Risks of myeloid leukaemia in children treated for solid tumours.
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Biomedical subjects
Publications and source records attributed to M M Hawkins.
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Among a cohort of 9,279 survivors of childhood neoplasms other than retinoblastoma treated in Britain before 1980, the cumulative risk of a second primary tumor (SPT) by 25 years from 3-year survival was 3.7%. This corresponds to about five times the number expected from rates of cancer occurring in the general population. In the absence of both radiotherapy and chemotherapy, there was four times the expected number of subsequent cancers. The risk of an SPT associated with radiotherapy but not chemotherapy and both radiotherapy and chemotherapy were 6 and 9 times that expected, respectively. There is evidence that radiotherapy was involved in the development of many of the SPT's observed. However, case-control investigations are required to examine the relationship between relative risk of an SPT and therapy in detail. Secondary leukemia appears to occur more frequently among more recently diagnosed children with cancer. It is important to continue to monitor the occurrence of SPT's with a view to identifying the least carcinogenic therapies that are consistent with not compromising survival prospects.
An investigation of 749 deaths occurring among 4082 patients surviving at least five years after the diagnosis of childhood cancer in Britain before 1971 has been undertaken. Of the 738 with sufficient information the numbers of deaths attributable to the following causes were: recurrent tumour, 550 (74%), a second primary tumour, 61 (8%), a medical condition related to treatment of the tumour, 49 (7%), an traumatic death unrelated to the tumour or its treatment, 34 (5%), finally, any other cause unrelated to the tumour or its treatment, 44 (6%). Less than 10% of five year survivors of non-Hodgkin lymphomas, neuroblastoma, retinoblastoma, Wilms' tumour, or a soft tissue sarcoma died of recurrent tumour during the next 15 years, while more than 25% of five year survivors of Hodgkin's disease, ependymoma, medulloblastoma, and Ewing's tumour died of recurrent tumour during the corresponding period. Almost 50% of five year survivors of acute lymphoblastic leukaemia died of recurrent disease during the corresponding 15 years, a large proportion of deaths being due to central nervous system relapse in an era before central nervous system prophylaxis was routinely given. Comparison of the mortality observed with that expected from mortality rates in the general population indicated three times the expected number of deaths from non-neoplastic causes. Five times the expected number of deaths from cardiovascular causes were observed, these were predominantly myocardial infarction and cerebrovascular accidents. There was no evidence of an excess in the number of suicides observed, but there were three times the expected number of deaths from accidents observed after central nervous system tumours. Two groups of patients were identified whose deaths were potentially avoidable. Seven patients with craniopharyngioma and panhypopituitarism presented with addisonian crises during periods of stress not adequately covered by exogenous corticosteroids. In the other group were children who received radiotherapy and later developed problems related to radiation fibrosis. We emphasize that our investigation relates to patients diagnosed with childhood cancer before 1971. The pattern of mortality that will emerge after recent treatment regimens, in which chemotherapy is being used more extensively, is likely to be different from that observed in our study.
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The occurrence of cancer among the 1,348 offspring of 2,441 survivors of childhood cancer, treated before 1978, was investigated. Information was obtained through a questionnaire sent to the general practitioners of these survivors. Twenty-three of 52 offspring born to survivors of heritable retinoblastoma developed retinoblastoma; the heritable form of retinoblastoma is known to be transmitted to offspring as an autosomal dominant. None of the 94 offspring born to the 54 survivors of unilateral retinoblastoma with no family history of the disease have developed the disease. This implies that it is unlikely that more than 9% of survivors of unilateral retinoblastoma with no family history have the germ-cell mutation; consequently it is unlikely that more than 4% of their offspring will be affected. Among the 1,199 offspring born to 629 survivors of other childhood malignant disease, who produced children, one acute monocytic leukaemia and one acute lymphoblastic leukaemia were observed. This is more than expected on the basis of the general population (one-tailed p = 0.04). However, the types of cancer observed in these 2 offspring and their parents conform to a previously described familial aggregation of cancers. Only a small number of children were born to survivors who received therapy that was potentially germ-cell mutagenic, and thus it is not possible to make any accurate estimation of their risk of malignant disease.
A postal survey addressed to 2,083 general practitioners of childhood cancer survivors of reproductive age has revealed that females having undergone direct abdominal irradiation (exposed), particularly for Wilms' tumour, have an increased risk of several adverse pregnancy outcomes as compared with female survivors of the same types of tumour who had not undergone direct abdominal irradiation (unexposed). Among female survivors, 22% of those exposed and 41% of those unexposed have children. The percentages of first pregnancies reported as ending in spontaneous abortion were 9/40 = 22% (exposed mothers) and 11/174 = 6% (unexposed mothers). The mean birth-weight of first singleton children born to exposed mothers was over 300 g less than the corresponding value for unexposed mothers. We conclude that radiation is probably involved in the mechanism producing these effects. The findings have implications for counselling survivors, monitoring their pregnancies and treating future patients.
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Investigations of long term survival and evidence concerning cure among children surviving at least three years after most of the more common childhood cancers treated in Britain between 1960 and 1981 are reported. The results indicate striking improvements in survival beyond three years for many childhood tumours over this period. For most childhood tumours considered over 80% of those who had survived at least three years were alive 10 years later. Comparison of mortality observed among survivors with that expected for the general population showed evidence of cure among those who had survived at least three years after non-Hodgkin lymphomas and non-genetic retinoblastoma. Survivors of other tumours, with sufficient cases surviving beyond 10 years to examine excess mortality, rarely experienced an excess that exceeded one extra death per 100 survivors per year. Children who had survived at least 10 years after other embryonal tumours, soft tissue sarcomas, or osteosarcoma never experienced an excess mortality exceeding one extra death per 200 survivors per year.
