Download Biobehavioral Factors and Cancer

*
Lois Ramondetta MD
Professor Gynecologic Oncology MD Anderson
Cancer Center
Chief Gynecologic Oncology and Director of
Gynecologic Cancer Research at
Lyndon Baines Johnson Hospital
Physical
Symptoms /State
Pain, Fatigue,
malnutrition
anemia
Social Support
Friends &
Family
Spiritual
Beliefs
Hope?
Personal
Qualities
(gender/coping
Style)
Therapeutic
Alliance
STRESS
Involvement
Meaningful
ActivitiesDignity
Financial
Situation
Number of
Treatments
Depression
Anxiety
Stress-
* Acute vs Chronic
* Psychological
* Emotional (depression, anxiety, hopelessness, death anxiety,
loss of meaning or dignity), financial, social, loss of control
* Physical
* Pain, surgical, fatigue, nutritional/cachexia, anemia
*
*
* Stress is a complex process consisting of environmental and
psychosocial factors that initiate a cascade of information-processing
pathways in both the peripheral and central nervous system
* Stress pathways elicit the “fight-or-flight” stress responses in the
autonomic nervous system or “defeat/withdrawal” responses
produced by the hypothalamic-pituitary-adrenal axis.
* Activation of these pathways prepares a person to endure a threat.
* Under chronic stress, most organs are negatively affected by
prolonged exposure to glucocorticoids and catecholamines
Effects of stress and psychosocial processes on the tumor microenvironment.
Copyright © 2011 by the American Psychosomatic Society
Lutgendorf S K , and Sood A K Psychosom Med
2011;73:724-730
Chronic Stress can alter
*adhesion of tumor cells to the extracellular matrix
*cancer cell migration and invasion
*angiogenesis
*cell survival
P.H. Thaker et al Nat Med 12 (2006) 939-44
Antoni MH et al. Nat Rev Cancer. 2006 Mar;6(3):240-8.
*
* In ovarian cancer cell lines, treatment with norepinephrine
resulted in increased expression of VEGF, IL-8, and IL-6
* IL-8 encourages angiogenesis, movement of tumor cells
toward blood vessels, and enhancement of growth in a
variety of tumors
* IL8 is
produced by tumor cells and macrophages
*
* Norepinephrine (NE) treatment of ovarian cancer cells
resulted in
* 250-300% increase in IL8 protein
* 240-320% increase in its mRNA levels.
* 3.5-4-fold increase in IL8 promoter activity.
* These effects were blocked by propranolol
* Reiche EM et al Lancet Oncol. 2004 Oct;5(10):617-25
* Glaser R et al Nat Rev Immunol. 2005;5:243-51.
*
IM STRESSED JUST
THINKING ABOUT IT!
*
* Meditation
* Breathing exercises
* Yoga
* Therapy-group, individual, how long, how?
* Meaning based
* Dignity based
* Social support
* Empowerment
* Sleep
* Diet
* Building hope
*
* Anti anxiety medications
* Anti depressants
* Anti inflammatory agents-Cox 2 inhibitors, ASA
* Adrenergic Blockade
* Statins?
* Better pain control (morphine)
* Minimally invasive surgery-surgical technique
* Less blood loss, transfusion?
