Sexually dimorphic and radiation dose dependent effect of cranial irradiation on body mass index.

OBJECTIVES: To investigate the relation between cranial irradiation received during treatment for childhood leukaemia and obesity at final height. DESIGN: Retrospective cross sectional study. SETTING: Paediatric oncology centres at Great Ormond Street Hospital for Children and the Royal Marsden Hospital. SUBJECTS: Survivors of childhood leukaemia who received cranial irradiation, were in continuous first remission, and had reached final height. An unirradiated group of patients from the United Kingdom acute lymphoblastic leukaemia XI trial was also included; these patients were in continuous first remission and had been followed for at least four years from diagnosis. MAIN OUTCOME MEASURES: Body mass index standard deviation score (BMI z score) at final height for irradiated patients and at most recent follow up for unirradiated patients. Regression analysis was used to examine the effect on BMI z score of sex, age at diagnosis, and the dose of radiation received. RESULTS: For cranially irradiated patients, an increase in the BMI z score at final height was associated with female sex and lower radiation dose, but not with age at diagnosis. Severe obesity, defined as a BMI z score of > 3 at final height, was only present in girls who received 18-20 Gy irradiation and had a prevalence of 8%. Both male and female unirradiated patients had raised BMI z scores at latest follow up and there was no association with age at diagnosis. CONCLUSIONS: These data are further evidence for a sexually dimorphic and dose dependent effect of radiation on the human brain.

Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT.

Few data are available on the long-term effect of bone marrow transplantation (BMT) on growth. This study examines those factors that play a role in the final height outcome of patients who underwent BMT during childhood. Data on 181 of 230 patients with aplastic anemia, leukemias, and lymphomas who had BMT before puberty (mean age, 9.8 +/- 2.6 years) and who had reached their final height were analyzed. An overall decrease in final height standard deviation score (SDS) value was found compared with the height at BMT (P < 10(7)) and with the genetic height (P < 10(7)). Girls did better than boys, and the younger in age the person was at time of BMT, the greater the loss in height. Previous cranial irradiation + single-dose total body irradiation (TBI) caused the greatest negative effect on final height achievement (P < 10(4)). Fractionation of TBI reduces this effect significantly and conditioning with busulfan and cyclophosphamide seems to eliminate it. The type of transplantation, graft-versus-host disease, growth hormone, or steroid treatment did not influence final height. Irradiation, male gender and young age at BMT were found to be major factors for long-term height loss. Nevertheless, the majority of patients (140/181) have reached adult height within the normal range of the general population.

Total body irradiation-induced osteochondromata.

Nine patients developed osteochondromata, a mean of 6 years after total body irradiation (TBI) given before bone marrow transplantation for childhood leukaemia. This represents 23% of patients receiving TBI during the period from 1981 to 1989 surviving > or =5 years after bone marrow transplantation. The patients were followed up for a mean of 12.5 years from diagnosis of leukaemia and a mean of 2.5 years from diagnosis of osteochondromata. No osteochondroma, including three lesions removed surgically, showed evidence of malignant change. Six patients received growth hormone for irradiation-induced growth hormone deficiency, but this did not appear to influence the natural history of the osteochondromata. Radiation-induced osteochondromata (RIO) are often multiple and are indistinguishable from the more common idiopathic type. The incidence of RIO after TBI was higher than that reported after local irradiation.

Survival and endocrine outcome after testicular relapse in acute lymphoblastic leukaemia.

Survival and endocrine status in a cohort of boys with acute lymphoblastic leukaemia (ALL) who started treatment between 1972 and 1987 and subsequently developed a testicular relapse were analysed. During this period there was a significant improvement in the overall event free survival for boys, but no significant decrease in the testicular relapse rate. Thirty three boys had an apparently isolated testicular relapse, whereas 21 boys had a combined relapse. The event free survival for boys with an isolated testicular relapse was 59% at six years (95% confidence interval (CI) 42 to 74%). The event free survival for the 16 patients with a combined relapse who received a second course of treatment was 32% (95% CI 17 to 60%). Those patients receiving adequate second line treatment for an isolated testicular relapse whose first remission was longer than or equal to two years had an event free survival of 82% (95% CI 63 to 93%) at six years. No boy relapsing within two years from diagnosis has survived. Endocrine late effects are significant, with 82% of the boys requiring hormonal treatment at some stage for induction of puberty or continuing pubertal maturation, or both. It is concluded that, despite the increasing intensity of initial treatment for ALL, isolated testicular relapse is treatable by conventional means in most patients. Careful endocrine follow up of these patients is essential as most will require hormone replacement treatment.

Secondary amenorrhoea after total body irradiation in pre-puberty.

