smita bhatia, m.d., m.p.h
DESCRIPTION
Health-related outcomes after pediatric cancer: Price of cureTRANSCRIPT
Health-related Outcomes after Pediatric Cancer
Price of Cure
Smita Bhatia, M.D., M.P.H.Director, Center for Cancer Survivorship
Currently in the US….
• Over 300,000 childhood cancer survivors
• 1 in 1,000 is a childhood cancer survivor
• 1 in 540 is a childhood cancer survivor (18-45 yr.)
Childhood Cancer Survivors
Distribution of Childhood Cancer Survivors
Landmarks in Pediatric Oncology by Decade
1970s• Recognition that cure was possible• Proliferation of clinical trials
• Effective multi-modality protocols
1980s• Tailoring therapy to risk factors• Defining late effects• Reducing radiation dose
• Substituting effective drugs for radiation
1990s• Understanding relationship of dose to late effects• Initiating efforts to track and educate survivors
Long-term Sequelae in Childhood Cancer Survivors
Fertility and ReproductionFertilityHealth of Offspring
Vital Organ FunctionCardiacPulmonaryRenalEndocrineGastrointestinalVision/Hearing
Second NeoplasmsBenignMalignant
Growth and developmentlinear growthskeletal maturationintellectual functionemotional/social maturationsexual developmentHealth-related Quality of LifeHealth-related Quality of Life
Cognitive Dysfunction
Cognitive Dysfunction
1 to 2 yrs following radiation• progressive
Academic difficulties • reading, language, mathematics • significant drops in IQ scores
Risk Factors• Leukemia, brain tumors• Radiation to the brain• Intrathecal chemotherapy• Young age – less than 5 years• Female gender
Cardiac Complications
Can occur years after completion of treatmentSpontaneous or coincide with exertion or pregnancy
• Chemotherapy (anthracyclines) • Chest radiation• Females • Younger age
Lung Complications
Prevention• Caution about smoking
• Frequent checks
Symptoms• Chronic cough • Shortness of breath
Causes• Radiation• Chemotherapy
• Brain tumors (30% to 35%)• Leukemia (10% to 15%) • Whole-brain irradiation• Younger age at treatment• Females
Growth Retardation
Second Primary Cancers
Radiation
Chemotherapy
Smoking
Diet
Exercise
Genetic susceptibility
Breast Cancer after Hodgkin disease in girls receiving radiation
Age in years
Cum
ulati
ve in
cide
nce
15.0 25.0 35.0 45.0
0.0
0.10
0.20
0.30
20%
SIR=55
Burden of Morbidity in Survivors of Childhood Cancer?
Growth Impairment After Radiation
R
Cardiac Complications
Pulmonary Dysfunction
The implications of cure are not trivial
Burden of morbidity in survivors of childhood cancer is substantial
Chronic Diseases in Childhood Cancer Survivors
Grade 1-5
Grade 3-5
1.0
0.8
0.6
0.4
0.2
0.010 20 300
Cum
ulati
ve In
cide
nce
N Engl J Med, 2006
Burden of Morbidity in Childhood Cancer Survivors
Need for continuing follow-up of childhood cancer survivors into adult life
Survivors and healthcare providers need to be aware of the “at risk” populations
Only 35% of survivors understand that serious health problems
could result from past treatment
Impairs survivors’ ability to seek and receive appropriate long-term follow-up care
