Transcript Methods Variables Measured

Radiation Therapy for
Childhood Cancer
You’ve got to love it,
But also hate it!
-- Louis S. Constine, MD, FASTRO
Professor, Radiation Oncology and Pediatrics
Five-Year Survival Rates for
Children with Cancer
100
90
80
70
All Cancers
ALL
60
AML
Bones/Joints
Brain/CNS
HD
50
NBL
NHL
40
Soft Tissue
WT
30
20
• Over 250,000 childhood cancer survivors in the US
• 1 in 1,000 is a childhood cancer survivor
• 1 in 570 is a childhood cancer survivor (ages 20 to 34 yr.)
10
0
'74 - '76
'83 - '85
'92 - '98
Cumulative Cause-Specific Mortality
JCO 2001;19:3163-72
Cumulative incidence of chronic physical health
conditions among 10,397 young adult survivors
of childhood cancer
Cumulative Incidence
1
0.9
0.8
Any chronic condition
0.7
0.6
Severe, disabling lifethreatening, or death
0.5
0.4
0.3
0.2
0.1
0
0
5
10
15
20
Years since cancer
Oeffinger NEJM 2006
25
30
Factors Contributing to Morbidity
Host Factors
Genetic
BRCA, ATM, p53
polymorphisms
Age
Gender
Race
Tumor
Factors
Cancer-Related
Morbidity
Health
Behaviors
Tobacco
Diet
Alcohol
Exercise
Sun
Premorbid
Conditions
Treatment
Factors
Aging
Histology
Site
Biology
Response
Surgery
Chemotherapy
Radiation therapy
Treatment
Events
Two Classes of Ionizing Radiation
• Electromagnetic
– X-rays and g-rays
• Particulate
– Produced by accelerators
and radioactive isotopes
How Radiation Works
Direct + Indirect Actions
Radiation may either:
– Directly ionize DNA (via
photon-produced
electrons) or
– Indirectly by first interacting
with H2O to produce free
radicals
Radiation Therapy is Getting Complicated…
Tables and Data and Lines, Oh My...
Late medical effects of
treatment depend
on the type of
therapy . . .
Surgery
Radiation
Therapy
and the specific
toxicities/organ
interactions of each therapy
Chemotherapy
Tissues at Risk for Late Toxicity
• Bone/soft tissues
• Immune system
• Cardiovascular
• Nervous system
• Dental
• Neuropsychologic
• Endocrine
• Ophthalmologic
• Gastrointestinal
• Pulmonary
• Hepatic
• Renal
• Hematological
• Reproductive
Being cured of childhood cancer
but suffering a broken heart!
Radiation Cardiac Injury
•
•
•
•
•
•
Manifestations
Restrictive
cardiomyopathy
Premature CAD
Myocardial infarction
Valvular disease
Autonomic
dysfunction
Conduction defects
•
•
•
•
•
•
•
•
Mantle Field
Risk Factors
Younger age (< 5 y)
Higher dose (> 35 Gy)
Higher daily fraction ( 2 Gy)
Larger volume of heart in
field
Anteriorly weighted field
Subcarinal shielding
Longer time from RT
Use of cardiotoxic chemoRx
CCSS
Cumulative Incidence (95% CI)
CHF and MI
Cumulative Incidence [%]
An NCI-funded
Resource
Congestive Heart
Failure
4
3
2
1
Myocardial
Infarction
0
5
10
15
20
Years Since Diagnosis
Mulrooney et al., 2009
25
30
CCSS
Risk of Congestive Heart Failure
Multivariate Analysis
An NCI-funded
Resource
6
Relative Risk*
5
*
4
2
1
