Neurocognitive
Outcomes of Radiation
Therapy in Children
Aaron S. Kusano, SM
University of Washington School
of Medicine
Outline
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Topic Choice
Background/Current Practices
Studies of Neurocognitive Effects
Predictive Model Research
Interventions
Conclusion
Why this topic?
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Balancing act of treatment objectives
Implications in Patient Counseling/Education,
Multidisciplinary Care and follow up
Increasing survival = increasing long term side
effects
Challenging research
– growing body of literature
– study design
– advancing technology and alternate approaches
Background
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Childhood cancer survivors have
changes/difficulties in:
1)Attention
2)Social Skills
3)Social Competence
4)Internalization 5)Externalization 6)Social Isolation
7)Mood and Behavioral Disorders
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40-100% of long term brain tumor
survivors have some form of cognitive
dysfunction
Glauser TA, Packer RJ: Cognitive deficits in long-term survivors of childhood brain tumors. Childs Nerv Syst 7:2-12, 1991
Schultz et al. Behavioral and Social Outcomes in Adolescent Survivors of Childhood Cancer: A report from the Childhood cancer survivor study.
Background
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Survivors of pediatric brain tumors have lower
rates of high school graduation and
employment relative to the overall population
There is fairly consistent evidence of
increased neurocognitive morbidity with
higher treatment doses and younger age at
the time of treatment
Hoppe-Hirsch E, Brunet L, Laroussinie F, et al: Intellectual outcome in children with malignant tumors of the posterior fossa: Influence of the field of irradiation and
quality of surgery. Childs Nerv Syst 11:340-346, 1995
Kelaghan J, Myers MH, Mulvihill JJ, et al: Educational achievement of long-term survivors of childhood and adolescent cancer. Med Pediatr Oncol 16:320-326, 198
Suc E et al. Brain tumours under the age of three. The price of survival. A retrospective study of 20 long-term survivors. Acta Neurochir (Wien). 1990;106(3-4):93-8
Pathophysiology
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Destruction of oligodendrocytes and
endothelial cells
Microvascular changes
– Endothelial injury leads to toxic reactions
– Formation of free radicals
– Cell swelling, increased vascular
permeability, ischemia, edema and cell
death
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Evident on MRI with white and gray
matter changes
Medulloblastoma
Epidemiology of
Medulloblastoma
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Embryonal tumor
~20% of pediatric CNS tumors
Median age at presentation 6 years
30-40% of patients have CSF spread
at time of diagnosis
5 year survival rates for children with
standard risk medulloblastoma
approaches 80%
Medulloblastoma Risk
Categories
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Average Risk (2/3)
– Age>3 years
– Resection with < 1.5cm2 residual
– No metastasis
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High Risk (1/3)
– Age<3years
– Resection > 1.5cm2 residual
– Metastasis
Current Practices
Categories
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Standard Risk
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High Risk
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Infants
Standard Risk
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Age > 3 years and
less than 1.5 cm2 of residual tumor and
No metastasis
Treatment
– CSI 23.4 Gy with posterior fossa boost
to 54 Gy + vincristine, adjuvant chemo
– Event free survival at 4 years+85%
(CCG/POG A9961)
Packer RH, Goldwein J, Nicholson HS, et al: Treatment of chilcren with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant
chemotherapy: A children’s Cancer Group Study. J Clin Oncol 17:2127-2136
Grill J, Renaux VK, Bulteau C, et al: Longterm intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes.
Int J Radiat Oncol Biol Phys 45: 137-145, 1999
High Risk
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Age < 3 years OR
greater than 1.5 cm2 of residual tumor OR
metastatic disease
Treatment
– CSI 36-39 Gy with posterior fossa boost to
54Gy + vincristine, adjuvant chemo
– POG 9031 demonstrated those with M1
disease had event free survival at 5 years
of 65%
Infants (<3yo)
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Surgeryintensive chemotherapy is
primary treatment
Radiotherapy reserved for salvage therapy
Worse prognosis
– Lower rate of complete resection
– Higher rates of leptomeningeal seeding at diagnosis
Cognitive Measurement
Wide Range Achievement
Test (WRAT)
 Ability
to
– Read words
– Comprehend sentences
– Spell
– Math calculations
Weschler Intelligence Scale
 Full
Scale IQ
 Indices
– Verbal Comprehension (vocab, comprehension)
– Perceptual Reasoning (block design, picture
concepts)
– Processing Speed (timed coding activities)
– Working Memory (repeating codes, sequences)
DSM-IV Criteria based on
IQ Scores
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50-55
35-40
20-25
20-25
to 70: Mild Mental Retardation
to 50-55: Moderate Mental Retardation
to 35-40: Severe Mental Retardation
and below: Profound Mental Retardation
Mulhern(1998)- Neuropsychologic
functioning of survivors of childhood
medulloblastoma
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POG 8631/CCG923
Treatment of average risk medulloblastomas
Hypothesis
– Children treated with lower initial radiation
levels would experience less intellectual toxicity
than those receiving higher levels
