Childhood cancer research in Oxford I: the Oxford Survey of Childhood Cancers.

BACKGROUND: Significant research on the epidemiology and natural history of childhood cancer took place in the Universities of Oxford and Birmingham over sixty years. This is the first of three papers recording this work and describes the Oxford Survey of Childhood Cancers (OSCC), the largest case-control survey of childhood cancer ever undertaken. METHODS: The OSCC studied deaths in Britain from 1953 to 1981. Parents were interviewed and medical records from ante-natal clinics and treatment centres were followed up and abstracted. The survey left Oxford in 1975 and was run subsequently from Birmingham. The data are now being documented and archived to make them available for future study. RESULTS: Many papers have resulted from this survey, most notably those relating to the association first reported therein between childhood cancer and ante-natal X-raying. This paper is a historical review of the OSCC. CONCLUSIONS: In spite of many analyses of the study, this historic data set has continuing value because of the large number of examples of some very rare tumours and the detailed clinical and family history data that are available; and also because of the possibility of carrying out new analyses to investigate emerging research issues.

Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004.

BACKGROUND: Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary tumours (SPTs). METHODS: This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated. RESULTS: We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9-2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)). CONCLUSION: The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families.

Childhood cancer and magnetic fields from high-voltage power lines in England and Wales: a case-control study.

BACKGROUND: Epidemiological evidence suggests that chronic low-intensity extremely-low-frequency magnetic-field exposure is associated with increased risk of childhood leukaemia; it is not certain the association is causal. METHODS: We report a national case-control study relating childhood cancer risk to the average magnetic field from high-voltage overhead power lines at the child's home address at birth during the year of birth, estimated using National Grid records. From the National Registry of Childhood Tumours, we obtained records of 28,968 children born in England and Wales during 1962-1995 and diagnosed in Britain under age 15. We selected controls from birth registers, matching individually by sex, period of birth, and birth registration district. No participation by cases or controls was required. RESULTS: The estimated relative risk for each 0.2 µT increase in magnetic field was 1.14 (95% confidence interval 0.57 to 2.32) for leukaemia, 0.80 (0.43-1.51) for CNS/brain tumours, and 1.34 (0.84-2.15) for other cancers. CONCLUSION: Although not statistically significant, the estimate for childhood leukaemia resembles results of comparable studies. Assuming causality, the estimated attributable risk is below one case per year. Magnetic-field exposure during the year of birth is unlikely to be the whole cause of the association with distance from overhead power lines that we previously reported.

Non-ocular tumours following retinoblastoma in Great Britain 1951 to 2004.

BACKGROUND: Retinoblastoma occurs in both a heritable and a non-heritable form. In the heritable form, there is a predisposition to the development of non-ocular tumours. OBJECTIVES: To identify the types of non-ocular tumour occurring in retinoblastoma survivors and to produce estimates of risk for these tumours. METHODS: We carried out a cohort study that included 1927 cases of retinoblastoma diagnosed in Great Britain between 1951 and 2004. Cases were ascertained through the National Registry of Childhood Tumours and followed up for the occurrence of non-ocular tumours using the routine notification system based on the National Health Service Central Registers in Britain. RESULTS: Of the 1927 cases, 809 were known to have the heritable form of the disease and 1118 assumed to have the non-heritable form. 102 of the heritable and 13 of those classified as non-heritable developed a non-ocular tumour. The cumulative risk of developing such a tumour 50 years after retinoblastoma diagnosis was 48.3% (95% confidence interval: 38.1 to 59.7%) in the heritable and 4.9% (1.9 to 12.4%) in the non-heritable cases. The main categories of non-ocular tumours observed in the heritable cases were soft-tissue sarcomas (36 of which 21 were leiomyosarcoma), osteosarcoma (32), carcinoma (13), brain and central nervous system tumours (10), melanoma (9), leukaemia (4) and others (4). There were a total of 108 non-ocular tumours in 102 cases. CONCLUSIONS: There is a high risk of non-ocular tumours occurring in survivors of heritable retinoblastoma. These results have important implications for the clinical follow-up and counselling of survivors.

Cancer in the offspring of female radiation workers: a record linkage study.

This study uses record linkage between the National Registry of Childhood Tumours (NRCT) and the National Registry for Radiation Workers to re-assess our earlier finding that the offspring of women radiation workers exposed to ionising radiation before the child's conception may be at an increased risk of childhood cancer. An additional 16,964 childhood cancer patients taken from the NRCT, together with the same number of matched controls, are included. Pooled analyses, based on the new and original datasets, include 52,612 cases and their matched controls. Relative risks (RRs) for maternal employment as a radiation worker, maternal exposure or not during the relevant pregnancy and pattern of employment relative to conception and diagnosis dates were calculated.The new data provide no evidence of an increased risk of childhood cancer associated with maternal preconception radiation work and thus do not support our earlier finding of a raised risk in the offspring of female radiation workers. Considering the pooled data, a weak association was found between maternal radiation work during pregnancy and childhood cancer in offspring although the evidence is limited by the small numbers of linked cases and controls.