F
*
M
* ≥35
≤4
3
*
*
5-9
*
*15-35
10-14
15-20
1-5
≥250
<250
6-15
0
0
0
Sex
P <0.05
Cardiac
RT dose
(Gy)
Anthracycline
(mg/m2)
* Adjusted for race, BMI, income, education, smoking, treatment era
Mulrooney et al., 2009
*
Age at
Diagnosis
(yrs)
Risk
Riskof
ofMyocardial
MyocardialInfarction
Infarction
CCSS
Multivariate
Analysis Analysis
Multivariate
An NCI-funded
Resource
4
Relative Risk*
* >35
3
2
* 15-35
5-9
<250
15-20
1
M
≤4
*F
10-14
0
1-5
0
>250
6-15
0
Sex
*
Age at
Diagnosis
(yrs)
Cardiac
RT dose
(Gy)
Anthracycline
(mg/m2)
P <0.05
* Adjusted for race, BMI, income, education, smoking, treatment era
Mulrooney et al, 2009
Risk of Valvular Disease
CCSS
Multivariate Analysis
An NCI-funded
Resource
6
Relative Risk*
5
*
4
*
3
F
*
2
1
M
≤4
*
Sex
*
5-9
10-14
Age at
Diagnosis
(yrs)
15-35
*
* 15-20
0
*
>35
<250
6-15
0
1-5
Cardiac
RT dose
(Gy)
>250
0
Anthracycline
(mg/m2)
P <0.05
* Adjusted for race, BMI, income, education, smoking, treatment era
Mulrooney et al, 2009
Mantle radiation therapy for
Hodgkin lymphoma - historic
Pulmonary Toxicity
Manifestations
• Paramediastinal fibrosis
• Asymptomatic pulmonary
dysfunction
– Diffusion
– Restriction
– Obstruction
• Pulmonary fibrosis
• Restrictive lung disease
• Pneumothorax
Risk factors
• Higher bleomycin dose
• Chest radiation
How about a broken thyroid gland?
or
A cancer in an irradiated thyroid
gland?
Hypothyroidism
• Female sex
• Older age (> 15 y)
• Higher radiation dose
– 30% if 35 - 44 Gy
– 50% if > 45 Gy
• Time < 5 y from Dx
Sklar et al, JCEM 2000
Secondary Thyroid Malignancy After RT
Ronckers et al, Rad Res, 166:618, 2006
Now that we are talking about
secondary malignancies…
Cumulative Incidence of
Subsequent Neoplasms
30 year cumulative
incidence of
any SN = 20.5%
SMN = 7.9%
NMSC = 9.1%
Meningioma = 3.1%
Friedman JNCI 2010
Cumulative Incidence of SMNs by
Primary Diagnosis
• Hodgkin Lymphoma – 18.4%
• Ewing Sarcoma – 10.1%
• Soft Tissue Sarcoma – 8.8%
• Medulloblastoma - 7.8%
• Osteosarcoma – 6.0%
• Non-Hodgkin Lymphoma – 5.8%
• Neuroblastoma – 5.9%
• Leukemia – 5.6%
• Astrocytoma – 4.7%
• Wilms tumor – 4.0%
CHILDHOOD CANCER SURVIVOR STUDY
Cumulative incidence of SMNs by exposure to radiotherapy
Histopathologic Types of Second Malignant
Neoplasms (SMN) after Hodgkin Lymphoma
Site
SIR Years to SMN
Breast
37.3
9 - 36
Thyroid
25.1
9 - 23
GI
27.2
10 - 33
Leukemia
21.5
2 - 18
STS
50.4
9 - 18
Bone
53.5
9 - 23
Lymphoma
5.2
1 - 24
CNS
9.7
8 - 29
H&N
12.9
15 - 20
Lung
4.6
11 - 16
Other
1.8
<1 - 25
Breast Cancer Risk by Radiation
Dose, Volume after Hodgkin Lymphoma
Inskip PD, et al. J Clin Oncol, 2009
De Bruin ML, et al. J Clin Oncol, 2009
Cumulative Incidence of Breast Cancer
in Hodgkin Lymphoma Survivors
20% at 45 years of age
Bhatia S, et al. J Clin Oncol, 2003 (and N Eng J Med, 1996)
Secondary CNS Tumors
Meningioma
Astrocytoma
How about fertility?
