of cancer recurrence

• 4917 women

– 3343, 68% (3 mo.); 94% (15 mo.); 90.4% (7‐9 yrs)

• Concerns About Recurrence Questionnaire, 7‐9

years – Brief questionnaire validated in the Danish Psychosocial Breast Cancer Cohort and in 218 Australian women.

Meta‐cognitive intervention (Conquer Fear) currently being adapted for group‐delivery

Gross, 1995; O’Toole et al. 2017

Fear of cancer recurrence

• Possible mechanism: Emotion

regulation flexibility

• No emotion regulation strategy is

inherently adaptive or maladaptive.

• Adaptive emotion regulation: the

ability to be flexible in the employment of emotion regulation strategies in the current context.

• Most psychotherapy research has

focused on the in‐ or decrease of specific emotion regulation strategies

• E.g., suppression, avoidance,

rumination, expression, approach, etc.

Experience sampling methods capture individuals’ subjective experiences as they occur. Participants to provide self‐reports of their thoughts, feelings and actions in their everyday lives. Prompting individuals at random moments during a period of time with a pager or a smartphone

• Current emotions and eight emotion

regulation strategies rated 4 X per day for 7 days, pre‐ and post intervention.

• Correlations calculated for all possible

pairs of emotion regulation strategies.

• The average Fisher’s z transformed

correlation => index of emotion regulation flexibility

• Larger average correlation indicating less

emotion regulation flexibility.

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Group‐delivered Conquer Fear trial

• Design: RCT: CF‐G (N=24) or CAU (N=24) (2‐day course for women who

have completed treatment for breast cancer) (MCID: d=0.6 (group x time); power: 0.95)

• Primary outcome: Fear of Cancer Recurrence Inventory (FCRI)
• Secondary outcomes: emotion regulation flexibility, IES, BDI, DASS‐21,

EORTC QLQ‐C30, Unmet Needs (SUNS).

• Mediators and moderators: Meta‐cognitions (MCQ‐30), Treatment

fidelity/adherence (CTS‐R), working alliance (WAI‐RS), expectancy (CEQ).

Informal caregiving (IC)

• Increased cancer incidence leads

to increased caregiver burden

• Caregiver burden:

– Biopsychosocial reaction to imbalance of care demands relative to personal time, social roles, physical and emotional states, financial and formal resources

• ICs have

– High levels of distress – Poorer physical functioning – Poor immune function – Increased mortality

Meta‐analysis of 36 trials (27 RCTs) of CBTs: Small overall effect: g=0.08, p= 0.014 No effect for RCT’s: g = 0.04, p=0.20 Moderators: Younger age and % women ‐> larger effects Alternatives to CBT are needed, e.g., third wave (meta‐cognitive) approaches

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Internet‐delivered interventions

• Dissemination barriers

– Lack of trained therapists – Costs – Geography, e.g., rural areas – Time‐ and mobility‐related barriers

• Internet‐delivered MBCT for distress in breast and prostate

cancer patients

– Adapting MBCT for delivery over the internet – Development project in collaboration with users – Ongoing study in collaboration with the Internet‐Psychiatry Unit, Karolinska Institute, Stockholm – Superiority trial (waitlist controls) – Non‐inferiority trial (compared to face‐to‐face delivered MBCT)

Cancer‐related pain

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Cancer‐related pain

• 4917 women

– 3343, 68% at 3 mo.; 94% of these at 15 mo.

• Cancer‐related pain, 15 months and 7‐9 years

– 1905 women eligible at both time points – pain “almost every day” or more frequently – 15 months: 32.7% – 7‐9 years: 20.4% – Predictors (15 mo.): Low SES, nodal status, ALND, endocrine treatment, smoking, BMI ≥ 30 <35, comorbidity, poorer physical function. – Predictors (7‐9 yr): ALND, endocrine treatment, poorer physical function, and weight training

Psychological pain management

• Cancer‐related pain undertreated
• Oncology Dept. pain audit 2011:

– 38% experienced pain within the last 7 days – 20% and 60% had not talked about their pain to oncology staff and GP

• Limited efficacy of pharmacological pain

management, in particular of neuropathic pain

• Pain multidimensional: biological (e.g.,

nociceptive), cognitive, affective, social, and cultural aspects (IASP)

