managing toxicities of therapy: fatigue, cognitive
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Managing Toxicities
of Therapy: Fatigue,
Cognitive Dysfunction
and Bone Health
Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
UCSF Comprehensive Cancer Center
Importance of Understanding Cognitive
Deficits Due to Cancer Therapy
• A challenge facing cancer survivors as identified by
the National Coalition for Cancer Survivorship
• Negative impact on work/school performance and
QOL
• Informed decision-making regarding risk benefit of
treatment
• Functioning of patients with subtle cognitive deficits
improves with cognitive rehabilitation approaches
Common Cognitive Problems Reported
with Systemic Cancer Therapy
Domain Impact on Function
Working memory Ability or organize activities, arrive on time,
make plans and decisions, correct errors,
conceptualize problems, react with
appropriate speed
Executive function
Psychomotor speed
Attention, concentration Ability to pay attention to and process new
information
Language and verbal memory Ability to fluently bring words to mind
Learning and episodic memory Ability to learn or recall new information
Visual memory Ability to integrate visual information and
motor activities
Visuospatial
Adapted from Mandelblatt et al, JCO 2014
Predictors of Cognitive Impairment after
Systemic Therapy for Cancer
• Type of chemotherapy/cancer therapy
• Education level and IQ
• History of traumatic brain injury
• Hormonal factors and treatment
• Co-morbidities/age
• Genetic variables
• Depression (contributing rather than
predictive)
Ahles T. Nature Reviews Cancer 2007; 7:192-201
Hypothesis of Risk
Mandelblatt, Jacobsen, and Ahles, JCO 2014
Endocrine Therapy and Cognition
• Estrogen receptors in the brain – Areas important for cognitive performance
• Animal models – Suggest a role of estrogen in learning
– Sudden drop in estrogen levels had the biggest impact
• Impact of induced menopause in 100 women after neoadjuvant chemotherapy (Hermelink et al, Cancer 2008)
– No impact on cognition observed up to one year after treatment, regardless of SERM or AI therapy
– Executive function better in those whose menses stopped
Comparison to AIs: Neuropsychological
Study of the TEAM Trial
• Neuropsychological tests were performed in Dutch
women before the start, and after one year of
treatment
– 80 tam users, 99 exemestane users
– Mean age 66-68, 90% of starting group)
– T2 compared between AI vs Tam, adjusting for T1
performance
– 120 healthy controls
• At baseline, patients had significantly worse overall
cognitive function compared to controls
– Verbal fluency was the only specific domain
affected
Schilder et al, JCO 2010
Results and Additional Data • At one year
– Exemestane users were similar to controls
– Tamoxifen users performed significantly worse than
controls
• Verbal memory, executive functioning
• Compared to exemestane, lower scores on
information processing speed
• Prospective study of chemotherapy (Ahles et al, 2010)
– 39 treated with tamoxifen compared to 20 who were
not
– Worse processing speed, verbal memory and verbal
ability in tam treated comparing to controls
– No impact of menopause or depression
Schilder et al, JCO 2010
Aromatase Inhibitors and Cognition
• IBIS II trial
– Randomized high-risk PM women to
anastrozole or placebo for 5 years
– Cognitive function sub-study
• Enrolled 227 women from 5 UK sites
• Cognitive assessments done at baseline, 6 and
24 months
• 67% completed 24 month evaluation
– No significant difference in cog testing
– More hot flashes at 24 mo with anastrozole
(30 v 15%) Jenkins, Lancet Oncol 2008
9
Recruitment by local
advertisement
Recruitment through the
Breast Cancer Center at
UCSF
Healthy Control
Subject
Breast cancer
patients scheduled
for chemotherapy
Breast cancer
patients scheduled
For chemo plus AI
Baseline
MRI, PET,
Neuropsych,
ApoE, E2
1 month post-chemo
(frequency matched)
MRI, PET,
Neuropsych, E2
18 months post-chemo
(frequency matched)
MRI, PET,
Neuropsych, E2
Breast cancer
patients scheduled
for aromatase
inhibitors
9 months post-chemo
(frequency matched)
Neuropsych
UCSF Cognitive Function Study
Prospective Trial: Multivariate conditional
logistic regression predicting decline at
any point (n=75)
Rugo et al, ASCO Breast 2013
Variable OR 95% CI χ2 df p
Hormone therapy 7.69 (2.20 – 27.03) 10.14 1 0.002
Average estradiol over time 0.99 (0.98 – 1.00) 1.50 1 0.22
Age (years) 1.03 (0.95 – 1.10) 0.49 1 0.48
Education (years) 0.89 (0.70 – 1.14) 0.84 1 0.36
Estimated baseline verbal IQ
(based on NAART)
0.96 (0.90 – 1.03) 1.53 1 0.22
NAART: North American Adult Reading Test
OR = odds ration, CI = confidence interval, X2 = chi squared, df = degrees of freedom
What about Chemotherapy?