* Pre op nutrition vs post op nutrition
* Supplements
* Better overall eating habits
*
* Perceived stress scale
* Responses to Stress Questionnaire-cancer version (RSQ-CV)
* QOL-FACT O/Sp
* ESAS (overall well being)
* Hope
* HADS
*
*
0 = Never 1 = Almost Never 2 = Sometimes 3 = Fairly Often 4 = Very Often
1. In the last month, how often have you been upset
because of something that happened unexpectedly?.................................. 0 1 2 3 4
2. In the last month, how often have you felt that you were unable
to control the important things in your life? ..................................................0 1 2 3 4
3. In the last month, how often have you felt nervous and “stressed”? ............ 0 1 2 3 4
4. In the last month, how often have you felt confident about your ability
to handle your personal problems? ............................................................. 0 1 2 3 4
5. In the last month, how often have you felt that things
were going your way?.................................................................................. 0 1 2 3 4
6. In the last month, how often have you found that you could not cope
with all the things that you had to do? ......................................................... 0 1 2 3 4
7. In the last month, how often have you been able
to control irritations in your life?................................................................... 0 1 2 3 4
8. In the last month, how often have you felt that you were on top of things?.. 0 1 2 3 4
9. In the last month, how often have you been angered
because of things that were outside of your control?................................... 0 1 2 3 4
10. In the last month, how often have you felt difficulties
were piling up so high that you could not overcome them? ......................... 0 1 2 3 4
* HR, BP
* Cortisol
* TH1 T helper 1
* TH2 T-helper 2
* TIL tumor infiltrating lymphocytes
* VEGF vascular endothelial growth factor
* IL-6 interleukin-6
* IL-8 interleukin-8
* IL-10 interleukin-10
* TNFα tumor necrosis factor alpha
* NE norepinephrine
* TAM tumor associated macrophage
* NK Natural Killer cells
* Matrix Metalloprotinease (MMP-3, MMP-9)
* TGF-β tumor growth factor beta
* NFκB nuclear factor kappa beta
* STAT signal transducers
*
I.
Longitudinally evaluating components of psychological
stress in ovarian cancer patients
II.
Retrospectively assessing adrenergic blockade in ovarian
cancer patients
III.
Prospectively assessing beta blockade in ovarian cancer
patients
IV.
Prospectively assessing beta blockade and relaxation in
cervical cancer patients
V.
Reducing surgical stress and prospective physical stress
studies
*
*
*
* Women with ovarian cancer beginning a new chemotherapy
regimen (254 pts)
* 55% acknowledged fear of dying
* Correlated with younger age, Caucasian, poor physical well being
* 32% acknowledged loss of hope in the fight
* Loss of hope correlated with depressive symptoms, lack of social
support, and number of treatments.
* Did not correlate with stage of disease, demographic variables or
religious affiliation.
Shinn Pall Supp Care 2009
*
Results:
Mean age (N=104) 55.3 yrs;
63% W; 19% H; 14% AA
65% married/partnered.
25% depressed/borderline depressed;
40% clinically anxious/borderline anxious
Death Anxiety scores negatively correlated with Hope (p <
0.001) and whether already had chemotherapy (p = 0.025)
In a multivariate analysis,
DA did not correlate with site, race, religiosity, or faith (HOGE or
FACT-Sp).
DA correlated with HOPE (HHS, p = 0.001) and cycle (p = 0.017).
After controlling for independent variables, M/P subscale (p =
0.005) and hope (p = 0.001) were associated with HADSDepression
Higher levels of M/P and HOPE (HHS) were associated with
decreased HADS-Anxiety (p < 0.001; p = 0.001 respectively)
*
Hope
PWB
EWB
FWB
SWB
OVCAWB
ESAS
Anxiety Depr
(HADS) (HADS)
0.49;
< 0.001
0.39;
< 0.001
0.62;
< 0.001
0.31;
0.001
0.66;
< 0.001
-1.01
0.015
-0.30;
0.001
-0.32;
0.001
NS
0.37;
< 0.001
0.40;
0.004
0.29;
0.001
NS
-1.11
0.006
-0.30;
< 0.001
-0.24;
0.005
NS
-0.14;
0.036
NS
NS
NS
NS
15.5;
0.005
2.20;
0.029
NS
NS
M/P
Hoge
NS
Black
NS
NS
NS
-2.11
0.040
NS
NS
-1.90
0.048
NS
Hispanic
NS
NS
*
NS
NS
Conclusions:
* Anxiety and Depression affects 25%-40% of our OC population.
* Hope associated with well being, decreased symptom burden,
less anxiety, and less depression
* Religiosity did not correlate with anxiety/depression/DA
* Directionality is unclear but increased hope, and to a lesser
extent M/P was associated with better QOL and decreased
symptom burden
* Interventions to decrease anxiety and depression should focus
on M/P and hope
*
OC pts at a cancer center (CC), academic hospital (AH) and county hospital (CH for
primarily uninsured) participated.