Retinoblastoma in Great Britain 1963-2002.

AIM: This paper describes the epidemiology and family history status of 1601 children with retinoblastoma in Great Britain diagnosed 1963-2002 and summarises the practical consequences for diagnosis and counselling of developments in molecular genetics. METHODS: Incidence rates were analysed according to year of diagnosis and tumour laterality. Cases were classified as heritable or non-heritable on the basis of laterality and family history of the disease. RESULTS: There were 998 unilateral cases, 581 bilateral and 22 of unknown laterality. Bilateral cases tended to be diagnosed at a younger age than unilateral. All bilateral cases are regarded as heritable, and 35% had a family history of the disease. 7% of the unilateral cases had a family history and are therefore heritable. Thus, at least (41%) of our cases are heritable. This is an underestimate, since these data on family history are incomplete. For unilateral cases aged below 1 year, the reported incidence rate increased significantly (p<0.0001) by about 2.5% per year; for the age group 1-4 years, the average increase was about 0.5% per year (not significant).

Retinoblastoma: treatment and survival in Great Britain 1963 to 2002.

AIM: This paper describes the treatment and survival of 1576 children with retinoblastoma in Great Britain diagnosed 1963-2002. METHODS: Survival rates were analysed according to period of diagnosis and tumour laterality. RESULTS: Survival was calculated by calendar period of diagnosis, 1963-1982 and 1983-2002. For both unilateral and bilateral retinoblastoma, survival improved between the two periods. The survival curves for the two periods were significantly different: for unilateral retinoblastoma p<0.00001, for bilateral p<0.01. For unilateral cases, the estimated 5-year survival rates rose from 85% for those diagnosed in 1963-1967 to 97% for those diagnosed in 1998-2002. The equivalent rates for bilateral cases were 88% and 100%. CONCLUSION: Survival rates were already high at the start of the study period. They increased with changes in treatment regimens.

Retinoblastoma incidence and survival in European children (1978-1997). Report from the Automated Childhood Cancer Information System project.

Based on 2283 cases of retinoblastoma diagnosed in children aged 0-14 years, incidence and survival in Europe during the period 1978-1997 are described. Data were provided to the Automated Childhood Cancer Information System (ACCIS) from 60 paediatric and general cancer registries. During 1988-1997, the cumulative incidence of retinoblastoma in the ACCIS regions was found to be between 44.2 and 67.9 per million births. The highest incidence was seen in the first year of life. The age-standardised (World standard) incidence rate for the age-range 0-14 years was 4.1 per million. Approximately one-third of cases had bilateral tumours. Overall incidence increased over the period 1978-1997 by 1% per year, as derived from a model adjusted for sex, age group and type of registry (general or paediatric). The 5-year survival rate improved from 89% to 95% during the period covered by the study. This improvement was seen in both unilateral and bilateral cases but was significant only for the unilateral tumours. Survival was lower in the East region, although smaller differences were also observed between the other four regions (British Isles, North, South and West). Availability and quality of registration data on retinoblastoma need to be improved for effective evaluation of incidence and survival.

Cancer in the offspring of radiation workers: an investigation of employment timing and a reanalysis using updated dose information.

An earlier case-control study found no evidence of paternal preconceptional irradiation (PPI) as a cause of childhood leukaemia and non-Hodgkin's lymphoma (LNHL). Although fathers of children with LNHL were more likely to have been radiation workers, the risk was most marked in those with doses below the level of detection. The timing of paternal employment as a radiation worker has now been examined. The previously reported elevated risk of LNHL in the children of male radiation workers was limited to those whose fathers were still radiation workers at conception or whose employment also continued until diagnosis. Children whose fathers stopped radiation work prior to their conception were found to have no excess risk of LNHL. It was not possible to distinguish between the risks associated with paternal radiation work at conception and at the time of diagnosis. A reanalysis of the original study hypothesis incorporating updated dosimetric information gave similar results to those obtained previously. In particular, the risks of LNHL did not show an association with radiation doses received by the father before conception. It seems likely that the increased risk of LNHL among the children of male radiation workers is associated with an increased exposure to some infective agent consequent on high levels of population mixing.

Uranium-235 and childhood leukaemia around Greenham Common airfield.

