Neurocognitive Neurocognitive Outcomes of Outcomes of

Radiation Therapy in Radiation Therapy in ChildrenChildren

Aaron S. Kusano, SMAaron S. Kusano, SM

University of Washington University of Washington School of MedicineSchool of Medicine

OutlineOutline

Topic ChoiceTopic Choice Background/Current PracticesBackground/Current Practices Studies of Neurocognitive EffectsStudies of Neurocognitive Effects Predictive Model ResearchPredictive Model Research InterventionsInterventions Conclusion Conclusion

Why this topic?Why this topic?

Balancing act of treatment objectivesBalancing act of treatment objectives Implications in Patient Implications in Patient

Counseling/Education, Multidisciplinary Counseling/Education, Multidisciplinary Care and follow upCare and follow up

Increasing survival = increasing long term Increasing survival = increasing long term side effectsside effects

Challenging research Challenging research – growing body of literaturegrowing body of literature– study designstudy design– advancing technology and alternate advancing technology and alternate

approachesapproaches

BackgroundBackground

Childhood cancer survivors have Childhood cancer survivors have changes/difficulties in:changes/difficulties in:1)Attention1)Attention 2)Social Skills 3)Social Competence2)Social Skills 3)Social Competence

4)Internalization4)Internalization 5)Externalization 6)Social 5)Externalization 6)Social IsolationIsolation

7)Mood and Behavioral Disorders7)Mood and Behavioral Disorders

40-100% of long term brain tumor 40-100% of long term brain tumor survivors have some form of cognitive survivors have some form of cognitive dysfunctiondysfunction

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.

BackgroundBackground

Survivors of pediatric brain tumors have Survivors of pediatric brain tumors have lower rates of high school graduation and lower rates of high school graduation and employment relative to the overall employment relative to the overall populationpopulation

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, 1995Kelaghan J, Myers MH, Mulvihill JJ, et al: Educational achievement of long-term survivors of childhood and adolescent cancer. Med Pediatr Oncol 16:320-326, 1988Suc 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

PathophysiologyPathophysiology

Destruction of oligodendrocytes and Destruction of oligodendrocytes and endothelial cellsendothelial cells

Microvascular changesMicrovascular changes– Endothelial injury leads to toxic reactionsEndothelial injury leads to toxic reactions– Formation of free radicalsFormation of free radicals– Cell swelling, increased vascular Cell swelling, increased vascular

permeability, ischemia, edema and cell permeability, ischemia, edema and cell deathdeath

Evident on MRI with white and gray Evident on MRI with white and gray matter changesmatter changes

MedulloblastomaMedulloblastoma

Epidemiology of Epidemiology of MedulloblastomaMedulloblastoma

Embryonal tumorEmbryonal tumor ~20% of pediatric CNS tumors~20% of pediatric CNS tumors Median age at presentation 6 yearsMedian age at presentation 6 years 30-40% of patients have CSF 30-40% of patients have CSF

spread at time of diagnosisspread at time of diagnosis 5 year survival rates for children 5 year survival rates for children

with standard risk medulloblastoma with standard risk medulloblastoma approaches 80%approaches 80%

Medulloblastoma Risk Medulloblastoma Risk CategoriesCategories

Average Risk (2/3)Average Risk (2/3)– Age>3 yearsAge>3 years– Resection with < 1.5cmResection with < 1.5cm2 2 residualresidual– No metastasisNo metastasis

High Risk (1/3)High Risk (1/3)– Age<3yearsAge<3years– Resection > 1.5cmResection > 1.5cm2 2 residualresidual– MetastasisMetastasis

Current PracticesCurrent Practices

CategoriesCategories

Standard RiskStandard Risk

High Risk High Risk

InfantsInfants

Standard RiskStandard Risk Age > 3 years andAge > 3 years and less than 1.5 cmless than 1.5 cm22 of residual tumor and of residual tumor and No metastasis No metastasis

