Health-related outcomes after pediatric cancer: Price of cure

1. Health-related Outcomes after Pediatric Cancer
Price of Cure
Smita Bhatia, M.D., M.P.H.
Director, Center for Cancer Survivorship

2. Childhood Cancer Survivors
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.)

3. Distribution of Childhood Cancer Survivors

4. 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

5. Long-term Sequelae in Childhood Cancer Survivors
Growth and development Vital Organ Function
linear growth Cardiac
skeletal maturation Pulmonary
intellectual function Renal
emotional/social maturation Endocrine
Health-related Quality of Life
sexual development Gastrointestinal
Vision/Hearing
Fertility and Reproduction Second Neoplasms
Fertility Benign
Health of Offspring Malignant

6. Cognitive Dysfunction

7. 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

8. Cardiac Complications
Can occur years after completion of treatment
Spontaneous or coincide with exertion or pregnancy
• Chemotherapy (anthracyclines)
• Chest radiation
• Females
• Younger age

9. Lung Complications
Causes
• Radiation
• Chemotherapy
Symptoms
• Chronic cough
• Shortness of breath
Prevention
• Caution about smoking
• Frequent checks

10. Growth Retardation
• Brain tumors (30% to 35%)
• Leukemia (10% to 15%)
• Whole-brain irradiation
• Younger age at treatment
• Females

11. Second Primary Cancers
Radiation
Chemotherapy
Smoking
Diet
Exercise
Genetic susceptibility

12. Breast Cancer after Hodgkin disease
in girls receiving radiation
0.30
SIR=55
Cumulative incidence
0.20
0.10
20%
0.0
15.0 25.0 35.0 45.0
Age in years

13. Burden of Morbidity in Survivors of
Childhood Cancer?

16. Growth Impairment After Radiation

17. R

18. Cardiac Complications
Pulmonary Dysfunction

19. The implications of cure are not trivial
Burden of morbidity in survivors of
childhood cancer is substantial

20. Chronic Diseases in Childhood Cancer Survivors
1.0
0.8
Grade 1-5
Cumulative Incidence
0.6
Grade 3-5
0.4
0.2
0.0 N Engl J Med, 2006
0 10 20 30

21. 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

22. Health Care Utilization by Young Adult Survivors
Ann Fam Med 2004;2:61-70
ov vr uS t necr e P
Years since Diagnosis
i

23. Conclusions
Primary care providers are unfamiliar with the problems
faced by childhood cancer survivors

24. 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

27. Care of Childhood Cancer Survivors
Long-term survival is an
expected outcome for most
children with cancer
Infrastructure for long-term specialized care for survivors

28. City of Hope
Childhood Cancer Survivorship Program
• 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

29. Childhood Cancer Survivorship Clinic:
Therapeutic Summary

30. Childhood Cancer Survivorship Clinic:
Recommendations for Follow-Up

31. Childhood Cancer Survivorship Clinic:
Health Links

32. Childhood Cancer Survivorship Clinic:
Lay Recommendations

33. Follow-Up – Patient Report

34. Follow-Up (PCP Report)

35. Comprehensive Follow-up of Cancer Survivors
Summarization of
Long-term Follow-up Guidelines
therapy exposures
End of
therapy

36. Cancer Survivors

37. Surviving Hematopoietic Cell Transplantation

38. Hematopoietic cell transplantation activity
worldwide >60,000 HCTs/ year
• Improved efficacy in many diseases
35,000
• Increased options of stem cell source
30,000
Number of HCTs
25,000
Autologous HCT
20,000
15,000 Allogeneic HCT
10,000
5,000 Growing number of HCT survivors
• Increasing focus on long-term health
0
'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
Year of HCT (1980 to 2009)

39. Post-transplantation Complications
Non-malignant late effects  New tumors
• Ocular • Benign
• Orodental • Malignant
• Pulmonary
• Gastrointestinal
• Cognitive dysfunction  Psychosocial outcomes
• Musculoskeletal
• Renal dysfunction • Fatigue
• Cardiac • Sexual functioning
• Social integration
• Metabolic syndrome
• Quality of life

