International Variation in Criteria for Internal Mammary Chain Radiotherapy.

AIMS: Evidence has emerged that internal mammary chain (IMC) radiotherapy reduces breast cancer mortality, leading to changes in treatment guidelines. This study investigated current IMC radiotherapy criteria and the percentages of patients irradiated for breast cancer in England who fulfilled them. MATERIALS AND METHODS: A systematic search was undertaken for national guidelines published in English during 2013-2018 presenting criteria for 'consideration of' or 'recommendation for' IMC radiotherapy. Patient and tumour variables were collected for patients who received breast cancer radiotherapy in England during 2012-2016. The percentages of patients fulfilling criteria stipulated in each set of guidelines were calculated. RESULTS: In total, 111 729 women were recorded as receiving adjuvant breast cancer radiotherapy in England during 2012-2016 and full data were available on 48 095 of them. Percentages of patients fulfilling IMC radiotherapy criteria in various national guidelines were: UK Royal College of Radiologists 13% (6035/48 095), UK National Institute for Health and Care Excellence 18% (8816/48 095), Germany 32% (15 646/48 095), Ireland 56% (26 846/48 095) and USA 59% (28 373/48 095). Differences between countries occurred because in Ireland and the USA, treatment may be considered in some node-negative patients, whereas in the UK, treatment is considered if at least four axillary nodes are involved or for high-risk patients with one to three positive nodes. In Germany, treatment may be considered for all node-positive patients. CONCLUSIONS: There is substantial variability between countries in criteria for consideration of IMC radiotherapy, despite guidelines being based on the same evidence. This will probably lead to large variations in practice and resource needs worldwide.

Radiation-related mortality from heart disease and lung cancer more than 20 years after radiotherapy for breast cancer.

BACKGROUND: Radiation-related heart disease and lung cancer can occur following radiotherapy for breast cancer but the duration of any mortality risk is uncertain. METHODS: Mortality ratios, by laterality of breast cancer, were estimated using Poisson regression for 558 871 women recorded with breast cancer during 1973-2008 in the Surveillance, Epidemiology and End Results (SEER) cancer registries and followed until 01 January 2009. RESULTS: For women diagnosed with breast cancer during 1973-1982 and given radiotherapy shortly afterwards, the cardiac mortality ratios, left-sided vs right-sided, were 1.19 (1.03-1.38), 1.35 (1.05-1.73), 1.64 (1.26-2.14) and 1.90 (1.52-2.37) at <10, 10-14, 15-19 and 20+ years since diagnosis (2p for trend: <0.001). The lung cancer mortality ratios, ipsilateral vs contralateral, in these women were 1.05 (0.57-1.94), 2.04 (1.28-3.23) and 3.87 (2.19-6.82) at <10, 10-19 and 20+ years, respectively, (2p for trend: 0.002). For women irradiated during 1983-92 there was evidence of radiation-related mortality for lung cancer, but not for heart disease. For women irradiated since 1993 there is, as yet, little evidence of any radiation-related mortality. CONCLUSION: In this population, the radiation-related risks were larger in the third decade after exposure than during the first two decades.

Impact of smoking on mortality and life expectancy in Japanese smokers: a prospective cohort study.

OBJECTIVE: To investigate the impact of smoking on overall mortality and life expectancy in a large Japanese population, including some who smoked throughout adult life. DESIGN: The Life Span Study, a population-based prospective study, initiated in 1950. SETTING: Hiroshima and Nagasaki, Japan. PARTICIPANTS: Smoking status for 27,311 men and 40,662 women was obtained during 1963-92. Mortality from one year after first ascertainment of smoking status until 1 January 2008 has been analysed. MAIN OUTCOME MEASURES: Mortality from all causes in current, former, and never smokers. RESULTS: Smokers born in later decades tended to smoke more cigarettes per day than those born earlier, and to have started smoking at a younger age. Among those born during 1920-45 (median 1933) and who started smoking before age 20 years, men smoked on average 23 cigarettes/day, while women smoked 17 cigarettes/day, and, for those who continued smoking, overall mortality was more than doubled in both sexes (rate ratios versus never smokers: men 2.21 (95% confidence interval 1.97 to 2.48), women 2.61 (1.98 to 3.44)) and life expectancy was reduced by almost a decade (8 years for men, 10 years for women). Those who stopped smoking before age 35 avoided almost all of the excess risk among continuing smokers, while those who stopped smoking before age 45 avoided most of it. CONCLUSIONS: The lower smoking related hazards reported previously in Japan may have been due to earlier birth cohorts starting to smoke when older and smoking fewer cigarettes per day. In Japan, as elsewhere, those who start smoking in early adult life and continue smoking lose on average about a decade of life. Much of the risk can, however, be avoided by giving up smoking before age 35, and preferably well before age 35.