• Meta-analysis (Jim et al, J Clin
Oncol 2012)
– 17 studies including 807 patients
treated with standard dose
chemotherapy
– Neurocognitive tests in 8 domains
– Studies compared results to
noncancer controls or to
prechemotherapy baseline
– Keeping in mind limitations of
design • Observed cognitive deficits were
small in magnitude
• Primary impact in domains of verbal
and visuospatial ability
Functional Imaging
• fPET or fMRI to detect possible metabolic changes
• 2 before chemo, 6 after chemo
• Small studies
• Most < 20 pts
• Overall results
• Areas of decreased activation during performance of a
cognitive task compared with controls
• Longitudinal study with fMRI (Mcdonald, JCO 2012)
• Frontal lobe hyperactivation to support a working memory
task pre Rx
• Decreased activation 1 month post chemo
• Return to pretreatment hyperactivation 1 year post Rx.
• Similar pattern in patients with endocrine treatment
Longitudinal Follow-up
• Impact is highly variable
– Not affected by age, education, time since
treatment, endocrine therapy
• At baseline
– 20 – 30%: lower than expected cognitive
performance based on age and education
• Studies with longer follow-up suggest
gradual improvement over time
– Fan, JCO 2007, Ahles, JCO 2010
Ahles et al, JCO 2012
Longitudinal Effect
• Acute effect of
chemotherapy
on verbal ability
which resolved
over time
Ahles et al, 2010
Risk Factors for Cognitive Loss: Pre to post treatment change in processing speed by
treatment, age groups, level of cognitive reserve
Baseline WRAT
below median
Baseline WRAT
above median
WRAT: wide range achievement test Ahles et al, JCO 2010
• Standard-dose adjuvant breast cancer chemotherapy
and hormone therapy appear to impair cognitive function
in a subset of women
– Effects resolve over time, but duration of time to
improvement and late decline are not well studied
– Current testing methods generally under report patient
reported symptoms
• Longitudinal assessment continues to be important
– Determine impact and duration of cognitive function
– Assess populations at risk
– Define role and effect of baseline defects in cognition
• Mechanisms?
Summary of Data
Interventions • Treat the obvious, beware of polypharmacy
• Pharmacologic intervention
– Modafinil (note severe dermatologic reaction, angioedema risk)
• Kohli, Cancer 2009 – ~70 pts, 4 weeks rx with improved speed of memory,
episodic memory, continuity of attention
– 4-8 week blinded randomization
» Significant improvement with modafinil
• Lundorff, Palliat Med 2009 – 28 pts, placebo controlled 4 day cross over, improved on 2
tests of cognitive function
– Herbal remedies • Gingko Biloba and Ginseng – no standardized formulation
• Cognitive rehabilitation structured programs (Ferguson, Psychooncology, 2012; Plassman, Ann Int Med, 2010)
• Exercise, memory tasks, puzzles, avoid fatigue
• Computer based programs
Treatment Related Fatigue
• The most widespread adverse symptom related to cancer and cancer therapy
• NCCN definition: – Cancer-related fatigue is a persistent, subjective sense of
tiredness related to cancer or cancer treatment that interferes with usual functioning.