Surveys completed at initiation of chemotherapy (CTX); completion of CTX; and 1 yr later.
Surveys included FACT-O, -SP, Herth Hope Index, Hospital Anxiety and Depression Scale
(HADS), ESAS, and Locus of Control (LOC).
Results: N=115. Median age=55 yrs, married 64%, Christian 96%.
CH had more AA/Hispanics pts (p=.001) and unmarried pts (p=.001).
QOL and symptoms improved for all sites over time (p =.03);
CH pts had the worst scores (p= <.001).
CC pts expressed more hope, less anxiety and depression (A/D) compared to CH and AC
pts for all time points (p=.03).
CH pts had higher and increasing A/D over time while CC pts had least (p=.02).
*
Ramondetta et al SGO 2012
LOC scores differed by site (p=.01).
CH pts -strongest belief that life controlled by chance and
“others”; CC pts had least.
No association between site/time for belief of internal control
CH pts consistently had the lowest M/P scores (p=004).
Adjusting for site, disease status and time,
Higher M/P associated with higher hope, better QOL,
symptoms and faith (p= <.0001).
Lower M/P associated with increased A/D (p=.003) and
symptoms (p<.0001).
Poorer M/P over time correlated with belief that life was
controlled by chance (p=.01) and "powerful others"(p=.02).
Level of M/P did not correlate with belief of internal control over
one’s life.
Conclusions:
M/P did not change over time. CC pts had highest M/P. Higher
M/P associated with higher hope and faith, better QOL, less
symptoms and A/D.
Lower M/P associated with sense that life is controlled by chance
and powerful others.
Data show medically underserved pts have poorer QOL, more
symptoms and A/D and may believe the future is determined by
luck/chance and by “others”.
Triaging for spiritual crisis may be important in these pts.
Interventions to decrease A/D and symptoms may improve pts’ sense
of M/P over the cancer journey.
*
Ovarian cancer pts undergoing primary treatment completed psychological selfreport measures and collected salivary cortisol and plasma IL-6 prior to surgery,
at 6 months, and at 1 year.
At 6 months, significant reductions in nocturnal cortisol secretion, plasma IL-6,
and more normalized diurnal cortisol rhythm, changes maintained at 1 year.
The reductions in IL-6 and nocturnal cortisol were associated with declines in
self-reported fatigue, vegetative depression, and disability.
Thus- primary treatment for ovarian cancer reduces the inflammatory response.
Moreover, patients who have not developed recurrent disease by 1 year appear
to maintain more normalized levels of cortisol and IL-6.
Brain Behav Immun. 2013 Mar;30 Suppl:S126-34 Schrepf A et al
Tissue from 10 ovarian carcinomas in pts with high depressive symptoms and low
social support and c/w pts with low levels of depressive symptoms were analyzed
Findings:
Increased activity of several B-adrenergically linked transcription control pathways,
including the cyclic-AMP response element-binding protein/activating transcription
factor and proinflammatory signal transducers
Gene expression profiles in primary ovarian tumor specimens are systematically
altered in association with the patient’s biobehavioral risk factors
B adrenergic transcription control pathways are the key mediators of differences in
gene expression profiles.
Tissue levels of the sympathetic catecholamine norepinephrine were elevated in
ovarian tumor specimens obtained from patients with high biobehavioral risk
profiles
S.K. Lutgendorf et al J Clin Oncol 26 (2008), 4820-7.
S.K. Lutgendorf, et al Brain Behav Immun 22 (2008), 890-900.
*
Adrenergic blockade may affect survival in several ways:
•Decreasing angiogenesis, VEGF , matrix metalloproteinase, IL-6
• Decreasing prometastatic immune response (eg, interleukin-8)
• Decreasing symptoms such as cachexia
*
Four β adrenergic receptors (bARs) exist,and characterized according to physiological functions
bARs are G protein-coupled receptors that are the targets of catecholamines such as
norepinephrine and epinephrine and whose primary function is to transmit information from
the extracellular environment to the interior of the cell, leading to activation of adenylyl cyclase
and accumulation of the secondary messenger cAMP
β1 antagonists have negative inotropic and chronotropic effects. (affecting the heart rate and
thereby increasing cardiac output), release renin, and increase lipolysis. Primarily in the heart
β2-adrenergic receptors cause dilation of blood vessels and bronchioles, stimulate insulin
release, and increase lipolysis, glycogenolysis, and gluconeogenesis.
