Post on 18-Feb-2020
Séquelles Endocriniennes
en Oncologie Pédiatrique
-Pathologies Neurohypophysaires- Jacques Grill
Programme Tumeurs Cérébrales
Département de Cancérologie de l’Enfant et de l’Adolescent
Institut Gustave Roussy, Villejuif
Craniopharyngiome
Cassure de la courbe de croissance
Parfois précédée d’une prise de poids
Signant l’atteinte de l’hypothalamus
Déficit visuel (héminopsie bitemporale)
Craniopharyngioma. Garnett et al, Orphanet J Rare Dis 2007.
Dodge III
Gliome des voies optiques
192 patients suivis à l’IGR • Cachexie diencéphalique: 20%
• Puberté précoce: 26%
– Surtout les enfants de moins de 5 ans au diagnostic (32% vs 21%, p=0.008)
• Mais surtout baisse de la vision.
• Séquelles:
– Obésité 34% (non lié à la chirurgie ou au Russel).
– Diabète insipide (8%) plus fréquent après chirurgie.
– Déficit en GH (56%) plus fréquent si irradiation.
– Déficits en TSH (36%), ACTH (22%), LH/FSH (24%).
Germinome/Diabète insipide
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 1. Cumulative incidence of chronic health conditions (grade 1 to 5 and grade 3 to 5)
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 2. Cumulative incidence of chronic health conditions by exposure (grade 3 to 5 only)
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 10. The proportion of women who achieve menarche over time, adjusted for ethnicity, birth year, and abdominal radiotherapy
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 6. Final height standard deviation score (SDS) according to original diagnosis and exposure to direct spinal radiation therapy (RT)
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 8. Percent of male and female survivors by primary diagnosis and body mass index category
Leucémies et obésité
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 9. Scatterplot for unadjusted body mass index (BMI) by age at diagnosis of acute lymphoblastic leukemia for females treated with >= 20 Gy cranial radiotherapy
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 5. Height standard deviation scores (SDS) across exposure groups by pubertal status at acute lymphoblastic leukemia diagnosis
Copyright © American Society of Clinical Oncology
Razzouk, B. I. et al. J Clin Oncol; 25:1183-1189 2007
Fig 1. Comparison of average rates of change in body mass index (BMI) among the high-dose intravenous/intrathecal methotrexate (IVIT), 18 Gy cranial radiation therapy (RT) and 24 Gy cranial RT
subgroup using a random coefficients model
LEPR polymorphism may influence obesity in female survivors of
childhood ALL, particularly those exposed to cranial radiation.
Maladie de Hodgkin et thyroïde
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 3. Probability of developing an underactive thyroid after diagnosis of Hodgkin's lymphoma
Copyright © American Society of Clinical Oncology
Metzger, M. L. et al. J Clin Oncol; 24:1516-1521 2006
Fig 1. Cumulative incidence of hypothyroidism for black and white patients after Hodgkin's lymphoma
Tumeurs cérébrales
et déficit hypohysaire
Morbidité endocrinienne
CCSS BT vs siblings
• Hypothyroïdie: RR=14
• Déficit en GH: RR=278
• Nécessité d’induire la puberté: RR=86
• Ostéopénie: RR=25
• Parfois présent avant l’irradiation lorsqu’on
fait des dosages dynamiques (TSH, GH).
Copyright © American Society of Clinical Oncology
Diller, L. et al. J Clin Oncol; 27:2339-2355 2009
Fig 4. Age- and sex-specific percentiles for height and body mass index (BMI) among brain cancer survivors by age at diagnosis (upper panel) and treatment types (lower panel)
Obésité
• Le BMI n’est pas lié aux doses de RT mais plutôt à la souffrance de l’hypothalamus, comme dans les craniopharyngiomes.
• Le BMI est inversement corrélé à l’âge à la puberté.
• Le BMI est plus élévé chez les filles jeunes au diagnostic.
• Risque accru d’AVC (RR=43) et de thromboses (RR=6) et d’angor (RR=2).
Post-Hypophyse
Diabète insipide /
Sodium wasting syndrome /
Soif
Anté-hypophyse
Copyright © American Society of Clinical Oncology
Laughton, S. J. et al. J Clin Oncol; 26:1112-1118 2008
Fig 2. Cumulative incidence of specific endocrine deficits following radiation therapy
medulloblastoma
Copyright © American Society of Clinical Oncology
Laughton, S. J. et al. J Clin Oncol; 26:1112-1118 2008
Fig 3. Cumulative incidence of (A) growth hormone deficiency, (B) thyroid-stimulating hormone (TSH) deficiency, and (C) adrenocorticotropic hormone (ACTH) deficiency by hypothalamic radiation dose
divided around the median (42 Gy)
medulloblastoma
Copyright © American Society of Clinical Oncology
Laughton, S. J. et al. J Clin Oncol; 26:1112-1118 2008
Fig 4. The decline of height z scores by risk group
medulloblastoma
Neuro-oncology LTFU clinic
vs general LTFU clinic vs general ped.onc.care
• More neuropsyc. testing
• Longer surveillance imaging
• More GH use in medulloblastoma survivors
• More GH use through adulthood
• Effect on cognition
– Bowers et al, Ped Blood Cancer 2009 Dec.
– Quik et al, Growth Horm IGF Res 2012 Jan.
GH in adult cancer survivors (pediatric
ALL) lowers cardiovascular risks
• All treated with CSI (Lund University, SWE).
• 16 received GH, 13 not.