– Also younger subjects suspected to have poorer
outcome
•Mulhern RK, Kepner JL, Thomas PR, et al: Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional
or reduced-dose craniospinal irradiation: A Pediatric Oncology Group study. J Clin Oncol 16:1723-1728, 1998
Mulhern et al (1998)
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Randomized to 36Gy or 23.4Gy
craniospinal radiation
Both groups receiving boost to 54 Gy
to posterior fossa
Patient’s received baseline testing
Surviving patients in 1996 with no
progressive disease were eligible for
study
Groupings
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Young (Y): Age < 9 years
Old (O): Age > 9 years
Standard dose radiation (SRT): 36 Gy
Reduced Dose (RRT): 23.4 Gy
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Predicted trend of scores:
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– Y/SRT < Y/RRT < O/SRT < O/RRT
Subjects
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Of 35 eligible participants, only 22
patients completed follow up testing
– Wechsler Scales of Intelligence
– Wide Range Achievement Test III
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Age 4.1-19.0 years (median 8.85)
13 treated with SRT, 9 treated w/ RRT
Mulhern et al (1998)
Mulhern et al (1998)
Mulhern et al (1998)
Mulhern et al (1998)
Mulhern et al (1998)
Conclusions
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Predicted ordering of distributions was seen
for Performance IQ, Full Scale and Attention
Index
Unable to confirm significant differences in
IQ change as a function of age or dose
Distribution of scores was in the ordered
direction for Reading and Arithmetic
– 12/22 subjects were receiving or had received
special educations services with similar
proportions in each treatment group
Limitations
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Small numbers, low power,
dichtomization of continuous variables
No longitudinal analysis
Studies of
Neurocognitive Decline
Question
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What is the pattern of neurocognitive
loss?
Loss vs. lack of gain vs. both?
Palmer et al. ( 2001 )- Patterns of Intellectual
Development Among Survivors of Pediatric
Medulloblastoma: A Longitudinal Analysis
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Children could lose previously acquired
information and skills, similar to adult
dementia conditions
OR
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Children could continue to acquire new
information and skills but at a slower
rate than healthy age-related peers
Palmer et al. ( Patterns of Intellectual Development Among Survivors of Pediatric Medulloblastoma: A Longitudinal Analysis
Journal of Clinical Oncology, Vol 19, No 8 (April 15), 2001: pp 2302-2308
Palmer et. al (2001)
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44 Patients
– Histologically confirmed MB before age 17
– More than 1 psychological follow up with testing
– No evidence of progressive disease
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CSI Dosages
– 33 treated with 35.2-38.4
– 7 treated with 23.4-25Gy
– 4 treated with >40Gy
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All received posterior fossa boost 49.2-55.8
Palmer et. al (2001)
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Median 3 examinations per patient
Age Range at treatment: 1.73-12.88
(mean 7.84)
Years since XRT: 1.9-12.6 (mean 5.2)
Palmer et. al (2001)
Palmer et. al (2001)
Palmer et. al (2001)
Palmer et. al (2001)
Palmer et. al (2001)
Conclusion of Palmer
Paper
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Declining pattern of functioning over
time since completion of XRT
Patients continue to acquire new
knowledge but at a fraction of the rate
Age at XRT ( <8.02 vs >8.02) was an
effect modifier
CSI dose (<35.2 vs >36.0) were
significantly different in their effects
on IQ
As technology changes, can we
develop better predictive
models for cognitive decline?
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Merchant et al. (2006)
Modelling Radiation Dosimetry to Predict
Cognitive Outcomes
Some studies had shown no difference in
cognitive decline when comparing doses
– Conventional boost treatments to the entire
posterior fossa40% of the entire brain
receiving prescribed dose of 54-55.8 Gy
(Mulhern et al 2004)
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In an effort to reduce radiation dose and
volume, attention now focuses on the
manner in which the primary site is treated
Merchant et al. Modeling Radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma. Int. J.
Radiation Oncology bio. Phys. Vol 65, No 1, pp 210-221, 2006
Volume, not just dose
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SJMB96 trial- Patients treated with 23.4 Gy
CSI with conformal posterior fossa
radiation to 36 Gy and conformal primary
site radiation to 55.8 Gy had IQ decline of
2.4 points per year
Similar patients treated with 23.4 Gy CSI
and conventional posterior fossa radiation
to 55.8 Gy had decline of 5.2 IQ points per
year
Merchant et al. (2006)
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Goal: Model the effects of the entire
distribution of dose to specific volumes
of brain on longitudinal IQ after
radiation therapy
Patients
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39 patients, newly diagnosed
embryonal tumors
– 14 average risk (<1.5cm2 residual, M0)
– 25 high risk
Treatment
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Avg Risk: 23.4 Gy CSI, conformal
posterior fossa boost to 36Gy and
conformal primary-site boost to
55.8Gy
High Risk: 36-39.6 Gy CSI with
conformal primary-site boost to 55.8
Gy.
