D Pearson

THE EFFECT OF VARYING DOSES OF CEREBRAL IRRADIATION ON GROWTH HORMONE PRODUCTION IN CHILDHOOD

The radiation dose, delivered to the hypothalamic‐pituitary region, has been calculated in thirty‐nine children irradiated for brain tumours and in seventeen children who had received prophylactic cranial irradiation for acute leukaemia. All subjects had an insulin tolerance test at least 2 years after their radiotherapy. There is a significant inverse correlation between radiation dose and peak GH response. Thirty‐seven of the fifty‐six patients showed an impaired GH response and thirty‐six of these received more than 2900 rads. Only five patients who received such a dose showed normal GH responses and four of these were aged over 13 years when treated.

Effect of spinal irradiation on growth.

Standing height, sitting height, and leg length were measured in 79 patients (aged 16-30 years), who had been given craniospinal irradiation (n = 37) or cranial irradiation (n = 42) in childhood for a brain tumour and had completed their growth. Their measurements were compared with established standards for sitting height and leg length in British children (aged 16-18 years). To examine the effects of spinal irradiation on spinal growth independent of growth hormone deficiency we analysed the leg length (LL) minus sitting height (SH) standard deviation score (SDS) and used the cranial group as controls. There was an overall significant difference between the median craniospinal LL-SH SDS (1.98) and the median cranial LL-SH SDS (0.545). Within the craniospinal group there was a significant correlation with age at treatment, but there was no such correlation for the cranial group. After splitting age at treatment into three groups (0 less than 5, 5 less than 10, and 10-15 years) there was a significant difference between the LL-SH SDS of the craniospinal and cranial groups for each of the age ranges. In conclusion, spinal irradiation has a profound effect on spinal growth and the younger the child is when given irradiation the greater the subsequent skeletal disproportion. Our most conservative figures indicate that the eventual loss in height is 9 cm when irradiation is given at 1 year, 7 cm when given at 5 years, and 5.5 cm when given at 10 years.

Normal growth despite abnormalities of growthhormone secretion in children treated for acute leukemia

We have studied the relationship between abnormalities of the growth hormone-somatomedin axis and growth in 26 children previously treated for acute lymphatic leukemia. Each child had previously received cranial irradiation, was in complete clinical and hematologic remission, and off all drugs. The mean standing height SDS of the 26 children was significantly less than normal. There was no significant difference between the mean standing height SDS, height velocity SDS, somatomedin activities, and degree of bone age retardation between the 17 children who received the higher dose of cranial irradiation (Group 1) and the nine who had the lower dose of cranial irradiation (Group II). Furthermore, there was no significant reduction in mean height velocity SDS, somatomedin activity, or bone age in either group when compared to normal age-matched controls. The peak GH responses to both insulin hypoglycemia and an arginine test were significantly lowered in Groups I and II when compared to a control group of children. We conclude that only a minority of children, who previously received cranial irradiation for ALL were clinically GH deficient and, therefore, likely to benefit from GH therapy despite the finding that the majority of these children had reduced GH responses to pharmacologic stimuli.

Usefulness of epoprostenol therapy in the severely ill adolescent/adult with Eisenmenger physiology

We showed that in selected severely impaired and symptomatic patients with Eisenmenger physiology, IV-PGI 2 therapy can significantly improve functional capacity, oxygen saturation, and cardiopulmonary hemodynamics. The long-term effects of this agent on morbidity and survival for this population, as well as its complications, remain unknown. A larger controlled prospective multicentered trial should be performed for patients with Eisenmenger physiology who fail conventional therapy and are at the highest risk for significant morbidity and early mortality.

Residual disabilities in children treated for intracranial space‐occupying lesions

A retrospective study of 30 long‐term survivors of cranial or craniospinal irradiation for intracranial space‐occupying lesions has demonstrated physical and mental handicaps in the majority. This is most severe in those cases treated before the age of 11 years, and is not confined to those children having craniospinal or whole‐brain irradiation. The mental handicap also appears to be progressive, but cannot be easily examined in this retrospective study.

