Cadmium exposure and risk of breast cancer: A meta-analysis.

BACKGROUND: Cadmium is a heavy metal with carcinogenic properties, highly prevalent in industrialized areas worldwide. Prior reviews evaluating whether cadmium influences breast cancer have been inconclusive and not reflected several recent studies. OBJECTIVE: To evaluate the association between cadmium exposure and female breast cancer incidence, with an emphasis on separately estimating dietary vs. airborne vs. biomarker measures of cadmium and studies published until October 2022. METHODS: We evaluated risk of bias using set criteria and excluded one study judged to have high risk based on self-report of breast cancer and insufficient adjustment. We conducted a random effects meta-analysis of epidemiological studies, including subgroups by exposure route and by menopausal status. RESULTS: A total of 17 studies were eligible for our meta-analysis. Only 2 studies addressed airborne cadmium directly. Breast cancer risk was elevated in women exposed to higher levels of cadmium across all studies - pooled odds ratio: 1.13 (95% confidence interval: 1.00, 1.28), with notable heterogeneity between studies (I2 = 77%). When examining separately by exposure route, dietary cadmium was not linked with an elevated risk - (OR: 1.05; 95%CI: 0.91, 1.21; I2 = 69%), consistent with prior reviews, but biomarker-based studies showed an elevated but non-significant pooled measure (OR: 1.37; 95%CI: 0.96, 1.94; I2 = 84%). We did not observe any clear patterns of different risk by menopausal status. CONCLUSION: Findings from our meta-analysis suggest that exposure to higher cadmium increases the risk of breast cancer in women, but with remaining questions about whether non-dietary exposure may be more risky or whether residual confounding by constituents of tobacco smoke may be at play.

Long-term adverse outcomes in survivors of childhood bone sarcoma: the British Childhood Cancer Survivor Study.

BACKGROUND: With improved survival, more bone sarcoma survivors are approaching middle age making it crucial to investigate the late effects of their cancer and its treatment. We investigated the long-term risks of adverse outcomes among 5-year bone sarcoma survivors within the British Childhood Cancer Survivor Study. METHODS: Cause-specific mortality and risk of subsequent primary neoplasms (SPNs) were investigated for 664 bone sarcoma survivors. Use of health services, health and marital status, alcohol and smoking habits, and educational qualifications were investigated for survivors who completed a questionnaire. RESULTS: Survivors were seven times more likely to experience all-cause mortality than expected, and there were substantial differences in risk depending on tumour type. Beyond 25 years follow-up the risk of dying from all-causes was comparable to the general population. This is in contrast to dying before 25 years where the risk was 12.7-fold that expected. Survivors were also four times more likely to develop a SPN than expected, where the excess was restricted to 5-24 years post diagnosis. Increased health-care usage and poor health status were also found. Nonetheless, for some psychosocial outcomes survivors were better off than expected. CONCLUSIONS: Up to 25 years after 5-year survival, bone sarcoma survivors are at substantial risk of death and SPNs, but this is greatly reduced thereafter. As 95% of all excess deaths before 25 years follow-up were due to recurrences and SPNs, increased monitoring of survivors could prevent mortality. Furthermore, bone and breast SPNs should be a particular concern. Since there are variations in the magnitude of excess risk depending on the specific adverse outcome under investigation and whether the survivors were initially diagnosed with osteosarcoma or Ewing sarcoma, risks need to be assessed in relation to these factors. These findings should provide useful evidence for risk stratification and updating clinical follow-up guidelines.

Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US-UK study.

BACKGROUND: Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors. METHODS: Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case-control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls. RESULTS: Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5). CONCLUSIONS: There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution.

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.

Educational attainment among adult survivors of childhood cancer in Great Britain: a population-based cohort study.

BACKGROUND: Previous studies of educational attainment among childhood cancer survivors were small, had contradictory findings, and were not population based. This study investigated educational attainment in a large population-based cohort of survivors of all types of childhood cancer in Great Britain. METHODS: Four levels of educational attainment among 10,183 cancer survivors--degree, teaching qualification, advanced (A') levels, and ordinary (O') levels--were compared with expected levels in the general population. A questionnaire was used to obtain educational attainment data for survivors, and comparable information for the general population was available from the General Household Survey. Factors associated with level of educational attainment achieved by cancer survivors were identified using multivariable logistic regression together with likelihood ratio tests. Logistic regression adjusting for age and sex was used for comparisons with the general population. All statistical tests were two-sided. RESULTS: Childhood cancer survivors had lower educational attainment than the general population (degree: odds ratio [OR] = 0.77, 99% confidence interval [CI] = 0.68 to 0.87; teaching qualification: OR = 0.85, 99% CI = 0.77 to 0.94; A'level: OR = 0.85, 99% CI = 0.78 to 0.93; O'level: OR = 0.81, 99% CI = 0.74 to 0.90; P < .001, all levels). Statistically significant deficits were restricted to central nervous system (CNS) neoplasm and leukemia survivors. For leukemia, only those treated with radiotherapy were considered. Odds ratios for achievement by irradiated CNS tumor survivors were 50%-74% of those for cranially irradiated leukemia or nonirradiated CNS tumor survivors. Survivors at greater risk of poorer educational outcomes included those treated with cranial irradiation, diagnosed with a CNS tumor, older at questionnaire completion, younger at diagnosis, diagnosed with epilepsy, and who were female. CONCLUSIONS: Specific groups of childhood cancer survivors achieve lower-than-expected educational attainment. Detailed educational support and implementation of regular cognitive assessment may be indicated for some groups to maximize long-term function.

ACTH deficiency, higher doses of hydrocortisone replacement, and radiotherapy are independent predictors of mortality in patients with acromegaly.