Estimating cardiac exposure from breast cancer radiotherapy in clinical practice.

PURPOSE: To assess the value of maximum heart distance (MHD) in predicting the dose and biologically effective dose (BED) to the heart and the left anterior descending (LAD) coronary artery for left-tangential breast or chest wall irradiation. METHODS AND MATERIALS: A total of 50 consecutive breast cancer patients given adjuvant left-tangential irradiation at a large U.K. radiotherapy center during 2006 were selected. For each patient, the following were derived using three-dimensional computed tomography (CT) planning: (1) mean dose and BED to the heart, (2) mean dose and BED to the LAD coronary artery, (3) MHD, (4) position of the CT slice showing the maximum area of the irradiated heart relative to the mid-plane slice, and (5) sternal and contralateral breast thickness (measures of body fat). RESULTS: A strong linear correlation was found between the MHD and the mean heart dose. For every 1-cm increase in MHD, the mean heart dose increased by 2.9% on average (95% confidence interval 2.5-3.3). A strong linear-quadratic relationship was seen between the MHD and the mean heart BED. The mean LAD coronary artery dose and BED were also correlated with the MHD but the associations were weaker. These relationships were not affected by body fat. The mid-plane CT slice did not give a reliable assessment of cardiac irradiation. CONCLUSION: The MHD is a reliable predictor of the mean heart dose and BED and gives an approximate estimate of the mean LAD coronary artery dose and BED. Doses predicted by the MHD could help assess the risk of radiation-induced cardiac toxicity where individual CT-based cardiac dosimetry is not possible.

Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials.

BACKGROUND: The long-term effects of adjuvant polychemotherapy regimens in oestrogen-receptor-poor (ER-poor) breast cancer, and the extent to which these effects are modified by age or tamoxifen use, can be assessed by an updated meta-analysis of individual patient data from randomised trials. METHODS: Collaborative meta-analyses of individual patient data for about 6000 women with ER-poor breast cancer in 46 trials of polychemotherapy versus not (non-taxane-based polychemotherapy, typically about six cycles; trial start dates 1975-96, median 1984) and about 14 000 women with ER-poor breast cancer in 50 trials of tamoxifen versus not (some trials in the presence and some in the absence of polychemotherapy; trial start dates 1972-93, median 1982). FINDINGS: In women with ER-poor breast cancer, polychemotherapy significantly reduced recurrence, breast cancer mortality, and death from any cause, in those younger than 50 years and those aged 50-69 years at entry into trials of polychemotherapy versus not. In those aged younger than 50 years (1907 women, 15% node-positive), the 10-year risks were: recurrence 33% versus 45% (ratio of 10-year risks 0.73, 2p<0.00001), breast cancer mortality 24% versus 32% (ratio 0.73, 2p=0.0002), and death from any cause 25% versus 33% (ratio 0.75, 2p=0.0003). In women aged 50-69 years (3965 women, 58% node-positive), the 10-year risks were: recurrence 42% versus 52% (ratio 0.82, 2p<0.00001), breast cancer mortality 36% versus 42% (ratio 0.86, 2p=0.0004), and death from any cause 39% versus 45% (ratio 0.87, 2p=0.0009). Few were aged 70 years or older. Tamoxifen had little effect on recurrence or death in women who were classified in these trials as having ER-poor disease, and did not significantly modify the effects of polychemotherapy. INTERPRETATION: In women who had ER-poor breast cancer, and were either younger than 50 years or between 50 and 69 years, these older adjuvant polychemotherapy regimens were safe (ie, had little effect on mortality from causes other than breast cancer) and produced substantial and definite reductions in the 10-year risks of recurrence and death. Current and future chemotherapy regimens could well yield larger proportional reductions in breast cancer mortality.

Measurement error in the explanatory variable of a binary regression: regression calibration and integrated conditional likelihood in studies of residential radon and lung cancer.