Testing
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Neurocognitive testing performed at
– Post surgery
– 1 year
– 2 years
– 5 years
Dosimetry
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Composite Radiation Dosimetry
– Merged 3D CSI dosimetry with 3D Primary
site dosimetry
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Normal volume contours made for
– Total (entire) brain
– Supratentorial brain
– Infratentorial brain
– Temporal lobes
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Dose volume data then extracted
Statistical Analysis
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Linear Mixed Model with Random
Coefficients
– IQ = dependent variable
– Distribution of dose divided into intervals
– Covariates
Fractional volume receiving dose over specified
interval
 Age, extent of disease, risk classification
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Part 1
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Determine effect of dose-volume
distribution on the change in IQ score
over 5 different volumes of brain tissue
– Total Brain
– Supratentorial Brain
– Infratentorial Brain
– Temporal lobes (right and left)
Example: Total Brain
age= years
time= months
Total Brain Volume
Supratentorial
Infratentorial
Left Temporal Lobe
Right Temporal Lobe
Mean Dose
Supratentorial model
application
Conclusions of Merchant
et al.
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Prediction of outcomes on basis of CSI
dose alone will lose relevance over time
– They’re approach is but one, requiring
further validation
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Limitations
– Assumption of linearity
– Limited follow up
– Inability to account for other factors that
might affect patient outcome
So what can we do?
Cognitive Remediation
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Luria-the brain is not a static organ and
functional reorganization of neuro
pathways can occur after a CNS insult
NIH consensus statement in 1998
supports use of cognitive rehabilitation
Educational intervention has been shown
to be effective in addressing academic
delays in children treated with cranial
radiation for ALL
Anderson VA et. Al. Cognitive and academic outcome following cranial irradiation and chemotherapy in children: A longitudinal study. Br J Cancer 82:255-262
Ecological
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Importance of educating patients,
caretakers, PCPs and teachers
Classroom accommodations
Impact of child’s disease on the family
Pharmacotherapy
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Mulhern et al. (2004) study of 83 ALL and
BT survivors
Methylphenidate
– Double blind, 3 week home crossover study
– Placebo vs. 0.3mg/kg vs. 0.6mg/kg
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Compared to placebo, parents and
teachers reported attentional and social
improvements
Ultimate effect on academic achievement?
Mulhern RK et al. Short-term efficacy of methylphenidate: a randomized, double-blind, placebo-controlled trial among survivors of childhood cancer.
J Clin Oncol. 2004 Dec 1;22(23):4795-803
Conclusions
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Clear association between radiation
therapy and cognitive decline
Decline appears to be progressive
Continued research with larger sample
sizes and validation of predictive models
Important point to address initially and
during follow up
Thanks!
Additional Slides
Palmer et al
Palmer et al
Ris et al. (2001) Intellectual Outcome After
Reduced-Dose Radiation Therapy Plus
Adjuvant Chemotherapy for Medulloblastoma:
A Children’s Cancer Group Study
Ris et al. (2001) Intellectual Outcome After Reduced-Dose Radiation Therapy Plus Adjuvant Chemotherapy for Medulloblastoma: A Children’s Cancer
Group Study. J Clin Oncol 19:3470-3476.
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Recently, treatment protocols have been developed
to reduce this morbidity. This can be accomplished
by simply decreasing the overall dose of RT to the
brain or by combining such reductions in RT dose
with adjuvant chemotherapy. Such approaches
have shown promise in producing survival and
tumor recurrence rates comparable to those of
conventional therapy
Deutsch M, Thomas PR, Krischer J, et al: Results of a prospective randomized trial comparing standard dose neuraxis irradiation (3600 cGy/20) with
reduced neuraxis irradiation (2340 cGy/13) in patients with low-stage medulloblastoma: A combined Children’s Cancer Group-Pediatric Oncology Group
Study. Pediatr Neurosurg 24:167-177, 1996
Bailey CC, Gnekow A, Wellek S: Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma: International
Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO)—SIOP II. Med Pediatr Oncol 25:166-178, 1995
Script your long term side
effect discussion for…
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7 year old boy, newly diagnosed
medulloblastoma
Script your long term side
effect discussion for…
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7 year old boy, newly diagnosed
medulloblastoma
65 year old woman, newly diagnosed
CNS lymphoma
Pharmacotherapy
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Meyers et al.- 30 patients with malignant
gliomas exhibiting neurobehavioral slowing
All patients met the DSM IV criteria for
personality change secondary to medical
condition
5 mg of MPH BID and titrated up by 10mg
every 2 weeks
Dramatic improvement in psychomotor speed,
memory , executive functioning, mood and
ADLs were seen even in with progressive
disease.
Meyers CA, Weitzner MA, Valentine AD, Levin VA. Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol.
1998 Jul;16(7):2522-7.