Neurocognitive Outcomes of Radiation Therapy in Children


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  • Oligodendrocytes: Myelinating cells of the CNS, other diseases that damage oligodendrocytes include MS, Leukodystrophies, CP
    White matter: multifocal hyperintensities, gray matter calcifications.
  • Current surgical techniques achieve complete or near total resection in approximately 80% of cases
  • Previously kids older than 3 were treated with craniospinal axis dose to 35-36 Gy followed by boost to the whole posterior fossa to a total dose of 54-55.8. This achieved long term event free survival of 65%. Hormal deficits, decreased bone growth and neurocognitive deficits were seen that coorelated to age an radiation dose. Adjuvant chemo consists of vincristine, cisplatin and CCNU or cyclophosphamide.
  • Intelligence is an individual’s capacity to learn, recall information, integrate information constructively and think rationally. IQ tests are designed to assess current levels of functioning and capacity for adaptive behavior.
  • POG 8631 /CCG 923 was an intergroup randmized trial of treatment of average risk medulloblastoma 1986-90. They looked at a number of factors such as patterns of recurrence and examination of disease free survival and survival. These were children greater than 3 years of age, average risk, randomized to either standard dose (36 Gy) or reduced dose (23.4) both receiving boost to the posterior fossa to 54 Gy
  • For each subtest, the rate of increase in raw scores for the MB patient group progressed at less than normal population expectations. To maintain an average score on the information subtest, the normal population sample gains a mean of 1.53 raw score points per year. In contrast, the MB patients gained only a mean of 0.95 points per year.
    In summary, the MB patient group acquired
    knowledge at only 62.1%, 49.9%, and 61.2% of the expected rate for the information, similarities, and block design subtests, respectively. As illustrated in Fig 1, the ultimate result of these trends is a widening cognitive deficit between patients treated for MB in childhood and their healthy same-age peers.
  • where the set of values of a categorical predictor variable are seen not as the complete set but rather as a random sample of all values (ex., the variable "product" has values representing only 5 of a possible 42 brands). Through random effects models, the researcher can make inferences over a wider population in LMM than possible with GLM.
  • Comment on Meaning of terms. They also
  • Reduced number of items on multiple choice tests, preferential seating in the classrooom, decreased expectation sin the volume of homework. Many children will need the classification of “other health impoared” by the local school system as a means of accessing resources for their special needs.
    There have been studies in children with traumatic brain injury which have found that the negative impact of the childn’s unjury on the family and the overal family adjustment are sginificant predictors of continued neurobehavioral symptoms following TBI.
  • Some children surviving cancer exhibit dehavioral symptoms similar to children with ADHD, particularly inateention. 83 long term survivors of ALL and brain tumors having attentional deficits and problems with academic achievement. 28 had chemo only, 14 had <24Gy of cranial radiotherapy and chemo, 41 had > 24 Gy of CRT and chemo. Conners rating scale and social skills rating scale.
  • Cognitive impairments in brain tumor patients that precede radiotherapy or chemotherapy are generally related to the site of the lesion. Patients with left-hemisphere tumors generally have difficulty with language function, verbal learning and memory, verbal reasoning, and right-sided motor dexterity, while patients with right-hemisphere tumors have difficulties with visual-perceptual skills and left-sided motor dexterity.2 In addition, many patients exhibit impairments of frontal lobe function (executive deficits manifested by apathy, lack of motivation, lack of spontaneity,impaired attention, impaired working memory, difficultyshifting mental set, etc) even if they do not have a frontal lesions. Following radiation and chemotherapy, brain tumor patients with no evidence of disease recurrence have impairments of information-processing speed, frontal lobe executive functions, memory, sustained attention, and motor coordination. Motor slowing is seen bilaterally and irrespective of tumor location,
  • Neurocognitive Outcomes of Radiation Therapy in Children

    1. 1. NeurocognitiveNeurocognitive Outcomes of RadiationOutcomes of Radiation Therapy in ChildrenTherapy in Children Aaron S. Kusano, SMAaron S. Kusano, SM University of Washington SchoolUniversity of Washington School of Medicineof Medicine
    2. 2. OutlineOutline  Topic ChoiceTopic Choice  Background/Current PracticesBackground/Current Practices  Studies of Neurocognitive EffectsStudies of Neurocognitive Effects  Predictive Model ResearchPredictive Model Research  InterventionsInterventions  ConclusionConclusion
    3. 3. Why this topic?Why this topic?  Balancing act of treatment objectivesBalancing act of treatment objectives  Implications in Patient Counseling/Education,Implications in Patient Counseling/Education, Multidisciplinary Care and follow upMultidisciplinary Care and follow up  Increasing survival = increasing long term sideIncreasing survival = increasing long term side effectseffects  Challenging researchChallenging research – growing body of literaturegrowing body of literature – study designstudy design – advancing technology and alternate approachesadvancing technology and alternate approaches
    4. 4. BackgroundBackground  Childhood cancer survivors haveChildhood cancer survivors have changes/difficulties in:changes/difficulties in: 1)Attention1)Attention 2)Social Skills 3)Social2)Social Skills 3)Social CompetenceCompetence 4)Internalization4)Internalization 5)Externalization 6)Social Isolation5)Externalization 6)Social Isolation 7)Mood and Behavioral Disorders7)Mood and Behavioral Disorders  40-100% of long term brain tumor40-100% of long term brain tumor survivors have some form of cognitivesurvivors 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.
