Limitations in Studies

2. Neurocognitive Outcomes of Radiation Therapy in Children Aaron S. Kusano, SM University of Washington School of Medicine

3. Outline Topic Choice Background/Current Practices Studies of Neurocognitive Effects Predictive Model Research Interventions Conclusion

4. 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

5. 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

6. 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

7. 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 Oligodendrocytes: Myelinating cells of the CNS, other diseases that damage oligodendrocytes include MS, Leukodystrophies, CP White matter: multifocal hyperintensities, gray matter calcifications. Oligodendrocytes: Myelinating cells of the CNS, other diseases that damage oligodendrocytes include MS, Leukodystrophies, CP White matter: multifocal hyperintensities, gray matter calcifications.

8. Medulloblastoma

9. 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%

10. Medulloblastoma Risk Categories Average Risk (2/3) Age>3 years Resection with < 1.5cm2 residual No metastasis High Risk (1/3) Age<3years Resection > 1.5cm2 residual Metastasis Current surgical techniques achieve complete or near total resection in approximately 80% of casesCurrent surgical techniques achieve complete or near total resection in approximately 80% of cases

11. Current Practices

12. Categories Standard Risk High Risk Infants

13. Standard Risk 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) 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. 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.

14. High Risk 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%

15. Infants (<3yo) 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

16. Cognitive Measurement

17. Wide Range Achievement Test (WRAT) Ability to Read words Comprehend sentences Spell Math calculations

18. 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) 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.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.

19. 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

20. 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 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 GyPOG 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

21. Mulhern et al (1998) 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

22. Groupings Young (Y): Age < 9 years Old (O): Age > 9 years Standard dose radiation (SRT): 36 Gy Reduced Dose (RRT): 23.4 Gy Predicted trend of scores: Y/SRT < Y/RRT < O/SRT < O/RRT

23. 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

24. Mulhern et al (1998)

25. Mulhern et al (1998)

26. Mulhern et al (1998)

27. Mulhern et al (1998)

28. Mulhern et al (1998)

29. 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

30. Limitations Small numbers, low power, dichtomization of continuous variables No longitudinal analysis

31. Studies of Neurocognitive Decline

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

33. 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

34. 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 >40Gy All received posterior fossa boost 49.2-55.8

35. 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)

36. Palmer et. al (2001)

37. Palmer et. al (2001)

38. Palmer et. al (2001) 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.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.

39. Palmer et. al (2001)

40. Palmer et. al (2001)

41. 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 ( <8.02 vs >8.02) was an effect modifier CSI dose (<35.2 vs >36.0) were significantly different in their effects on IQ

42. As technology changes, can we develop better predictive models for cognitive decline?

43. 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

44. 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

45. Goal: Model the effects of the entire distribution of dose to specific volumes of brain on longitudinal IQ after radiation therapy Merchant et al. (2006)

46. Patients 39 patients, newly diagnosed embryonal tumors 14 average risk (<1.5cm2 residual, M0) 25 high risk

47. 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.

48. Testing Neurocognitive testing performed at Post surgery 1 year 2 years 5 years

49. 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

50. 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 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. 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.

51. 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)

52. Example: Total Brain

53. Total Brain Volume

54. Left Temporal Lobe

55. Mean Dose Comment on Meaning of terms. They also Comment on Meaning of terms. They also

56. Supratentorial model application

57. Conclusions of Merchant et al. Prediction of outcomes on basis of CSI dose alone will lose relevance over time They�re 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

58. So what can we do?

59. 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

60. Ecological Importance of educating patients, caretakers, PCPs and teachers Classroom accommodations Impact of child�s disease on the family 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.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.

61. 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? 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. 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.

62. 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

63. Thanks!

64. Additional Slides

65. Palmer et al

66. Palmer et al

67. Ris et al. (2001) Intellectual Outcome After Reduced-Dose Radiation Therapy Plus Adjuvant Chemotherapy for Medulloblastoma: A Children�s Cancer Group Study

68. 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

69. Script your long term side effect discussion for� 7 year old boy, newly diagnosed medulloblastoma

70. Script your long term side effect discussion for� 7 year old boy, newly diagnosed medulloblastoma 65 year old woman, newly diagnosed CNS lymphoma

71. 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. 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,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,