– E.g., pain catastrophizing: “an exaggerated negative mental set brought to bear during actual or anticipated painful experience” (Sullivan, 2001) – Predictor of both acute and persistent pain

• Effects of various psychological

interventions (CBTs, mind‐body):

Zachariae Hollen et al. 2015; Kwon et al. 2014; Johannsen et al. 2013; Sullivan et al. 2009

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Mindfulness‐Based Cognitive Therapy for persistent pain after treatment for primary breast cancer

• Mindfulness‐based therapy teaches

non‐judgmental ways of relating to bodily sensations and unpleasant physical and emotional experiences with greater acceptance and

• penness
• Mindfulness‐Based Cognitive

Therapy (MBCT) may be particularly efficacious in treating persistent cancer‐related pain

• Few small sample studies available

Zachariae

Mindfulness‐Based Cognitive Therapy for persistent pain after treatment for primary breast cancer

Zachariae

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Mindfulness‐Based Cognitive Therapy for persistent pain after treatment for primary breast cancer

• Mediators of the effect of MBCT on pain intensity:

– Mindfulness non‐reactivity facet; Pain catastrophizing

Zachariae Johannsen, O’Toole, O’Connor, Jensen & Zachariae (under review)

Mindfulness‐Based Cognitive Therapy for persistent pain after treatment for primary breast cancer

Evaluating interventions:

• Statistical

significance

• Clinical relevance
• Cost‐effectiveness

Zachariae

Cost‐effectiveness for Minimal Clinically Important Difference (MCID) pain intensity score of 2 on a 11 pt NRS

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Sleep disturbance

Sleep difficulties in cancer survivors

• 30‐50% of cancer survivors experience insomnia
• 3‐4 mo. after surgery: 57.9% of women (N=3343) in

a national cohort of Danish women treated for primary breast cancer report clinically significant sleep problems (PSQI score > 5) Colagiuri et al. 2011

• Sleep problems associated with:

– More depressive symptoms – Poorer physical function – Older age – More anxiety symptoms – Smoking – Breast conserving surgery – Less physical activity

• 7‐9 yrs post‐treatment: 51.9% report sleep

difficulties Colagiuri et al. IPOS 2012

Irwin, 2013; Savard & Morin, 2001

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• 772 Australian women

treated for ovarian cancer

– 19 (+/‐ 10) months after diagnosis – 43.7% have subclinical or clinical significant sleep disturbance – Main predictors:

• Younger age
• Unmet needs within

physical/daily activities

• High anxiety levels (HADS)

Zachariae

Sleep difficulties in cancer survivors

Sleep medication

• Hypnotics, e.g.,

benzodiazepines and similar drugs:

– Limited long‐term efficacy – Not curative – Tolerance – Dependence – Side‐effects – Possible increased risk of

• Cognitive impairment
• Mortality

– Not recommended for long‐term use

Kripke et al. BMJ Open, 2012 Stewart J Clin Psychiatry 2005 Buchemi et al. Gen Intern Med 2007 Bilioti et al. BMJ 2012 Kripke et al. BMJ Open 2012

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Non‐pharmacological approaches

Zachariae Morin & Espie, 2003

Sleep restriction Stimulus‐ control Cognitive therapy Relaxation Cognitive‐Behavioral Therapy for Insomnia CBT‐I Sleep hygiene

Efficacy of non‐pharmacological treatments for insomnia

Effects: Standardized Mean Difference; SE: Sleep efficiency; SQ: Subjective sleep quality; SOL: Sleep Onset Latency; WASO: Wake after sleep onset; TST: Total Sleep Time

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CBT‐I for comorbid insomnia

Zachariae

Geiger‐Brown et al. 2014

CBT‐I for comorbid insomnia

Zachariae

11 studies: Effects (Cohen’s d) on: Sleep (0.78, p<0.000001) Pain (0.18, p=0.05) Fatigue (0.38, p=0.004)) Depression (0.18, p=0.14)

Tang et al. 2015

Chronic pain patients

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Comparing CBT‐I and sleep medication

Zachariae

Meta‐analysis of 21 studies with 470 patients: CBT‐I is (at least) as efficacious as sleep medication (Smith et al. 2002)

