Oxford Survey Of Childhood Cancers Research Articles

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

BackgroundSignificant 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.MethodsThe 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.ResultsMany 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.ConclusionsIn 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.

TU‐F‐CAMPUS‐T‐02: Risk Assessment of Scattered Neutrons for a Fetus From Proton Therapy of a Brain Tumor During Pregnancy

Purpose:To determine the scattered neutron dose and the resulting risk for a fetus from proton therapy for brain tumors during pregnancy.Methods:Using the Monte Carlo platform TOPAS, the ICRP reference parameters based anthropomorphic pregnancy phantoms for three stages (3‐, 6‐, 9‐month) were applied to evaluate the scattered neutron dose and dose equivalent. To calculate the dose equivalent, organ specific linear energy transfer (LET) based quality factor was used. Treatment plans from both passive scattering (PS) and pencil beam scanning (PBS) methods were considered in this study.Results:For pencil beam scanning, the neutron dose equivalent in the soft tissue of the fetus increases from 1.53x10−3 to 2.84x10−3 mSv per treatment Gy with increasing stage of gestation. This is due to scattered neutrons from the patient as the main contaminant source in PBS and a decrease in distance between the soft tissue of the fetus and GTV with increasing stage of gestation. For passive scattering, neutron dose equivalent to the soft tissue of the fetus shows a decrease from 0.17 to 0.13 mSv per treatment Gy in different stages, while the dose to the brain shows little difference around 0.18 mSv per treatment Gy because scattered neutrons from the treatment head contribute predominantly in passive scattering.Conclusion:The results show that the neutron dose to the fetus assuming a prescribed dose of 52.2 Gy is negligible for PBS, and is comparable to the scattered dose (0–10 mSv) from a head and neck CT scan for PS. It can be concluded that the dose to fetus is far lower than the thresholds of malformation, SMR and lethal death. The excess relative risk of childhood cancer induction would be increased by 0.48 and 0.103 using the Oxford Survey of Childhood Cancers and Japanese atomic model, respectively.Changran Geng is supported by the Chinese Scholarship Council (CSC) and the National Natural Science Foundation of China (Grant No. 11475087).

Childhood leukaemia following medical diagnostic exposure to ionizing radiation in utero or after birth

A statistical association between childhood leukaemia and an abdominal X-ray examination of the pregnant mother was first reported in 1956 from a case-control study of childhood cancer mortality conducted in Great Britain. This study, later called the Oxford Survey of Childhood Cancers (OSCC), was continued and eventually showed a highly statistically significant approximately 50% proportional increase in the risk of childhood leukaemia associated with antenatal diagnostic radiography. The association has been confirmed by many case-control studies carried out around the world, the appropriately combined results of which show a highly statistically significant increase in risk that is compatible with the OSCC finding. There is no doubt about the reality of the statistical association, but a causal interpretation has been questioned. On balance, however, the evidence points to low-level irradiation of the fetus increasing the risk of leukaemia in childhood, with an excess relative risk coefficient of around 50 Gy(-1) (equivalent to an excess absolute risk coefficient of about 3% Gy(-1)), although the uncertainty associated with these coefficients is considerable and they are likely to be overestimates. In contrast to exposure in utero, the evidence from case-control studies for an association between childhood leukaemia and postnatal exposure to medical diagnostic irradiation is equivocal and sometimes conflicting. Since standard radiation risk models predict that low-level exposure in the early years of life should produce an increased risk of childhood leukaemia that is roughly similar to that arising from fetal exposure, this absence of persuasive evidence is likely to be due to various problems with the studies. This is unfortunate given the rise in relatively high dose diagnostic procedures (e.g. paediatric CT scans) that would be predicted to materially increase the relative risk of childhood leukaemia.

