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.

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.

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.

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.

Ifosfamide/etoposide alternating with high-dose methotrexate: evaluation of a chemotherapy regimen for poor-risk osteosarcoma.

Fifteen patients with relapsed osteosarcoma were treated with an intensive combination chemotherapy schedule. Ifosfamide 2.5 g m(-2) daily and etoposide 150 mg m(-2) daily coincidentally for 3 days and high-dose methotrexate 8 g m(-2) (with folinic acid rescue) on days 10-14 in a planned 21 -day cycle. Feasibility, toxicity and response to this alternative combination for the treatment of relapsed osteosarcoma was assessed. There were 98 evaluable cycles for toxicity and tolerability. The majority of cycles were well tolerated. Haematological toxicity of grade 3/4 (common toxicity criteria) was seen in all courses. Renal tubular loss of electrolytes, particularly magnesium, occurred in 71% of cycles. Thirteen per cent of cycles were repeated within 21 days and 61% within 28 days. In the thirteen patients evaluable for response, a partial response rate of 31% was seen after two cycles. However, patients with stable disease continued on therapy, and an overall consequent response rate of 62% was observed. Four patients were alive with no evidence of disease at 8-74 months. Three are alive with disease (at 8-19 months). There were six deaths, all disease related. This regimen exhibits an encouraging response rate in a group of children with poor prognosis disease, with a tolerable toxicity profile.

Spinal cord compression--do we miss it?

Four children with spinal cord compression due to malignant tumours are presented. The severity of the condition was not initially recognized by parents, or the nature of the likely cause by the initial physicians. Lower limb asymmetrical weakness, clear-cut sensory levels, and marked pain indicate need for urgent imaging and exclusion of a space occupying lesion. In 1997 diagnosis of Guillain-Barré syndrome should not be made without careful prior spinal imaging.

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.

Relapse of intracranial germinoma 23 years postirradiation in a patient given growth hormone replacement.

There is no clear evidence that growth hormone replacement therapy for treatment-related growth hormone deficiency in patients with childhood intracranial malignancies has a role in tumour relapse or second malignancy. A 16-year-old girl with an intracranial germinoma was treated with local radiotherapy and subsequently received growth hormone replacement therapy as an adult. Three years after starting growth hormone therapy, 23 years after her radiotherapy treatment, the patient's tumour recurred. Surveillance requirements for patients receiving growth hormone in this setting are discussed.

Survival and late effects in medulloblastoma patients treated with craniospinal irradiation under three years old.

Conventional treatment of medulloblastoma has involved surgery to the primary tumour and radiotherapy to the primary site and craniospinal axis. However CNS irradiation in a young child may result in significant side effects. Thus new treatment strategies have emerged which include chemotherapy, given in order to delay radiotherapy, to enable radiation dose reduction to the primary site and craniospinal axis, or even to eliminate radiotherapy completely. Such treatments have not yet been adequately evaluated in terms of survival and late effects. We report a retrospective study of 37 patients under the age of 36 months treated with postoperative craniospinal irradiation, in which the radiation dose to the neuroaxis was below conventional dosage. The overall actuarial 10-year survival rate was 44% and the actuarial 10-year relapse tree survival rate was 54%. Both radiotherapy and chemotherapy contributed to morbidity and mortality. Tour of 16 patients who survived longer than 10 years had no hard neurological signs; all but one patient have required extra support at school. Of nine patients available for work, two have obtained employment but only one has maintained this. No young adults have married. Despite lower doses of radiation, all but 1 survivor has significant spine shortening, and all who reached final height were short. Further work is needed to complete the profile of late effects in this group, which should include the survivors own perceptions of quality of life. It is hoped that multimodality treatment and supportive care can sustain acceptable survival rates but reduce the burden of late effects.

Pediatric oncology and hematology in Manchester, England.

The Manchester pediatric oncology unit is the third largest unit in the United Kingdom, with approximately 120 new referred cases per annum (10% of the U.K. total). Research activities include a gene therapy program, peripheral blood stem cell studies, the genetic epidemiology of childhood cancer, late-effects research (growth, body composition, pulmonary, quality of life), psychosocial studies, and clinical trial organization. Both the clinical oncology service and research activities involve close team coordination and collaboration with scientists both within and outside Manchester. A comprehensive pediatric hematology service is provided. The unit contains the second largest children's hemophilia service in the United Kingdom, serving 200 patients with congenital blood disorders. Twenty-five bone marrow transplants are performed each year (allogeneic, unrelated donor, autologous, and peripheral stem cell) for malignant and nonmalignant disorders. These activities are closely related to local, national, and international research groups.

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.

An intensive multiagent chemotherapy regimen for brain tumours occurring in very young children.

Standard treatment for the majority of malignant brain tumours consists of surgery and radiotherapy. This treatment has late morbidity which is accentuated in the very young child. As part of a strategy to improve quality of life and overall survival of young children with brain tumours, members of the United Kingdom Children's Cancer Study Group (UKCCSG) have piloted an intensive chemotherapy regimen which aims to avoid or delay radiotherapy following surgery. Twenty eight children with a variety of malignant brain tumours have received the regimen, which contains carboplatin, vincristine, cyclophosphamide, methotrexate, and cisplatin. The treatment is toxic, resulting in one death from infection. The bulk of the toxicity was associated with the administration of carboplatin. All but three children eventually required adjuvant radiotherapy and this was given between 1.5 and 27 months from diagnosis (median delay to radiotherapy, 12 months). Using this treatment regimen, overall survival at four years is 35% (confidence intervals 10% to 60%). While there is no evidence from this study that radiotherapy can be abandoned in the management of malignant brain tumours, its introduction may be delayed using suitable chemotherapy, thus allowing time for further CNS development. This treatment strategy has been taken forward as an international clinical trial run through the International Society for Paediatric Oncology, but using a smaller dose of carboplatin to reduce toxicity.

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.

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.

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).

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.

Second primary neoplasms in a population-based series of patients diagnosed with renal tumours in childhood.

Eight second malignant tumours developed in a population-based series of 218 patients diagnosed with renal tumours in childhood: renal cell carcinoma of the contralateral kidney, hepatocellular carcinoma, Hodgkin's disease, and 4 basal cell and 1 squamous cell carcinomas of skin. Excess risk of developing a second malignancy (excluding skin carcinomas but including a registrable spinal neurofibroma) was 14.7 (95% CI 4.0-37.7, P = 0.0003) for Wilms' tumour patients. Cumulative incidence of second malignant neoplasms (excluding skin carcinoma) was zero at 10 years, 5.0% at 20 years, and 10.2% at 30 years. The most common second neoplasms seen were benign osseous/chondromatous tumours and 4 of the 7 Wilms' tumour patients with malignant tumours had previous or synchronous tumours of this kind. Development of bony exostoses may be a marker for those patients at particularly high risk of subsequent malignancy.