Health Care Utilization by Young Adult SurvivorsPe
rcen
t Sur
vivo
rs w
ith M
edic
al V
isits
Years since Diagnosis
Ann Fam Med 2004;2:61-70
Conclusions
Primary care providers are unfamiliar with the problems
faced by childhood cancer survivors
Survivorship Issues
Extended and standardized follow-up of survivors
Who provides the follow-up?• Primary oncologist• Primary health care provider• Both
Issues related to transitioning of care• From pediatrics to adult-centered care• From oncology to primary care
Issues related to lack of insurance
Issues related to lack of awareness regarding potential late effects• Survivors• Health care providers
Long-term survival is an
expected outcome for most
children with cancer
Care of Childhood Cancer Survivors
Infrastructure for long-term specialized care for survivors
• Diagnosis of cancer at age 21 or younger
• In remission and off-therapy for 2 yr
• Consent to participate in IRB-approved protocol
• No upper age limit
City of Hope
Childhood Cancer Survivorship Program
Childhood Cancer Survivorship Clinic:
Therapeutic Summary
Childhood Cancer Survivorship Clinic:
Recommendations for Follow-Up
Childhood Cancer Survivorship Clinic:
Health Links
Childhood Cancer Survivorship Clinic:
Lay Recommendations
Follow-Up – Patient Report
Follow-Up (PCP Report)
Long-term Follow-up Guidelines
End of therapy
Summarization of therapy exposures
Comprehensive Follow-up of Cancer SurvivorsComprehensive Follow-up of Cancer Survivors
Cancer Survivors
Surviving Hematopoietic Cell Transplantation
Num
ber o
f HCT
sHematopoietic cell transplantation activity worldwide
'80 '81 '82'83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09
20,000
25,000
35,000
30,000
15,000
10,000
5,000
0
Autologous HCT
Allogeneic HCT
Year of HCT (1980 to 2009)
>60,000 HCTs/ year• Improved efficacy in many diseases
• Increased options of stem cell source
Growing number of HCT survivors• Increasing focus on long-term health
Post-transplantation Complications
Non-malignant late effects New tumors
Psychosocial outcomes
• Ocular• Orodental• Pulmonary • Gastrointestinal• Cognitive dysfunction• Musculoskeletal• Renal dysfunction• Cardiac• Metabolic syndrome
• Benign• Malignant
• Fatigue• Sexual functioning• Social integration• Quality of life
Post-transplantation late effects
Non-malignant late effects
Malignant late effects
Psychosocial well being
Chronic Graft versus Host disease
Diabetes, hypertension, and cardiovascular events in HCT survivors
Blood, 2007;109:1765-72
Increased risk of DM in HCT survivors•Prolonged exposure to steroids•Exposure to TBI
Increased risk of hypertension in HCT survivors•Prolonged exposure to steroids, cyclosporine•Exposure to other immunosuppressive agents
Increased risk for cardiovascular disease
Diabetes, Hypertension, Cardiovascular diseaseComparison with siblings
%
Adjusted for current age, age at HCT, and sex*p
<0.05
Diabetes HTN Arterial Disease
MI Stroke BMI 30+
OR 3.0* 1.6* 0.8 0.9 6.4 0.7*
CI 1.6-5.6 1.1-2.1 0.3-1.8 0.2-4.0 0.8-49.6 0.5-0.9