Ionizing Radiation and Childhood Leukemia

I read with interest the recent review by Belson et al. (2007) on childhood leukemia, particularly the sections dealing with radiation exposure. Like the authors, I believe that ionizing radiation is strongly associated with childhood acute leukemia. I would like to point out that several critical pieces of information were overlooked; these support stronger and more meaningful conclusions. Although atomic bomb survivors offer the clearest evidence of leukemia risk after childhood exposures to ionizing radiation, studies of children exposed to fallout in other contexts should not be downplayed. Belson et al. (2007) stated that “radiation exposure secondary to the Chernobyl accident has not been shown to increase the risk of leukemia in children who were exposed after birth …,” but they failed to mention the case–control study of Noshchenko et al. (2002), which found significant increases in childhood and acute leukemias in association with estimated childhood exposures. Children living downwind of the Nevada Test Site have also shown a significant increase in leukemia related to estimated fallout exposure (Stevens et al. 1990). In utero exposure to ionizing radiation has been a known causal factor for childhood cancer for > 50 years. Although Belson et al. (2007) stated that the lack of evidence for a childhood leukemia risk among atomic bomb survivors constitutes the “most notable reason for doubt of a true association,” they overlooked the reviews of Wakeford and Little (2002, 2003); these authors demonstrated that the highly uncertain atomic bomb survivor data are statistically compatible with the robust set of data found in the Oxford Survey of Childhood Cancers and related X-ray exposure cohorts. There is no valid reason to doubt this association at present. The association between preconception paternal irradiation (PPI) and childhood leukemia has always been controversial. Two of the major objections to the “Gardner hypothesis,” as Belson et al. (2007) pointed out, have been mixed evidence from studies of radiation-exposed fathers and a lack of positive evidence in the children of the atomic bomb survivors. Regarding the first objection, Belson et al. overlooked the two largest studies of the children of radiation workers. Draper et al. (1997) conducted a UK-wide case–control study of childhood cancers in relation to paternal radiation exposure. This study showed, based on > 13,000 cases not included in the study of Gardner et al. (1990), that children with leukemia or non-Hodgkin lymphoma were significantly more likely than controls to have fathers who were radiation workers. Dickinson and Parker (2002) conducted a cohort study of > 250,000 births in Cumbria, England, including the cases of Gardner et al. (1990), and found a significant 2-fold increase in the risk of leukemia and non-Hodgkin lymphoma among the children of radiation workers. These and other studies, taken together, give statistical support to the idea that paternal radiation work is a risk factor for childhood leukemia. When interpreting the evidence for a PPI effect in atomic bomb survivors, it is important to consider what is known about potential mechanisms. As reviewed by Niwa (2003), Nomura (2003), and others, animal studies have consistently demonstrated that PPI can cause or increase the susceptibility to leukemia in offspring. In addition to fascinating evidence of postconception genomic instability after preconception exposure, many studies suggest that there may a window of sensitivity corresponding to post-meiotic stages of spermatogenesis; in humans, this would mean the few months leading up to conception (Adler 1996). Of the roughly 30,000 children of atomic bomb survivors, only about 2% were conceived in the 6 months after the bombings. Based on the spontaneous leukemia rate reported by Yoshimoto (1990), the expected number of spontaneous cases in this subcohort would be < 1, and an excess on the order suggested by the radiation worker studies would not be statistically apparent. For this and other reasons, the atomic bomb survivors may not be an appropriate comparison group. To summarize, it is not unreasonable to observe that the weight of evidence generated to date supports the idea that preconception, prenatal, and postnatal exposures to ionizing radiation are all risk factors for childhood leukemia.

Breastfeeding and childhood cancer risks: OSCC data.

Matched pair analysis relating to 3376 mothers of children who died of cancer 1972–1981 and of healthy control children from the Oxford Survey of Childhood Cancers showed no evidence of protection from breastfeeding for acute lymphocytic leukaemia (OR 1.04, 95% CI 0.86–1.26), for all cancers combined (OR 1.04, 95% CI 0.93–1.15) or for other groupings. Analyses by duration of breastfeeding also failed to support the protective hypothesis.

The Role of Epidemiology in the Detection of Harmful Effects of Radiation

Data relating to acute injuries of atomic bomb survivors show that the life span study cohort is biased in favor of exceptionally low levels of radiosensitivity. These data also show that factors influencing the death rates of this cohort include irreversible damage to the immune system. These impressions are still awaiting confirmation. Meanwhile, the Oxford Survey of Childhood Cancers and surveys of nuclear workers show that at low dose levels the cancer risk is much greater than estimates based on atomic bomb survivors; the special association between leukemia and radiation is an exclusively high dose effect, and levels of radiosensitivity are much lower in the middle of the life span than at either extreme.

The role of epidemiology in the detection of harmful effects of radiation.

Data relating to acute injuries of atomic bomb survivors show that the life span study cohort is biased in favor of exceptionally low levels of radiosensitivity. These data also show that factors influencing the death rates of this cohort include irreversible damage to the immune system. These impressions are still awaiting confirmation. Meanwhile, the Oxford Survey of Childhood Cancers and surveys of nuclear workers show that at low dose levels the cancer risk is much greater than estimates based on atomic bomb survivors; the special association between leukemia and radiation is an exclusively high dose effect, and levels of radiosensitivity are much lower in the middle of the life span than at either extreme.