There has been considerable publicity recently concerning the possible release of enriched uranium from the Greenham Common USAF base near Newbury in Berkshire. Evidence for the release relies on an internal report of the Atomic Weapons Research Establishment at Aldermaston, the authors of which postulated that it resulted from a fire in 1958 involving a B47 bomber standing on the runway. Their report contained a much publicised contour map of excess 235U levels estimated from the ratio of 235U to 238U in 26 evergreen leaf samples examined. The current concern of the inhabitants of Newbury centres mostly on the incidence of leukaemia, which was known beforehand to be slightly elevated in parts of West Berkshire, at least for young children. A number of cases have received considerable press publicity, with suggestions that their homes are located close to the base or the flight-path. The reports are, however, anecdotal and are not based on a complete register of cases. We have examined the evidence for this putative association by re-analysing the uranium data and determining the spatial relationship to the base of cases of childhood leukaemia diagnosed in the years 1966-87. We conclude that, although the excess uranium found has a non-random distribution, it does not support the pattern depicted by the contours and bears no relation to the incidence of childhood leukaemia for the period we examined. In any case, the increase in level of environmental radiation as a result of the putative release must be very small and is at variance with the reporting in some of the national press.

Spatial temporal patterns in childhood leukaemia: further evidence for an infectious origin. EUROCLUS project.

The EUROCLUS project included information on residence at diagnosis for 13351 cases of childhood leukaemia diagnosed in the period 1980-89 in defined geographical regions in 17 countries. A formal algorithm permits identification of small census areas as containing case excesses. The present analysis examines spatial-temporal patterns of the cases (n = 970) within these clustered areas. The objectives were, first, to compare these results with those from an analysis conducted for UK data for the period 1966-83, and, second, to extend them to consider infant leukaemias. A modification of the Knox test investigates, within the small areas, temporal overlap between cases in a subgroup of interest at a putative critical time and all other cases at any time between birth and diagnosis. Critical times were specified in advance as follows: for cases of acute lymphoblastic leukaemia aged 2-4 years, the 18-month period preceding diagnosis; for cases of total leukaemia aged 5-14 years, 1 year before to 1 year after birth; and for infant cases (diagnosed < 1 year), 1 year before to 6 months after birth. Each of the analyses found evidence of excess space-time overlap compared with that expected; these were 10% (P = 0.005), 15% (P= 0.0002) and 26% (P= 0.03) respectively. The results are interpreted in terms of an infectious origin of childhood leukaemia.

Spatial clustering of childhood leukaemia: summary results from the EUROCLUS project.

The interpretation of reports of clusters of childhood leukaemia is difficult, first because little is known about the causes of the disease, and second because there is insufficient information on whether cases show a generalized tendency to cluster geographically. The EUROCLUS project is a European collaborative study whose primary objective is to determine whether the residence locations of cases at diagnosis show a general tendency towards spatial clustering. The second objective is to interpret any patterns observed and, in particular, to see if clustering can be explained in terms of either infectious agents or environmental hazards as aetiological agents. The spatial distribution of 13351 cases of childhood leukaemia diagnosed in 17 countries between 1980 and 1989 has been analysed using the Potthoff-Whittinghill method. The overall results show statistically significant evidence of clustering of total childhood leukaemia within small census areas (P=0.03) but the magnitude of the clustering is small (extra-Poisson component of variance (%) = 1.7 with 90% confidence interval 0.2-3.1). The clustering is most marked in areas that have intermediate population density (150-499 persons km[-2]). It cannot be attributed to any specific age group at diagnosis or cell type and involves spatial aggregation of cases of different ages and cell types. The results indicate that intense clusters are a rare phenomenon that merit careful investigation, although aetiological insights are more likely to come from investigation of large numbers of cases. We present a method for detecting clustering that is simple and readily available to cancer registries and similar groups.

Cancer in the offspring of radiation workers: a record linkage study.