Blood, 2007;109:1765-72
Diabetes HTN Arterial Disease
MI Stroke BMI 30+
OR 3.1* 1.2 1.1 1.2 2.7 0.8
CI 1.5-6.3 0.8-1.6 0.4-3.6 0.2-5.9 0.6-12.5 0.5-1.1
*P<0.05
%
Adjusted for age, age at HCT, and sex
Blood, 2007;109:1765-72
Diabetes, Hypertension, Cardiovascular diseaseRole of TBI
Osteonecrosis in HCT survivors
Cancer. 2009;115:4127-35
Late osteonecrosis after HCTCu
mul
ative
Inci
denc
e (%
)
6% at 10 years
Cancer. 2009;115:4127-35
1+ year survivors of HCT
N=1346
15%
10%
5%
0%0 1825 3650 5475 7300 9125 10950
DAYS
Cum
ulati
ve In
cide
nce
(%)
P<0.001
Late osteonecrosis by stem cell donor type
Cancer. 2009;115:4127-35
15%
10%
5%
0% 0 182
5365
05475
7300
9125
10950DAYS
Unrelated donor HCT(15% at 10 years)
Allogeneic related HCT(6% at 10 years)
Autologous HCT4% at 10 years
Osteonecrosis Risk factors in allogeneic HCT recipients
Diagnosis of Hodgkin lymphoma or multiple myeloma• RR=11.7 (2.3-60.01)
Exposure to cyclosporine, tacrolimus, prednisone, mycophenolate mofetil • RR=6.8 (1.5-30.9)
Presence of chronic GvHD• RR=2.2 (1.0-4.8)
Cancer. 2009;115:4127-35
Chronic Kidney Disease in HCT survivors
Cancer, 2008, 113(7):1580-7
Chronic Kidney Disease
Sustained compromise of renal function• Variety of causes of renal injury• May lead to progressive loss of renal function
• terminate in end-stage renal disease
Important to understand the populations at risk• Institute appropriate monitoring• Judicious use of potentially nephrotoxic drugs
Late Chronic Kidney Disease after HCT
5.7% at 10 years
Cancer, 2008, 113:1580-7 Years post-HCT
0 5 10 15 20 25 30
14%
12%
8%
0%
10%
6%
4%
2%
Cum
ulati
ve In
cide
nce
(%)
Who is at highest risk for chronic kidney disease after Allogeneic transplant
RR 95% CI
Age at HCT
Increments of 5 years 1.3 1.3-1.34
Drug combinations for prophylaxis/ treatment of GvHD
None/ methotrexate alone 1.0 __
Cyclosporine without tacrolimus 1.8 0.6-5.20
Cyclosporine with tacrolimus 4.3 1.3-14.9
Primary diagnosis
Primary diagnosis other than myeloma
1.0 __
Multiple myeloma 5.4 1.8-16.2
Cancer, 2008, 113:1580-7
Risk of Chronic Kidney Disease after transplant
P< 0.01
0 5 10 15 20 25 30
Cum
ulati
ve In
cide
nce
(%)
Years
25%
20%
10%
15%
5%
0%
Exposure to Calcineurin Inhibitors; Age at HCT > 45 years
No Exposure to Calcineurin Inhibitors; Age at HCT < 45 years
Cancer, 2008, 113:1580-7
Solid tumors after Hematopoietic Cell Transplantation
J Clin Oncol, 2001;19:464-71
Solid cancers after transplantation
Age at HCT < 34 years
RR=4.8, p<0.05
0 3 6 9 12
15
.40
.30
.10
.20
018
Time (Years)
J Clin Oncol, 2001;19:464-71
Cum
ulati
ve In
cide
nce
(%)
Total Body Irradiation
RR=2.7, p<0.05
Excess Risk of Solid CancersSt
anda
rdiz
ed In
cide
nce
Ratio
J Clin Oncol, 2001;19:464-71
Therapy-related leukemia after autologous transplantation for lymphoma
Blood, 2000;95:1588-93
Therapy-related leukemia after autologous transplantation
.30
.20
.0
.10
0 2 4 6 8 10
Cum
ulati
ve In
cide
nce
(%)
Time in Years from aHCT
8.6% at 6 years
Blood, 2000;95:1588-93
Who is at risk for therapy-related leukemia?
