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!!