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Late Effects After Cancer Therapy: The Cost of Cure

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Title: Late Effects After Cancer Therapy: The Cost of Cure


1
Late Effects After Cancer Therapy The Cost of
Cure
  • Melissa M. Hudson, M.D
  • Director, Cancer Survivorship Division

2
Overview
  • Late effects definition, frequency, spectrum
  • Multi-factorial etiology of late effects
  • Clinical, treatment and biological risk factors
    for selected late effects
  • How knowledge about late effects can be used to
    prevent morbidity in newly diagnosed patients
  • How knowledge about late effects can be used to
    reduce cancer-related morbidity through
    risk-based care of survivors

3
Late Effects After Cancer
  • Health condition persisting or developing 5 or
    more years from cancer diagnosis
  • Commonly reported by cancer survivors
  • Reported to impact almost every aspect of health
  • Includes life-threatening to life-altering events
  • Contribute to cancer-related morbidity
  • Predispose to early mortality

4
Physical Late Effects
Organ Function Cardiac Pulmonary Renal Endocr
ine Gastrointestinal Vision/Hearing
Growth and development Linear growth Skeletal
maturation Intellectual function Emotional/social
maturation Sexual development
Fertility and Reproduction Fertility Health of
Offspring
Second Neoplasms Benign Malignant
5
Psychosocial Late Effects
  • Social Interaction
  • - Family/peer relationships
  • - Social withdrawal/isolation
  • Social competence
  • Ability to live independently
  • Intimacy/marriage/family

Mental Health - Depression/mood problems -
Cancer-related anxiety/fears - Post-traumatic
stress
Education/Vocation - Academic underachievement -
Vocational limitations - Under/unemployment Insura
nce discrimination - Access to Health Care
Health Risking Behaviors - Tobacco/Alcohol/Drugs
- Medical noncompliance
6
Selected Late Effects
  • Anthracycline cardiotoxicity
  • Overweight/Obesity
  • Subsequent malignant neoplasms

7
Anthracycline Cardiotoxicity
  • 50-60 of childhood cancer patients will
    receive anthracyclines as a component of curative
    therapy.
  • Anthracyclines cause dose-related cardiac injury
    that may be asymptomatic and progressive.
  • Cardiovascular complications comprise a
    significant proportion of non-cancer-related
    mortality.
  • Variable definitions of cardiac toxicity have
    complicated predicting risk of cardiac injury.
  • Congestive heart failure
  • Subclinical changes on cardiovascular testing

8
Anthracycline Cardiotoxicity
  • Risk modified by
  • Cumulative dose, dose intensity, administration
    route
  • Age at treatment, gender, race
  • Combined modality therapy cardiac radiation
  • Other conditions obesity, insulin resistance,
    dyslipidemia
  • Lifestyle tobacco, physical activity, diet
  • Aging (increased interval from treatment)
  • Genetics

9
Threshold Dose for Toxicity
  • gt 550 mg/m2 historic threshold dose in adults
    (Lefrak, Cancer , 1973)
  • 4 _at_ 500 -500 mg/m2
  • 18 _at_ 551-600 mg/m2
  • 36 after gt 600 mg/m2
  • Toxicity observed in pediatric cohorts at lower
    doses (Kremer, Ann Oncol, 2002).
  • CHF (0-16) Subclinical (0-57)
  • 250-300 mg/m2 appears to be pediatric threshold
    in recent studies
  • Query whether any dose is safe

10

Non-Invasive Cardiac Testing Hudson M, J Clin
Oncol 2007
  • St. Jude Cohort n 278
  • - Median age Dx 4.7 y
  • - Median age F/U 17 y
  • - Median time off Rx 9 y
  • Results
  • Low-moderate anthracycline
  • - Median 202 (25-510) mg/m2
  • Subclinical dysfunction in 14
  • - None with cardiac symptoms
  • Treatment with anthracyclines gt 100 mg/m2 with
    lower FS and higher afterload
  • Treatment with gt 270 mg/m2 associated with
    highest risk
  • - (OR 4.5, 95 CI 2.1-9.6)
  • Abnormalities noted after 100-269 mg/m2.
  • .