Risk Factors Total Cohort HD NHL
Priming with VP-16 6.1* 5.9* 6.7*
PSC 2.8* 1.7 4.9*
Primary Dx (HD) 1.6 __ __
Gender (females) 1.8 2.4 1.3
Age at BMT (> 40 yr) 0.8 1.2 0.9
Blood, 2000;95:1588-93
Longitudinal Trajectory of Fatigue and Vigor
after HCT
J Clin Oncol, 2008
Fatigue and Vigor
• Describe longitudinal trends in fatigue, vigor and quality of life
• Identify predictors of fatigue, vigor and QOL
• Understand the impact of fatigue and vigor on return to work after HCT
• Profile of Mood States• standardized self-report instrument measuring fatigue, vigor
• City of Hope HCT-QOL Questionnaire
Methods
2 yearsPre-HCT 6 months 1 year
HCT
3 years
Longitudinal trends in Fatigue
Fatigue decreased across time after transplantation•Maximum effect observed at the 2 and 3 year points
Longitudinal trends in Vigor scores
Vigor increased across time after transplantation•Improvement observed across all time points
Longitudinal trends in Physical well-being by Fatigue
Physical well being scores were significantly lower
among patients with higher levels of fatigue
Low fatigue
High fatigue
Longitudinal trends in Psychological well-being by Fatigue
Psychological well being scores were significantly
lower among patients with higher levels of fatigue
Longitudinal trends in Psychological well-being by Vigor
Psychological well being scores were significantly
lower among patients with lower levels of vigor
High vigor
Low vigor
Longitudinal trends in Spiritual well-being by Vigor
Spiritual well being scores were significantly lower
among patients with low levels of vigor
Low vigor
High vigor
Longitudinal trends in Social well-being by Vigor
Social well being scores were significantly lower among
patients with low levels of vigor
High vigor
Low vigor
Percent Returning to Full-time Work
Pre 6m 1y 2y 3y0
10
20
30
40
50
60
70
80
90
100P
erc
en
t
Time after HCT
57.6%
50.0%
42.5%
23.7%
p<.0001, df=3
Blood, 2010;115:2508-19
Income cGVHD BMI Avg Fatigue0.0
0.2
0.4
0.6
0.8
1.0
1.2
RR=.40
RR=.56RR=.56
RR=.25
Worst 40%vs
Least 60%
<Obesevs
>Obese
Withvs
Without
< 20Kvs
> 20K
Upper 95% CI Lower 95% CI
Re
lati
ve
Ris
kVariables associated with successful return to full time work
Blood, 2010;115:2508-19
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 6 12 18 24 30 36
Months after HCT
Cum
ulat
ive
inci
denc
e
High vigor (75th percentile)
Low vigor (25th percentile)
P = .02*
Cumulative incidence of return to work by baseline vigor scores
Low vigor
High vigor
Sexual functioning after hematopoietic cell
transplantation
Blood. 2008;112: 743a
100
90
DIS
F-SR
T To
tal S
core
Months since HCT
80
70
60
50
40
306 1
218
24 30 36
P<.0001
Sexual Functioning after HCT
0
Men
Women
Pre-HCT
6 mo. 1 year 2 years 3 years
HCT
Blood. 2008;112: 743a
DIS
F-SR
Tot
al S
core
P=.002
Sexual Functioning – age effect
90
Months since HCT
80
70
6 12
18
24 30 36
Men
60
50
40
0
<40y
>40y
40-60y
60y
Blood. 2008;112: 743a
DIS
F-SR
Tot
al S
core
Months since HCT
6 12
18
24 30 36
Women100
90
80
70
60
50
40
P=.006
Sexual Functioning – age effect
<30y
>30y
Blood. 2008;112: 743a
100
90
DIS
F-S
R T
ota
l S
core
Months since HCT
80
70
60
50
40
300 6 1
218
24 30 36
P=.006
Impact of total body irradiation
Men
No TBI
TBI
Blood. 2008;112: 743a
Neuropsychological outcomes after transplantation
Blood. 2009a
COH Neurocognitive Function Study
HCT
3yPre 6m 1y 2yPatients
Healthy Controls
5y
Study design 5-year longitudinal study Standardized 2-hour battery of neurocognitive tests
The rate at which mental activities are performed
Wechsler Adult Intelligence Scale – Digital Symbol Coding•Measures visual-motor coordination; motor/ mental speed
“Copy the symbols corresponding to the numbers into the empty boxes as fast as you can.”
Processing Speed
Wechsler Adult Intelligence Scale – Symbol Search• Measures speed of visual perception
“Does the shape on the left match any of the shapes in the group on the right? Answer as many as you can before time runs out.”
Processing Speed
Working Memory
Memory for, or information processing of, material or events in a temporary mental workspace•On-line information processing and manipulation system•Related to attention and concentration
Wechsler Adult Intelligence Scale•Digit Span•Arithmetic•Letter-Number Sequencing
Digit SpanTo assess attention, concentration, mental controlItems range from easy (2 digits) to difficult (9 digits)
“Repeat these numbers: 2-4-3-8-1.”“Repeat these numbers, but in reverse sequence: 9-2-1-5-4.”