    5. 5. BackgroundBackground  Survivors of pediatric brain tumors have lowerSurvivors of pediatric brain tumors have lower rates of high school graduation andrates of high school graduation and employment relative to the overall populationemployment 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
    6. 6. PathophysiologyPathophysiology  Destruction of oligodendrocytes andDestruction 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 vascularCell swelling, increased vascular permeability, ischemia, edema and cellpermeability, ischemia, edema and cell deathdeath  Evident on MRI with white and grayEvident on MRI with white and gray matter changesmatter changes
    7. 7. MedulloblastomaMedulloblastoma
    8. 8. Epidemiology ofEpidemiology 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 spread30-40% of patients have CSF spread at time of diagnosisat time of diagnosis  5 year survival rates for children with5 year survival rates for children with standard risk medulloblastomastandard risk medulloblastoma approaches 80%approaches 80%
    9. 9. Medulloblastoma RiskMedulloblastoma Risk CategoriesCategories  Average Risk (2/3)Average Risk (2/3) – Age>3 yearsAge>3 years – Resection with < 1.5cmResection with < 1.5cm22 residualresidual – No metastasisNo metastasis  High Risk (1/3)High Risk (1/3) – Age<3yearsAge<3years – Resection > 1.5cmResection > 1.5cm22 residualresidual – MetastasisMetastasis
    10. 10. Current PracticesCurrent Practices
    11. 11. CategoriesCategories  Standard RiskStandard Risk  High RiskHigh Risk  InfantsInfants
    12. 12. Standard RiskStandard Risk  Age > 3 years andAge > 3 years and  less than 1.5 cmless than 1.5 cm22 of residual tumor andof residual tumor and  No metastasisNo metastasis  TreatmentTreatment – CSI 23.4 Gy with posterior fossa boostCSI 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 17:2127-2136 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
    13. 13. High RiskHigh Risk  Age < 3 yearsAge < 3 years OROR  greater than 1.5 cmgreater than 1.5 cm22 of residual tumorof residual tumor OROR  metastatic diseasemetastatic disease  TreatmentTreatment – CSI 36-39 Gy with posterior fossa boost toCSI 36-39 Gy with posterior fossa boost to 54Gy + vincristine, adjuvant chemo54Gy + vincristine, adjuvant chemo – POG 9031 demonstrated those with M1POG 9031 demonstrated those with M1 disease had event free survival at 5 yearsdisease had event free survival at 5 years of 65%of 65%
    14. 14. Infants (<3yo)Infants (<3yo)  SurgerySurgeryintensive chemotherapy isintensive chemotherapy is primary treatmentprimary treatment  Radiotherapy reserved for salvage therapyRadiotherapy reserved for salvage therapy  Worse prognosisWorse prognosis – Lower rate of complete resectionLower rate of complete resection – Higher rates of leptomeningeal seeding at diagnosisHigher rates of leptomeningeal seeding at diagnosis
    15. 15. Cognitive MeasurementCognitive Measurement
    16. 16. Wide RangeWide Range Achievement TestAchievement Test (WRAT)(WRAT)  Ability toAbility to – Read wordsRead words – Comprehend sentencesComprehend sentences – SpellSpell – Math calculationsMath calculations
    17. 17. Weschler IntelligenceWeschler Intelligence ScaleScale  Full Scale IQFull Scale IQ  IndicesIndices – Verbal Comprehension (vocab,Verbal Comprehension (vocab, comprehension)comprehension) – Perceptual Reasoning (block design, picturePerceptual 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)