Risk of Abnormal Fractional Shortening (FS) or
Afterload in Relation to Time After Rx
11
Questions to Address
  • What are the mechanisms leading to early cardiac
    mortality in cancer survivors beyond what we have
    known for 20 years?
  • How do models of the etiology of cardiovascular
    disease in the general population apply to cancer
    survivors?

12
Obesity
  • Currently gt 1/3 of U.S. population is clinically
    obese 65 are overweight.
  • Between 1960s and 1980s childhood obesity
    increased by 54
  • At present 1/3 of 1-5 yr old children in
    industrialized countries are overweight.

13
Trends in Overweight Prevalence (), Adults 18
and Older, US, 1992
14
Trends in Overweight Prevalence (), Adults 18
and Older, US, 1995
15
Trends in Overweight Prevalence (), Adults 18
and Older, US, 1998
16
Trends in Overweight Prevalence (), Adults 18
and Older, US, 2002
17
Obesity after Childhood Cancer
  • Data confounded by
  • Lack of prospective studies
  • Small cohort numbers
  • Conflicting results
  • Cranial radiation
  • CRT dose
  • Sex
  • Age at Dx
  • Pathophysiology
  • Hypothalamic injury
  • Leptin resistance
  • Increased energy intake
  • Decreased energy expenditure
  • Other factors
  • GH deficiency
  • Hypogonadism

18
Obesity After Childhood Cancer
  • High risk diagnostic groups
  • Childhood leukemia
  • Obesity prevalence 11 to 57
  • CNS tumors (craniopharyngioma)
  • Predisposing therapies
  • Cranial radiation
  • Corticosteroids
  • Surgery

19
BMI by Age Dx after CRT 20 GyOeffinger et al. J
Clin Oncol 2003
N1765 ALL Survivors
CRT gt 20 Gy (n841) OR 95 CI Females
2.59 1.88 - 3.55 Males 1.86 1.33 - 2.57
20
Obesity in Adult Survivors of Childhood ALL
Females with CRT gt 20 Gy
Age at Dx OR 95 CI
0-4 3.81 2.34 - 5.99 5-9 2.30 1.39 -
3.59 10-14 2.16 1.11 - 3.61 15-21 0.88 0.0
0 - 2.63
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Oeffinger et al, J Clin Oncol, 2003
21
Mean Body Mass Index Among 706 Long-term
Survivors of Childhood ALL with gt20 Gy Cranial RT
30
30
Siblings
Siblings
Survivors
Survivors
29
29
28
28
Mean BMI
Mean BMI
27
27
Female (n359)
26
26
Male (n347)
25
25
p0.39
p0.02
24
24
Follow-up
Follow-up
Baseline
Baseline
Baseline
Baseline
Assessment
Mean Age
25.9 yrs.
33.7 yrs.
26.2 yrs.
34.0 yrs.
Mean from Dx
19.0 yrs.
26.8 yrs.
19.0 yrs.
26.9 yrs.
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Unpublished data
22
Risk of BMI gt25 (Overweight or Obese) in 294
Female Childhood ALL Survivors
Leptin Receptor Polymorphism Q223R
Homozygous Arg
Percent
lt25
gt25
Body Mass Index
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Ross et al, J Clin Oncol, 2004
23
BMI Change Diagnosis to Final HeightRazzouk et
al, J Clin Oncol 2007
  • N456 ALL/NHL
  • CNS-Treatment
  • 24 Gy
  • 18 Gy
  • IVIT MTX
  • Predictors of overweight BMI
  • Age Dx lt 6 years
  • BMI at Dx
  • Type of CNS therapy not predictive

24
Obesity Complications
  • Insulin resistance
  • Impaired glucose tolerance
  • Diabetes mellitus
  • Dyslipidemia
  • Cardiovascular disease
  • Hypertension
  • Metabolic syndrome
  • Hepatic steatosis
  • Cholelithiasis
  • Pseudotumor cerebri
  • Sleep apnea
  • Slipped capital femoral epiphysis
  • Increased cancer risk
  • Inferior survivor after cancer