In epidemiology, one approach to investigating the dependence of disease risk on an explanatory variable in the presence of several confounding variables is by fitting a binary regression using a conditional likelihood, thus eliminating the nuisance parameters. When the explanatory variable is measured with error, the estimated regression coefficient is biased usually towards zero. Motivated by the need to correct for this bias in analyses that combine data from a number of case-control studies of lung cancer risk associated with exposure to residential radon, two approaches are investigated. Both employ the conditional distribution of the true explanatory variable given the measured one. The method of regression calibration uses the expected value of the true given measured variable as the covariate. The second approach integrates the conditional likelihood numerically by sampling from the distribution of the true given measured explanatory variable. The two approaches give very similar point estimates and confidence intervals not only for the motivating example but also for an artificial data set with known properties. These results and some further simulations that demonstrate correct coverage for the confidence intervals suggest that for studies of residential radon and lung cancer the regression calibration approach will perform very well, so that nothing more sophisticated is needed to correct for measurement error.

Cardiac risks of breast-cancer radiotherapy: a contemporary view.

For some time, there has been compelling evidence both from randomised-controlled trials and from observational studies, that some of the breast-cancer radiotherapy regimens used in the past have led to increased risk of mortality from heart disease. There is also some evidence that the more recent regimens used in the USA are associated with lower risks than previous ones, but it is not clear whether current regimens are free from cardiac risk, especially in the light of recent evidence from the survivors of the bombings of Hiroshima and Nagasaki, in whom a clear relationship was observed between the risk of mortality from heart disease and radiation dose for doses in the range 0-4 Gy. Mortality from radiation-induced heart disease usually occurs at least a decade after irradiation. Symptomatic heart disease might have a much shorter induction period, but little information about it is available at present. Subclinical vascular abnormalities have been observed within months of irradiation, via myocardial perfusion imaging studies, but little is known about the relationship between these and later overt heart disease. At present, few data relate heart dose and other specific characteristics of breast radiotherapy to cardiac outcome. Further information on these topics is needed to enable estimation of the cardiac risk, that is likely to arise from radiotherapy regimens in current use and from those being considered for future use. Such knowledge would facilitate radiotherapy treatment planning and enable a reduction in cardiac risk while maintaining the known benefit in terms of breast cancer mortality.

Epidemiological studies of UK test veterans: I. General description.

This review gives a general account of how and why epidemiological studies of UK participants in the nuclear weapons test programme were set up. There is a short description of the circumstances in which the tests were planned and executed and a discussion of the general considerations involved in designing studies to show whether the health of test participants suffered as a result of the tests. The companion review article summarises the results of the epidemiological studies.

Epidemiological studies of UK test veterans: II. Mortality and cancer incidence.

An epidemiological study was set up in the 1980s of UK participants in the UK atmospheric nuclear weapons testing programme. A large cohort of test participants was established along with a closely matched comparison or control group. Three analyses of mortality and cancer incidence have been carried out. This review describes the development of the evidence on possible effects on test participants with especial emphasis on the most recent analysis. Other sources of evidence, particularly from studies of other groups of test participants, are also considered. It was concluded that overall levels of mortality and cancer incidence in UK nuclear weapons test participants were similar to those in a matched control group, and overall mortality was lower than expected from national rates. There was no evidence of an increased raised risk of multiple myeloma among test participants in recent years, and the suggestion in the first analysis of this cohort of a raised myeloma risk relative to controls is likely to have been a chance finding. There was some evidence of a raised risk of leukaemia other than chronic lymphatic leukaemia among test participants relative to controls, particularly in the early years after the tests. Whilst this could be a chance finding, the possibility that test participation caused a small absolute risk of leukaemia other than chronic lymphatic leukaemia cannot be ruled out.

The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977-99.