TreatmentTreatment– CSI 23.4 Gy with posterior fossa boost CSI 23.4 Gy with posterior fossa boost

to 54 Gy + vincristine, adjuvant chemoto 54 Gy + vincristine, adjuvant chemo– Event free survival at 4 years+85% Event free survival at 4 years+85%

(CCG/POG A9961)(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 17:2127-2136Grill 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 High Risk

Age < 3 years Age < 3 years OROR greater than 1.5 cmgreater than 1.5 cm22 of residual tumor of residual tumor OROR metastatic diseasemetastatic disease

TreatmentTreatment– CSI 36-39 Gy with posterior fossa boost to CSI 36-39 Gy with posterior fossa boost to

54Gy + vincristine, adjuvant chemo54Gy + vincristine, adjuvant chemo– POG 9031 demonstrated those with M1 POG 9031 demonstrated those with M1

disease had event free survival at 5 years disease had event free survival at 5 years of 65%of 65%

Infants (<3yo)Infants (<3yo)

SurgerySurgeryintensive chemotherapy is intensive chemotherapy is primary treatmentprimary treatment

Radiotherapy reserved for salvage Radiotherapy reserved for salvage therapytherapy

Worse prognosisWorse prognosis– Lower rate of complete resectionLower rate of complete resection– Higher rates of leptomeningeal seeding at Higher rates of leptomeningeal seeding at

diagnosisdiagnosis

Cognitive Cognitive MeasurementMeasurement

Wide Range Wide Range Achievement Test Achievement Test

(WRAT)(WRAT) Ability toAbility to

– Read wordsRead words– Comprehend sentencesComprehend sentences– SpellSpell– Math calculationsMath calculations

Weschler Intelligence Weschler Intelligence ScaleScale

Full Scale IQFull Scale IQ IndicesIndices

– Verbal Comprehension (vocab, comprehension)Verbal Comprehension (vocab, comprehension)– Perceptual Reasoning (block design, picture Perceptual Reasoning (block design, picture

concepts)concepts)– Processing Speed (timed coding activities)Processing Speed (timed coding activities)– Working Memory (repeating codes, sequences)Working Memory (repeating codes, sequences)

DSM-IV Criteria based DSM-IV Criteria based on IQ Scoreson IQ Scores

50-55 to 70: Mild Mental Retardation50-55 to 70: Mild Mental Retardation 35-40 to 50-55: Moderate Mental 35-40 to 50-55: Moderate Mental

RetardationRetardation 20-25 to 35-40: Severe Mental Retardation20-25 to 35-40: Severe Mental Retardation 20-25 and below: Profound Mental 20-25 and below: Profound Mental

RetardationRetardation

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

medulloblastomamedulloblastoma

POG 8631/CCG923POG 8631/CCG923 Treatment of average risk Treatment of average risk

medulloblastomas medulloblastomas HypothesisHypothesis

– Children treated with lower initial radiation Children treated with lower initial radiation levels would experience less intellectual levels would experience less intellectual toxicity than those receiving higher levelstoxicity than those receiving higher levels

– Also younger subjects suspected to have Also younger subjects suspected to have poorer outcomepoorer 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)Mulhern et al (1998)

Randomized to 36Gy or 23.4Gy Randomized to 36Gy or 23.4Gy craniospinal radiationcraniospinal radiation

Both groups receiving boost to 54 Both groups receiving boost to 54 Gy to posterior fossaGy to posterior fossa

Patient’s received baseline testingPatient’s received baseline testing Surviving patients in 1996 with no Surviving patients in 1996 with no

progressive disease were eligible progressive disease were eligible for studyfor study

GroupingsGroupings

Young (Y): Age < 9 years Young (Y): Age < 9 years Old (O): Age > 9 yearsOld (O): Age > 9 years Standard dose radiation (SRT): 36 Standard dose radiation (SRT): 36

GyGy Reduced Dose (RRT): 23.4 GyReduced Dose (RRT): 23.4 Gy

Predicted trend of scores:Predicted trend of scores:– Y/SRT < Y/RRT < O/SRT < O/RRTY/SRT < Y/RRT < O/SRT < O/RRT

