1. Risk of Obesity in ALL survivors Dr. Abdulmajeed AlSubaihin, MBBS, FRCPC

2. Introduction The survival rate of ALL patients significantly improved with the evolution of Chemotherapy and Radiotherapy. The expansion of ALL survivors population is associated with increased long term morbidity. Long term follow up is imperative to determine and treat any associated long term morbidities.

4. Late complications of ALL Secondary Neoplasm Impaired cognition function Stroke Short stature Obesity Impaired glucose metabolism Hypo/Hyper thyroidism Growth hormone deficiency Cardiotoxicity Infertility

5. Objectives Review early studies that looked at obesity in ALL survivor population Association between Obesity and CRT Other risk factors for Obesity in ALL survivors Growth hormone, Leptin and Obesity

7. 414 children and adolescents aged <6 years to 20 years of age. (70 % <6yrs) Retrospective review of data from 1966-1984 at St Jude children’s hospital. Measured (body fatness) which is weight divided by height squared. Used Vegisiles (= 5 percentiles) to measure distribution.

9. 5 years following cessation of therapy: 31-35% were overweight (>85 th percentile) 8% were Obese (>95 th %ile) NHANES i (1970s) Prevalence of obesity was 5%

11. Reviewed data retrospectively in 86 children from Edinburgh, Glasgow and Cardiff. Less than 10 years at diagnosis All were in remission, non had relapse. All children were followed up for 4 years at least. 35% had follow up for 8 years.

18. 142 Children from three regional pediatric oncology centers in the UK. All children have received chemotherapy and prophylactic Cranial irradiation (18-24 Gy). All were in first remission. Included those who attained final height.

26. Methods Retrospective Cohort of 126 patients diagnosed between 1969 and 1982 Mean age of Dx 6.4, Mean age of height attainment 18.3 Factors assessed in the study: 1. Chemotherapy: (standard) (moderate) (intensive) 2. Cranial radiation: (none) (18 Gy) (24 Gy) 3. Prednisone cumulative dose: ( 9.4) 4. Age at diagnosis: (0-4) (5-11) 5. Gender Outcome assessed: BMI-SDS (BMI – Mean BMI / BMI SD of reference group) BMI-SDS for an average person is 0

27. Methods Diagnosis Final Height End of treatment

28. Results

31. Discussion/ conclusion Association between Dexamethasone and adiposity is still possible since most of subjects in the study received only prednisone. Weight gain is unlikely to be due to Growth hormone deficiency Growth hormone deficiency plays an important role in maintaining the gained weight.

32. All previous studies were limited by small sized samples and lack of controls.

34. Childhood Cancer survival study > 5 year survivors of cancer Cancers include: Leukemia, Hodgkin’s, non-Hodgkin, CNS tumor, Kidney tumor, neuroblastoma, soft tissue sarcoma or bone tumor. Dx between 1970 and 1986 ALL: n=5854 Cases 2,447 participants with ALL survivors were alive and > 18 years of age at time on interview Mean age at Dx 7.5 Mean time interval from diagnosis 17.1 yrs Controls Random sample of siblings of CCSS (all cancers) N= 2,565

35. Methods Outcome measure: BMI. Age of diagnosis was used as effect modifier. Analysis was stratified by sex (significant independent variable on body weight. Influence of each chemotherapeutic agent was analyzed individually and in combination Cumulative doses of CRT were calculated and grouped by 5 Gy intervals from 0 to 50 Gy

39. Results: No association between the following and overweight/obesity: Chemotherapy (individually or Combined) and overweight. Chemotherapy and CRT < 20 Gy. Dose response was not observed with increments of CRT so all categories of > 20 Gy were collapsed into 1 group

40. Results

43. Age sensitive hypothalamic insult secondary to radiotherapy (growing hypothalamus being more sensitive) Decreased Growth hormone secretion Decreased sensitivity to Leptin

47. Methods Cross-sectional study included >1800 participants from the CCSS. Completed the questionnaire in 2003. Aim was to assess risk factors associated with obesity (BMI >= 30)

51. Methods Cohort of ALL survivors in west Sweden, 1973-1985 ALL patients finished treatment before puberty, followed for 15 years and with minimum age of 20 years at time of the study Spontaneous GH secretion was studied 35 patients agreed to participate All patients were Euthyroid (normal TSH and FT4)

52. Methods (cont) Patients were treated with 3 different protocols All received similar chemotherapy protocols Majority received total of 24 Gy of CRT. None was treated with Growth hormone. 72 samples were taken over 24 hours (20 minutes apart) for GH, IGF-I concentration, final height and Midparental Height SDS, Waist and hip measures

53. Results

54. Results (cont)

55. Results

56. Tendency of towards greater difference in GH max secretions in Men with CRT+ was not statistically significant No significant difference of IGF-1 concentrations between the two groups.

57. Results (height)

58. GH secretion was impaired in 69% of CRT + patients GHD in 49% of CRT + patients Patients in CRT+ group had a median loss of 0.8 SD of final height in comparison with Mid-parental height, this loss was not severe enough to suspect GHD As there was no obese patients and there was no significant difference in BMI between the 2 groups normal BMI does not exclude GH secretion impairment or deficiency.

60. Methods Case-control study with a purpose of assessing: Increased adiposity Changes in leptin Changes in insulin-insulin sensitivity Then to assess the effect of GH supplement in reversing any metabolic differences.

61. Methods Cases 11 females and 1 male. Median age 29. All were treated for ALL(1972- 1985) All received CRT (18-24 Gy) Median age of Dx: 5yrs Randomly selected controls were matched by sex, age and BMI GH supplement for 12 months 1-Hormones: IGF-1,GH Peak, T4/T3, Cortisol, Prolactin,Testosterone 2- Anthropometrical Data: Height, weight, BMI, FFM, FM 3- Insulin resistance and Leptin

62. Methods Insulin resistance was assessed by Euglycemic- hyperinsulinemic clamp technique Growth hormone deficiency was assessed by 2 tests 1- Insulin tolerance test 2- GHRH+ Arginine test

63. Results

66. Raised baseline insulin levels and normoglycemia in patients is suggestive of increased insulin resistance. Tendency to insulin resistance in patient group did not reach statistical significance (? Small sample size) GH peak response was lower in ITT test than GHRH+ Arginine test, this observation is suggestive of hypothalamic rather than pituitary pathology. Insulin Resistance is most likely due to increased fat mass.

67. Growth hormone supplement led to an improvement in FM% and FFM. No change in insulin resistance or Leptin levels after GH supplement.

68. Take Home Messages Increased Adiposity is well established in patient with ALL who received CRT of more than 18 Gy. Impaired growth hormone secretions seem to paly an important role in increased adiposity and maintaining the gained weight. Leptin resistance indicates possible impairment in satiety. Eating behaviors should be examined in ALL survivors. Growth hormone supplement was shown to to improve adiposity with no effect on insulin resistance and Leptin levels.

69. Further studies are needed to assess the benefit of growth hormone supplements in preventing other outcomes associated with adiposity (type 2 DM, HTN, Coronary artery disease) ALL patients need to be followed up closely for longer periods to assess for other metabolic and cardiovascular complications.

70. Thank you Merci شكرا