25
Subsequent Malignancies after Childhood Cancer
  • Overall risk ranges from 5-!2 by 25 years
  • Higher risk is specific subgroups
  • Determinants of risk
  • Presence of cancer-predisposing genetic mutation
  • Specific cancer treatment modalities
  • Environmental factors
  • Lifestyle factors

26
Subsequent Cancers AML/MDS
  • Treatment alkylators, epipodophyllotoxins, other
    topo II inhibitors
  • Late effect Acute myeloid leukemia/myelodysplasia
  • Highest risk Dose/schedule relationships. ?
    Others, e.g., G-CSF
  • Screening CBC/differential yearly up to 10 years

27
Subsequent Cancers Solid Tumors
  • Long latency (without plateau beyond 10 years)
  • Primarily associated with radiation
  • Spectrum of benign and malignant tumors
  • Outcome variable based on tumor histology

Astrocytoma
Meningioma
28
Subsequent Cancers after ALL
Hijiya et al, JAMA, 2007 ALL survivors (n2169)
treated at St. Jude from 1962-1998, median f/u
18.7 (range, 2.4-41.3) years
29
Subsequent Cancers Solid Tumors
From Hijiya et al, JAMA 2007 ALL survivors
(n2169) treated at St. Jude from 1962-1998,
median f/u 18.7 (range, 2.4-41.3) years
30
Childhood Cancer Survivor Study (U24 CA 55727)
SECOND NEOPLASMS
N 14,131 five-years survivors of leukemia,
lymphoma, neuroblastoma, CNS, bone, soft-tissue
and kidney cancer Includes non-melanoma skin
cancers
25
03.27.08
31
Childhood Cancer Survivor Study (U24 CA 55727)
SECOND NEOPLASMS
N 14,131 five-years survivors of leukemia,
lymphoma, neuroblastoma, CNS, bone, soft-tissue
and kidney cancer Includes non-melanoma skin
cancers
SMN other than NMSC
NMSC
03.27.08
32
Childhood Cancer Survivor Study (U24 CA 55727)
SECOND NEOPLASMS
Includes non-melanoma skin cancers
Females
Males
03.27.08
33
Childhood Cancer Survivor Study (U24 CA 55727)
SECOND NEOPLASMS
Includes non-melanoma skin cancers
RT
No RT
03.27.08
34
Subsequent Neoplasm Among Long-term Survivors of
Childhood Cancer
Cumulative Incidence (20 Yrs) 2.9
4.5 15.7 4.2 2.8
3.2 6.3 8.0 Abs.
Excess Risk 1.22 1.79
7.69 1.39 1.17 1.67
3.36 2.99
8
7
6
5
Standardized Incidence Ratio
4
3
2
1
0
Leukemia
CNS
Hodgkin
Non-
Wilms
NBL
ST
Bone
Hodgkin
Sarcoma
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Unpublished 1/08
35
Subsequent Neoplasm Among Long-term Survivors of
Childhood Cancer
20
15
10
Standardized Incidence Ratio
5
0
n 751 218 38 107
81 60 29 36
28 154
Total
Bone
CNS
Other
Breast
Thyroid
Melanoma
Leukemia
Lymphoma
ST Sarcoma
Subsequent Malignancy
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Unpublished 1/08
36
Subsequent Neoplasm Among Long-term Survivors of
Childhood Cancer
20
15
10
Standardized Incidence Ratio
5
0
n 751 218 38 107
81 60 29 36
28 154
Total
Bone
CNS
Other
Breast
Thyroid
Melanoma
Leukemia
Lymphoma
ST Sarcoma
Subsequent Malignancy
CCSS CHILDHOOD CANCER SURVIVOR STUDY
37
Cumulative Incidence of Breast Cancer in Adult
Females Surviving Childhood Cancer
(n 4810)
(n 1258)
NO CHEST RT
CHEST RT
Cumulative Incidence ()
AGE (years)
AGE (years)
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Kinney et al. Ann Intern Med 2004 141590-97
38
Breast Cancer Risk by Breast Radiation Dose
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Inskip P (submitted for publication)
39
Breast Cancer Risk by Breast Ovarian Radiation
Dose
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Inskip P (submitted for publication)
40
Subsequent Neoplasm Among Long-term Survivors of
Childhood Cancer
20
15
10
Standardized Incidence Ratio
5
0
n 751 218 38 107
81 60 29 36
28 154
Total
Bone
CNS
Other
Breast
Thyroid
Melanoma
Leukemia
Lymphoma
ST Sarcoma
Subsequent Malignancy
CCSS CHILDHOOD CANCER SURVIVOR STUDY
41
Thyroid Cancer in Long-term Survivors of
Childhood Cancer
Dose Response Models of Relative Risk
Linear 1 0.5117(dose)
Linear Exponential 11.316(dose)e-
0.00189(dose x dose)
Dose in Gy
CCSS CHILDHOOD CANCER SURVIVOR STUDY
Sigurdson et al, Lancet, 2005
42
Subsequent Neoplasm Among Long-term Survivors of
Childhood Cancer
20
15
10
Standardized Incidence Ratio
5
0
n 751 218 38 107
81 60 29 36
28 154
Total
Bone
CNS
Other
Breast
Thyroid
Melanoma
Leukemia
Lymphoma
ST Sarcoma
Subsequent Malignancy
CCSS CHILDHOOD CANCER SURVIVOR STUDY
43
Brain Tumors After Childhood Cancer Glioma vs.
Meningioma
CCSS CHILDHOOD CANCER SURVIVOR STUDY
J. Neglia, JNCI, 2006
44
Brain Tumors After Childhood Cancer Risk by
Radiation Dose
CCSS CHILDHOOD CANCER SURVIVOR STUDY
J. Neglia et al, JNCI, 2006
45
Issues Relating to Interventions
DIAGNOSIS TREATMENT
HEALTH-RELATED AND QOL OUTCOMES
LONG-TERM SURVIVORS
46
Prevention of Late Effects
  • Primary
  • Risk-adapted therapy
  • Limit cytotoxic chemotherapy
  • Limit radiation
  • Undertake measures to preserve normal tissue
    function and integrity
  • Secondary
  • Identify groups at high risk for morbidity
  • Institute appropriate surveillance
  • Provide preventive/remedial interventions

