Cranial radiotherapy of childhood brain tumours: Growth hormone deficiencyand its relation to the biological effective dose of irradiation in a large population based study

OBJECTIVE The study was to determine the incidence of GH deficiency (GHD) f ollowing cranial radiotherapy (RT) for a childhood brain tumour in a large population based study and analyse the biological effective dose (BED) to t he hypothalamus/pituitary (HP) region as a risk factor. DESIGN BED was assessed by use of the linear-quadratic (LQ) model, which gi ves a means of expressing the biological effect of various treatment schedu les in a uniform way. In patients aged greater than or equal to 18 years (n = 53) GH status was assessed by an insulin-tolerance test (ITT) (n = 34), however, in patients with seizure disorders (n = 19), and in 20 children ag ed <18 years GH status was assessed by an arginine test. Cut-off levels for GHD, indicating GH substitution, were defined by a peak GH response of < 9 mU/l and <15 mU/l for patients greater than or equal to 18 and <18 years, respectively. PATIENTS Ninety-one children aged <15 years eligible for the study, diagnos ed between 1970 and 1997 in the Eastern part of Denmark, the Faroe Islands and Greenland, with a primary brain tumour not directly involving the HP ax is. 84% (n = 76) agreed to participate. Three patients were excluded due to hypothyroidism detected at time of testing. MEASUREMENTS Serum GH and levels of serum insulin-like growth factor-I (s-I GF-I) and serum insulinlike growth factor binding protein-3 (s-IGFBP-3) wer e measured. BED was assessed to the HP region. RESULTS The median age at the time of RT was 8.7 years (range: 0.8-14.9 yea rs) and the median time of follow-up was 15 years (range: 2-28 years). Fift y-eight patients (80%) had GHD and they had received a median BED of 77.5 G y to the HP region, whereas the median BED was 54.5 Gy for 15 patients with out GHD (P = 0.002). Peak GH and BED were correlated (r(s) = -0.53, P <0.00 1). Median IGF-I SDS and IGFBP-3 SDS were -2.5 (-5.2-0.7 SDS) and -1.7 (-5. 8-0.9 SDS), respectively, and IGF-I SDS was correlated to peak GH (r(s) = 0 .45, P < 0.001). Peak GH and length of follow-up were related (r(s) = -0.28 , P=0.018). Stepwise backward multiple linear regression analysis showed th at the best-fit model to predict the peak GH release following ITT/arginine stimulation included BED (P < 0.0001) and length of follow-up (P = 0.05). CONCLUSIONS The data of this study suggest that the majority of long-term s urvivors of brain tumours develop GH deficiency following radiotherapy in c hildhood and that the adverse effects of radiotherapy may be directly relat ed to the biologically effective dose. With longer follow-up fewer patients might respond normally to GH stimulation tests.