Working Memory
Arithmetic Measures concentration while manipulating mental math problems Items range from very easy to very difficult
"How many 45-cent stamps can you buy for 5 dollars?"
Letter-Number Sequencing To measure attention and working memory Items range from very short to very long
“Repeat the sequence Q-8-B-3-J-2, but place the numbers in numerical order and then the letters in alphabetical order.”
Auditory Memory
The ability to store, retain, and recall information after it is orally presented
Wechsler Memory Scale•Logical Memory
“I will read a short story aloud. When I’m done, repeat the whole story to me.”
Visual Memory
The ability to store, retain, and recall information after it is visually presented
Wechsler Memory Scale•Family Pictures
• Examiner shows participant pictures of characters doing things, then participant must recall the scenes
“Remember as much as you can about this
picture. I’m going to ask you about it later.”
“Where was the mother? What was she doing?”
Visual Memory
Verbal Speed
Assesses the speed at which an examinee can name/read high-frequency, repeating stimuli/words
Delis-Kaplan Executive Function System
•Color Naming
•Word Reading
Color Naming: “Name the colors. Go as fast as you can.”
Word Reading: “Read the words. Go as fast as you can.”
GREEN BLACK REDPURPLE BLUE GREEN
BLACK RED BLUE
Verbal Speed
Processes that guide, direct, and manage cognitive, emotional and behavioral functions, esp. during active, novel, problem solving•Delis-Kaplan Executive Function System
• Color-Word Interference: Inhibition: Assesses verbal inhibition
“Name the colors of the words. Do NOT read the words. Go as fast as you can.”
Executive Function
Verbal Fluency
Assesses fluent productivity in the verbal domainDelis-Kaplan Executive Function System•Letter Fluency•Category Fluency
“Say as many words as possible from a category before time runs out.”•Letter Fluency: Words that start with the letter P•Category Fluency: Animals•Switch between two categories (animal, tool, animal, tool, etc.)
“Put the pegs into the board as fast as you can, using only your dominant hand.”
Coordination of small muscle movements which occur e.g., in the fingers, usually in coordination with the eyes
•Grooved Pegboard –Measures motor speed and dexterity
Participants insert a peg into a board containing holes angled in different directions.–Each peg has a ridge along one side, requiring rotation for correct insertion into the hole
Fine Motor Dexterity
Intelligence
“Global capacity of the individual to act purposefully, to think rationally, and to deal effectively with the environment”
Wide Range Achievement Test: Word Reading•To assess single word reading ability
• Established as a reliable estimate of IQ • Word reading is an over-learned ability
– Relatively resistant to cognitive impairment and can be used as a predictor of pre-morbid intelligence
•Words range from very easy to very difficult“Read the following words aloud."