• Five years of therapy led to significant improvements (compared to 8
years without therapy) in plasma glucose (-0.5 vs 0.6 mmol/L, p =
0.02), high-density lipoprotein cholesterol (0.20 vs -0.01 mmol/L, p =
0.008), and apolipoprotein B/A1 ratio (-0.1 vs 0.0, p = 0.03). In
addition, the prevalence of metabolic syndrome fell significantly (p =
0.008) in those treated with growth hormone.
• No difference in QOL or physical activity or cardiovascular functions.
• Erfurth M, J Endocrin. Metab. 2010
Darzy KH, Shalet SM. Endocr Dev 2009.
Hypopituitarism following radiotherapy revisited.
• Dose relationship:
– If < 30Gy, GH deficiency only in 30%.
– If > 30 Gy, GH deficiency in 50-100%, Gonadotropin deficiency in 20-30%, TSH and ACTH deficiencies in 5-10%.
– The higher the dose, the sooner the deficit(s).
– Precocious puberty with doses as low as 30 Gy, especially in girls.
– Hyperprolactinemia if surgical hypothalamic damage plus high-dose irradiation in young women.
Ostéopénie
• Connue dans les TC depuis 1990.
• Plus fréquente après une TC (67% vs 27%).
• Impact de l’irradiation spinale.
• Plus de douleurs et de fractures et une moins bonne qualité de vie en cas d’ostéopénie.
• Efficacité de la supplémentation vitamino-calcique.
Osteopenia
• Bilariki et al, Horm Res Paediatr 2010
• 51 patients (metabolic/radiologic)
• No significant changes of Z scores
• Survivors of childhood solid cancer have
high rates of insufficient calcium intake
(75%), vitamin D deficiency (62%), low
bone mass (32% spine/21%femur) and
fractures (20%, not correlated with BMD).
Ostéoporose chez l’adulte
survivant d’une TGM
• 28 survivants.
• Ostéodensitométrie.
• 25 % d’ostéoporose, 43 % d’ostéomalacie.
• Plus fréquent chez les hommes (92%).
• Plus fréquent chez ceux dont la GH est
introduite tard à l’âge adulte.
• Kang et al, Osteoporos Int 2011, Nov.
Fertilité - Gonades
Les alkylants et la radiothérapie
Les ovaires
Copyright © American Society of Clinical Oncology
Green, D. M. et al. J Clin Oncol; 27:2374-2381 2009
Fig 1. Percentage of subjects with acute ovarian failure (AOF) by age at diagnosis of cancer of 0 to 12 years, 13 to 20 years, and radiation dose to the ovary
Copyright © American Society of Clinical Oncology
Green, D. M. et al. J Clin Oncol; 27:2374-2381 2009
Fig 2. Cumulative incidence curves of nonsurgical premature menopause in survivors compared with siblings
Copyright © American Society of Clinical Oncology
Green, D. M. et al. J Clin Oncol; 27:2374-2381 2009
Fig 3. Cumulative incidence curves of nonsurgical premature menopause in survivors according to treatment exposures
Copyright © American Society of Clinical Oncology
Green, D. M. et al. J Clin Oncol; 27:2374-2381 2009
Fig 4. Distribution of birthweight of the offspring of female cancer survivors by abdominal-pelvic radiation (A-P RT)
Copyright ©2003 The Endocrine Society
Larsen, E. C. et al. J Clin Endocrinol Metab 2003;88:5307-5314
Ovarian volume in survivors with spontaneous menstrual cycles 1) No AA/No RT; 2) Pelvic RT and/or AA; 3) TBI + AA
Copyright ©2003 The Endocrine Society
Larsen, E. C. et al. J Clin Endocrinol Metab 2003;88:5307-5314
Total number of antral follicles per ovary 1) No AA/No RT; 2) Pelvic RT and/or AA; 3) TBI + AA
Ovarian Failure & CRT
• 3619 patients from the CCSS
• No increased infertility in CCS.
• Dose threshold of CRT 22-27 Gy
• Green et al, Fertil Steril 2011, May.
Les testicules
Dépistage de l’infertilité
• FSH > 9 UI/l
• LH > 5 UI/l
• LH >Inhibin B et AMH utile chez les
patients irradiés sur l’hypophyse dont les
taux de gonadotrophines ne peuvent
s’élever.
• Cuny et al, J Pediatr 2011, Jun.
Greenfield et al, Cancer March 2010:
QOL, self-esteem, fatigue, and sexual function in young men
after cancer: a controlled cross-sectional study.
• Marked impairment in QOL, energy levels and
quality of sexual functioning.
• Exacerbation by androgen deficiency.
• No increased psychological distress.
• Normal self-esteem.
• Sexual relationship not impaired.
• Adults but adolescents…
Copyright ©2007 The Endocrine Society
Greenfield, D. M. et al. J Clin Endocrinol Metab 2007;92:3476-3482
FIG. 1. Box and whisker plot of tT (nmol/liter) in survivors and controls on the y-axis by half-decades of age on the x-axis
Copyright ©2007 The Endocrine Society
Greenfield, D. M. et al. J Clin Endocrinol Metab 2007;92:3476-3482
FIG. 2. The relationship between TFM (kg) and tT (nmol/liter) in controls and survivors
TFM=truncal fat mass linked with hyperinsulinism
Copyright © American Society of Clinical Oncology
Green, D. M. et al. J Clin Oncol; 28:332-339 2010
Fig 2. Relationship between summed alkylating agent dose score and the relative risk for siring a pregnancy
Male
Suivi au long cours après un cancer
Une grande place
pour les endocrinologues