Limitations in Studies

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(No Transcript)
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Neurocognitive Outcomes of Radiation Therapy in
Children

• Aaron S. Kusano, SM
• University of Washington School of Medicine

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Outline

• Topic Choice
• Background/Current Practices
• Studies of Neurocognitive Effects
• Predictive Model Research
• Interventions
• Conclusion

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Why this topic?

• 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

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Background

• 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
• 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 72-12, 1991 Schultz et al.
Behavioral and Social Outcomes in Adolescent
Survivors of Childhood Cancer A report from the
Childhood cancer survivor study.
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Background

• 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 11340-346, 1995 Kelaghan J,
Myers MH, Mulvihill JJ, et al Educational
achievement of long-term survivors of childhood
and adolescent cancer. Med Pediatr Oncol
16320-326, 1988 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). 1990106(3-4)93-8
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Pathophysiology

• 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
• Evident on MRI with white and gray matter changes

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Medulloblastoma
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Epidemiology of Medulloblastoma

• 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

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Medulloblastoma Risk Categories

• Average Risk (2/3)
• Agegt3 years
• Resection with lt 1.5cm2 residual
• No metastasis
• High Risk (1/3)
• Agelt3years
• Resection gt 1.5cm2 residual
• Metastasis

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Current Practices
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Categories

• Standard Risk
• High Risk
• Infants

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Standard Risk

• Age gt 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 years85 (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 childrens Cancer Group
Study. J Clin Oncol 172127-2136 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
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High Risk

• Age lt 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

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Infants (lt3yo)

• 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

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Cognitive Measurement
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Wide Range Achievement Test (WRAT)

• Ability to
• Read words
• Comprehend sentences
• Spell
• Math calculations

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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)

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DSM-IV Criteria based on IQ Scores

• 50-55 to 70 Mild Mental Retardation
• 35-40 to 50-55 Moderate Mental Retardation
• 20-25 to 35-40 Severe Mental Retardation
• 20-25 and below Profound Mental Retardation

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Mulhern(1998)- Neuropsychologic functioning of
survivors of childhood medulloblastoma

• 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
  161723-1728, 1998

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Mulhern et al (1998)

• Randomized to 36Gy or 23.4Gy craniospinal
  radiation
• Both groups receiving boost to 54 Gy to posterior
  fossa
• Patients received baseline testing
• Surviving patients in 1996 with no progressive
  disease were eligible for study

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Groupings

• Young (Y) Age lt 9 years
• Old (O) Age gt 9 years
• Standard dose radiation (SRT) 36 Gy
• Reduced Dose (RRT) 23.4 Gy
• Predicted trend of scores
• Y/SRT lt Y/RRT lt O/SRT lt O/RRT

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Subjects

• Of 35 eligible participants, only 22 patients
  completed follow up testing
• Wechsler Scales of Intelligence
• Wide Range Achievement Test III
• Age 4.1-19.0 years (median 8.85)
• 13 treated with SRT, 9 treated w/ RRT

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Mulhern et al (1998)
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Mulhern et al (1998)
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Mulhern et al (1998)
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Mulhern et al (1998)
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Mulhern et al (1998)
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Conclusions

• 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

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Limitations

• Small numbers, low power, dichtomization of
  continuous variables
• No longitudinal analysis

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Studies of Neurocognitive Decline
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Question

• What is the pattern of neurocognitive loss?
• Loss vs. lack of gain vs. both?

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Palmer et al. ( 2001 )- Patterns of Intellectual
Development Among Survivors of Pediatric
Medulloblastoma A Longitudinal Analysis

• Children could lose previously acquired
  information and skills, similar to adult dementia
  conditions
• OR
• 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 AnalysisJournal
of Clinical Oncology, Vol 19, No 8 (April 15),
2001 pp 2302-2308
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Palmer et. al (2001)

• 44 Patients
• Histologically confirmed MB before age 17
• More than 1 psychological follow up with testing
• No evidence of progressive disease
• CSI Dosages
• 33 treated with 35.2-38.4
• 7 treated with 23.4-25Gy
• 4 treated with gt40Gy
• All received posterior fossa boost 49.2-55.8

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Palmer et. al (2001)

• 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)

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Palmer et. al (2001)
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Palmer et. al (2001)
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Palmer et. al (2001)
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Palmer et. al (2001)
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Palmer et. al (2001)
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Conclusion of Palmer Paper

• 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 ( lt8.02 vs gt8.02) was an effect
  modifier
• CSI dose (lt35.2 vs gt36.0) were significantly
  different in their effects on IQ

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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)
• 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
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Volume, not just dose

• 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

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Merchant et al. (2006)

• Goal Model the effects of the entire
  distribution of dose to specific volumes of brain
  on longitudinal IQ after radiation therapy

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Patients

• 39 patients, newly diagnosed embryonal tumors
• 14 average risk (lt1.5cm2 residual, M0)
• 25 high risk

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Treatment

• 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.

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Testing

• Neurocognitive testing performed at
• Post surgery
• 1 year
• 2 years
• 5 years

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Dosimetry

• Composite Radiation Dosimetry
• Merged 3D CSI dosimetry with 3D Primary site
  dosimetry
• Normal volume contours made for
• Total (entire) brain
• Supratentorial brain
• Infratentorial brain
• Temporal lobes
• Dose volume data then extracted

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Statistical Analysis

• 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

• 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)

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Example Total Brain
age years time months
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Total Brain Volume
Supratentorial
Infratentorial
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Left Temporal Lobe
Right Temporal Lobe
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Mean Dose
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Supratentorial model application
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Conclusions of Merchant et al.

• Prediction of outcomes on basis of CSI dose alone
  will lose relevance over time
• Theyre approach is but one, requiring further
  validation
• Limitations
• Assumption of linearity
• Limited follow up
• Inability to account for other factors that might
  affect patient outcome

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So what can we do?
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Cognitive Remediation

• 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 82255-262
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Ecological

• Importance of educating patients, caretakers,
  PCPs and teachers
• Classroom accommodations
• Impact of childs disease on the family

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Pharmacotherapy

• 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
• 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
122(23)4795-803
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Conclusions

• 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

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Thanks!
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Additional Slides
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Palmer et al
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Palmer et al
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Ris et al. (2001) Intellectual Outcome After
Reduced-Dose Radiation Therapy Plus Adjuvant
Chemotherapy for Medulloblastoma A Childrens
Cancer Group Study
Ris et al. (2001) Intellectual Outcome After
Reduced-Dose Radiation Therapy Plus Adjuvant
Chemotherapy for Medulloblastoma A Childrens
Cancer Group Study. J Clin Oncol 193470-3476.
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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 Childrens Cancer Group-Pediatric
  Oncology Group Study. Pediatr Neurosurg
  24167-177, 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
  25166-178, 1995

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Script your long term side effect discussion for

• 7 year old boy, newly diagnosed medulloblastoma

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Script your long term side effect discussion for

• 7 year old boy, newly diagnosed medulloblastoma
• 65 year old woman, newly diagnosed CNS lymphoma

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Pharmacotherapy

• 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 Jul16(7)2522-7.