    18. 18. DSM-IV Criteria basedDSM-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 Retardation35-40 to 50-55: Moderate Mental Retardation  20-25 to 35-40: Severe Mental Retardation20-25 to 35-40: Severe Mental Retardation  20-25 and below: Profound Mental Retardation20-25 and below: Profound Mental Retardation
    19. 19. Mulhern(1998)-Mulhern(1998)- NeuropsychologicNeuropsychologic functioning of survivors of childhoodfunctioning of survivors of childhood medulloblastomamedulloblastoma  POG 8631/CCG923POG 8631/CCG923  Treatment of average riskTreatment of average risk medulloblastomasmedulloblastomas  HypothesisHypothesis – Children treated with lower initial radiation levelsChildren treated with lower initial radiation levels would experience less intellectual toxicity thanwould experience less intellectual toxicity than those receiving higher levelsthose receiving higher levels – Also younger subjects suspected to have poorerAlso younger subjects suspected to have poorer outcomeoutcome•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
    20. 20. Mulhern et al (1998)Mulhern et al (1998)  Randomized to 36Gy or 23.4GyRandomized to 36Gy or 23.4Gy craniospinal radiationcraniospinal radiation  Both groups receiving boost to 54 GyBoth groups receiving boost to 54 Gy to posterior fossato posterior fossa  Patient’s received baseline testingPatient’s received baseline testing  Surviving patients in 1996 with noSurviving patients in 1996 with no progressive disease were eligible forprogressive disease were eligible for studystudy
    21. 21. GroupingsGroupings  Young (Y): Age < 9 yearsYoung (Y): Age < 9 years  Old (O): Age > 9 yearsOld (O): Age > 9 years  Standard dose radiation (SRT): 36 GyStandard dose radiation (SRT): 36 Gy  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
    22. 22. SubjectsSubjects  Of 35 eligible participants, only 22Of 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/ RRT13 treated with SRT, 9 treated w/ RRT
    23. 23. Mulhern et al (1998)Mulhern et al (1998)
    24. 24. Mulhern et al (1998)Mulhern et al (1998)
    25. 25. Mulhern et al (1998)Mulhern et al (1998)
    26. 26. Mulhern et al (1998)Mulhern et al (1998)
    27. 27. Mulhern et al (1998)Mulhern et al (1998)
    28. 28. ConclusionsConclusions  Predicted ordering of distributions was seenPredicted ordering of distributions was seen for Performance IQ, Full Scale and Attentionfor Performance IQ, Full Scale and Attention IndexIndex  Unable to confirm significant differences inUnable to confirm significant differences in IQ change as a function of age or doseIQ change as a function of age or dose  Distribution of scores was in the orderedDistribution of scores was in the ordered direction for Reading and Arithmeticdirection for Reading and Arithmetic – 12/22 subjects were receiving or had received12/22 subjects were receiving or had received special educations services with similarspecial educations services with similar proportions in each treatment groupproportions in each treatment group
    29. 29. LimitationsLimitations  Small numbers, low power,Small numbers, low power, dichtomization of continuous variablesdichtomization of continuous variables  No longitudinal analysisNo longitudinal analysis
    30. 30. Studies ofStudies of Neurocognitive DeclineNeurocognitive Decline
    31. 31. QuestionQuestion  What is the pattern of neurocognitiveWhat is the pattern of neurocognitive loss?loss?  Loss vs. lack of gain vs. both?Loss vs. lack of gain vs. both?