Maternal occupational exposure to electromagnetic fields before, during, and after pregnancy in relation to risks of childhood cancers: Findings from the Oxford survey of childhood cancers, 1953-1981 deaths

The concern that maternal exposure to electromagnetic fields (EMF) might be related to childhood cancer risks, particularly leukemia risks. Maternal occupational data already collected as part of the Oxford Survey of Childhood Cancers have been reviewed. Information on occupations held before, during, and after the pregnancy was sought for 15,041 children dying of cancer in Great Britain in the period 1953-1981, and for an equal number of matched controls. Each period of working was classified under one of five headings: (1) sewing machinist; (2) textile industry workers (other than sewing machinists) with likely exposures to EMF; (3) other machinists and other jobs with likely "higher" EMF exposure; (4) other jobs with likely exposure to some EMF, and (5) jobs with little potential for EMF exposure. Relative to risks in the children of mothers who held occupations with little potential for EMF exposure during pregnancy (a category that included housewives), risks of all childhood cancers were close to unity both for the children of sewing machinists (22 case and 31 control mothers, RR 0.72, 95% CI 0.42 to 1.25) and for the children of other machinists with likely "higher" EMF exposures (44 case and 47 control mothers, RR 0.93, 95% CI 0.61 to 1.41). Corresponding risks for all childhood leukemias and for all childhood brain cancers were similarly unexceptional. Simultaneous adjustment for social class, maternal age at birth of child, and sibship position had little effect. The study findings did not indicate that maternal occupational exposure to EMF during pregnancy is a risk factor for childhood leukemias, childhood brain cancers, or the generality of all childhood cancers.

Maternal occupational exposure to electromagnetic fields before, during, and after pregnancy in relation to risks of childhood cancers: Findings from the Oxford survey of childhood cancers, 1953–1981 deaths

Maternal occupational exposure to electromagnetic fields before, during, and after pregnancy in relation to risks of childhood cancers: Findings from the Oxford survey of childhood cancers, 1953–1981 deaths

Childhood cancer and parental use of tobacco: deaths from 1971 to 1976.

Parental smoking data have been reabstracted from the interview records of the Oxford Survey of Childhood Cancers (deaths from 1971 to 1976). Reported smoking habits for the parents of 2587 children who died with cancer were compared with similar information for the parents of 2587 healthy controls (matched pairs analysis). Maternal daily consumption of cigarettes and paternal use of pipes or cigars were unimportant, but there was a statistically significant positive trend between paternal daily consumption of cigarettes and the risk of childhood cancer (P < 0.001). This association could not be explained by maternal smoking, social class, parental ages at the birth of the survey child, sibship position or obstetric radiography. Relations between maternal consumption of cigarettes and birth weights suggested that (maternal) smoking data were equally reliable for case and control subjects. About 14% of all childhood cancers in this series could be attributable to paternal smoking. These data were combined with smoking data from two previously published reports from the Oxford Survey (deaths from 1953 to 1955, deaths from 1977 to 1981) to obtain further information on risks for different types of cancer and different ages at onset of disease. Paternal cigarette smoking emerged as a potential risk factor both for the generality of childhood cancer and for all ages at onset.

Childhood cancer and parental use of tobacco: deaths from 1953 to 1955.

Parental smoking data have been abstracted from the interview records of the case-control study that first indicated that pregnancy radiographs are a cause of childhood cancer (Oxford Survey of Childhood Cancers, deaths from 1953 to 1955). Reported smoking habits for the parents of 1549 children who died from cancer were compared with similar information for the parents of 1549 healthy controls (matched pairs analysis). There was a statistically significant positive trend between paternal daily consumption of tobacco and the risk of childhood cancer (P< 0.001). This association could not be explained by maternal smoking, social class, paternal or maternal age at the birth of the survey child, sibship position or obstetric radiography. About 15% of all childhood cancers in this series could be attributable to paternal smoking.