β3-adrenergic receptors are involved in lipolysis and mediate vascular relaxation but are
activated by higher concentrations of catecholamines.
*
*bARs have been found in breast, esophageal,
pancreatic, ovarian, lung, head and neck,
prostate, and colon cancer tissue
* Badino GR Pharmacol Res. 1996 Apr-May;33(4-5):255-60.
* Liu X Cell Biochem. 2008 Sep 1;105(1):53-60.
* Ramberg H Prostate. 2008;Jul 1:68(10):1133-42.
* Madden KS Breast Cancer Res Treat. 2011;Jan 14.
* Al-Wadei HA PLoS One. 2012;7(1):e29915.
* in vivo model demonstrated the incidence of lymph node
metastases increased with the administration of norepinephrine
but decreased with the introduction of the B-blocker
propranolol
* Palm D et al. Int J Cancer. 2006;118:2744–9
*
First-generation β-blocker
Non-selectively blocks both β1- and β2-adrenergic receptors.
Used with an orthotopic mouse model of ovarian cancer
Chronic behavioral stress resulted in increased levels of tissue
catecholamines, an increased tumor burden, increased VEGF and
increasingly invasive growth of ovarian carcinoma in that model.
These effects appeared to be mediated by activation of the tumor cell
cyclic AMP-protein kinase A signaling pathway by β2-adrenergic receptor.
The effects of chronic behavioral stress abrogated by β-blockers
Thaker PH Nat Med. 2006 Aug;12(8):939-44
*
Retrospective data on a cohort of ovarian cancer patients in whom use of B blockers
reduced the risk of death by 56% below that in nonusers.
Diaz E, et al Gyn Onc 2011;120:S81.
Retrospectively studied breast cancer patients and showed that -blocker–based
therapy reduced the number of distant metastases, the incidence of cancer
recurrence, and mortality
*
Powe DG. Oncotarget. 2010 October 19:1-11.
Improved relapse-free survival durations in patients with triple-negative breast
cancers using beta-blockers
Melhem-Berrandt A. J Clin Oncol. 2011;29(19):2645-52
B blockers was associated with a reduced risk of progression of thick malignant
melanoma and that Bblocker intake was associated with increased survival durations
in melanoma patients
Lemeshow S Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2273-9.
*
*
A multicenter review of 1,425 women with histopathologically
confirmed EOC was performed.
Comparisons were made between patients with documented
beta blocker use during their chemotherapy and those without
beta blocker use.
Median age was 61 years (range; 31-93)
91.5% had tumors of serous histology
90.2% had advanced stage (III or IV) disease.
501 (35.2%) pts with hypertension and 269 (18.9%) of whom were on beta blockers.
195 (13.7%) were on β1 selective agents and remaining on non-selective beta-antagonists.
Median disease-specific survival (DSS) for
Patients with HTN was 41.4 months c/w 47.4 months for those without HTN (p=0.004).
Patients on beta blockers, the median DSS was 48.6 versus 42.4 months (p=0.02).
The median DSS based on beta blocker receptor selectivity was 90 months for those on nonselective beta blockers versus 38.2 months for those on β1 selective agents (p<0.001).
Conclusions:
Use of beta blockers in patients treated for EOC was associated with improved survival compared
to non-beta blocker users. Our findings of improved survival for those on non-selective beta
antagonists have implications for new therapeutic approaches.
*
* Imposed behavioral stress results in higher levels of tissue
catecholamines, greater tumor burden, and a more invasive pattern of
ovarian cancer growth in an orthotopic mouse model
* mediated by b2 adrenergic receptor activation
* Ovarian carcinomas in patients with high depressive symptoms and low
social support compared to low risk patients and found increased
activity of several beta-adrenergically-linked transcription control
pathways
* Elevated tissue levels of sympathetic catecholamine norepinephrine
found in tumor samples from high biobehavioral risk profile patients
Thaker PH,et al. Nat Med 2006;12: 939-44.