Bone marrow transplant (BMT) has been used as part of the overall treatment of refractory malignant diseases. High dose cyclophosphamide and total body irradiation (TBI) are frequently used as conditioning for BMT. Initial regimens included a single fraction of TBI, with doses varying from 7.5-10 Gy, but this was associated with a high incidence of late sequelae including multiple endocrinopathies. A fractionated irradiation course over 3-4 days of a higher total dose, 12-15 Gy, of TBI is now used. Successfully treated patients with childhood cancer have an increased risk, of developing second tumours. We describe a patient successfully treated for AML who developed multiple endocrine dysfunction and a second benign ovarian tumour.

Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex.

Cognitive outcome, as measured by verbal and performance IQs, was compared in 35 girls and 47 boys who were in first remission for acute lymphoblastic leukaemia. All children had received presymptomatic cranial radiotherapy and intrathecal methotrexate. The mean age at diagnosis was 4.2 years and the mean elapsed time from initial diagnosis to intellectual assessment was 7.1 years. Results showed that children irradiated before the age of 4 years were impaired in certain aspects of non-verbal ability, as well as in measures of short term memory and attention, calculated by factor scores derived from selected subtests of the IQ test. Subtests requiring verbal and non-verbal reasoning showed the greatest impairment after early diagnosis and treatment. In addition girls were selectively impaired in verbal IQ and other aspects of verbal ability, with the degree of impairment exacerbated by early treatment. No relationship was found between degree of impairment and either time since treatment or number of methotrexate injections. It is concluded that early age at irradiation increases the risk of impaired intellectual outcome, particularly in girls.

Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood.

PURPOSE: To perform a comprehensive assessment of the late effects of short-term intensive chemotherapy for childhood acute myeloid leukemia (AML) and myelodysplasia, and compare the sequelae of intensive chemotherapy alone with those of total-body irradiation (TBI). PATIENTS AND METHODS: Of 33 survivors studied, 26 (group A) received intensive chemotherapy including anthracyclines, one also received busulfan, cyclophosphamide (Bu/Cy), and bone marrow transplantation (BMT). Seven patients (group B) received chemotherapy, TBI, and BMT. Hearing, sight, growth, and endocrine, renal, and cardiac function were assessed. RESULTS: The mean height standard deviation score of 25 nontransplanted group A patients was +0.67 at diagnosis, -0.11 following treatment (P = .016), and +0.34 7 years later (P > .05), indicating no long-term growth impairment. The patients had normal gonadal function and the girls had normal uterine size and ovarian volume. The Bu/Cy patient had primary ovarian failure. Four group B children required growth hormone and four sex steroids for growth or gonadal failure. The girls had reduced uterine size and ovarian volume. Three had thyroid dysfunction and six had cataracts. Abnormalities of renal function were found in both groups and hearing loss in group A only. The mean cardiac shortening fraction was significantly reduced at 29.2% in group A and 28.6% in group B compared with 36% in normal subjects. Two group A patients have developed cardiac failure. CONCLUSION: Chemotherapy and TBI before BMT for AML has resulted in growth failure, gonadal and thyroid damage, and cataracts in most children, whereas chemotherapy alone caused cardiac, renal, and hearing abnormalities only.

Bone mineralization after treatment of growth hormone deficiency in survivors of childhood malignancy.

Having noted symptomatic osteoporotic vertebral collapse in young adult survivors of childhood malignancy, bone mineral density (BMD) was examined at three sites by dual-energy X-ray absorptiometry in 64 patients treated in childhood for intracranial malignancy (group 1; n = 21) or acute leukaemia (group 2; n = 43). Patients in group 1 were selected for growth hormone deficiency (GHD) by auxological and biochemical criteria before the end of puberty (Tanner stage V). Seven patients (six men; mean (+/- SEM) age at study, 28.0 +/- 2.9 years; mean age at diagnosis, 8.7 +/- 1.5 years) in this group had been treated with human pituitary growth hormone (GH) for 1-12 years; and 14 patients (nine men; mean age at study, 26.8 +/- 1.0 years; mean age at diagnosis, 10.7 +/- 1.4 years) had not received GH. Bone densities in group 1 were normal in the GH-treated patients at the femoral neck (98.4 +/- 3.8% of control), lumbar spine (100.4 +/- 6.1% of control) and Ward's triangle (101.0 +/- 6.1% of control) but markedly reduced in the untreated group (femoral neck, 81.2 +/- 2.6% of control (p = 0.002); lumbar spine, 79.1 +/- 4.1% of control (p = 0.04); Ward's triangle, 80.1 +/- 3.6% of control (p = 0.01)). The majority of patients in group 2 had been treated for acute lymphoblastic leukaemia (ALL) and were in three subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropsychological and neurological outcome after relapse of lymphoblastic leukaemia.