BACKGROUND: Previous studies of the development of inhibitors and their impact on mortality have been small. OBJECTIVES: To examine the development of inhibitors in people with hemophilia in the UK and their effect on subsequent mortality. PATIENTS: 6078 males with hemophilia A and 1172 males with hemophilia B registered in the UK Haemophilia Centre Doctors' Organisation database, 1977-98. RESULTS: In severe hemophilia A inhibitors developed at rates of 34.4, 5.2 and 3.8 per 1000 years at ages <5, 5-14 and 15+years; cumulative risks at ages 5 and 75 were 16% and 36%. In hemophilia A the rate of inhibitor development decreased during 1977-90, but increased during the 1990s. In severe hemophilia B inhibitors developed at rates of 13.3 and 0.2 per 1000 years at ages <5 and 5+ and cumulative risks at ages 5 and 75 were 6% and 8%. With HIV, inhibitor development did not increase mortality. In severe hemophilia without HIV, inhibitor development doubled mortality during 1977-92, but during 1993-99 mortality was identical with and without inhibitors. In severe hemophilia without HIV but with inhibitors, mortality from causes involving bleeding decreased during 1977-99 (P = 0.001) as did mortality involving intracranial hemorrhage (P = 0.007). CONCLUSIONS: These data provide estimates of the rate of inhibitor development in hemophilia A and hemophilia B, and they show that the rate of inhibitor development has varied over time, although the reasons for this remain unclear. They also show that in severe hemophilia the substantial increase in mortality previously associated with inhibitors is no longer present.

Health effects of residential radon: a European perspective at the end of 2002.

Surveys of indoor radon concentrations, when taken together with estimates of the risk of lung cancer from studies in miners of uranium and other hard rocks, suggest that residential radon is responsible for many thousands of deaths from lung cancer each year in Europe. The vast majority of these deaths are likely to occur in individuals who also smoke cigarettes. Because of the skewed nature of the distribution of the indoor radon concentrations in most populations, most of the deaths will occur in individuals who are exposed at moderate rather than at very high radon concentrations. In order to enable appropriate policies to be developed for managing the consequences of exposure to radon, more reliable estimates of the risk of lung cancer resulting from it are needed. To achieve this, a European Collaborative Group on Residential Radon and Lung Cancer was initiated and its findings should be published in 2004.

100 years of observation on British radiologists: mortality from cancer and other causes 1897-1997.

Radiologists and radiotherapists were one of the earliest occupational groups to be exposed to ionizing radiation. Their patterns of mortality provide information on the long-term effects of fractionated external radiation exposure. British radiologists who registered with a radiological society between 1897 and 1979 have now been followed-up until 1 January 1997, and the mortality experience examined among those who registered with a society after 1920, when the first radiological protection recommendations were published. The observed number of cancer deaths in those who registered after 1920 was similar to that expected from death rates for all medical practitioners combined (SMR=1.04; 95% CI 0.89-1.21). However, there was evidence of an increasing trend in risk of cancer mortality with time since first registration with a radiological society (p=0.002), such that in those registered for more than 40 years there was a 41% excess risk of cancer mortality (SMR=1.41; 95% CI 1.03-1.90). This is probably a long-term effect of radiation exposure in those who first registered during 1921-1935 and 1936-1954. There was no evidence of an increase in cancer mortality among radiologists who first registered after 1954, in whom radiation exposures are likely to have been lower. Non-cancer causes of death were also examined in more detail than has been reported previously. There was no evidence of an effect of radiation on diseases other than cancer even in the earliest radiologists, despite the fact that doses of the size received by them have been associated with more than a doubling in the death rate among the survivors of the Japanese atomic bombings.

Lung cancer and cigarette smoking in Europe: an update of risk estimates and an assessment of inter-country heterogeneity.

Ten case-control studies have been carried out in 6 European countries to investigate the major risk factors for lung cancer. Carcinogenic effect from cigarette smoke was the most relevant interest in our study, which has included 7,609 cases of lung cancer and 10,431 controls, mainly population based. The results indicate elevated odds ratios (ORs; 23.9 among men and 8.7 among women) with attributable risks exceeding 90% for men and close to 60% for women. A large, and statistically significant, variability of the results across countries was detected after adjusting for the most common confounding variables, and after controlling, at least in part, for the instability of the ORs due to the small number of non-smokers in some of the study subsets. This pattern of lung cancer risk associated with cigarettes smoke, across different European regions, reflects inherent characteristics of the studies as well as differences in smoking habits, particularly calendar periods of starting, and it is likely to have been influenced by effect modifiers like indoor radon exposure, occupation, air pollution and dietary habits.

Lung cancer and cigarette smoking in women: a multicenter case-control study in Europe.