• Impacted by – Impaired cognitive function
– Mood disorders
– Physical symptoms • Muscle weakness
• Lack of stamina
• Reduced alertness/lack of motivation
Fatigue Following Adjuvant
Chemotherapy for Breast Cancer
• 82% of patients report fatigue after first treatment or cycle
• Levels of fatigue are 50% greater than women with no history of cancer or chemotherapy
• Fatigue is associated with the following:
– Worse quality of life
– Greater physical and mental symptoms of fatigue
– Poorer sleep quality
– More menopausal symptoms
– Greater use of catastrophizing as a coping strategy
Greene. Cancer Pract. 1994;2:57.
NCCN Guidelines for Assessing and
Managing Fatigue (www.nccn.org)
• Important considerations
– Assess the underlying cause
– Treatment considerations
• Careful medication review, avoid polypharmacy
• Treat depression, recognize that anti-depressants can
cause fatigue in some cases
• Epoetin alfa
• Improve nutrition
• Exercise programs targeted to patient’s level of ability
• Cancer rehabilitation programs
– Treatment generally covered by insurance,
chemotherapy induced fatigue covered by most
disability insurance
Psychostimulants and Other Interventions
• Methylphenidate
– Small trials, patient determined dosing with improvement in
intensity of fatigue (Bruera, JCO 2006; fixed dose: Hanna,
Support Care Cancer 2006)
• Dexmethylphenidate
– Improved fatigue after cancer chemotherapy in 8 week placebo
controlled trial (Lower, J Pain Sympt Management, 2009)
– Subsequent data suggested no effect
• Modafinil
– Several pilot studies suggest benefit in fatigue, sense of well-
being, improvement in cognitive function (Escalante, J Gen Intern
Med 2009, Kohli et al, Cancer 2009, note warnings of rare severe toxicity)
• Other interventions
– Acupuncture
– Yoga
Assessing Bone Health in At
Risk Patients DEXA: • Provides a 2-dimensional measure of bone density
• Office based
• Central DEXA
– Gold standard
– Measures spine, hip, or total body BMD
• Peripheral DEXA
– Measures wrist, heel, or finger BMD
© SLP / Photo Researchers, Inc.
Measuring BMD
T-score The number of SDs by which the patient’s bone mass
falls above or below the mean peak bone mass for a healthy 30-year-old female
For every 1 SD decrease in T-score, relative risk of fracture increases ~1.5- to 2.5-fold
Z-score The number of SDs by which the patient’s bone mass
falls above or below the mean bone mass for age- and sex-matched controls
Decreases in Z-score suggest pathologic bone loss beyond that seen with normal aging
National Osteoporosis Foundation; 2003.
World Health Organization (WHO):
Criteria for Assessing Bone Density
National Osteoporosis Foundation; 2003.
Diagnosis T-Score
Normal –1
Osteopenia < –1 to > –2.5
Osteoporosis –2.5
Severe
osteoporosis
–2.5 and 1
fragility fracture
Fracture Risk in the Normal
Population
Gradient risk of
osteoporosis fracture
+1.0T 0 -1.0T -2.0T -3.0T -4.0T
1X 2X
4X
8X
16X
Normal Osteopenia Osteoporosis
0.5X
World Health Organization Definition of Osteoporosis
• Fracture risk as estimated by bone mineral density
• T score = comparison to young women (25 years)
T score > -1 = normal
T score -1 to -2.5 = osteopenia
T score < -2.5 = osteoporosis
Assessing Bone Turnover
Urine
Pyridinoline (Pyr)
Urine N-telopeptides of type I collagen (NTx)
Urine
Urine
Deoxypyridinoline (D-Pyr)
C-telopeptides of type I collagen (CTx)
Bone Resorption Markers
Osteocalcin (OC) Serum
Serum Bone-specific alkaline phosphatase (BAP)
Bone Formation Markers
.
Miller PD et al. J Clin Densitom. 1999;2:323-342.
AIBL = Aromatase inhibitor-associated bone loss; BC = Breast cancer; AI = Aromatase inhibitor.
1. Warming L, et al. Osteoporos Int. 2002;13:105-112. 2. Kanis JA. Osteoporosis.1997:22-55. 3. Eastell R, et al. J Bone Miner Res.