SubjectsSubjects

Of 35 eligible participants, only 22 Of 35 eligible participants, only 22 patients completed follow up testingpatients completed follow up testing– Wechsler Scales of IntelligenceWechsler Scales of Intelligence– Wide Range Achievement Test IIIWide Range Achievement Test III

Age 4.1-19.0 years (median 8.85)Age 4.1-19.0 years (median 8.85) 13 treated with SRT, 9 treated w/ 13 treated with SRT, 9 treated w/

RRTRRT

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

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

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

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

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

ConclusionsConclusions

Predicted ordering of distributions was Predicted ordering of distributions was seen for Performance IQ, Full Scale and seen for Performance IQ, Full Scale and Attention IndexAttention Index

Unable to confirm significant differences Unable to confirm significant differences in IQ change as a function of age or dosein IQ change as a function of age or dose

Distribution of scores was in the ordered Distribution of scores was in the ordered direction for Reading and Arithmeticdirection for Reading and Arithmetic– 12/22 subjects were receiving or had 12/22 subjects were receiving or had

received special educations services with received special educations services with similar proportions in each treatment groupsimilar proportions in each treatment group

LimitationsLimitations

Small numbers, low power, Small numbers, low power, dichtomization of continuous dichtomization of continuous variablesvariables

No longitudinal analysisNo longitudinal analysis

Studies of Studies of Neurocognitive DeclineNeurocognitive Decline

QuestionQuestion

What is the pattern of What is the pattern of neurocognitive loss?neurocognitive loss?

Loss vs. lack of gain vs. both?Loss vs. lack of gain vs. both?

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

Children could lose previously Children could lose previously acquired information and skills, acquired information and skills, similar to adult dementia conditionssimilar to adult dementia conditions

OROR Children could continue to acquire Children could continue to acquire

new information and skills but at a new information and skills but at a slower rate than healthy age-slower rate than healthy age-related peersrelated peers

Palmer et al. ( Patterns of Intellectual Development Among Survivors of Pediatric Medulloblastoma: A Longitudinal AnalysisPalmer 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 2302-2308Journal of Clinical Oncology, Vol 19, No 8 (April 15), 2001: pp 2302-2308

Palmer et. al (2001)Palmer et. al (2001)

44 Patients 44 Patients – Histologically confirmed MB before age 17Histologically confirmed MB before age 17– More than 1 psychological follow up with testingMore than 1 psychological follow up with testing– No evidence of progressive diseaseNo evidence of progressive disease

CSI DosagesCSI Dosages– 33 treated with 35.2-38.433 treated with 35.2-38.4– 7 treated with 23.4-25Gy7 treated with 23.4-25Gy– 4 treated with >40Gy4 treated with >40Gy

All received posterior fossa boost 49.2-55.8All received posterior fossa boost 49.2-55.8

Median 3 examinations per Median 3 examinations per patientpatient

Age Range at treatment: 1.73-Age Range at treatment: 1.73-12.88 (mean 7.84)12.88 (mean 7.84)

Years since XRT: 1.9-12.6 (mean Years since XRT: 1.9-12.6 (mean 5.2)5.2)

Palmer et. al (2001)Palmer et. al (2001)

Palmer et. al (2001)Palmer et. al (2001)

Palmer et. al (2001)Palmer et. al (2001)

Palmer et. al (2001)Palmer et. al (2001)

Palmer et. al (2001)Palmer et. al (2001)

Palmer et. al (2001)Palmer et. al (2001)

Conclusion of Palmer Conclusion of Palmer PaperPaper

Declining pattern of functioning Declining pattern of functioning over time since completion of XRTover time since completion of XRT

Patients continue to acquire new Patients continue to acquire new knowledge but at a fraction of the knowledge but at a fraction of the raterate

Age at XRT ( <8.02 vs >8.02) was Age at XRT ( <8.02 vs >8.02) was an effect modifier an effect modifier

CSI dose (<35.2 vs >36.0) were CSI dose (<35.2 vs >36.0) were significantly different in their significantly different in their effects on IQeffects on IQ

As technology changes, can As technology changes, can we develop better predictive we develop better predictive

models for cognitive models for cognitive decline?decline?

