Overtreatment of children with Wilms' tumour outside paediatric oncology centres.
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Biomedical subjects
Publications and source records attributed to C A Stiller.
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During a 10 year period, 1971-80, there were 234 children in Great Britain younger than 15 years with a diagnosis of carcinoma registered in Great Britain. These cases represented approximately 2% of all childhood malignant disease. The most common primary site was the thyroid, followed by the nasopharynx and the adrenal cortex. With the exception of adrenocortical tumors, most of the carcinomas occurred in children older than 10 years. In some patients there was a genetic predisposition to neoplasia. Children with carcinomas of the thyroid and female genital tract have an excellent prognosis with 5-year survival rates of over 90%. The prognosis for other sites was generally less favorable; 60% of children with nasopharyngeal tumors were alive at 5 years from diagnosis but less than 20% of those with carcinomas of the gastrointestinal tract or the adrenal cortex.
In a population based series of 4070 children with acute lymphoblastic leukaemia treated in Britain during 1971-82, the five year survival rate improved from 37% for those treated in 1971-3 to 66% in 1980-2. During the same period there was an increase in the proportion of children included in the Medical Research Council trials and an increase in the proportion who were treated at centres with an average of at least six new patients per year. Survival rates were significantly higher for children who were included in the trials than for those who were not. Among children not in the trials, the survival rate was highest at centres treating at least six children per year and lowest at those with fewer than one per year. The increase in the numbers of children treated according to standardised protocols, particularly within controlled clinical trials, has had a major impact on the mortality from childhood acute lymphoblastic leukaemia.
The International Agency for Research on Cancer has coordinated a worldwide study of the incidence of cancer in childhood. Contributors from over 50 countries have provided data. This paper presents a summary of some of the major results. The incidence rates and relative frequencies of childhood cancers are described according to 12 diagnostic groups, defined mainly in terms of tumour morphology. Variations in the risk of those tumours between different countries and different ethnic groups provide important information on the relative importance of environmental and genetic factors in their aetiology.
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The association between obstetric X-raying and childhood cancer was first identified by the Oxford Survey of Childhood Cancers in 1956. The present re-analysis exploits the case-control matching of the study while incorporating the effects of important risk determinants, notably year of birth, trimester of exposure and number of films exposed. The decline in risk over time is closely mirrored by the estimated decline in dose per film and, by constraining these two relationships to be parallel, time-invariant estimates of the extra risk per mGy are obtained. For example, it is now estimated that irradiating 10(6) foetuses with 1 mGy of X-rays would, in the absence of other causes of death, yield 175 extra cases of cancer and leukaemia in the first 15 years of life.
The Inter-Regional Epidemiological Study of Childhood Cancer included 43 cases of soft tissue and 30 cases of bone sarcomas, together with their 146 matched controls. Analysis of a wide range of aetiological factors revealed few risk factors relating to events during the index pregnancy, the earlier medical experiences of the case child, or parental medical, occupational and smoking history. Associations which did emerge included: lower birth weight in children with Ewing's tumour, an excess of mothers of children with soft tissue sarcoma with symptoms of toxaemia in pregnancy; and more children with rhabdomyosarcoma who received antibiotics soon after birth. There was some evidence that mothers of children with soft tissue sarcoma may have had reduced fertility with a significant excess of the case mothers having no other pregnancies. Slight excesses of congenital malformations in the case children and of malignant and benign/borderline neoplastic disease in the older mothers were consistent with the existence of a degree of genetic predisposition in the development of the tumours in this series.
Between 1977 and 1984 the proportion of children with malignant disease in Britain initially referred to specialist paediatric oncology centres increased from 44% to 71%. The percentage varied considerably with type of disease and region of residence. Children with acute non-lymphoblastic leukaemia, non-Hodgkin's lymphoma, Ewing's tumour, rhabdomyosarcoma, and (during 1981-84) osteosarcoma treated at paediatric oncology centres had significantly higher survival rates than those treated elsewhere. Children with cancer should be referred to specialist centres so that they may benefit as early as possible from the latest advances in treatment.
