Reassessment of growth hormone status is required at final height in children treated with growth hormone replacement after radiation therapy.

The most appropriate way to manage GH replacement in the transition period to adulthood in children treated with GH for GH deficiency (GHD) is controversial. The Growth Hormone Research Society suggests that the retesting of GH status at final height (FH) is unnecessary in the presence of severe organic GHD, and cranial irradiation falls into this etiological category. This recommendation has never been validated. To investigate whether patients diagnosed in childhood as GHD secondary to irradiation require retesting after FH, GH status has been reassessed in a large cohort of irradiated children treated with GH during childhood. Seventy-three children underwent biochemical assessment of GH status after irradiation and again at FH after GH therapy had been discontinued; 66 and 67 of the 73 patients underwent two provocative tests at the two time points, respectively. The characteristics of the cohort include a median age at irradiation of 5 yr (range, 1-11 yr), a median biological effective dose (BED) of irradiation to the hypothalamic pituitary axis of 54 Gy (range, 23-82 Gy), and a median time of GH status reassessment after FH of 0.4 yr (range, 0-8.4 yr). During childhood, patients with all degrees of GHD (peak GH responses to provocative test < 6.7 ng/ml) are treated, whereas in adulthood, only patients with severe GHD (peak GH responses to provocative test < 3 ng/ml) are considered for GH replacement. GH status has been grouped as follows: group 1, peak GH less than 3 ng/ml to both tests (severe GHD); group 2, one test with a peak GH less than 3 ng/ml and the other test with a peak of 3 ng/ml or greater; group 3, peak GH of 3-6.7 ng/ml to both tests; group 4, one test with a peak GH of 3-6.7 ng/ml and the other test with a peak of more than 6.7 ng/ml; and group 5, peak GH more than 6.7 ng/ml to both tests (normal GH status). In childhood, the number of patients in groups 1, 2, 3, and 4 were 33, 22, 17, and one, respectively. At retesting, severe GHD was diagnosed in 21 (64%) of 33 patients who were diagnosed in childhood with severe GHD (group 1) and 17 (44%) of 39 patients who were diagnosed in childhood with moderate GHD (groups 2 and 3). In total, 35 (48%) of 73 patients in the whole cohort and 12 (36%) of 33 patients with severe GHD in childhood did not fulfill the severe GHD biochemical criteria for GH replacement in adulthood. Using multiple linear regression, GH status at retesting is predicted by BED, age at irradiation, and use of chemotherapy. In conclusion, the diagnosis of severe GHD in childhood secondary to irradiation should not be taken as irrefutable evidence of permanent severe organic GHD, and our recommendation is that retesting of GH status at FH should be mandatory.

Improvements in final height over 25 years in growth hormone (GH)-deficient childhood survivors of brain tumors receiving GH replacement.

Final height (FH) outcome is important in survivors of childhood brain tumors. GH replacement is indicated in those found to be GH deficient (GHD). More recently, GnRH analogs (GnRHa) have been introduced to delay early or rapidly progressing puberty to allow more time for linear growth. Studies to FH are important to determine the effectiveness of growth-promoting strategies. Our aim was to assess whether evolving endocrine strategies have improved FH outcome and to determine whether GnRHa therapy has contributed auxologically. FH data were examined in 58 children (31 males and 27 females) with radiation-induced GHD who had been treated with GH. All had received a combination of cranial (CI; n = 17) or craniospinal (CSI; n = 41) irradiation with or without chemotherapy for a brain tumor. Eleven patients received GnRHa therapy. Throughout the 25 yr of the study patients came closer to achieving target height (i.e. a reduction in height loss), both those receiving CI (r = 0.5; P = 0.03) and those receiving CSI (r = 0.6; P < 0.001). The patients receiving GH therapy before 1988 compared with from 1988 onward had a similar age at irradiation [mean (+/-SD), 5.8 (3.0) vs. 6.2 (2.9) yr; P = 0.6], but experienced a more prolonged time interval from completing irradiation to starting GH [5.4 (2.4) vs. 3.3 (1.6) yr; P < 0.001]. Forward stepwise regression analysis revealed that height loss is affected by age at irradiation (P < 0.001), previous spinal irradiation (P = 0.02), chemotherapy (P < 0.001), and exposure to GnRHa therapy (P < 0.001). In the 11 patients treated with GnRHa therapy FH SD scores were improved compared with FH predictions calculated from a model derived from the patients not treated with GnRHa [-0.8 (1.6) vs. -2.4 (0.8) SD score; P < 0.001]. We have demonstrated an overall improvement in FH in children treated with GH for GHD after therapy for brain tumors over the last 25 yr. In the subset of children in whom the growth prognosis was adversely affected by early puberty, the combination of GnRHa and GH improved their prospects of achieving target height. The improved auxological outcome may reflect 1) the use of more standardized GH schedules and better dosing regimens, 2) a reduction in the time interval between finishing radiotherapy and receiving GH replacement, and 3) the use of GnRHa in addition to GH replacement in carefully selected patients.