(effects on ovaries and testes)
Ovarian Failure
6
Million
5
4
3
2
1
0
20 weeks
gestation
Birth
Puberty
Menopause
2.5 - 5.0 Gy:
< 15 years - OK
15-40 years - 30-40% sterility
> 40 years - 90% sterility
5 - 8 Gy:
< 15 years - variable
15-40 years - 50-70% sterility
>40 years - 90% sterility
Sperm Recovery After Radiation Therapy
Radiation to the brain and
hypothalamus-pituitary
Brain radiation can affect
learning & memory, motor
function and sensation
Endocrine gland radiation can affect
growth, metabolism, and reproduction
Neurocognitive Effects of Irradiation
Severity and type of effects depend upon
• age of child when irradiated
• dose of XRT
• volume of brain and specific areas treated
• other contributing factors (surgery, chemo,
pre-existing abnormalities)
Neuroimaging Abnormalities
•
•
•
•
•
•
Brain atrophy
Encephalomalacia
Cerebral lacunes
Dystrophic calcification
Leukoencephalopathy
Necrosis/gliosis
IQ After Conformal RT for Low Grade Glioma
Merchant TE et al. J Clin Oncol 2009; 27:3691-7
Overall Index (Attention Problems) after Conformal Radiation
Therapy (CRT) for Pediatric Patients with Different Brain Tumors
(Normal Overall Index < 10)
Ependymoma
Kiehna, E. N. et al. J Clin Oncol; 24:5283-5290 2006
Endocrine Effects of Cranial Irradiation
Growth Hormone (GH) Deficiency following XRT is dose
related
– 18 Gy
0% GH deficient
– 24 Gy
20-40%
– 30-35 Gy
80-85%
– >35Gy
100%
Onset: 55% within 1st year, 67% within 5 yrs
Peak Growth Hormone (GH) According to
Hypothalamic Mean Dose and Time After Start of
Irradiation
Merchant et al, JCO 29:4776, 2011
Relative Risk (RR) of Death Due to
Cerebrovascular Disease vs Radiation Dose
Haddy et al, Brain 134:1362, 2011
Hearing Loss
Hearing Loss
Radiation Dose
Chemotherapy
CSF Shunting
0
no chemotherapy
10
dBHL
20
30
Dose > 32 Gy
(~ 45 Gy)
40
50
0
chemotherapy
60
10
chemotherapy
70
0
12
24
36
48
20
Time (months)
dBHL
no chemotherapy
30
40
No shunt
Shunt
Dose < 32 Gy
(~18-20 Gy)
50
60
70
0
12
24
Time (months)
Merchant, TE et al. Int J Radiat Oncol Biol Phys 2004;58:1194-207
36
48
Dental Abnormalities After ChemoRx
• Tooth/root agenesis
Adontia
Microdontia
• Root thinning or
shortening
• Enamel dysplasia
Dental Abnormalities After Radiation
• Salivary gland
dysfunction
• Xerostomia
• Dental caries
• Periodontal disease
How about Muscles and Bones?
Fortunately, these effects are mostly
historic because we use lower
radiation doses, and smaller fields
Growth Impairment
Risk factors
• Younger age
(prepubertal)
• Higher dose (> 20 Gy)
• Higher daily fraction
( 2 Gy)
• Larger treatment field
• Epiphysis in treatment
field
Wilm’s Tumor
Treated at 10 Mos With Nephrectomy and RT for
Wilm’s Tumor, Now 10 Yrs Post
Post RT for Ewing’s Sarcoma
Radiation to the Kidney and Bladder
Radiation cause renal damage
and bladder, ureteral fibrosis
Resulting sequela:
• Hypertension
• Hematuria
• Incontinence
• Hesitancy
• Obstruction
Renal Complications
• Hypertension
• Tubular dysfunction
Renal tubular acidosis
Fanconi’s syndrome
Hypophosphatemic rickets
• Glomerular injury
• Renal insufficiency
Bladder Complications
•
•
•
•
•
Hemorrhagic cystitis
Bladder fibrosis
Dysfunctional voiding
Urinary incontinence
Bladder carcinoma
• Design cancer treatments to
reduce the risk of late effects
• Develop therapies to protect
normal tissues
• Monitor childhood cancer
patients for late effects
• Prescribe corrective therapy
• Have regular check-ups so late
effects can be prevented or
detected in earlier stages
• Follow doctor’s advice about
medications and other interventions
Practice health behaviors that
reduce the risk of late effects
We are working hard:
»To cure children with cancer
»To minimize late effects
And we are making progress!