40. Post-transplantation late effects
Non-malignant late effects
Malignant late effects
Psychosocial well being
Chronic Graft versus Host disease

41. Diabetes, hypertension, and cardiovascular events in HCT
survivors
Blood, 2007;109:1765-72

42. 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

43. Diabetes, Hypertension, Cardiovascular disease
Comparison with siblings
Blood, 2007;109:1765-72
%
Diabetes HTN Arterial MI Stroke BMI 30+
Disease
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
Adjusted for current age, age at HCT, and sex
*p <0.05

44. Diabetes, Hypertension, Cardiovascular disease
Role of TBI
Blood, 2007;109:1765-72
%
Diabetes HTN Arterial MI Stroke BMI 30+
Disease
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
Adjusted for age, age at HCT, and sex
*P<0.05

45. Osteonecrosis in HCT survivors
Cancer. 2009;115:4127-35

46. Late osteonecrosis after HCT
15%
1+ year survivors of HCT
N=1346
10%
6% at 10 years
5%
ne d c n ev t a u m C
i I i l u
0%
0 1825 3650 5475 7300 9125 10950
DAYS
Cancer. 2009;115:4127-35

47. Late osteonecrosis by stem cell donor type
15
%
Unrelated donor HCT
(15% at 10 years)
10
%
Allogeneic related HCT
(6% at 10 years)
5
%
e d c n ev t a u m C
Autologous HCT
u
P<0.001
4% at 10 years
i I i l
0%
0 182 365 547 730 912 1095
5 0 5 0 5 0
DAYS
Cancer. 2009;115:4127-35

48. 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

49. Chronic Kidney Disease in HCT survivors
Cancer, 2008, 113(7):1580-7

50. 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

51. Late Chronic Kidney Disease after HCT
14%
12%
10%
8%
5.7% at 10 years
6%
ec ne d c n ev t a u m C
4%
u
2%
i I i l
0%
0 5 10 15 20 25 30
Years post-HCT
Cancer, 2008, 113:1580-7

52. 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 1.0 __
myeloma
Multiple myeloma 5.4 1.8-16.2
Cancer, 2008, 113:1580-7

53. Risk of Chronic Kidney Disease after transplant
25%
Exposure to Calcineurin Inhibitors;
Age at HCT > 45 years
20%
15%
P< 0.01
10%
No Exposure to Calcineurin Inhibitors;
% ec ne d c n ev t a u m C
Age at HCT < 45 years
u
5%
i I i l
0%
0 5 10 15 20 25 30
Year
s
Cancer, 2008, 113:1580-7
(

54. Solid tumors after Hematopoietic Cell
Transplantation
J Clin Oncol, 2001;19:464-71

55. Solid cancers after transplantation
.
40
Age at HCT < 34 years
.
30 RR=4.8, p<0.05
.20 Total Body Irradiation
RR=2.7, p<0.05
.
10
c ne d c n ev t a u m C
u
0
i I i l
0 3 6 9 1 1 1
2 5 8
Time (Years)
J Clin Oncol, 2001;19:464-71

56. Excess Risk of Solid Cancers
ezi dr a dnat S
J Clin Oncol, 2001;19:464-71

57. Therapy-related leukemia after autologous
transplantation for lymphoma
Blood, 2000;95:1588-93

58. Therapy-related leukemia after autologous
transplantation
.30
.20
8.6% at 6 years
.10
ec ne d c n ev t a u m C
u
.0
0 2 4 6 8 10
i I i l
Time in Years from aHCT
Blood, 2000;95:1588-93

59. 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

60. Longitudinal Trajectory of Fatigue and Vigor
after HCT
J Clin Oncol, 2008

61. 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

62. Methods
• Profile of Mood States
• standardized self-report instrument measuring fatigue, vigor
• City of Hope HCT-QOL Questionnaire
HCT
Pre-HCT 6 months 1 year 2 years 3 years

