melphalan and Growth-Disorders

Previously, we reported that 26 children with stage III or IV neuroblastoma (NBL) treated with BMT grew poorly post-BMT and significantly worse than a comparison group of hematologic BMT patients. Furthermore, unlike the hematologic patients, there was no apparent catch-up growth. Six of these previously reported long-term (> 2 years) NBL patients surviving BMT were evaluated with growth hormone (GH) provocative testing, frequent (every 20 min) overnight GH sampling and IGF-1 determinations. Three of 6 patients were GH deficient based on subnormal responses to provocative stimuli and subnormal pooled 12 h GH values. Only one child had completely normal GH testing and his growth was normal. Four patients were tested with recombinant GH for a period of 12-21 months. Three patients demonstrated an improvement in their growth velocity on therapy. However, the overall response to GH treatment was significantly less than the growth response in children who are GH-deficient due to causes other than BMT. In summary, GH deficiency may be a frequent complication of BMT treatment of NBL. It also appears that the BMT treatment protocol employing total body irradiation and high-dose melphalan may induce GH resistance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Cranial Irradiation; Drug Resistance; Female; Growth Disorders; Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Melphalan; Neuroblastoma; Radiation Injuries; Recombinant Proteins; Survivors; Whole-Body Irradiation

This study analyses the growth and the growth hormone secretion of children given various conditioning protocols before bone marrow transplantation (BMT). Twenty nine children (14 boys, 15 girls) given BMT were classified according to their conditioning protocol: total body irradiation (TBI) given as a single exposure of 10 Grays (Gy, group I, 11 cases), or 8 Gy (group II, four cases), 12 Gy given as six fractionated doses (Group III, seven cases), or chemotherapy alone (group IV, seven cases). The arginine-insulin stimulated growth hormone peak, 2-7.5 years after BMT, was > 10 micrograms/l in all patients except four from group I (6.9-8.9 micrograms/l). A second growth hormone secretion evaluation was performed in 10 group I patients because of persistent low growth velocity despite a normal growth hormone peak. There were no significant changes in the mean (SEM) stimulated growth hormone peak (18.4 (2.2) v 20.1 (3.6) micrograms/l) at 3 (0.3) to 5.2 (0.6) years after BMT. The sleep growth hormone peaks and concentrations (n = 6) were normal. The mean cumulative height changes (SD) during the three years after BMT were: -1.4 (0.2) in group I, -0.1 (0.4) in group II, -0.4 (0.2) in group III, and 1.5 (0.5) in group IV; this was significant in groups I and IV. The final heights of two monozygotic twins (BMT donor and recipient) had differed by 17.5 cm, despite them both having normal growth hormone peaks and puberty. Eight patients, treated for congenital immune deficiency syndrome, were growth retarded at the time of BMT. Of these, only those conditioned by chemotherapy alone had significant catch up growth (2(0.6)SD) while those conditioned by a single Gy exposure did not (0(0.4)SD). It is concluded that the total radiation dose is critical for growth evolution, as is the fractionation schedule. For the TBI doses and the interval since BMT studied, there was no correlation between growth hormone peak and the height loss. The rapidity of decreased growth velocity after TBI and the comparison between the monozygotic twins suggest that radiation induced skeletal lesions are partly responsible for the decreased growth.

Topics: Bone Marrow Transplantation; Child; Child, Preschool; Clinical Protocols; Cyclophosphamide; Etoposide; Female; Growth; Growth Disorders; Growth Hormone; Humans; Infant; Insulin-Like Growth Factor I; Leukemia; Male; Melphalan; Radiotherapy Dosage; Whole-Body Irradiation