Risk of Obesity in ALL survivors

Dr. Abdulmajeed AlSubaihin, MBBS, FRCPC

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.

Late complications of ALL

• Secondary Neoplasm• Impaired cognition function• Stroke• Short stature• Obesity• Impaired glucose metabolism• Hypo/Hyper thyroidism• Growth hormone deficiency • Cardiotoxicity• Infertility

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

• 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.

5 years following cessation of therapy:

31-35% were overweight (>85th percentile)

8% were Obese (>95th %ile)

NHANES i (1970s) Prevalence of obesity was 5%

• 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.

• 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.

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: (<3.5) (3.5 to 9.4) (>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

Methods

Diagnosis

Final Height

End of treatment

Results

Results

Results

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.

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

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

Cases2,447 participants with ALL survivors were alive and > 18 years of age at time on

interviewMean age at Dx 7.5

Mean time interval from diagnosis 17.1 yrs

ControlsRandom sample of

siblings of CCSS (all cancers)N= 2,565

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

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

Results

Age sensitive hypothalamic insult secondary to radiotherapy

(growing hypothalamus being more sensitive)

Decreased Growth hormone secretion

Decreased sensitivity to Leptin

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)

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)

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

Results

Results (cont)

Results

Results• 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.

Results (height)

• 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.

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.

MethodsCases

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, FM3- Insulin resistance

and Leptin

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

Results

Results

Results

• 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.

• Growth hormone supplement led to an improvement in FM% and FFM.

• No change in insulin resistance or Leptin levels after GH supplement.

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.

• 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.

Thank you

Merci

شكرا