Fourteen children who relapsed after initial remission of leukaemia were studied. Six received a second course of cranial radiotherapy, while the remaining eight children were given total body irradiation before bone marrow transplantation. The postirradiation somnolence syndrome was common after cranial radiotherapy. All children had mild/soft neurological signs, mostly of coordination. None had a major motor disability. All but the youngest child had cataracts; two children required an operation for these. All children were growth hormone deficient. Verbal IQ, attention, and concentration were selectively reduced (with respect to normative levels). The time between the two treatments, age at relapse, and higher doses of radiotherapy all correlated with cognitive outcome, with girls showing greater impairments than boys. Only two children were performing at age appropriate levels on measures of academic achievement. It is concluded that neurological and neuropsychological morbidity is significantly increased by the current treatments prescribed after the relapse of leukaemia.

A second course of treatment for childhood acute lymphoblastic leukaemia: long-term follow-up is needed to assess results.

We report the results of long-term follow-up of 94 children who completed treatment for acute lymphoblastic leukaemia (ALL) between 1974 and 1986 and subsequently experienced a bone marrow relapse before 1992. 91 children received further induction, intensification and CNS directed therapy; 19 proceeded to BMT or ABMT and the remainder were treated on one of three protocols which increased in intensity. The duration of second remission improved significantly with increasing intensity of treatment and bone marrow transplantation was followed by fewer relapses than chemotherapy. Analysis of factors influencing the duration of second remission showed that only length of first remission was of additional significance; the median duration of second remission being only 19 months in children with a first remission of less than 4 years and 62 months in those with longer first remissions. 29 children electively stopped chemotherapy a second time but only 11 of these remain still in second remission with recurrences occurring for up to 7 years from the the time first relapse. Only three of the 24 long-term survivors had no significant late effects of treatment; these were most marked in children who had received a second course of radiotherapy. We conclude that very long follow-up is necessary to determine whether patients may be successfully re-treated following late bone marrow relapse and that all such treatment is associated with a high incidence of late effects.

Growth following single fraction and fractionated total body irradiation for bone marrow transplantation.

Total body irradiation (TBI) is used as preparative regimen prior to bone marrow transplantation (BMT). Since there are more long-term survivors, follow up studies are important. We have performed a retrospective analysis of growth for 49 children, who had undergone treatment with cyclophosphamide and TBI before BMT. Of these patients 26 received single fraction (SF) TBI as a dose of 900-1000 cGy, whereas 23 received fractionated (FF) TBI as a total dose of either 1200 cGy divided in six fractions or 1440 cGy divided in eight fractions over 3 days. Half of the patients in the SF-TBI group, and 9 in the FF-TBI group had received low-dose cranial irradiation prior to TBI. In all groups a decrease in height SDS was observed. By evaluating the major factors leading to growth impairment the influence of cranial irradiation, which was demonstrable in the 1st year after TBI, could not be shown after 3 years. At this time growth was significantly more impaired in the SF group with a mean height SDS of -0.9 (+/- SD 0.9) compared to a mean height SDS -0.22 (1.02) in the FF group (P < 0.05). Measurement of segmental proportions showed a significant difference in SDS for sitting height in comparison to SDS for subischial leg length, irrespective of the TBI regimen. This was already evident 1 year after TBI and decreased during the following years. Twenty four of the patients (17 in the single fraction and 7 in the fractionated TBI group) were treated with growth hormone, but demonstrated an inappropriate response with absent catch-up growth in their legs.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine function following single fraction and fractionated total body irradiation for bone marrow transplantation in childhood.

Forty-nine children who had undergone treatment with cyclophosphamide and total body irradiation before bone marrow transplantation were investigated for impaired endocrine function. Twenty-six patients received single fraction total body irradiation as a dose of 9-10 Gy, whereas 23 patients received fractionated total body irradiation as a total dose of either 12 Gy divided into six fractions or 14.4 Gy divided into eight fractions, administered over 3 or 4 days. Half of the patients in the single fraction group and nine in the fractionated group had received cranial irradiation prior to total body irradiation. Pathological changes in thyroid function were observed in 19 patients (73%) of the single fraction group (elevated thyrotrophin (58%) and decreased thyroxine levels (15%)), whereas in the fractionated group only six patients (25%) developed transient raised thyrotrophin levels: the mean observation period was 3.2 years in the single fraction group and 2.7 years in the fractionated group. The stimulated growth hormone peak concentration was influenced significantly by previous cranial irradiation and was independent of the type of total body irradiation administered. In the patients who had received cranial irradiation, the mean growth hormone peak levels were 8.4 mU/l (single fraction group) and 13.9 mU/l (fractionated group), whereas in those who received only total body irradiation they were 24.9 mU/l(single fraction group) and 28.1 mU/l (fractionated group). The basal gonadotrophin concentration in children older than 9 years showed elevated levels in nine patients (50%) of the single fraction group and in only three patients (30%) of the fractionated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadotropin releasing hormone analogue and growth hormone therapy in precocious and premature puberty following cranial irradiation for acute lymphoblastic leukaemia.