The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) collected interview and medical information relating to the child's past medical experiences from parents of 555 children diagnosed with cancer and parents of 1110 unaffected matched controls. No significant associations emerged overall for ante-natal care, place and mode of delivery, length of gestation, birth weight, condition at birth, special care, neonatal procedures or breast-feeding. Few risk factors relating to previous illnesses and medication were found, although increasing numbers of illnesses appeared to be associated with an increased risk of childhood cancer, particularly acute lymphoblastic leukaemia. A highly significant excess of case children had not been immunised (p = 0.005). In general, these results indicate that past medical experiences have little influence on the development of cancer in children.
Survival rates were analyzed for an effectively population-based series of 77 children with acute lymphoblastic leukemia treated at one hospital during 1970-1981. Treatment was according to Medical Research Council protocols UKALL I to UKALL VII but with a great emphasis on compliance. The relapse-free survival rate was 54.5% at 5 years. The overall 5-year survival rate of 64% was substantially higher than the 47% recorded during a similar period over the rest of Britain. The difference between survival rates in this series and nationally was especially marked for children aged 2-9 years (76% versus 50%) and with white blood count under 10 x 10(9)/L (87% versus 57%). For both of these groups, the survival rates achieved were similar to those now being recorded for the UKALL VIII trial in which treatment is more sustained than in its predecessors and there is greater emphasis on doctor compliance with protocol. These results suggest that although the advantage of UKALL VIII over previous trials for poor prognosis patients may be attributed to the more sustained treatment, the improvement for good prognosis patients may be due to more rigorous compliance with protocol.
The present study has been based on a detailed, computer-assisted, analysis of 112 astrocytomas from patients of all ages seen at The Radcliffe Infirmary between 1938 and 1984. There have been only six studies larger than the present one. From the results obtained in the present study, and the review of the literature, the following conclusions have been reached. Between 70 and 80% of cerebellar astrocytomas are found in children. Few patients are less than 1 year of age or older than 40 at the time of diagnosis. There appear to be no age peaks. Prognosis is poorest at the extremes of life, children less than 5 years old tending to suffer an early recurrence and patients in the oldest age groups having not only a very rapid recurrence but also a very low overall survival rate. In the present study, there was a slight predominance of males although basically, when all studies are considered, the incidence appears to be equal amongst the sexes. Around puberty there appears to be an abrupt drop in the number of tumours in females and a concomitant rise in the number of males. There appears to be no relationship between sex and the length of survival. It would appear that cerebellar astrocytomas can begin either within the vermis or one hemisphere. There appears to be no laterality, the right and left sides of the cerebellum being affected equally. In the present study, the hemispheres were affected three times more frequently than the vermis (34.8%: 12.5%). The rate of recurrence is much faster with tumors of the vermis, whilst the length of survival to death is much longer with tumours of one hemisphere at least up to 10 years after surgery. The most rapid recurrences take place in tumours which involve both hemispheres and the vermis whilst the poorest survival is associated with tumours infiltrating the brain stem. The average length of history is 18.7 months, being under forty-eight months in approximately 60% of patients, but only greater than 60 months in 6.2% of cases. The length of history was not related to either patient age or survival time. Most patients present with obstructive hydrocephalus with or without localising symptoms. The presentation is usually chronic and intermittent but may also be acute.(ABSTRACT TRUNCATED AT 400 WORDS)
In a population-based series of 8045 children with malignant neoplasms in Great Britain, the incidence of septal defects was 0.40%. The high rate of 19% in Down's syndrome children and the overall rate of 0.28% in children without Down's syndrome were both comparable with rates found in previous large prospective studies. The incidence of septal defects in children with Wilms' tumour was 1.82%, greater than 10 times that for non-Down's children with other neoplasms. The presence of this association in Wilms' tumour patients with and without aniridia and the recent finding of a loss of heterozygosity in chromosome 11 in many Wilms' tumours taken from patients without aniridia suggest the possibility of a link between Wilms' tumour, some septal defects and chromosomal abnormalities.