    32. 32. Palmer et al. ( 2001 )-Palmer et al. ( 2001 )- Patterns of IntellectualPatterns of Intellectual Development Among Survivors of PediatricDevelopment Among Survivors of Pediatric Medulloblastoma: A Longitudinal AnalysisMedulloblastoma: A Longitudinal Analysis  Children could lose previouslyChildren could lose previously acquired information and skills, similaracquired information and skills, similar to adult dementia conditionsto adult dementia conditions OROR  Children could continue to acquireChildren could continue to acquire new information and skills but at anew information and skills but at a slower rate than healthy age-relatedslower rate than healthy age-related peerspeers 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 Analysis Journal 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
    33. 33. Palmer et. al (2001)Palmer et. al (2001)  44 Patients44 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
    34. 34.  Median 3 examinations per patientMedian 3 examinations per patient  Age Range at treatment: 1.73-12.88Age Range at treatment: 1.73-12.88 (mean 7.84)(mean 7.84)  Years since XRT: 1.9-12.6 (mean 5.2)Years since XRT: 1.9-12.6 (mean 5.2) Palmer et. al (2001)Palmer et. al (2001)
    35. 35. Palmer et. al (2001)Palmer et. al (2001)
    36. 36. Palmer et. al (2001)Palmer et. al (2001)
    37. 37. Palmer et. al (2001)Palmer et. al (2001)
    38. 38. Palmer et. al (2001)Palmer et. al (2001)
    39. 39. Palmer et. al (2001)Palmer et. al (2001)
    40. 40. Conclusion of PalmerConclusion of Palmer PaperPaper  Declining pattern of functioning overDeclining pattern of functioning over time since completion of XRTtime since completion of XRT  Patients continue to acquire newPatients continue to acquire new knowledge but at a fraction of the rateknowledge but at a fraction of the rate  Age at XRT ( <8.02 vs >8.02) was anAge at XRT ( <8.02 vs >8.02) was an effect modifiereffect modifier  CSI dose (<35.2 vs >36.0) wereCSI dose (<35.2 vs >36.0) were significantly different in their effects onsignificantly different in their effects on IQIQ
    41. 41. As technology changes, canAs technology changes, can we develop better predictivewe develop better predictive models for cognitive decline?models for cognitive decline?
    42. 42. Merchant et al. (2006)Merchant et al. (2006) Modelling Radiation Dosimetry to PredictModelling Radiation Dosimetry to Predict Cognitive OutcomesCognitive Outcomes  Some studies had shown no difference inSome studies had shown no difference in cognitive decline when comparing dosescognitive decline when comparing doses – Conventional boost treatments to the entireConventional boost treatments to the entire posterior fossaposterior fossa40% of the entire brain40% of the entire brain receiving prescribed dose of 54-55.8 Gyreceiving prescribed dose of 54-55.8 Gy (Mulhern et al 2004)(Mulhern et al 2004)  In an effort to reduce radiation dose andIn an effort to reduce radiation dose and volume, attention now focuses on thevolume, attention now focuses on the manner in which the primary site is treatedmanner 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
    43. 43. Volume, not just doseVolume, not just dose  SJMB96 trial- Patients treated with 23.4SJMB96 trial- Patients treated with 23.4 Gy CSI with conformal posterior fossaGy CSI with conformal posterior fossa radiation to 36 Gy and conformal primaryradiation to 36 Gy and conformal primary site radiation to 55.8 Gy had IQ decline ofsite radiation to 55.8 Gy had IQ decline of 2.4 points per year2.4 points per year  Similar patients treated with 23.4 Gy CSISimilar patients treated with 23.4 Gy CSI and conventional posterior fossa radiationand conventional posterior fossa radiation to 55.8 Gy had decline of 5.2 IQ points perto 55.8 Gy had decline of 5.2 IQ points per yearyear
    44. 44.  Goal: Model the effects of the entireGoal: Model the effects of the entire distribution of dose to specific volumesdistribution of dose to specific volumes of brain on longitudinal IQ afterof brain on longitudinal IQ after radiation therapyradiation therapy Merchant et al. (2006)Merchant et al. (2006)
    45. 45. PatientsPatients  39 patients, newly diagnosed39 patients, newly diagnosed embryonal tumorsembryonal tumors – 14 average risk (<1.5cm14 average risk (<1.5cm22 residual, M0)residual, M0) – 25 high risk25 high risk
    46. 46. TreatmentTreatment  Avg Risk: 23.4 Gy CSI, conformalAvg Risk: 23.4 Gy CSI, conformal posterior fossa boost to 36Gy andposterior fossa boost to 36Gy and conformal primary-site boost toconformal primary-site boost to 55.8Gy55.8Gy  High Risk: 36-39.6 Gy CSI withHigh Risk: 36-39.6 Gy CSI with conformal primary-site boost to 55.8conformal primary-site boost to 55.8 Gy.Gy.