OBJECTIVES: To test the "Gardner hypothesis" that childhood leukaemia and non-Hodgkin lymphoma can be caused by fathers' exposure to ionising radiation before the conception of the child, and, more generally, to investigate whether such radiation exposure of either parent is a cause of childhood cancer. DESIGN: Case-control study. SETTING: Great Britain. SUBJECTS: 35,949 children diagnosed as having cancer, together with matched controls. MAIN OUTCOME MEASURES: Parental employment as radiation worker as defined by inclusion in the National Registry for Radiation Workers and being monitored for external radiation before conception of child; cumulative dose of external ionising radiation for various periods of employment before conception; dose during pregnancy. RESULTS: After cases studied by Gardner and colleagues were excluded, fathers of children with leukaemia or non-Hodgkin lymphoma were significantly more likely than fathers of controls to have been radiation workers (relative risk 1.77, 95% confidence interval 1.05 to 3.03) but there was no dose-response relation for any of the exposure periods studied; indeed, the association was greatest for those with doses below the level of detection. No increased risk was found for fathers with a lifetime preconception dose of 100 mSv or more, or with a dose in the 6 months before conception of 10 mSv or more. There was no increased risk for the group of other childhood cancers. Mothers' radiation work was associated with a significant increase of childhood cancer (relative risk 5.00, 1.42 to 26.94; based on 15 cases and 3 controls). Only four of the case mothers and no controls were radiation workers during pregnancy. CONCLUSIONS: These results do not support the hypothesis that paternal preconception irradiation is a cause of childhood leukaemia and non-Hodgkin lymphoma; the observed associations may be chance findings or results from exposure to infective or other agents. If there is any increased risk for the children of fathers who are radiation workers, it is small in absolute terms: in Britain the average risk by age 15 years is 6.5 per 10,000; our best estimate, using all available data, is that the increase is 5.4 per 10,000. For mothers, the numbers are too small for reliable estimates of the risk, if any, to be made.

The analysis of registry data in relation to various different types of hypothesis regarding the geographical distribution of disease.

Disease registries will often contain the addresses of cases included in the registry. If the registry includes information on all cases, or deaths, occurring in a defined geographical area and time period and if there is a postcode/zip code or map reference for each case it is possible to carry out a variety of different types of geographical analysis that may give clues to the aetiology of the disease. For such analyses it will usually also be necessary to have population data for the region covered by the registry and for separate sub-regions within it. In this paper we review types of analysis that may be applied to such data and give references to examples of applications and the statistical methods used. These include, first, methods of presenting incidence rates, and particularly the use of maps; of particular concern is the development of methods for presenting data that take into account the problems of rates calculated for small populations and which may therefore happen to be high or low simply by chance. Secondly, we consider, the analysis of "clustering" and "clusters" of cases of disease. These problems have been the subject of considerable methodological development in recent years. Analyses of clustering address the question of whether there is a general tendency for there to be aggregations of cases or areas of high incidence the analysis of clusters is concerned with problems of detecting specific locations where there are unusual aggregations of cases. The third type of problem considered here is whether there are, within the registry region, aetiological factors that vary geographically with consequent variations in disease incidence in different sub-regions. Where there is geographical variation it may be possible to use regression analysis to relate such variation to factors such as socio-economic status or levels of some environmental hazard. Finally we consider the problem of determining whether disease rates in certain areas may be related to distance from the source of some potential causative agent.

Patterns of childhood cancer among siblings.

The National Registry of Childhood Tumours contains over 51000 records of children born in Great Britain who developed cancer under the age of 15 years. Patterns of childhood cancer among families containing more than one child with cancer have been studied. A total of 225 "sib pair' families have been ascertained from interviews with parents of affected children, from hospital and general practitioner records and from manual and computer searches of names and addresses of patients. A number of special groups have been identified, including those with a known genetic aetiology such as retinoblastoma, twins and families with three or more affected children. A further 148 families not in any of the above groups contain two children with cancer: in 46 families the children had tumours of the same type, most commonly leukaemia. Some of the families are examples of the Li-Fraumeni syndrome; some are associated with other conditions, including Down's syndrome. There is clearly a genetic element in the aetiology of cancer in some families discussed here; shared exposure to environmental causes may account for others and some will be simply due to chance.

Concordance for childhood cancer in twins.

The causes of most childhood cancer remain elusive; some children clearly have a genetic predisposition, but in the majority the relative contributions of environmental and host factors are not established. One approach to this question is through twin concordance studies, but only the most common malignancy, acute leukemia, has been studied to date, owing to the rarity of other forms of childhood cancer. The aim of the study was to determine the concordance rates for childhood cancer in twins, in order to clarify the importance of constitutional predisposition for a range of tumor types. Twins with cancer were ascertained through three cooperative clinical trials groups, a cancer-twin registry, and a large pediatric hospital. Subjects were sent a postal questionnaire requesting information on cancer concordance and zygosity. Data were obtained on 556 twins with cancer. Three twin pairs, out of 197 twin pairs (76 monozygous, MZ, twin pairs), were concordant for leukemia, giving an MZ case-wise concordance rate (5%) that is substantially lower than previously reported. The case-wise concordance for non-retinoblastoma solid tumors was 2.2%: Two twin pairs were concordant for CNS tumors, one was concordant for neuroblastoma, and two twin pairs were concordant for cancer but not for the type of cancer. The results of the present study, together with previous data from population studies of siblings and offspring, suggest that there is not in general a strong constitutional genetic component for childhood cancers other than retinoblastoma.