Symptom interval in young people with bone cancer.

Symptom interval (SI), the time from first symptom/sign to diagnosis and initiation of treatment, appears to be principally influenced by tumour biology. Whether the age of the patient, patient delay, professional delay and access to health professionals influences the SI in bone tumours was investigated in this study. 115 patients with newly diagnosed osteosarcoma and Ewing's sarcoma were retrospectively reviewed. The median total SI for all bone tumours was 3.8 months (range 1-46 months). Patients older than 12 years had a longer SI (P = 0.05) and more patient delays (P = 0.02). Total SI and professional delays were longer if the General Practitioner was first seen compared with an Accident and Emergency Consultant (P = 0.02 and 0.02, respectively). However, SI did not influence overall and event-free survival in this series. Bone tumour patients have long SIs that are significantly affected by age and local health-care support systems. Early referral to specialists would help to alleviate anxiety and distress to the patient and family, even if currently delay does not influence outcome.

Late carmustine lung fibrosis. Age at treatment may influence severity and survival.

Previously, we have reported in 1990 that 35% of carmustine treated patients (6 of 17) who survived childhood brain tumors died of pulmonary fibrosis between 2 and 13 years after treatment. In addition, 8 patients studied in 1989 (13 to 17 years post treatment), had physiologic and biopsy or radiologic evidence of pulmonary fibrosis. We now report 3 more years of follow-up on these patients. Between 1989 and 1992, two more patients have died of pulmonary fibrosis, giving an overall mortality of 47%. Of the eight patients who died of pulmonary fibrosis, the median age at treatment was 2.5 years, whereas the nine long-term survivors had a median age at treatment of 10 years. All five patients treated below the age of 5 years have died of lung fibrosis. Analysis by the standard survival curve method indicated that patients treated at an age less than 6 years were more likely to die than those treated at an age older than 7 years (p = 0.03). Of the nine survivors, seven were observed over 3 more years. There was a gradual decline in mean forced vital capacity from 55% predicted (range, 44 to 81) to 51% predicted (range, 41 to 72) and total lung capacity fell from 65% predicted (range, 51 to 89) to 57% predicted (range, 47 to 77).

Genitourinary tumors in the families of children with renal tumors.

The occurrence of genitourinary tumors in the relatives of a population-based series of 218 children diagnosed with renal tumors was investigated. Family data on 92% (176 of 192) of Wilms' tumor (WT) patients and 77% (20 of 26) of other renal tumor patients were obtained. In all, 21 genitourinary tumors in first-degree relatives in 19 families were ascertained, together with 30 such tumors in second-degree relatives. Ten families were diagnosed with multiple genitourinary tumors, although none of these manifested familial WT. It is proposed that a small proportion of families of children with renal tumors has a genetic predisposition to develop genitourinary tumors and that these tumors may represent further manifestations of the pleiotropic effects of the WT1 gene or of other genes involved in WT predisposition.