Vitamin K at birth

Haemorrhagic disease of the newborn can be eradicated without risk of leukaemia or cancer That all newborn infants are deficient in vitamin K is apparent from their low plasma concentrations of vitamin K and a deficiency of the vitamin K dependent coagulation factors II, VII, IX, and X. This deficiency results in (early) haemorrhagic disease of the newborn in 0.4%-1.7% of babies in the first week of life.1 Late haemorrhagic disease occurs almost exclusively in breast fed infants, from 2 to 12 weeks of age, who did not receive intramuscular vitamin K at birth. The incidence has been reported to vary from 4.4 to 10.5 per 100 000 births.2 Vitamin K given intramuscularly at a dose of 1.0 mg corrects deficiency, prevents haemorrhagic disease of the newborn, and was standard practice until 1990. But in that year Golding et al reported an increased incidence of leukaemia and cancer in children who had received vitamin K intramuscularly at birth.3 This study, based on observations from the Oxford Survey of Childhood Cancers, was followed by a case-control study at two hospitals in Bristol, showing that the incidence of cancer in children who had received vitamin K at birth was twice that of children who had received either no vitamin K or an oral dose only.4 Golding et al's conclusions were supported by observations of the potential carcinogenicity of vitamin K. Israels et al reported that the addition of vitamin K to lymphocyte suspensions increased the rate of sister chromatic exchange,5 which correlates with a …

Pregnancy ultrasound and childhood cancer: a second report from the Oxford Survey of Childhood Cancers.

BJOG: An International Journal of Obstetrics & GynaecologyVolume 102, Issue 10 p. 831-832 Pregnancy ultrasound and childhood cancer: a second report from the Oxford Survey of Childhood Cancers Tom Sorahan, Corresponding Author Tom Sorahan Senior Research Fellow Department of Public Health and Epidemiology, University of BirminghamCorrespondence: Dr T. Sorahan, Senior Lecturer in Epidemiology, Institute of Occupational Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.Search for more papers by this authorRobert Lancashire, Robert Lancashire Computer Oficer Department of Public Health and Epidemiology, University of BirminghamSearch for more papers by this authorAlice Stewart, Alice Stewart Senior Research Fellow Department of Public Health and Epidemiology, University of BirminghamSearch for more papers by this authorIvy Peck, Ivy Peck Research Nurse Department of Public Health and Epidemiology, University of BirminghamSearch for more papers by this author Tom Sorahan, Corresponding Author Tom Sorahan Senior Research Fellow Department of Public Health and Epidemiology, University of BirminghamCorrespondence: Dr T. Sorahan, Senior Lecturer in Epidemiology, Institute of Occupational Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.Search for more papers by this authorRobert Lancashire, Robert Lancashire Computer Oficer Department of Public Health and Epidemiology, University of BirminghamSearch for more papers by this authorAlice Stewart, Alice Stewart Senior Research Fellow Department of Public Health and Epidemiology, University of BirminghamSearch for more papers by this authorIvy Peck, Ivy Peck Research Nurse Department of Public Health and Epidemiology, University of BirminghamSearch for more papers by this author First published: October 1995 https://doi.org/10.1111/j.1471-0528.1995.tb10851.xCitations: 21Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume102, Issue10October 1995Pages 831-832 RelatedInformation

Childhood cancer and paternal exposure to ionizing radiation: A second report from the oxford survey of childhood cancers

Paternal occupational data already collected as part of the Oxford Survey of Childhood Cancers have been reviewed. Information on paternal occupation was available for 14,869 children dying from cancer in England, Wales, and Scotland in the period 1953-81 and for an equal number of matched controls. The importance of fathers working, at any time before or after conception of the survey child, in any of the following occupations was assessed: radiologists (clinical), surgeons and anesthetists, veterinary surgeons, dental surgeons, nuclear industry workers, industrial radiographers. There was no indication that preconception employment in any of these occupations was more important than postconception employment with regard to the risks of all childhood cancers or all childhood leukemias. Findings were consistent with neither paternal preconception exposure to external ionizing radiation nor exposure to unsealed sources of radionuclides being an important risk factor for childhood leukemia or for the overall grouping of all childhood cancers.

Childhood cancer and paternal exposure to lonizing radiation: Preliminary findings from the oxford survey of childhood cancers

Paternal occupational data already collected as part of the Oxford Survey of Childhood Cancers have been reviewed. Information on occupations during or before the relevant pregnancy was sought for 15,279 children dying from cancer in England, Wales, and Scotland in the period 1953-81, and for an equal number of matched controls. Estimates were made for paternal exposure to human-made external ionizing radiation in the six months before conception of the survey child--as judged from job histories and dates of birth. Assessments were also made for potential exposure to unsealed sources of radionuclides. Of the eight fathers placed in the highest dose group (> or = 10 mSv, external radiation), four were cases and four were controls. For the second dose group (5-9 mSv), the corresponding numbers were eight and four, and for the lowest exposed group (1-4 mSv), they were 55 and 42. There were 27 case fathers with potential exposure to radionuclides and only 10 control fathers. The independent effects of the two radiation variables were assessed by means of multiple logistic regression. Relative risks for estimated doses of external radiation were close to unity, but for radionuclide exposure the relative risk was 2.87 (95% CI = 1.15-7.13). These preliminary findings suggest that paternal exposure to radionuclides is a more likely risk factor for childhood cancer than exposure to external radiation.

