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