2006;21:1215-1223.
Naturally
occurring bone
loss
Premenopausal
women1
AIBL
Postmenopausal
women
BC + AI3
Postmenopausal
women2
1
2.6
< 0.4
0
0.5
1
1.5
2
2.5
3
An
nu
al
bo
ne lo
ss,
%
Breast Cancer and AI Therapy Increase
Bone Loss
Fracture Rates in Breast Cancer Patients
Receiving AI Therapy
AI = Aromatase inhibitor. 1. Howell A, et al. Lancet. 2005;365:60-62; 2. Thurlimann B, et al. N Engl J Med. 2005;353:2747-2757; 3. Coleman RE, et al.
Lancet Oncol. 2007;8:119-127; 4. Jones SE et al. SABCS 2008, San Antonio, Tex. Abstract 15; 5. Goss PE, et al. J Natl
Cancer Inst. 2005;97:1262-1271.
Fra
ctu
res
, %
11
7.7
5.7
4.0
5.3
4.6
7.0
5.0
P < .0001
P < .001
0
2
4
6
8
10
12
14
P = .003
P = .25
Tamoxifen
Letrozole
Anastrozole
Placebo Exemestane
ATAC1
(68 months)
IES3
(58 months)
BIG 1-982
(26 months)
MA.175
(30 months –
extended adjuvant)
2.7 2.3
TEAM4
(33 months)
P = NS
ATAC Trial: Fracture Risk Factor Analysis Howell A et al, ASCO 2006, abstract # 563
Statistically significant predictors of fracture
Risk factor No of
patients
HR (95% CI)
Age (years)
<60
60-70
>70
2195
2329
1662
1.41 (1.13, 1.76)
2.17 (1.74, 2.70)
Geographical region
Low or moderate risk
High risk
Very high risk
628
3904
1654
1.15 (0.82, 1.60)
2.25 (1.60, 3.16)
Statin use
No
Yes
5398
788
0.62 (0.47, 0.81)
Treatment
Tamoxifen
Anastrozole
3094
3092
1.54 (1.30, 1.84)
ATAC BMD Substudy • After 5 years, anastrozole is associated with a 6%-7%
loss in BMD, however:
– No patient with normal bone at baseline became osteoporotic after 5 years of treatment
– Normal bone loss over this period due to aging is 2%-3%
• To develop osteoporosis, a woman needs to lose 15%-20% of normal peak bone mass
• Greater increases in bone markers were associated with a greater loss in BMD
• Bone loss did not continue after cessation of therapy with some improvements seen
• Patients at risk for clinically relevant BMD loss during therapy can be identified and managed according to evolving clinical guidelines
Eastell, JCO 2008, Ann Oncol 2011
ZoledronateZoledronate Significantly Increases BMD: Significantly Increases BMD:
Phase II Osteoporosis StudyPhase II Osteoporosis Study
•• OnceOnce--perper--year IV injection of year IV injection of zoledroniczoledronic acidacid produces effects on boneproduces effects on boneturnover and bone density as great as those seen with daily or wturnover and bone density as great as those seen with daily or weekly oral dosing eekly oral dosing of other of other bisphosphonatesbisphosphonates
Lumbar Spine % Change BMD Femoral Neck % Change BMD
0
1
2
3
4
5
6
0 3 6 9 12
Months
Pe
rce
nt
Placebo
1 x 4 mg
-1
0
1
2
3
3 6 9 12
Months
Pe
rce
nt
Placebo
1 x 4 mg
Reid et al. N Engl J Med. 2002;346:653.
Bisphosphonates to Reduce Bone Loss
• Effects of induced menopause
– ABCSG-12 substudy • OS and tamoxifen or anastrozole for 3 years
• Randomized: zoledronic acid q 6 mos or not
• Complete abrogation of bone loss in those receiving ZA
• Bone loss more severe with AI compared to tam
• Some evidence of recovery after completion of Rx
• Effects in PM women
– Z-Fast and Zo-Fast • ZA q 6 months upfront or at time of fracture/osteoporosis
– ZA increased BMD compared to decrease on delayed rx.