Leukemia, lymphoma, and related disorders in families of children diagnosed with Wilms' tumor.

Leukemias and lymphomas occurring in a series of families with Wilms' tumor (WT) are described. One surviving case developed a large cell anaplastic Ki-1 lymphoma at age 20 years, and 23 second- and higher degree relatives were affected. In two instances leukemia/lymphoma occurred in the context of Li-Fraumeni syndrome (LFS) and two other families showed striking clusters of unusual and early-onset malignancies. In several cases, children had genitourinary abnormalities of the type associated with the WT1 gene on chromosome 11p13. Some of these families may provide important subjects for study of WT genes in hematologic disease and lymphomas and for investigation of interaction between different tumor-suppressor genes, e.g., WT1 and other candidate WT genes, and p53.

Prognostic relevance of DNA ploidy in rhabdomyosarcomas and other sarcomas of childhood.

A study of DNA content by flow cytometry revealed a significant difference between rhabdomyosarcomas, which were mainly non-diploid, and other sarcomas of children which were mainly diploid (p = 0.01). There was no association between DNA ploidy and survival or aggressive behaviour of the tumour as indicated for example by advanced clinical stage or unfavourable histology. While DNA ploidy correlated with age, it did not correlate with any other clinical characteristic. The apparent lack of prognostic value of DNA content may have been masked by some high CV values and overridden by the effect of chemotherapy which was the most significant variable in determining a patient's survival (p = 0.00005).

Ovarian failure following abdominal irradiation in childhood: the radiosensitivity of the human oocyte.

Ovarian function has been studied sequentially since 1975 in 19 patients treated in childhood for an intra-abdominal tumour with surgery and whole abdominal radiotherapy (total dose 30 Gy). Eleven patients received chemotherapeutic agents that are not known to cause gonadal dysfunction. All but one patient have developed ovarian failure with persistently elevated gonadotrophin levels (FSH and LH greater than 32 IU/litre) and low serum oestradiol values (less than 40 pmol/litre) before the age of 16 years. The majority (n = 12) did not progress beyond breast stage 1 without sex steroid replacement therapy. As the number of oocytes within the ovary declines exponentially by atresia from approximately 2,000,000 at birth to approximately 2000 at the menopause, we have been able to estimate that the LD50 for the human oocyte does not exceed 4 Gy.

Investigation of dose homogeneity in paediatric anthropomorphic phantoms for a simple total body irradiation technique.

The technique for treating total body irradiation patients used at the centre involves no compensation for the inhomogeneity of patient shape. Dose is prescribed to the lung, and monitor units are derived from standard data depending on the external dimensions of the patient at nipple level. Dose measurements were made during standard treatments on three paediatric anthropomorphic phantoms representing children of 5, 10 and 15 years of age. The results confirmed that the measured dose to the lung was within 4% of the prescribed dose, and dose homogeneity was within +/- 5%, excluding the neck, where the higher measured doses were still within tissue tolerance.

Ovarian failure following abdominal irradiation in childhood: natural history and prognosis.

Ovarian function has been reviewed sequentially since 1975 in 53 patients treated in childhood between 1942 and 1985 for an intraabdominal tumour with surgery and external abdominal radiotherapy (XRT). Of 38 patients who received whole abdominal XRT (20-30 Gy), 27 failed to undergo or complete pubertal development (pubertal failure) and a premature menopause (median age 23.5 years) occurred in a further ten. Of 15 patients who received flank XRT (20-30 Gy), ovarian function (median age at last assessment 15.2 years) was normal in all but one in whom pubertal failure occurred. In only one patient, who developed pubertal failure after whole abdominal XRT and required sex steroid replacement therapy (HRT) to achieve normal secondary sexual characteristics, has there been evidence of reversibility of ovarian function with a documented conception at the age of 22.7 years. Five patients who developed pubertal failure required bilateral augmentation mammoplasties despite sex steroid replacement therapy. Four patients have had documented conceptions, all received whole abdominal XRT (20-26.5 Gy) and subsequently developed a premature menopause. There have been no live births, with all miscarriages occurring in the second trimester. The outlook for normal ovarian function following whole abdominal XRT is poor, flank XRT introduced intermittently from 1972, has resulted in less pubertal failure but the possibility of a premature menopause may with time become a reality.