DOG LICORICE PRESTIGIOUS
Fine Motor DexterityP
erc
en
t Im
pair
ed
Executive FunctionP
erc
en
t Im
pair
ed
Auditory MemoryP
erc
en
t Im
pair
ed
Visual MemoryP
erc
en
t Im
pair
ed
Processing SpeedP
erc
en
t Im
pair
ed
Working Memory (Letter Number Sequencing)P
erc
en
t Im
pair
ed
Verbal Speed (Word Reading Score)P
erc
en
t Im
pair
ed
Verbal Fluency (Letter Fluency)P
erc
en
t Im
pair
ed
Significant increase in prevalence of impaired individuals from pre-HCT to 1 years• Allogeneic HCT recipients
• Fine Motor Dexterity, Auditory Memory, Visual Memory, Processing Speed, Working Memory
•Autologous HCT recipients• Fine Motor Dexterity, Visual Memory, Working memory, Verbal
Fluency
Trajectory of Cognitive Impairment
Significant decrease in prevalence of impaired individuals from pre-HCT to 1 year•Allogeneic HCT recipients
• none
•Autologous HCT recipients• Processing Speed, Verbal Speed
Trajectory of Cognitive Impairment
Stable prevalence rates from pre-HCT to 1 year post-HCT•Allogeneic HCT recipients
• Executive Function, Verbal Speed, Verbal Fluency
•Autologous HCT recipients• Executive Function, Auditory Memory
Trajectory of Cognitive Impairment
Burden of Morbidity
Blood, 2010;116:3129-39
Survivors
Siblings
Severe or life-threatening Conditions
Chronic Health Conditions – Survivors vs. Siblings
51% (10 yr)
14% (10 yr)
RR=5.0 (95% CI:3.4-7.4 )
Blood, 2010;116:3129-39
Chronic Health Conditions
Adverse Psychological outcome
• Chemotherapy/ radiation
• cGVHD and its sequelae
• Prolonged immune suppression
Burden of Long-term Morbidity
Psychological Health Status
Survivorship issues in 10+Year Survivors of HCT
Unknown for 10+ year survivorsHealthcare utilization
Prevalence of chronic health conditions
Survivors compared to siblings
P<0.001
BBMT, 2012, in press
Risk of Chronic Health ConditionsSurvivors compared to siblings
Adjusted for age at questionnaire, sex, race/ethnicity, education, income and insurance status
Re
lativ
e R
isk
BBMT, 2012, in press
Cumulative Incidence of Chronic Health Conditions
Among 10+ year Survivors
71% (15 yr)Any chronic health condition
40% (15 yr)
Severe/ life-threatening condition or death
BBMT, 2012, in press
Prevalence of Adverse Psychological Outcomes
P=0.55
P=0.1
P=0.11
P<0.001
Blood, 2011;118:4723-31
Are survivors at a higher risk of psychological problems when compared with siblings?
Odd
s Ra
tio
P=0.9 P=0.52
P=0.2
P=0.03
Adjusted for age at questionnaire, sex, marital status, race/ethnicity, education, income, insurance status, health status, and chronic health conditions.
Blood, 2011;118:4723-31
Healthcare utilization among long-term survivors
90% of the survivors carried health insurance
BBMT, 2013, in press
Health-related Outcomes after HCT
Quality of Life
Impact of long-
term sequelae
on HRQL is
unknown
Long-term sequelae
Impact of Chronic Health Conditions on Health-
related Quality of Life
Blood, 2006;108: 73a
demographics education income employment insurance marital status health habits family history
medication use medical conditions Graft vs. host disease surgical procedures recurrent cancer new neoplasms offspring/pregnancy history utilization of medical care
BMT-SSQuestionnaire
Physical Well BeingPhysical Physical
Well BeingWell BeingPsychological
Well BeingPsychologicalPsychological
Well BeingWell Being
Social Well Being
Social Social Well BeingWell Being
Spiritual Well BeingSpiritual Spiritual
Well BeingWell Being
Overall QOL
Physical Well BeingPhysical Well Being
PsychologicalWell Being
PsychologicalWell Being
Social Well Being
Social Well Being
Spiritual Well BeingSpiritual
Well Being
HCT-QOL
Physical Well Being
Adj
uste
d LS
M
Adjusted for inability to return to work, cGVHD, pain or anxiety, inability to exercise, age at HCT
Blood, 2006;108: 73a
Social Well Being
Adjusted for inability to return to work, cGVHD, pain or anxiety, marital status
A
dju
sted
LS
M
Blood, 2006;108: 73a
Aims of hematopoietic cell transplantation
Sustained remission/ cure of primary disease
Complete recovery of health status
Normal physical and psychological functioning
Normal and orderly social integration
• Substantial burden of chronic morbidity
• Challenges in social integration
• Need for life-long follow-up of HCT survivors
Long-term consequences of hematopoietic cell transplantation
Recommendations
Intervention Strategies
Genetic PredispositionLifestyle Exposures
Viral infections
Therapeutic Exposures
Late Effects
Primary CancerModification of Modification of
Therapeutic ProtocolsTherapeutic Protocols
Identification and Screening of “High Risk” Populations