Improvements in survival from childhood cancer: results of a population based survey over 30 years

Survival from cancer of children whose cancer was diagnosed during the 30 years 1954-83 was analysed. The study was population based with nearly 3000 cases covering about 30 million child years at risk. When survival during the three decades 1954-63, 1964-73, and 1974-83 was compared striking improvements were observed. For all childhood cancer five year survival increased from 21% in the first decade to 49% in the third decade. During the first and third decades five year survival rates for acute lymphocytic leukaemia increased from 2% to 47%, Hodgkins disease from 44% to 91%, non-Hodgkins lymphoma from 18% to 45%, Wilmss tumour from 31% to 85%, and germ cell tumours from 10% to 64%. Twenty patients developed second primary tumours, but otherwise there were few late deaths. Less than 1% of children who survived without a relapse for 10 years subsequently died of their initial cancer. Survival from childhood cancer is no longer rare, and people who have been cured of cancer during childhood should be accepted as normal members of society.

Ovarian failure following abdominal irradiation in childhood.

Ovarian function was studied in 18 female patients treated for abdominal tumours during childhood. All received abdominal radiotherapy as part of their treatment and were studied between 1 and 26 years after irradiation. The serum gonadotrophins and oestradiol levels were consistent with ovarian failure in each case but there was a disproportionate elevation in serum follicle stimulating hormone (FSH) when compared to serum luteinizing hormone (LH) in 16. In 2 patients, the radiotherapeutic field extended downwards only as far as the sacral promontory. However, these 2 girls show similar evidence of ovarian failure to that in the other 16.

Growth hormone deficiency after treatment of acute leukaemia in children.

Growth hormone (GH) secretion was studied in 15 children at various times after treatment for acute lymphatic leukaemia. Impaired GH responses both to hypoglycaemia and to Bovril were found in 4 children. 13 of the children had been given prophylactic cranial irradiation of either 2500 rads in 10 fractions or 2400 rads in 20 fractions. The reduction in GH responses in those given the former dose was highly significant compared with the reduction in those given the latter dose. However, other differences between the two groups included the length of time since cranial irradiation and the chemotherapy used. The main cause of the GH deficiency is not yet clear, but we conclude that it may occur in children treated successfully for acute lymphatic leukaemia.

Endocrine function following the treatment of acute leukemia in childhood.

Pituitary function has been studied in 25 children after treatment of acute leukemia. Impaired growth hormone responses both to hypoglycemia and to Bovril were found in 11 subjects. Elevated basal thyroid-stimulating hormone levels were seen in five children, three of whom had an augmented TSH response to thyrotrophin-releasing hormone. Radiation-induced damage to the hypothalamic-pituitary region is thought to be the cause of these abnormalities in growth hormone and in secretion of TSH. The peak cortisol response to hypoglycaemia is significantly decreased in the group of subjects who received the higher dose of cranial radiation therapy, but no individual child is hypothyroid or shows impaired adrenal function, clinically or biochemically. Three prepubertal girls studied have biochemical evidence of ovarian failure following the use of combination chemotherapy.

Thyroid dysfunction following external irradiation to the neck for Hodgkin's disease in childhood.

Thyroid function was studied in 32 patients who had received neck irradiation during childhood for Hodgkins disease. All except one patient received a dose of 2500-3000 rad over a period of 19-25 days. In 12 patients lymphangiography was performed. Clinically all patients were considered euthyroid. One had a thyroid swelling which was cystic in nature. Five (16%) patients were biochemically hypothyroid, 17 (53%) were euthyroid with an elevated basal serum TSH concentration and a further seven (22%) were euthyroid with a normal basal serum TSH level but an augmented thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH). Only three (9%) patients had completely normal thyroid function tests. The basal serum TSH concentration and the peak serum TSH response to TRH were significantly greater in the patients who received neck irradiation and lymphangiography than in those who received neck irradiation alone. In addition the free thyroxine index decreased significantly as the time interval between treatment and study increased in the lymphangiography group. These data demonstrate that the normal thyroid gland is vulnerable to the damaging effects of external irradiation, and that the combination of neck irradiation and lymphangiography is more likely to result in thyroid dysfunction than is neck irradiation alone. Furthermore, in view of the deterioration in thyroid function with time, periodic clinical and biochemical assessment of thyroid function is clearly indicated.