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A postal survey is being carried out among the general practitioners of survivors of childhood cancer born before 1963 and treated in Britain. The response rate is currently about 88%. Based on a preliminary analysis of 2001 questionnaires it emerged that fewer childhood cancer survivors married than was expected from the general population. The number of live births to female survivors was 57% of that expected from general population rates. The frequency of congenital malformations among the offspring was not in excess of that expected on the basis of large population based surveillance rates and the number of malignant tumours observed was broadly similar to that expected from general population rates, although the results were based on very small numbers. The present data, taken together with other studies of the offspring of cancer survivors, provides grounds for optimism with regard to the inherited component of childhood cancer and the effects of radiotherapy and cytotoxic drugs on germ cell mutation.
One hundred and sixty one children who have developed more than one primary neoplasm have been identified. Children with tumours of the central nervous system, retinoblastoma and leukaemia were those most frequently observed to develop a second malignancy whilst osteosarcoma was the most common second tumour. The patterns of second neoplasms appear to be changing and a recent increase in the number of children with leukaemia and lymphoma who develop second primary tumours has been observed. In this series, the two most frequent associations of tumours were retinoblastoma followed by osteosarcoma and the combination of acute leukaemia with a tumour of the central nervous system. Genetic factors which may have contributed to the development of the second primary tumour were identified in 53 patients (33%), 33 of whom had the genetic form of retinoblastoma. In an analysis of the treatment of 151 patients, for whom the interval between the two neoplasms was greater than 12 months, the second malignancy was considered to be 'radiation associated' in 93 (61%). Fifty children (33%) had been treated with either single or multiple agent chemotherapy which included an alkylating agent in 38. Forty five children had received a combination of chemotherapy and radiotherapy and of these, 10 developed leukaemia as their second tumour. Of the 19 secondary leukaemias, 16 have occurred in patients treated since 1970.
Among a cohort of 10,106 three-year survivors of childhood cancer, 90 second primary tumours (SPTs) were observed. Within 25 years of 3-year survival about 4% developed a SPT, about 6-fold expected, the relative risk not varying much with increasing follow-up. Following genetic retinoblastoma we observed 30-fold the expected number of SPTs, and over 400-fold the expected number of osteosarcomas. The risk of SPT in the absence of radiotherapy and chemotherapy (inherent risk) following genetic retinoblastoma was 13-fold expected and over 200-fold the expected number of osteosarcomas were observed. There was evidence that both radiotherapy and cyclophosphamide were associated with an increased risk of SPT. After all first primary tumours (FPTs) excluding retinoblastoma we observed almost 5-fold the expected number of SPTs. The inherent risk was 4-fold expected, the relative risks associated with radiotherapy but no chemotherapy, and both radiotherapy and chemotherapy were 6- and 9-fold expected respectively. There were about 20-fold the number of malignant bone tumours expected, most were osteosarcoma; also 7-fold the number of central nervous system tumours expected. There were 8 basal cell carcinomas and it seems likely that radiotherapy was involved in the development of some of these. Radiotherapy appears to have been involved in the development of many of the SPTs observed following all FPTs excluding retinoblastoma, particularly after CNS tumours, Wilms' tumour and Hodgkin's disease. Currently there is insufficient follow-up to examine the risk following chemotherapy. After acute leukaemia there was 20-fold the expected number of central nervous system tumours, though this is based on only 3 cases; whether therapy is directly involved in their development is uncertain. The risks we report are rarely greater than those reported in previous large-scale studies; in most instances they are substantially less. It is very unlikely that many SPTs were missed with our follow-up system so alternative explanations require further investigation; in particular it is possible the lower risks in our data compared to series treated in the United States may be explained, in part, by less combination therapy and lower doses of radiotherapy.
Increasing attention is being given to the occurrence of second primary tumours among survivors of childhood cancer. Our aims are to examine the risk of a subsequent primary, particularly in relation to chemotherapy, in a well-defined cohort; and to examine interesting associations between first and second primary tumours in relation to therapy generally and chemotherapy in particular among a less well-defined group of cases developing at least two primary tumours. There is suggestive evidence from our data that chemotherapy is involved either directly or indirectly in the development of secondary leukaemia, and this confirms previous work. Our data, although based on small numbers, indicate consistent evidence of an association between cyclophosphamide and an increased risk of a second primary tumour following retinoblastoma; this may be due to cyclophosphamide, radiotherapy or an interaction between the two. Two cases of uterine cancer were observed among three patients given oestrogen replacement therapy.
Combined effects of pregravid weight, weight gain and smoking on birth weight, length, and head circumference was investigated in uncomplicated, term pregnancies. Each gravida was categorized by height and pregravid weight as underweight, normal, moderately overweight, or massively overweight. Weight gain was grouped: poor, low-normal, high-normal, and excessive. Women who smoked 10 to 20 cigarettes daily were studied. Women who did not smoke were used as controls. Birth weights, lengths, and head circumferences were evaluated. Within each pregravid category and each gain group there was nearly uniform incremental increase in mean birthweight with advancing weight gain in both smoking and nonsmoking women. Infants born to smoking women fell behind nonsmoking counterparts by an entire gain group regardless of the mother's pregravid classification. Similar trends were observed in length and head circumference, although not as pronounced. Encouragement of higher weight gains helps correct the growth retardation observed in infants born to women who smoke.
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In regional perinatal projects, which include emphasis on service coordination and education, nursing must be planned to coordinate with the general goals of regionalization that go beyond the limits of individual institutions. This approach was applied in one such program where the nursing departments were successfully united to develop nursing care standards. A multifaceted educational program, based on these standards and a survey of 200 nurses, is in operation. This experience suggests that it is possible to organize perinatal nursing care throughout regions as long as due consideration of hospital individuality and autonomy is extended.
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