    47. 47. TestingTesting  Neurocognitive testing performed atNeurocognitive testing performed at – Post surgeryPost surgery – 1 year1 year – 2 years2 years – 5 years5 years
    48. 48. DosimetryDosimetry  Composite Radiation DosimetryComposite Radiation Dosimetry – Merged 3D CSI dosimetry with 3D PrimaryMerged 3D CSI dosimetry with 3D Primary site dosimetrysite 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
    49. 49. Statistical AnalysisStatistical Analysis  Linear Mixed Model with RandomLinear 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 specifiedFractional volume receiving dose over specified intervalinterval  Age, extent of disease, risk classificationAge, extent of disease, risk classification
    50. 50. Part 1Part 1  Determine effect of dose-volumeDetermine effect of dose-volume distribution on the change in IQ scoredistribution on the change in IQ score over 5 different volumes of brain tissueover 5 different volumes of brain tissue – Total BrainTotal Brain – Supratentorial BrainSupratentorial Brain – Infratentorial BrainInfratentorial Brain – Temporal lobes (right and left)Temporal lobes (right and left)
    51. 51. Example: Total BrainExample: Total Brain age= years time=
    52. 52. Total Brain VolumeTotal Brain Volume SupratentorialSupratentorial InfratentorialInfratentorial
    53. 53. Left Temporal LobeLeft Temporal Lobe Right Temporal LobeRight Temporal Lobe
    54. 54. Mean DoseMean Dose
    55. 55. Supratentorial modelSupratentorial model applicationapplication
    56. 56. Conclusions of MerchantConclusions of Merchant et al.  Prediction of outcomes on basis of CSIPrediction of outcomes on basis of CSI dose alone will lose relevance over timedose alone will lose relevance over time – They’re approach is but one, requiringThey’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 thatInability to account for other factors that might affect patient outcomemight affect patient outcome
    57. 57. So what can we do?So what can we do?
    58. 58. Cognitive RemediationCognitive Remediation  Luria-the brain is not a static organ andLuria-the brain is not a static organ and functional reorganization of neurofunctional reorganization of neuro pathways can occur after a CNS insultpathways can occur after a CNS insult  NIH consensus statement in 1998NIH consensus statement in 1998 supports use of cognitive rehabilitationsupports use of cognitive rehabilitation  Educational intervention has been shownEducational intervention has been shown to be effective in addressing academicto be effective in addressing academic delays in children treated with cranialdelays in children treated with cranial radiation for ALLradiation 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
    59. 59. EcologicalEcological  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 familyImpact of child’s disease on the family
    60. 60. PharmacotherapyPharmacotherapy  Mulhern et al. (2004) study of 83 ALL andMulhern 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 andCompared to placebo, parents and teachers reported attentional and socialteachers reported attentional and social improvementsimprovements  Ultimate effect on academic achievement?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
    61. 61. ConclusionsConclusions  Clear association between radiationClear association between radiation therapy and cognitive declinetherapy and cognitive decline  Decline appears to be progressiveDecline appears to be progressive  Continued research with larger sampleContinued research with larger sample sizes and validation of predictive modelssizes and validation of predictive models  Important point to address initially andImportant point to address initially and during follow upduring follow up
    62. 62. Thanks!Thanks!
    63. 63. Additional SlidesAdditional Slides
    64. 64. Palmer et alPalmer et al
    65. 65. Palmer et alPalmer et al
    66. 66. 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.
    67. 67.  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
    68. 68. Script your long term sideScript your long term side effect discussion for…effect discussion for…  7 year old boy, newly diagnosed7 year old boy, newly diagnosed medulloblastomamedulloblastoma
    69. 69. Script your long term sideScript your long term side effect discussion for…effect discussion for…  7 year old boy, newly diagnosed7 year old boy, newly diagnosed medulloblastomamedulloblastoma  65 year old woman, newly diagnosed65 year old woman, newly diagnosed CNS lymphomaCNS lymphoma
    70. 70. PharmacotherapyPharmacotherapy  Meyers et al.- 30 patients with malignantMeyers et al.- 30 patients with malignant gliomas exhibiting neurobehavioral slowinggliomas exhibiting neurobehavioral slowing  All patients met the DSM IV criteria forAll patients met the DSM IV criteria for personality change secondary to medicalpersonality change secondary to medical conditioncondition  5 mg of MPH BID and titrated up by 10mg every5 mg of MPH BID and titrated up by 10mg every 2 weeks2 weeks  Dramatic improvement in psychomotor speed,Dramatic improvement in psychomotor speed, memory , executive functioning, mood andmemory , executive functioning, mood and ADLs were seen even in with progressiveADLs were seen even in with progressive disease.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.