SOL NA WASO TST SQ

Pharmacother. 0.45 0.97 0.89 0.84 1.30 CBT‐I 1.05* 0.83ns 1.03(na) 0.46ns 1.20ns

Challenges

• CBT‐I recommended as first choice by the

American Academy for Sleep Medicine (AASM)

• Challenge: To make CBT‐I available to meet

population needs:

– Few trained therapists – Costs of face‐to‐face CBT‐I – Limited availability to geographically and physically challenged groups

• Possible solution: to deliver CBT‐I over the

internet (eCBT‐I)

AASM, 2008; Ritterband et al. 2006

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Internet‐delivered CBT‐I

* Robust outcomes: Failsafe N > criterion (5K+10)

Zachariae et al. Sleep Medicine Reviews, 2016

Comparing iCBT‐I with Face‐to‐Face and pharmacotherapy

Treatment Studies

• Min. falling asleep
• Min. awake
• Min. asleep

eCBT‐I

Zachariae et al. 2016

‐20.6 ‐ 25.5 +37.5 Face‐to‐face CBT‐I

Koffel et al. 2014 Okajima et al. 2011

‐23.3 ‐38.4 +19.6 Pharmacotherapy

Smith et al. 2002

‐14.5 ‐25.6 +40.5

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Direct comparisons: iCBT‐I and f‐t‐f CBT‐I

Study N Cohen’s d (ftf vs. iCBTI ) De Bruin et al. 2013 26 0.60 Blom et al. 2015 48 0.39 Lancee et al. 2016 60 0.23 Taylor et al. 2017 100 0.20 Combined 234 0.29, p=0.03

Zachariae

Internet‐delivered CBT‐I

* Robust outcomes: Failsafe N > criterion (5K+10)

Zachariae et al. Sleep Medicine Reviews, 2016

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Internet‐delivered CBT‐I

Zachariae

Internet‐delivered CBT‐I

Zachariae et al. Sleep Medicine Reviews, 2015

Comparison with F‐t‐F and group CBT‐I

Sources: (1) Okajima et al. 2011; (2) Koffel et al. 2015

Comparing iCBT‐I with Face‐to‐Face and pharmacotherapy

Treatment Studies

• Min. falling asleep
• Min. awake
• Min. asleep

eCBT‐I

Zachariae et al. 2016

‐20.6 ‐ 25.5 +37.5 Face‐to‐face CBT‐I

Koffel et al. 2014 Okajima et al. 2011

‐23.3 ‐38.4 +19.6 Pharmacotherapy

Smith et al. 2002

‐14.5 ‐25.6 +40.5

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Non‐inferiority: iCBT‐I and pharmacotherapy

Study N Cohen’s d (ftf vs. iCBTI ) De Bruin et al. 2013 26 0.60 Blom et al. 2015 48 0.39 Lancee et al. 2016 60 0.23 Taylor et al. 2017 100 0.20 Combined 234 0.29, p=0.03

Zachariae

SHUTi

Zachariae

• SHUTi (Sleep Healthy Using The internet): BeHealth, University of Virginia, Behavioral

Health and Technology (Ritterband, et al. 2009)

• Components: Sleep restriction, sleep hygiene, stimulus‐control, cognitive therapy
• Six cores to be completed within 6‐9 weeks, fully automated, interactive, instructions

and feedback tailored to the input of the participants

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SHUTi

Zachariae

Zachariae, et al., J. National Cancer Institute (accepted for publication)

RCT: National sample of 255 women treated for breast cancer with insomnia (PSQI > 5)

SHUTi

Zachariae

Changes in proportion of participants with clinically significant impairment (ISI, PSQI, Fatigue, SE)

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Comparing effects

Sleep outcome SHUTi breast cancer survivors (SMD) N=255 Internet‐deliv. CBT‐I General population 1 (SMD) K=11 Face‐to‐face CBT‐I Cancer survivors 2 (SMD) K=8 Insomnia severity 1.17 1.09 0.77 SE 1.06 0.58 0.53 SOL 0.39 0.41 0.43 WASO 0.33 0.45 0.41 NA 0.45 0.21 ‐ TST 0.64 0.29 ‐