63. Longitudinal trends in Fatigue
Fatigue decreased across time after transplantation
•Maximum effect observed at the 2 and 3 year points

64. Longitudinal trends in Vigor scores
Vigor increased across time after transplantation
•Improvement observed across all time points

65. 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

66. Longitudinal trends in Psychological well-being by
Fatigue
Psychological well being scores were significantly
lower among patients with higher levels of fatigue

67. 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

68. Longitudinal trends in Spiritual well-being by
Vigor
Spiritual well being scores were significantly lower
among patients with low levels of vigor
High vigor
Low vigor

69. 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

70. Percent Returning to Full-time Work
100
90
p<.0001, df=3
80
70
60 57.6%
Percent
50
50.0%
42.5%
40
30
23.7%
20
10
0
Pre 6m 1y 2y 3y
Time after HCT
Blood, 2010;115:2508-19

71. Variables associated with successful return to
full time work
1.2 Upper 95% CI
Lower 95% CI
1.0
Blood, 2010;115:2508-19
0.8
Relative Risk
0.6
RR=.56 RR=.56
0.4 RR=.40
RR=.25
0.2
0.0
Income cGVHD BMI Avg Fatigue
< 20K With <Obese Worst 40%
vs vs vs vs
> 20K Without >Obese Least 60%

72. Cumulative incidence of return to work
by baseline vigor scores
1 High vigor
0.9
0.8
Cumulative incidence
0.7
0.6 Low vigor
0.5
0.4 P = .02*
0.3
High vigor (75th percentile)
0.2
Low vigor (25th percentile)
0.1
0
0 6 12 18 24 30 36
Months after HCT

73. Sexual functioning after hematopoietic cell
transplantation
Blood. 2008;112: 743a

74. Sexual Functioning after HCT
10 HCT
0
90
8 Pre- 6 mo. 1 year 2 years 3 years
0 HCT
7
0
Men
6
0
er oc Sl at oT T RS- FS D
5
I
0
Women
4
0 P<.0001
3
0 0 6 1 1 24 30 36
2 8
Months since HCT
Blood. 2008;112: 743a

75. Sexual Functioning – age effect
Men
9
0 <40y
8
0
7 40-60y
0
6
0 >40y
5 60y
er oc Sl at oT RS- FSI D
0
4 P=.002
0
0 6 1 1 24 30 36
2 8
Months since HCT
Blood. 2008;112: 743a

76. Sexual Functioning – age effect
Women
10
0
9
0 P=.006
8
0
7 <30y
0
6
0
er oc Sl at oT RS- FS D
5 >30y
I
0
4
0
6 1 1 24 30 36
2 8
Months since HCT
Blood. 2008;112: 743a

77. Impact of total body irradiation
10 Men
0
9
0
8
0
No TBI
7
0
6
er oc Sl a oT RS F S D
0 TBI
- I
5
0
4
0
t
P=.006
3
0 0 6 1 1 24 30 36
2 8
Blood. 2008;112: 743a Months since HCT

78. Neuropsychological outcomes after transplantation
Blood. 2009a

79. COH Neurocognitive Function Study
 Study design
 5-year longitudinal study
 Standardized 2-hour battery of neurocognitive tests
HCT
Pre 6m 1y 2y 3y 5y
Patients
Healthy Controls

80. Processing Speed
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.”

81. 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.”

82. 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

83. Working Memory
Digit Span
To assess attention, concentration, mental control
Items 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.”
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.”

84. 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.”

85. 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.”

86. Visual Memory
“Where was the mother? What was she doing?”

87. 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

88. Verbal Speed
Color Naming: “Name the colors. Go as fast as you can.”
Word Reading: “Read the words. Go as fast as you can.”
GREEN BLACK RED
PURPLE BLUE GREEN
BLACK RED BLUE

89. Executive Function
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.”

90. Verbal Fluency
Assesses fluent productivity in the verbal domain
Delis-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.)