Merchant et al. (2006) Merchant et al. (2006) Modelling Radiation Dosimetry to Modelling Radiation Dosimetry to

Predict Cognitive OutcomesPredict Cognitive Outcomes Some studies had shown no difference in Some studies had shown no difference in

cognitive decline when comparing dosescognitive decline when comparing doses– Conventional boost treatments to the entire Conventional boost treatments to the entire

posterior fossaposterior fossa40% of the entire brain 40% of the entire brain receiving prescribed dose of 54-55.8 Gy receiving prescribed dose of 54-55.8 Gy (Mulhern et al 2004)(Mulhern et al 2004)

In an effort to reduce radiation dose and In an effort to reduce radiation dose and volume, attention now focuses on the volume, attention now focuses on the manner in which the primary site is manner in which the primary site is treatedtreated

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 doseVolume, not just dose

SJMB96 trial- Patients treated with SJMB96 trial- Patients treated with 23.4 Gy CSI with conformal posterior 23.4 Gy CSI with conformal posterior fossa radiation to 36 Gy and fossa radiation to 36 Gy and conformal primary site radiation to conformal primary site radiation to 55.8 Gy had IQ decline of 2.4 points 55.8 Gy had IQ decline of 2.4 points per yearper year

Similar patients treated with 23.4 Gy Similar patients treated with 23.4 Gy CSI and conventional posterior fossa CSI and conventional posterior fossa radiation to 55.8 Gy had decline of radiation to 55.8 Gy had decline of 5.2 IQ points per year5.2 IQ points per year

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

Merchant et al. (2006)Merchant et al. (2006)

PatientsPatients

39 patients, newly diagnosed 39 patients, newly diagnosed embryonal tumorsembryonal tumors– 14 average risk (<1.5cm14 average risk (<1.5cm22 residual, residual,

M0)M0)– 25 high risk25 high risk

TreatmentTreatment

Avg Risk: 23.4 Gy CSI, conformal Avg Risk: 23.4 Gy CSI, conformal posterior fossa boost to 36Gy and posterior fossa boost to 36Gy and conformal primary-site boost to conformal primary-site boost to 55.8Gy55.8Gy

High Risk: 36-39.6 Gy CSI with High Risk: 36-39.6 Gy CSI with conformal primary-site boost to conformal primary-site boost to 55.8 Gy.55.8 Gy.

TestingTesting

Neurocognitive testing performed Neurocognitive testing performed atat– Post surgeryPost surgery– 1 year1 year– 2 years2 years– 5 years5 years

DosimetryDosimetry

Composite Radiation DosimetryComposite Radiation Dosimetry– Merged 3D CSI dosimetry with 3D Merged 3D CSI dosimetry with 3D

Primary site dosimetryPrimary site dosimetry Normal volume contours made forNormal volume contours made for

– Total (entire) brainTotal (entire) brain– Supratentorial brainSupratentorial brain– Infratentorial brainInfratentorial brain– Temporal lobesTemporal lobes

Dose volume data then extractedDose volume data then extracted

Statistical AnalysisStatistical Analysis

Linear Mixed Model with Random Linear Mixed Model with Random CoefficientsCoefficients– IQ = dependent variableIQ = dependent variable– Distribution of dose divided into intervalsDistribution of dose divided into intervals– CovariatesCovariates

Fractional volume receiving dose over Fractional volume receiving dose over specified intervalspecified interval

Age, extent of disease, risk classificationAge, extent of disease, risk classification

Part 1Part 1

Determine effect of dose-volume Determine effect of dose-volume distribution on the change in IQ distribution on the change in IQ score over 5 different volumes of score over 5 different volumes of brain tissuebrain tissue– Total BrainTotal Brain– Supratentorial BrainSupratentorial Brain– Infratentorial BrainInfratentorial Brain– Temporal lobes (right and left)Temporal lobes (right and left)

Example: Total BrainExample: Total Brain

age= years time= months

Total Brain Total Brain VolumeVolume

SupratentorialSupratentorial

InfratentoriaInfratentoriall

Left Temporal LobeLeft Temporal Lobe

Right Temporal LobeRight Temporal Lobe

Mean DoseMean Dose

Supratentorial model Supratentorial model applicationapplication

Conclusions of Conclusions of Merchant et al. Merchant et al.