Ten girls with early puberty secondary to cranial irradiation as a part of the treatment for acute lymphoblastic leukaemia (ALL) were treated with either gonadotropin-releasing hormone analogue (GnRHa) and human growth hormone (GH) (8 girls) or with GnRHa alone (2 girls). After 4 years of treatment, height SDS for bone age was improved in the group who received combined treatment (from -0.97 to +0.07, p < 0.001), in contrast to the 2 patients who received GnRHa alone in whom height standard deviation scores for bone age decreased (from -1.10 to -1.33). Sitting height in all patients was relatively shorter than leg length, and there was no significant alteration during the 4 years of treatment.

Impaired pubertal growth in acute lymphoblastic leukaemia.

The growth of 182 patients who were long term survivors of childhood acute lymphoblastic leukaemia was retrospectively analysed. All remained in first remission and were treated with either 1800 or 2400 cGy of cranial irradiation. None had been treated with either testicular or spinal irradiation. Ninety three (51 boys, 42 girls) were treated with 2400 cGy and 89 (42 boys, 47 girls) were treated with 1800 cGy cranial irradiation. All patients were treated with standard chemotherapy including intrathecal methotrexate in similar dose regimens in either group. Mean age (SD) at diagnosis in the group treated with 2400 cGy was 4.8 (2.6) years and mean age in the group treated with 1800 cGy was 6.5 (3.3) years. Mean height SD score at diagnosis in the 2400 cGy group was +0.29 and final height achieved was -0.63. Mean height SD score at the start of treatment in the group treated with 1800 cGy was +0.40 and mean final height was -0.53. There was a similar reduction in height SD score in both groups during the pubertal growth spurt. The decrement in height SD score was greater when treatment was administered at less than 7 years of age in either dose regimen, both in prepubertal and pubertal growth. However, the decrease in height SD score was found to be greater in girls than boys. There was a trend in both sexes for the onset of puberty to be at a younger age with a lower treatment dose of radiotherapy. However, in girls treated with the lower dose regimen there was a significant reduction in the mean age of onset of puberty which was 9.9 years. Our data suggest that girls treated at less than 7 years of age have a severe impairment of pubertal growth, which is probably a combination of the dual endocrinopathy of premature puberty and growth hormone insufficiency.

Growth hormone treatment of growth failure secondary to total body irradiation and bone marrow transplantation.

Growth hormone was given to 13 children (nine boys, four girls) with acute leukaemia who had undergone treatment with cyclophosphamide and total body irradiation before bone marrow transplantation. Mean age at total body irradiation and bone marrow transplantation was 9.0 years (range 3.7-15.8). Endocrinological investigation was carried out at a mean of 2.0 years (range 0.4-4.0) after bone marrow transplantation. Peak serum growth hormone responses to hypoglycaemia were less than 10.0 micrograms/l (less than 20.0 mU/l) in 10, 10.5 micrograms/l (21.0 mU/l) in one, greater than 16.0 micrograms/l (greater than 32.0 mU/l) in two patients. Mean age of the patients at the start of growth hormone treatment was 12.2 years (range 5.8-18.2). The mean time between total body irradiation and bone marrow transplantation and the start of growth hormone treatment was 3.2 years (range, 1.1-5.0). Height velocity SD score (SD) increased from a mean pretreatment value of -1.27 (0.65) to + 0.22 (0.81) in the first year, +0.16 (1.11) in the second year, and +0.42 (0.71) in the third year of treatment. Height SD score (SD) changed only slightly from -1.52 (0.42) to -1.50 (0.47) in the first year, to -1.50 (0.46) in the second year, and -1.74 (0.92) in the third year. Measurement of segmental proportions showed no significant increase in subischial leg length from -0.87 (0.67) to -0.63 (0.65) in the first year, to -0.58 (0.70) in the second year, and -0.80 (1.14) in the third year of treatment. Our data indicate that children who have undergone total body irradiation and bone marrow transplantation respond to treatment with growth hormone in either of two dose regimens, with an increase in height velocity that is adequate to restore a normal growth rate but not to 'catch up', and that total body irradiation impairs not only spinal but also leg growth, possibly by a direct effect of irradiation on the epiphyses and soft tissues.