91. Fine Motor Dexterity
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 “Put the pegs into the board as
the hole fast as you can, using only your
dominant hand.”

92. 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

93. Fine Motor Dexterity
Percent Impaired

94. Executive Function
Percent Impaired

95. Percent Impaired
Auditory Memory

96. Percent Impaired
Visual Memory

97. Processing Speed
Percent Impaired

98. Working Memory (Letter Number Sequencing)
Percent Impaired

99. Verbal Speed (Word Reading Score)
Percent Impaired

100. Verbal Fluency (Letter Fluency)
Percent Impaired

101. Trajectory of Cognitive Impairment
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

102. 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

103. 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

104. Burden of Morbidity
Blood, 2010;116:3129-39

105. Chronic Health Conditions – Survivors vs. Siblings
Severe or life-threatening Conditions
51% (10 yr) Survivors
RR=5.0 (95% CI:3.4-7.4 )
14% (10 yr)
Siblings
Blood, 2010;116:3129-39

106. Survivorship issues in 10+Year Survivors of HCT
• Chemotherapy/ radiation
• cGVHD and its sequelae
• Prolonged immune suppression
Chronic Health Conditions
Adverse Psychological outcome
Unknown for 10+ year survivors
Healthcare utilization
Burden of Long-term Morbidity
Psychological Health Status

107. Prevalence of chronic health conditions
Survivors compared to siblings
P<0.001
BBMT, 2012, in press

108. Risk of Chronic Health Conditions
Survivors compared to siblings
Adjusted for age at questionnaire, sex,
race/ethnicity, education, income and
Relative Risk
insurance status
BBMT, 2012, in press

109. Cumulative Incidence of Chronic Health Conditions
Among 10+ year Survivors
Any chronic health
71% (15 yr) condition
Severe/ life-threatening
condition or death
40% (15 yr)
BBMT, 2012, in press

110. Prevalence of Adverse Psychological Outcomes
P<0.001
P=0.1
P=0.11
P=0.55
Blood, 2011;118:4723-31

111. Are survivors at a higher risk of psychological
problems when compared with siblings?
Adjusted for age at questionnaire, sex, marital status, race/ethnicity, education,
income, insurance status, health status, and chronic health conditions.
Odds Ratio
P=0.03
P=0.2
P=0.9
P=0.52
Blood, 2011;118:4723-31

112. Healthcare utilization among long-term survivors
90% of the survivors carried health insurance
BBMT, 2013, in press

113. Health-related Outcomes after HCT
Long-term sequelae
Impact of long-
term sequelae
on HRQL is
unknown
Quality of Life

114. Impact of Chronic Health Conditions on Health-
related Quality of Life
Blood, 2006;108: 73a

115.  demographics  medication use
 education  medical conditions
 income  Graft vs. host disease
BMT-SS  employment  surgical procedures
Questionnaire  insurance  recurrent cancer
 marital status  new neoplasms
 health habits  offspring/pregnancy history
 family history  utilization of medical care
Physical
Physical Psychological
Psychological
Psychological
Well Being
Well Being Well Being
Well Being
HCT-QOL Overall
QOL
Social
Social Spiritual
Spiritual
Well Being
Well Being Well Being
Well Being

116. Physical Well Being
Blood, 2006;108: 73a
ML det s u d A
S j
Adjusted for inability to return to work, cGVHD, pain or anxiety,
inability to exercise, age at HCT

117. Social Well Being Blood, 2006;108: 73a
MSL de s u d A
t j
Adjusted for inability to return to work, cGVHD, pain or
anxiety, marital status

118. 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

119. Long-term consequences of hematopoietic cell
transplantation
• Substantial burden of chronic morbidity
• Challenges in social integration
• Need for life-long follow-up of HCT survivors

120. Recommendations

122. Intervention Strategies
Modification of
Primary Cancer
Therapeutic Protocols
Genetic Predisposition
Therapeutic Lifestyle Exposures
Exposures Viral infections
Identification and Screening of
Late Effects “High Risk” Populations