Book reviews

Few people can have published scientific papers for over 50 years, and this book celebrates Alice Stewart's achievement in doing this. It is essentially a collection of some of her papers from her early work on the effects of trinitrotoluene and carbon tetrachloride through to her important work with the Oxford Survey of Childhood Cancers and the Hanford workers, together with some of her colleague's papers.

A new calculation of the carcinogenic risk of obstetric X-raying.

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.

Pregnancy x-rays and childhood cancers:effects of exposure age and radiation dose

Using data from the Oxford Survey of Childhood Cancers this paper examinesthe effect of foetal age and number of films used on the subsequent risk of childhoodcancer associated with prenatal x-rays. X-rays early in pregnancy were taken for differentreasons and required more films when compared with those taken in late pregnancy.Therefore, Mantel-Haenszel techniques were used to estimate the independent effects of(a) exposure age and (b) number of films. Age at exposure had a clearly significant effect;x-rays taken in the first trimester of pregnancy were 2.69 times as effective as x-rays takenin the third trimester. First trimester exposures were often the result of maternal illnesses,so these maternal illnesses were then included among the controlling factors. When thiswas done the first trimester x-rays were 2.73 times as effective as later exposures. Firsttrimester x-rays were most strongly associated with the cancers which were diagnosedbetween 4 and 5 years of age. Although the number of films had no detectable effect uponrelative risk calculated over all ages, multiple exposures were demonstrably associated withearly age at diagnosis.

Malignant ovarian tumours in childhood in Britain, 1962-78.

The files of the Childhood Cancer Research Group and of the Oxford Survey of Childhood Cancers were scrutinized for all the ovarian neoplasms registered in England, Scotland and Wales in children under age 15 years throughout the period 1962-78. Among 172 cases confirmed as malignant ovarian tumours, 145 (84%) were tumours of germ cell origin (54 dysgerminomas, 36 malignant teratomas, 26 endodermal sinus tumours, 4 embryonal carcinomas, 2 pure choriocarcinomas, 20 mixed germ cell neoplasms, 3 gonadoblastomas), 13 (8%) were epithelial carcinomas (3 serous or undifferentiated, 10 mucinous), 9 (5%) were sex-cord stromal tumours (3 granulosa cell, 3 Sertoli-Leydig, 3 unclassified) and 5 (3%) were other miscellaneous tumour types. Less than 10% of the neoplasms occurred at age less than 5 years, approximately 20% from 5-9, and greater than 70% from 10-14 years. Germ cell neoplasms of greater malignancy (immature teratomas, endodermal sinus tumours) occurred in a significantly higher proportion at younger age (less than 10 years) than dysgerminomas (P = 0.01). The overall incidence (approximately 1.7 cases per 10(6) per annum) did not show any noticeable trend over the 17-year period considered. The clustering of two confined cases and, possibly, a third case, of germ cell neoplasms in three generations of the same family pointed to a genetic component in the aetiology of some of these neoplasms. A large number of sex related and mental or neurological abnormalities was also reported in case children. The 10-year survival rates, determined by the life-table method were: epithelial carcinomas 73%, sex-cord stromal tumours 44%, dysgerminomas 73%, malignant teratomas 33%, endodermal sinus tumours 39%, embryonal carcinomas 25%, other germ cell neoplasms 30% and gonadoblastomas 100%. Apart from cell-type, factors associated with prognosis were clinical stage (in all types), size and degree of histological differentiation (in malignant teratomas, but only when stage was not allowed for). The adoption of efficacious polychemotherapy regimens completely changed the prognosis of germ cell tumours other than dysgerminomas (from 29% to greater than 85% disease-free survivors in the present series).

The immune system and cancers of foetal origin.

Evidence of early loss of immunological competence in cases of neoplasms occurring in juveniles was found in an analysis of OSCC data (Oxford Survey of Childhood Cancers). The effects observed included heightened sensitivity to infection from birth onwards for all types of childhood cancer, higher levels of sensitivity for leukaemia than for lymphomas, and higher levels for lymphomas than for other solid tumours. The findings as a whole are consistent with in utero loss of immunological competence, which is an essential promoter of cancers of foetal origin and thus allows the outcome of an in utero cancer induction to be influenced both by maternal levels of immunological competence and postnatal infection.