– No difference in fracture rates at 3 years
• For Z-Fast: 21% in delayed group started ZA at 36 mo
Gnant et al, Brufsky et al, JCO 2007, Bundred et al, Cancer 2008
Bisphosphonates to Reduce
Bone Loss: Other
• CALGB 79809
– Upfront vs one year ZA q 3 months in women
with chemotherapy induced ovarian failure
– Less bone loss compared to control, more
marked in those not on tam
• Risedronate phase III trial
– Weekly vs placebo x 1 year in premenopausal
women receiving adjuvant chemotherapy
– No difference in BMD at one year
Shapiro et al, ASCO 2008, # 512, Hines ASCO 2008, #525
RANK Ligand Is a Key Mediator in the
“Vicious Cycle” of Bone Destruction in Metastatic
Cancer
Bone RANK
RANKL
Bone
Resorption
Osteoclast
Cancer Cells in Bone
Growth Factors (TGF-b, IGFs, FGFs,
PDGFs, BMPs)
Cytokines and Growth
Factors (IL-6, IL-8, IL-1b,
PGE-2, TNF-, CSF-1, PTHrP)
Adapted from Roodman GD. N Engl J Med. 2004;350:1655-64.
RA
NK
L
Direct effects
on tumor?
Denosumab: Effect on Lumbar Spine BMD in
Women Receiving Adjuvant AIs
• 60 mg SC every 6 months
• 4.7 % difference at hip (p<.0001)
• More serious adverse events in denosumab arm (15%) vs placebo (9%)
• Calcium replacement is critical
Ellis G, et al. JCO 2008
Secondary Causes of Bone Loss in Breast
Cancer Survivors
• 64 early breast cancer pts with bone health
evaluation prior to AI therapy
– 37.5% vitamin D deficiency (< 30ng/ml)
– 15.6% idiopathic hypercalcuria
– 4.7% hyperparathyroidism
• 61% breast cancer survivors had a metabolic
bone disorder – evaluate prior to AI therapy
Camacho P, Albain, K, J Clin Oncol, 2008
Vitamin D Deficiency in Women with Early
Stage Breast Cancer:
Association with Disease Recurrence
• Vitamin D deficiency has been inconsistently
associated with breast cancer risk
– May be an inverse association of vitamin D level with
premenopausal breast cancer risk
• Analysis of 512 patients with newly diagnosed, T1-3,
N0-1, M0 locoregional breast cancer
• Mean follow-up of 11.6 years
• Mean 25-OH vitamin D level = 58.1 +/- 23.4 nmol/L
• Factors significantly associated with vitamin D deficiency: – Age < 50 years, higher tumor grade, BMI > 30 kg/m2,
adjuvant chemotherapy, no vitamin D supplement
Goodwin et al, JCO 2009
Vitamin D Deficiency and Outcome
Deficient
< 50 nmol/L
Insufficient
≥ 50 – 72
nmol/L
Sufficient
> 72 nmol/L
P
value
Distant DFS (HR) 1.94 1.37 1.0 .02
5-year DDFS 82% 85% 88%
10-year DDFS 69% 79% 83%
Overall survival (HR) 1.73 1.01 1.0 .02
5-year OS 87% 93% 92%
10-year OS 74% 85% 85%
Conclusions: • Vitamin D deficiency/insufficiency was common in breast cancer
patients at diagnosis (76%)
• Vitamin D deficiency was associated with an increased risk of distant
recurrence and death.
• Results are preliminary; randomized trials are required to
demonstrate that replacing vitamin D changes outcome
Vitamin D Deficiency 25(OH) D level
ng/mL nmol/L Health Status
< 20 <50 Associated with deficiency
21-30 52.5- 75 Inadequate for bone/overall health
> 30 > 75 Desirable for overall health
Consistently
> 200
Consistently
> 500
Potentially toxic, leading to
hypercalcemia, hyperphophatemia
1 ng/mL = 2.5 nmol/L.
• 50,000 IU D2 q week for 8 weeks. Repeat for another 8 weeks if level still
less than 30. Maintenance of 1000-2000 IU D3 daily.