The association between cigarette smoking and lung cancer risk in women was investigated within the framework of a case-control study in 9 centres from 6 European countries. Cases were 1,556 women up to 75 years of age with histologically confirmed primary lung cancer; 2, 450 controls with age distribution similar to cases were selected. The predominant cell type was adenocarcinoma (33.5%), with similar proportions for squamous-cell type (26.4%) and small-cell carcinoma (22.3%). Overall, smoking cigarettes at any time was associated with a 5-fold increase in lung cancer risk (odds ratio 5.21, 95% confidence interval 4.49-6.04); corresponding figures for current smoking habits were 8.94, 7.54-10.6. The association showed a dose-response relationship with duration of the habit and daily and cumulative lifetime smoking. A significant excess risk of 70% was associated with every 10 pack-years smoked. After 10 years of smoking cessation, the relative risk decreased to 20% compared to current smokers. The following characteristics were associated with a higher relative risk: inhalation of smoke, smoking non-filter cigarettes, smoking dark-type cigarettes and starting at young age. The association was observed for all major histological types, being the strongest for small-cell type carcinoma, followed by squamous-cell type and the lowest for adenocarcinoma. The proportion of lung-cancer cases in the population attributable to cigarette smoking ranged from 14% to 85%. We concluded that women share most features of the association between cigarette smoking and lung cancer observed in men.

Risks of leukemia in Japanese atomic bomb survivors, in women treated for cervical cancer, and in patients treated for ankylosing spondylitis.

The dose-response relationship for radiation-induced leukemia was examined in a pooled analysis of three exposed populations: Japanese atomic bomb survivors, women treated for cervical cancer, and patients irradiated for ankylosing spondylitis. A total of 383 leukemias were observed among 283,139 study subjects. Considering all leukemias apart from chronic lymphocytic leukemia, the optimal relative risk model had a dose response with a purely quadratic term representing induction and an exponential term consistent with cell sterilization at high doses; the addition of a linear induction term did not improve the fit of the model. The relative risk decreased with increasing time since exposure and increasing attained age, and there were significant (P < 0.00001) differences in the parameters of the model between datasets. These differences were related in part to the significant differences (P = 0.003) between the models fitted to the three main radiogenic leukemia subtypes (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia). When the three datasets were considered together but the analysis was repeated separately for the three leukemia subtypes, for each subtype the optimal model included quadratic and exponential terms in dose. For acute myeloid leukemia and chronic myeloid leukemia, there were reductions of relative risk with increasing time after exposure, whereas for acute lymphocytic leukemia the relative risk decreased with increasing attained age. For each leukemia subtype considered separately, there was no indication of a difference between the studies in the relative risk and its distribution as a function of dose, age and time (P > 0.10 for all three subtypes). The nonsignificant indications of differences between the three datasets when leukemia subtypes were considered separately may be explained by random variation, although a contribution from differences in exposure dose-rate regimens, inhomogeneous dose distribution within the bone marrow, inadequate adjustment forcell sterilization effects, or errors in dosimetry could have played a role.

Intercomparison of passive radon-detectors under field conditions in epidemiological studies.

The Ardennes and Eifel region is a geologically distinct area covering parts of Germany, Belgium, France, and Luxembourg where enhanced concentrations of radon occur in some houses and other buildings. An international case-control study is being conducted to examine the role of radon in the etiology of lung cancer in this area. The radon detectors used are issued by different laboratories involving a variety of detector types and processes. A series of intercomparisons in houses was therefore conducted under similar conditions of exposure in the field. In most situations the different detectors gave similar results. Nevertheless, in some situations open and closed detectors yielded different results. Therefore, estimates of radon exposure have to be adjusted if results are to be pooled.

Some aspects of measurement error in explanatory variables for continuous and binary regression models.

A simple form of measurement error model for explanatory variables is studied incorporating classical and Berkson cases as particular forms, and allowing for either additive or multiplicative errors. The work is motivated by epidemiological problems, and therefore consideration is given not only to continuous response variables but also to logistic regression models. The possibility that different individuals in a study have errors of different types is also considered. The relatively simple estimation procedures proposed for use with cohort data and case-control data are checked by simulation, under the assumption of various error structures. The results show that even in situations where conventional analysis yields slope estimates that are on average attenuated by a factor of approximately 50 per cent, estimates obtained using the proposed amended likelihood functions are within 5 per cent of their true values. The work was carried out to provide a method for the analysis of lung cancer risk following residential radon exposure, but it should be applicable to a wide variety of situations.