Prediction of outcomes on basis of CSI Prediction of outcomes on basis of CSI dose alone will lose relevance over dose alone will lose relevance over timetime– They’re approach is but one, requiring They’re approach is but one, requiring

further validationfurther validation LimitationsLimitations

– Assumption of linearityAssumption of linearity– Limited follow upLimited follow up– Inability to account for other factors that Inability to account for other factors that

might affect patient outcomemight affect patient outcome

So what can we do?So what can we do?

Cognitive RemediationCognitive Remediation

Luria-the brain is not a static organ Luria-the brain is not a static organ and functional reorganization of neuro and functional reorganization of neuro pathways can occur after a CNS insultpathways can occur after a CNS insult

NIH consensus statement in 1998 NIH consensus statement in 1998 supports use of cognitive supports use of cognitive rehabilitationrehabilitation

Educational intervention has been Educational intervention has been shown to be effective in addressing shown to be effective in addressing academic delays in children treated academic delays in children treated with cranial radiation for ALLwith 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 Ecological

Importance of educating patients, Importance of educating patients, caretakers, PCPs and teacherscaretakers, PCPs and teachers

Classroom accommodationsClassroom accommodations Impact of child’s disease on the Impact of child’s disease on the

familyfamily

PharmacotherapyPharmacotherapy Mulhern et al. (2004) study of 83 ALL and Mulhern et al. (2004) study of 83 ALL and

BT survivorsBT survivors MethylphenidateMethylphenidate

– Double blind, 3 week home crossover studyDouble blind, 3 week home crossover study– Placebo vs. 0.3mg/kg vs. 0.6mg/kgPlacebo vs. 0.3mg/kg vs. 0.6mg/kg

Compared to placebo, parents and Compared to placebo, parents and teachers reported attentional and social teachers reported attentional and social improvementsimprovements

Ultimate effect on academic Ultimate effect on academic achievement?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

ConclusionsConclusions

Clear association between radiation Clear association between radiation therapy and cognitive decline therapy and cognitive decline

Decline appears to be progressiveDecline appears to be progressive Continued research with larger Continued research with larger

sample sizes and validation of sample sizes and validation of predictive modelspredictive models

Important point to address initially Important point to address initially and during follow upand during follow up

Thanks!Thanks!

Additional SlidesAdditional Slides

Palmer et alPalmer et al

Palmer et alPalmer et al

Ris et al. (2001)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) 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.

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 Script your long term side effect discussion for…effect discussion for…

7 year old boy, newly diagnosed 7 year old boy, newly diagnosed medulloblastomamedulloblastoma

Script your long term side Script your long term side effect discussion for…effect discussion for…

7 year old boy, newly diagnosed 7 year old boy, newly diagnosed medulloblastomamedulloblastoma

65 year old woman, newly 65 year old woman, newly diagnosed CNS lymphomadiagnosed CNS lymphoma

PharmacotherapyPharmacotherapy Meyers et al.- 30 patients with malignant Meyers et al.- 30 patients with malignant

gliomas exhibiting neurobehavioral slowing gliomas exhibiting neurobehavioral slowing All patients met the DSM IV criteria for All patients met the DSM IV criteria for

personality change secondary to medical personality change secondary to medical conditioncondition

5 mg of MPH BID and titrated up by 10mg 5 mg of MPH BID and titrated up by 10mg every 2 weeksevery 2 weeks

Dramatic improvement in psychomotor Dramatic improvement in psychomotor speed, memory , executive functioning, speed, memory , executive functioning, mood and ADLs were seen even in with mood and ADLs were seen even in with progressive disease.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.