• Malabsorption syndromes: 50,000 IU D2 every other day with goal to
achieve serum 25-OH of 30-60. Maintain with 50,000 IU q week.
Holick MF. NEJM. 2007;357:266-81
Prevention of Bone Loss in Patients on
Treatments Known to Increase Risk of Fracture
• Baseline risk fracture assessment – BMD, age (>65), steroids, low BMI (<20 kg/m2), family hx
hip fx, fragility fx > age 50, smoking
• Bone mineral density (Dexa scan)
• Lifestyle changes – Weight bearing exercise
– Stop smoking
– Reduce alcohol consumption
• Dietary supplements – Adequate calcium (1000 mg/day)
– Supplementary vitamin D (1000-2000 units/d)
• Anti-resorptive therapy – Low BMD or rapid bone loss
Adapted from Coleman et al, Ann Oncol 2014
Guidelines for reference: Hadji et al, Ann Oncol 2008, Hillner et al, JCO 2003
Summary
• Cognitive dysfunction is a real complication of adjuvant chemotherapy, and maybe tamoxifen? – Prolonged or disabling symptoms are relatively uncommon
• Cancer related fatigue is common – The NCCN provides guidelines for screening and possible
therapeutic options
• Osteoporosis and fractures are an important complication of treatment for early stage breast cancer – Screening and recommendations for appropriate treatment
should be part of oncology practice
– Prophylaxis is not recommended at this time
– New drugs are currently under evaluation for the prevention of bone loss in postmenopausal women
Adapted from Roodman GD. N Engl J Med 2004;350:1655–64;
Mundy GR. Nat Rev Cancer 2002;2:584–93;
Green JR. Oncologist 2004;9(Suppl 4):3–13.
Bisphosphonates Embed In Bone And Interrupt The Vicious Cycle
Osteoblasts
Bisphosphonate
Growth factors
(eg, TNF, IL-1, TGF-β)
PDGF, BMPs, TGF-β,
IGFs, FGFs, Ca2+
Activated
osteoclasts
Tumour
Osteoblasts
RANK Ligand
Role of Bisphosphonates on Risk
of Recurrence • Highly controversial with conflicting trial results,
heterogeneous patient populations and adjuvant
therapy
• Meta-analysis of randomized trials
– Data received on 22 out of 36 trials testing clodronate
and aminobisphosphonates
• 17,791 patients (77% of total available)
– Goal
• Evaluate impact on recurrence
– Bone vs non-bone sites
– Pre- and post-menopausal women
Coleman R et al, SABCS 2013
Summary of Results Induced menopause, age>55
• 10 yr risk of breast cancer recurrence
– 3.5% decrease in distant recurrence
• 21.9 vs 18.4% (p=.0003)
– 2.9% decrease in bone recurrence
• 8.8 vs 5.9% (p<.00001)
– No difference in non-bone recurrence
– No difference in local or CL recurrence
• Mortality
– 3.1% decrease in breast cancer mortality
• 18.3 vs 15.2% (p=.004)
– 2.3% decrease in all cause mortality
• 23.8 vs 21.5% (p=.007)
Coleman R et al, SABCS 2013
Conclusions • Adjuvant bisphosphonates reduce bone metastases and
improve survival in post-menopausal women.
– 34% reduction in risk of bone recurrence (p=0.00001).
– 17% reduction in risk of breast cancer death (p=0.004).
– Risk reductions similar irrespective of ER, node status, use/non use of
chemotherapy.
– Benefits similar for aminobisphosphonates and clodronate.
• For post-menopausal women taking aromatase inhibitors for early stage breast cancer – Bisphosphonates should be considered in those with at least
osteopenia • No indication as yet to reduce risk of recurrence
– Zoledronate IV q 6mo, or other aminobisphosphonates
– Dental education!
• Denosumab trial ongoing
Bone Recurrence By Menopausal Status
Significantly Reduced Bone Recurrence in Postmenopausal Women
*
* Includes women aged 45-55 if menopausal status unknown
‡
‡ includes women aged < 45 if unknown
Thank you!!
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