The inter-regional epidemiological study of childhood cancer analysed data on 234 children diagnosed with leukaemia or lymphoma and 468 controls matched for age and sex. A wide range of potential risk factors was examined, including prenatal exposure to x rays, maternal drug ingestion and smoking, child's medical history, and parental medical conditions and occupation. Calculations were completed for leukaemia or lymphoma and diagnostic subgroups, as defined by laboratory confirmed cell type. In utero exposure to narcotic analgesics was weakly associated with leukaemia or lymphoma but no other antenatal factors gave significant risks. New associations were identified for skin diseases in both parents and congenital abnormalities in the mothers of children with leukaemia. For past medical conditions in the child, viral disease occurring under 6 months of age increased the risk for acute lymphoblastic leukaemia. Fewer children in the leukaemia or lymphoma group had been immunised compared with the control groups. Case children diagnosed over the age of 9 years were more likely than controls to have had four or more previous episodes of illness. Overall, these results indicate that prenatal factors may be less important than postnatal or genetic influences in the development of leukaemia or lymphoma in children.
The therapeutic management of cerebellar astrocytomas is almost exclusively surgical. Although a few patients survive for long periods without treatment, the majority die without surgery. Total excision is advised to prevent recurrence which almost always follows non-total removal of tumour. Moreover, radical excision is feasible since the cerebellum has a remarkable capacity to compensate after large amounts of tissue have been removed. Morbidity is related to damage to the deep cerebellar nuclei, infiltration of the brain stem, secondary adhesions, and infection. Tumours may not be macroscopically visible at the time of first operation which in turn emphasizes the need for a detailed radiological work-up using, in particular, the CT scan. Biopsy alone, decompression alone, and/or aspiration are usually followed by rapid recurrence and no more than 30% of patients thus treated are recurrence-free five years after surgery. Approximately 40% of patients have subtotal resections and, of these, only 35% are recurrence-free five years post-operatively. Despite the high risk of recurrence following subtotal removal, subtotal excision may still be followed by prolonged survival since two thirds of the patients in the present study were still alive ten years or more after surgery. This is due in part to the unpredictable behaviour of cerebellar astrocytomas, a fact clearly demonstrated by serial CT studies of patients with partially excised tumours which demonstrate that residual tumour may occasionally regress or even remain static for many years. Total removal, when possible, is the treatment of choice and was carried out in 41% of patients in the present study. Ninety-five per cent of patients were free of recurrence for 25 years or more following total removal. In fact, recurrence following total removal has only rarely been recorded and is more often found when the initially excised tumour contains atypical and/or malignant features. Still, a benign histology does not preclude recurrence even when a total macroscopic excision has been achieved. This again emphasises the unpredictable nature of these tumours and the need for long-term radiological follow-up. Overall, operative mortality should be around 5% and even less for unilateral, hemispheric, circumscribed, nodular cerebellar astrocytomas. Conversely, the operative mortality for tumours of the vermis may approach 30% and generally increase with each subsequent operation, being maximal in the first post-operative month. Radiotherapy does not reduce the rate of recurrence nor prolong the overall survival period to death in patients with subtotal removal of tumour.(ABSTRACT TRUNCATED AT 400 WORDS)
Concern has been expressed recently about apparent increases in the incidence of leukaemia amongst young people living in certain geographical areas. We analysed the incidence of childhood leukaemia in South-East Scotland (excluding North-East Fife) from 1970 to 1984. There was a significant geographical variation in incidence of ALL with an excess in Fife concentrated in a small area of one district partly balanced by a relative decrease in Edinburgh. We feel that the variation is unlikely to be an artefact of geographically biased mis-diagnosis.
A child with a primary malignant cardiac tumor prompted a review of all 13 cases reported in Great Britain from 1962-1983. Only 4 definitely malignant tumors were identified, giving an incidence of between 1 in 38 and 1 in 90 x 10(6). All 4 patients died without evidence of metastases. Cardiac transplantation should be considered.
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