47
Anthracycline Cardiotoxicity
Recommended Echo/MUGA Screening
  • Late effects
  • Cardiomyopathy
  • Arrhythmia
  • Subclinical LV systolic dysfunction
  • Highest risk
  • Females
  • Age lt 5 years at treatment
  • Higher cumulative doses
  • Screening
  • Periodic eval of LV fxn (Echo/MUGA) based on
    age/dose
  • EKG baseline

48
Evaluate Other Risk Factors
  • Medical
  • Congenital heart disease
  • Hypertension
  • Obesity
  • Dyslipidemia
  • Diabetes
  • GH deficiency
  • Ovarian failure
  • Pregnancy
  • Behavioral
  • Smoking
  • High dietary fat
  • Sedentary lifestyle
  • Isometric exercise
  • Recreational drugs
  • Cocaine
  • Ephedra
  • Familial
  • Dyslipidemia
  • Premature coronary artery disease
  • Diabetes

49
Secondary Breast Cancer
  • High risk group women treated with chest
    radiation (especially gt 20 Gy)
  • Heightened surveillance for high risk women
  • Breast self-exam monthly beginning at puberty
  • Clinician exam yearly from puberty to 25 years,
    then biannually
  • Mammography/adjunct MRI beginning 8 to 10 years
    after radiation or no later than 25 years
  • Counsel regarding lifestyle issues that impact
    risk
  • Physical activity
  • Weight control
  • Alcohol use

50
Approach to Risk-Based Care
  • Age at treatment
  • Sex/race of survivor
  • Type/strength of therapy
  • Chemotherapy
  • Radiation therapy
  • Surgery
  • Transplant
  • Transfusions
  • Time from treatment
  • Type of cancer
  • History of relapse
  • Family history
  • Health habits
  • Tobacco
  • Diet/alcohol
  • Exercise/weight control
  • Sun exposure
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