Zachariae

SMD: Standardized mean differences 1) Zachariae et al. 2016 2) Johnson et al. 2016

Possible mediators

Sleep regulatory process Possible CBT‐I mediators Behavior Less time in bed Less sleep in the daytime Less variability in bedtime and wake‐up times Cognition Fewer maladaptive cognitions and beliefs about sleep Reduced sleep effort Improved sleep‐related self‐efficacy Increased sleep‐related locus of control Hyper activation Reduced physiological activation (arousal) Reduced cognitive activations

Zachariae Schwartz & Carney 2012

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Cancer‐related cognitive impairment

”Chemo‐brain”

– High prevalence of subjective compaints (21%‐ 90%) (Meta‐analysis of 27 studies of women treated for breast cancer) – Even modest impairment of cognitive function may negatively influence: – Quality of life, ability to work and fulfill other social and societal roles

Calvio et al. 2009; Pullens et al. 2010; Zachariae & Mehlsen, 2011

Zachariae

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Possible causes

• Neurotoxic effects of cancer

treatments?

• Effects of the cancer itself, e.g.,

inflammation, hormonal factors?

• Emotional reactions to the disease

and treatment, e.g., depression, stress?

• Behavioral reactions, e.g., sleep

problems?

• Expectancy (”nocebo”)?
• Age?
• Genetic factors (vulnerabilities)?

Zachariae

Assessing cognitive function

Objektive Neurophysiological assessment Functional Neuropsychological testing Subjective Interviews/questionnaires

Zachariae

The three types of outcomes do not always correlate

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Cognitive impairment

• 4917 women

– 3343, 68% (3 mo.); 94% (15 mo.); 90.4% (7‐9 yrs)

• Self‐reported cognitive failures, 7‐9 years

– 1889 recurrence‐free women eligible – Frequency of impairment 7% – Comparable to normative data – No difference between standard DBCG treatment protocols

Cognition and cancer

• No differences in changes over time in

neuropsychological test performance between breast cancer patients (N=34), cardiac patients (N=12) and healthy controls (N=12).

• No differences between testicular cancer

patients receiving surgery+chemotherapy (N=36) and surgery only (N=36) in neuropsychological test performance and percent cognitive impaired 2‐7 years after treatment.

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Cognition and cancer

• Compared to normative data, testicular

cancer patients (N=72) show higher prevalence of cognitive impairment (9 of 12 domains) – regardless of treatment received.

• Lower scores (6 of 11 domains) among 66

testicular cancer patients than healthy controls both before and after treatment (surgery or surgery+chemotherapy).

• Neuropsych scores associated with cortisol

levels and cognitive complaints with IL‐6 and psychological distress

• APOE4 allele associated with greater

cognitive impairment in chemother. pt’s.

• Structural MRI data support the findings

Cognition and cancer

Amidi, Agerbæk, Zachariae et al. 2015

Reductions in grey matter from pre to post chemotherapy – controlled for changes in the non‐chemotherapy group Global neuropsychological test scores correlated with reductions in grey matter volume in the chemotherapy group (r = ‐0.47, p=0.04), but not in the surgery‐only group (r = ‐0.08, p=0.67).

Zachariae

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Cognition and cancer

• Genetic vulnerability

– MDR1: influences the brain’s ability to remove toxins – 5‐HTTLPR: associated with increased physiological stress‐reactivity – ApoE4 associated with increased risk of dementia

• ApoE4 was associated with

increased cognitive impairment in the chemotherapy group, but not in the surgery‐only group

Change‐scores (z) Genetic factors Chemotherapy Radiotherapy Antihormonal treatment Hormonal changes Age

Cognition and cancer – a multifactorial model

Inflammation Cancer disease Cancer treatment Stress Depression Emotional reactions Anxiety Sleep disturbance Fatigue Behavioral reactions Background factors

Zachariae

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Cognition and cancer

• Internet‐delivered cognitive

training

– RCT with 157 women treated for breast cancer with self‐reported cognitive complaints – Effects found for verbal learning and working memory compared with waitlist controls

Zachariae

Prevention and rehabilitation

• Physical activity
• Mental activity

– Cognitive activities, e.g., reading, problem solving, learning new languages, etc., reduce the risk of dementia in the generalpopulation