Lutgendorf SK, et al. Brain Behav Immunity 2008;22: 890-900.
*
1) Chronic stress results in physiological changes
2) Retrospective studies indicate that use of beta-blocking antihypertensives is associated with improved survival and that the
presence of adrenergic receptor beta (ADRB) correlates with
prognostic indicators in certain cancer subtypes
3) In vitro and animal studies describing anticancer signaling activity,
including reduction of serum and tumor VEGF levels with the use of
beta adrenergic blocking agents
*
*
Primary Objectives:
Feasibility of pharmacologic beta-adrenergic blockade in women with Stages II-IV
epithelial ovarian cancer patients (n=25) either during initial tumor reductive surgery
and through the first six cycles of standard intravenous chemotherapy or during
neoadjuvant chemotherapy followed by surgery and further chemo up to a total of 6
cycles
Secondary Objectives:
* To characterize the biobehavioral states of these patients by using the Functional
Assessment of Chronic Illness and Therapy- Ovary (FACT-O), Hospital Anxiety and
Depression Survey (HADS) and the Center for Epidemiologic Studies Depression Scale
(CESD) and serum levels of angiogenic cytokines at points pre- and post-treatment with
beta-blockers.
To follow patients for progression-free survival (PFS)
Translational objectives
To determine VEGF, IL-6, IL-8, MMP-2 and MMP-9
levels in pts with ovarian cancer who are receiving
beta-blockers and comparing these levels pretreatment and during treatment with chemotherapy.
* Blood drawn prior to administration of Propranolol after consented for study
* Fill out questionnaires (HADs, FACT O, ESAS, etc)
* Propranolol 20mg po bid x 48-72 hours pre-treatment (surgery or neoadjuvant
chemotherapy) after being identified as having a possible ovarian, fallopian
tube, or primary peritoneal carcinoma
* Restart oral Propranolol when patient is tolerating oral intake post-operatively
(take continuously with neoadjuvant chemotherapy)
* For post-op patients, start intravenous platinum or taxane chemotherapy
(without bevacizumab) x 6 cycles at the discretion of treating physician.
* For neoadjuvant patients give 3 cycles of intravenous platinum or taxane
chemotherapy (without bevacizumab) followed by surgery, then 3 more cycles
of chemotherapy.
*
2013-0113 - Effect of a Beta Andrenergic Blockade &
Relaxation/Guided Imagery Audio Intervention on symptom distress
in Advanced, Recurrent Incurable Cx Ca - Feasibility study
SCHEMA
Blood drawn prior to administration of Propranolol after consented for study
Fill out questionnaires
Instruct on use of R/GI MP3 use and diary
Propranolol 20mg po bid initiated
Patient instructed to listen to MP3 2x a week and record in diary
Increase propranolol to 40 mg po bid if the patient is tolerating at one month time point. Continue oral Propranolol until
removal from study
Blood drawn and completion of questionnaires after the completion of every two cycles (2 mos and 4 mos)
• Proven recurrent cervical cancer of any histology not
eligible for curative radiotherapy or surgery
• Failed chemotherapy for first recurrence (excluding
chemotherapy with concurrent irradiation)
• Measurable or non-measurable disease
• 1-3 prior therapies
*
*
* Patients whose disease may be cured by surgery or radiaotherapy.
* Contraindications to use of a Beta-Blocker or already receiving a Beta-Blocker.
* Performance status>3. (must have had treatment for first line recurrence)
* With exception of non-melanoma skin cancer & other specific malignancies,
pts with other invasive malignancies who had (or have) any evidence of the
other cancer present within the last five years or whose previous cancer
treatment contraindicates this protocol therapy are excluded.
* Patients with a Zubrod Performance status 3 or 4.
* Comorbid conditions: Addison’s disease, autoimmune hepatitis, hepatitis B,
hepatitis C, AIDS or HIV, lupus erythematosus, rheumatoid arthritis.