Synovial sarcoma of the pharynx.

Synovial sarcoma is rarely seen in the head and neck region. A case of synovial sarcoma of the pharynx in a child is presented.

Malignancies in Down syndrome.

Down Syndrome (DS) is associated with an increased incidence of malignancies, especially leukaemias. We came across 8 DS children presenting with malignancies and having trisomy 21 as the sole cytogenetic abnormality. Of these 8 DS cases, 4 presented with acute lymphocytic leukaemia, 2 with acute myeloid leukaemia and one case each with Hodgkin's disease and Wilms' tumour. There are contradictory reports regarding the distribution of myeloid versus lymphoid malignancies in DS children and their response to therapy. The exact mechanism by which patients with DS are predisposed to develop malignancies is unclear. However, presence of the extra chromosome no. 21 is presumed to disrupt the genetic balance which increases generalized susceptibility to genetic and environmental trauma. Furthermore, an increased methotrexate toxicity observed in these patients should also be taken into consideration in designing treatment for DS children with malignancies.

Growth hormone and tumour recurrence.

OBJECTIVE: To determine whether using growth hormone to treat radiation induced growth hormone deficiency causes tumour recurrence. DESIGN: Comparison of tumour recurrence rates in children treated with growth hormone for radiation induced deficiency and an untreated population. Computed tomograms from children with brain tumours were reviewed when starting growth hormone and subsequently. SETTING: North West region. PATIENTS: 207 children treated for brain tumour, 47 of whom received growth hormone and 161 children with acute lymphoblastic leukaemia 15 of whom received growth hormone. MAIN OUTCOME MEASURES: Tumour recurrence and changes in appearances on computed tomography. RESULTS: Among children with brain tumour, five (11%) who received growth hormone had recurrences compared with 42 (26%) who did not receive growth hormone. Also adjusting for other variables that might affect tumour recurrence the estimated relative risk of recurrence was 0.82 (95% confidence interval 0.28 to 2.37). The only child with acute lymphoblastic leukaemia who relapsed while taking growth hormone had relapsed previously before starting treatment. Two of the five children with brain tumours who relapsed had abnormal appearances on computed tomography when growth hormone was started. 14 other children who remained relapse free and had follow up computed tomography showed no deterioration in radiological appearance during treatment. CONCLUSIONS: In this population growth hormone did not increase the risk of tumour recurrence but continued surveillance is essential. Abnormal results on computed tomography are not a contraindication to treatment with growth hormone.

Long-term safety of growth hormone replacement after CNS irradiation.

CONTEXT: Radiotherapy is a central component in the treatment of many brain tumors, but long-term sequelae include GH deficiency and increased risk of secondary neoplasms. It is unclear whether replacement therapy with GH (GHRT) further increases this risk. OBJECTIVE: The objective of the study was to assess the effect of GHRT on the incidence of secondary tumors and tumor recurrence after cranial irradiation. DESIGN AND SETTING: We conducted a retrospective matched-pairs analysis of previously irradiated patients, with and without GHRT, attending a tertiary center between 1994 and 2009. PATIENTS: We reviewed the records for all patients undergoing GHRT at our institution over the study period. PATIENTS were included if they had received cranial irradiation, GHRT for at least 12 months, and records of serial magnetic resonance imaging data and data for dose and fractionation of irradiation were available. GH-naïve control patients were selected from a radiotherapy database of patients attending the same hospital. PATIENTS were matched for date of radiotherapy, age, site of primary diagnosis, radiation dose, and fractionation. MAIN OUTCOME MEASURE: The primary outcome measure was risk of tumor recurrence or secondary tumor. RESULTS: Matched controls were identified for 110 GH-treated patients. Median follow-up was 14.5 yr. No significant differences were apparent in the number of tumor recurrences (six vs. eight, GHRT vs. control group) or secondary tumors (five vs. three, respectively) between groups. CONCLUSIONS: Our study demonstrates no increased risk for recurrent or secondary neoplasms in patients receiving GHRT, thus supporting a high safety profile of GHRT after central nervous system irradiation.