Zachariae

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Use of Complementary and Alternative Medicine

CAM use

• 4917 women

– 3343, 68% (3 mo.); 94% (15 mo.); 90.4% (7‐9 yrs)

• CAM use:

– 3 months: 40.2% used various CAMs in time since diagnosis – 15 months: 49.9% used CAMs between 3 and 15 months. – Predictors: Younger, healthier life style, higher income, living in metropolitan areas

• CAM use and depression, 3 and 15 months

– CAM users more depressed at both 3 and 15 months – CAM users (especially dietary/vitamin supplement users) more depressed at 15 months when adjusting for depression at 3 months.

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CAM and cancer

• Effects of energy healing performed by

three healers on proliferation and viability

• f 2 cancer cell lines (human BC and

murine) in vitro.

• Active healing compared to sham healing
• Increasing dose (10, 20, 30, 40, 50 min)
• A total of 34 out of 66 independent

comparisons (51.6%) yielded results in the expected direction, corresponding to a probability of 0.90 (two‐tailed).

CAM and cancer

• Limited results of RCTs of CAMs, e.g.,

spiritual/ energy healing

• CAM proponents argue:

– RCTs have low external validity, – CAMs such as healing are highly individualized – Effects are related to treatment preferences.

• Pragmatic trial

– 247 colorectal cancer patients after completed treatment – Randomized to 2 x 2 groups: – 1 and 2: randomized to healing or control – 3 and 4: self‐selected healing or control – Self‐selected healer (from a group of healers) – Healing took place in healer’s clinic – QoL outcomes prioritized by patients

Results:

• No statistically significant
• verall healing x control effect
• Subgroup effect: self‐selected

healing + positive attitude towards CAM

22‐02‐2018 42

CAM and cancer

– CAM use among cancer patients is increasing – CAM users are more likely to reject or delay adjuvant therapy – Overall and disease‐free survival is reduced by 15% and 16%, respectively, for every 4‐week delay in initiation of adjuvant chemotherapy – CAM use associated with increased risk of depression, which in turn is associated with poorer prognosis – CAM use may interact with conventional treatment – CAM‐related decision‐making by cancer patients occurs as a complex, nonlinear, dynamic process of information‐seeking and evaluation – 20‐77% of CAM users do not disclose their CAM use to their

• ncologists

– Main reasons for nondisclosure: the physician’s lack of inquiry; the patient’s anticipation of the physician’s disapproval, disinterest, or inability to help

Greenlee et al.2016; Pedersen at al. 2013; Yu et al. 2013; Davis et al. 2012

CAM, acupuncture, pain

• Evaluating placebo acupuncture

needles

• Results suggest single but not

double blinding:

• Acupuncturists were more likely to

identify active needle (83%, p<0.05) than patients (63%, ns.)

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CAM, acupuncture, pain

• A total of 101 patient undergoing third

molar surgery

• Double‐blinded randomized controlled

study comparing effects of active and placebo acupuncture on pain.

• No difference between active and

placebo acupuncture

• Patients who believed that they

received active treatment experienced larger effects, regardless of treatment received

Breast reconstruction

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Breast reconstruction

• 4917 women

– 3343, 68% (3 mo.); 94% (15 mo.); 90.4% (7‐9 yrs)

• Factors associated with receipt of breast

reconstruction – Predictors of receiving reconstruction: younger age, radio therapy, higher income, ethnicity other than Danish – Health‐related factors (BMI, physical function, comorbidity, smoking, alcohol) were unrelated to reconstruction – Receipt of information about reconstruction options decreased 8% per year of age

Breast reconstruction

• Participants

– All women who underwent unilateral BR in Central Denmark Region between January 2005 and July 2011 (N=166)

• Satisfaction with outcome

– Abdominal flap recipients expressed higher satisfaction with their aesthetic

• utcome, compared with remaining

BR types. – Higher aesthetic satisfaction was associated with higher self‐reported QoL.

• Personality (NEO‐PI‐R) (in press)

– Baseline body image, immediate reconstruction, and Neuroticism predicted satisfaction with body image at 6 month followup. (R2 = 0.36)