* Severe sinus bradycardia; heart block, second or third degree or sick sinus
syndrome (if no artificial pacemaker present).
* Severe hyperactive airway disease (COPD, asthma).
* Any patients on Avastin or any other anti-angiogenic drugs.
* Patients with brittle diabetes mellitus.
* Pts participating in or who plan to participation in other trials during course of
study.
*
Higher levels of distress among pts with ov ca at time of
surgery associated with-
* Poor NK cell activity in TILs
* Lower T cell production of TH1 vs TH2 cytokines in
peripheral blood and TIL
* Social support related to greater NK activity
* Clin Cancer Res. 2009 Apr 15;15(8):2695-702. Lee JW…Sood AK et al
*
Pre surgical clinic visit (FACT sp, BDI, Perceived Stress Scale)
165 pts with ovarian cancer (Measured IL6, IL8, VEGF (ELISA))
Higher spirituality correlated with lower depression (p<.001)
and perceived stress (p<.001)
Higher spirituality correlated with lower IL6
Spirituality not related to IL8 or VEGF
Thaker et al Abstract SGO 2013
*
*
YOGA
MEDITATION
PROZAC
*
Pts undergoing elective colorectal resection randomized to ERAS (n = 299) or
the control group (n = 298).
Results
Pts in the ERAS group showed improved nutritional status when compared to
control group.
Cortisol level of the control group was elevated on both POD 1 (p = 0.007)
and POD 5 (p = 0.002) compared to the preoperative level.
Cortisol level of the ERAS group was not increased until POD 5 (p = 0.001).
Reduced levels of TNF-α, IL-1β, IL-6, and IFN-γ in the ERAS group indicated
less postoperative stress responses.
* World J Surg. 2012 Feb;36(2):407-14. doi: 10.1007/s00268-011-1348-4.
*
*
Eligible participants will be randomly assigned:
Usual Care Group or Lifestyle Intervention Group.
* Participants assigned to the lifestyle intervention group will be asked to modify
their diet and physical activity levels while those assigned to the usual care
group will be asked to continue usual diet/exercise routine.
* They will be asked to fill out questionnaires, give a blood specimen, wear a
*
pedometer, and participate in telephone coaching calls over a period of two
years
Groups will be compared to see if diet and exercise impact the incidence of
ovarian, fallopian tube and primary peritoneal cancer recurrence.
*
You can't stop the waves, but
you can learn to surf.”
― Jon Kabat-Zinn
“Everything can be taken from a man
but one thing: the last of the human
freedoms—to choose one’s attitude in
any given set of circumstances, to
choose one’s own way.”
*
* Meaning Centered Group Therapy
Developed to help advanced cancer patients sustain or
enhance a sense of meaning, peace and purpose even
near the end of life.
8-week intervention influenced by work of Viktor Frankl
Utilizes didactics, discussion and experiential exercises
Decreased distress, increased mindfulness and post
traumatic growth
Stafford et al Suppor Care Cancer 2013
Psycho-Oncology 19: 21–28 (2010)
“Man does not simply exist but always decides what his
existence will be, what he will become the next moment. By
the same token, every human being has the freedom to change
at any instant.”
― Viktor E. Frankl, Man's Search for Meaning
Discovering Meaning…
* Creating a work or doing a deed
* Experiencing something or encountering
someone
*Truth, goodness, beauty…nature,
culture…loving another
* By the Attitude we take toward
unavoidable suffering turning personal
tragedy into a triumph, a human
achievement
* Frankl
*
*Video legacy
*Dignity Therapy
*Faith Based
*Letters to special people
*Support groups +/*Gratitude Diary
*Enhancing control
* Tape recorder?
*
*Recognize hope exists at every stage of illness
*Ask
*Help identify goals, create plan and instill hope
*Address depression and anxiety
*Have a shared presence, listen
*Encourage closeness of friends and family
*Address lack of social supports
*Introduce patients to others who have done well
*Build sense of control by informing
*Assist transitioning “hope objects”
* Arthur Zajonc on Holding Life Consciously
* http://www.onbeing.org/program/arthurzajonc-on-holding-life-consciously/109
*