Survival and quality of life of paediatric intracranial germ cell tumour patients treated at the Christie Hospital, 1972-1993.

From 1972 to 1993, 25 patients under 16 years old were treated at the Christie Hospital for intracranial germ cell tumours (ICGCTs). A retrospective analysis of the case notes was undertaken. The cases comprised 10 germinomas, nine non-germinomatous germ cell tumours (NGGCTs), and six cases with no histology. Ten patients had either complete or incomplete removal of the tumour. All patients received radiotherapy (20 patients received craniospinal irradiation [CSI]). Thirteen patients received chemotherapy at presentation (six platinum-based). All marker-negative pure germinomas treated with CSI survived. The actuarial 5-year survival for NGGCTs was 44%. Although CSI resulted in spine shortening, the overall effect on growth was not marked and the neuropsychologic sequelae were minimal with good overall functional results.

Carcinoma of the thyroid in children: a 25-year experience.

Over the past 25 years, 23 children with carcinoma of the thyroid have been treated at the Christie Hospital, Manchester. Twenty-one cases were well-differentiated carcinoma, and two were medullary carcinoma. They were all treated by resection, 14 with total thyroidectomy and 9 with lobectomy or subtotal thyroidectomy. Sixteen children also had surgery for nodal disease. Two children presented with lung metastases. Sixteen children received post-operative radiotherapy (4 external beam, 12 131I). Median follow-up of 67 months (range 7-233), was the same for the 21 well-differentiated carcinomas and the whole group including the two medullary carcinomas. All 21 children with well-differentiated carcinomas are alive with no evidence of progressive disease. Two relapsed after total thyroidectomy, but both were salvaged, one with external beam radiotherapy, one with 131I. One child with medullary carcinoma died with progressive disease after 43 months, the other is alive, but with slowly progressive disease 145 months after diagnosis. Ten of 14 children experienced post-operative hypocalcaemia following total thyroidectomy, in 7 cases it persisted long-term. 131I and external beam radiotherapy were both well tolerated. The long-term results of treatment of well-differentiated carcinoma of the thyroid are excellent, but there remains disagreement over the extent of treatment required. Some authors believe the condition is multifocal and requires total thyroidectomy, others argue that lobectomy or subtotal thyroidectomy avoids the possible post-operative complications of total thyroidectomy and gives equal long-term cure rates. We agree with the latter view. Although a small series cannot be conclusive, we feel that our results are consistent with this. We also believe, that for children, radiotherapy can be reserved for relapse only, as long as regular follow-up is available.

Salivary gland carcinomas in children: a review of 15 cases.

Salivary gland carcinomas are rare in childhood. We have reviewed the case records of 15 children aged 3-14 years (median 11) identified from children's tumour registries. Primary sites were parotid: 11, submandibular: 3, and base of tongue: 1. The range of histologies was similar to that occurring in adults. Six were treated by complete excision, with one given post-operative radiotherapy (RT). All six remain disease-free at 2 months to 21 years after completion of treatment. Five were treated by partial or sub-total excision. Four were given post-operative RT, of whom 3 are disease-free at 3 years, 6 months--18 years and 1 lost to follow-up (LTFA). One not given RT developed a local recurrence at 11 months and was given RT and LTFA. Four patients had a biopsy only. Three were treated by RT. One is disease-free at 8 years, one died of metastatic disease at 6 months, and one developed a local recurrence at 11 years and has remained disease-free following salvage surgery. One patient with advanced disease not suitable for RT died 3 months after diagnosis. Complete excision is the treatment of choice. Following sub-total or incomplete excision post-operative RT can prevent recurrence. Careful RT planning is necessary to minimise late effects.