CONTEXT: A number of retrospective studies report that patients with acromegaly have increased morbidity and premature mortality, with standardized mortality ratios (SMR) of 1.3-3. Many patients with acromegaly develop hypopituitarism as a result of the pituitary adenoma itself or therapies such as surgery and radiotherapy. Pituitary radiotherapy and hypopituitarism have also been associated with an increased SMR. METHODS: Using the West MIDLANDS: Acromegaly database (n = 501; 275 female), we assessed the influence of prior radiotherapy and hypopituitarism (and replacement therapy) on mortality in patients with acromegaly. Median duration of follow-up was 14.0 yr (interquartile range, 7.9-21 yr). RESULTS: All-cause mortality was elevated [SMR, 1.7 (1.4, 2.0); P < 0.001]. On external analysis, prior radiotherapy, ACTH, and gonadotropin deficiency were associated with an elevated SMR [radiotherapy SMR, 2.1 (1.7-2.6); P = 0.006; ACTH deficiency SMR, 2.5 (1.9-3.2); P < 0.0005; and gonadotropin deficiency SMR, 2.1 (1.6-2.7); P = 0.037]. On internal analysis, the relative risk (RR) of mortality was increased in the radiotherapy [RR, 1.8 (1.2-2.8); P = 0.008] and ACTH-deficiency groups [RR, 1.7 (1.2-2.5); P = 0.004], but not in the gonadotropin- or TSH-deficiency groups. In the ACTH-deficient group, increased replacement doses of hydrocortisone greater than 25 mg/d were associated with increased mortality compared to lower doses. CONCLUSIONS: Radiotherapy and ACTH deficiency are significantly associated with increased mortality in patients with acromegaly. In ACTH-deficient patients, a daily dose of more than 25 mg hydrocortisone is associated with increased mortality compared to lower doses. These results have important implications for the treatment of patients with acromegaly and also raise issues as to the optimum hydrocortisone treatment regimens for ACTH-deficient patients.

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.

The British Childhood Cancer Survivor Study: Objectives, methods, population structure, response rates and initial descriptive information.

BACKGROUND: In Britain 75% of individuals diagnosed with childhood cancer survive at least 5 years. The British Childhood Cancer Survivor Study was established to determine the risks of adverse health and social outcomes among survivors. To be eligible individuals were diagnosed with childhood cancer in Britain between 1940 and 1991 and survived at least 5 years. The entire cohort of 17,981 form the basis of population-based studies of late mortality and the risks/causes of second malignant neoplasms using national registration systems. METHODS: A postal questionnaire was sent to survivors who were alive and aged at least 16 years via their primary care physician. RESULTS: Of the 14,836 survivors eligible to receive a questionnaire, 10,483 (71%) returned it completed. Of the 13,211 who were mailed a questionnaire by their primary care physician 10,483 (79%) returned it completed. Outline treatment information concerning initial radiotherapy, chemotherapy and surgery is available. CONCLUSIONS: This is the largest available population-based cohort of childhood cancer survivors to have included investigation of a wide spectrum of adverse outcomes (the risk of which might be increased as a result of childhood cancer or its treatment). The study should provide useful information for counselling survivors, planning long-term clinical follow-up and evaluating the long-term risks likely to be associated with proposed treatment strategies.

A study of soft tissue sarcomas after childhood cancer in Britain.

Among 16 541 3-year survivors of childhood cancer in Britain, 39 soft tissue sarcomas (STSs) occurred and 1.1 sarcomas were expected, yielding a standardised incidence ratio (SIR) of 16.1. When retinoblastomas were excluded from the cohort, the SIR for STSs was 15.9, and the cumulative risk of developing a soft tissue tumour after childhood cancer within 20 years of 3-year survival was 0.23%. In the case-control study, there was a significant excess of STSs in those patients exposed to both radiotherapy (RT) and chemotherapy, which was five times that observed among those not exposed (P=0.02). On the basis of individual radiation dosimetry, there was evidence of a strong dose-response effect with a significant increase in the risk of STS with increasing dose of RT (P<0.001). This effect remained significant in a multivariate model. The adjusted risk in patients exposed to RT doses of over 3000 cGy was over 50 times the risk in the unexposed. There was evidence of a dose-response effect with exposure to alkylating agents, the risk increasing substantially with increasing cumulative dose (P=0.05). This effect remained after adjusting for the effect of radiation exposure.

Offspring sex ratio and gonadal irradiation in the British Childhood Cancer Survivor Study.

We investigated offspring sex ratio among 6232 offspring born to 3218 survivors of childhood cancer in relation to therapeutic irradiation, and pooled our data with those from two other large-scale studies giving a total of 9685 offspring. Exposure to high-dose gonadal irradiation was not associated with a significant alteration in offspring sex ratio compared to low doses (men: P=0.58, women: P=0.66). There was also no evidence that the ratio varied with time since cancer diagnosis when comparing survivors treated with radiotherapy vs those without (men: P=0.51; women: P=0.46). This, the largest study to date, finds no evidence that exposure to radiation affects the offspring sex ratio among survivors of childhood cancer.

Non-coronary heart disease mortality and risk of fatal cancer in patients with treated heterozygous familial hypercholesterolaemia: a prospective registry study.

BACKGROUND: The prognosis from coronary heart disease (CHD) for patients with heterozygous familial hypercholesterolaemia has improved substantially since the introduction of HMG Co-A reductase inhibitors (statins), but the effect of lipid-lowering drug therapy combined with dietary and life style advice on non-coronary mortality and the risk of fatal cancer is unclear. METHODS: The cohort of 2871 patients was recruited from 21 outpatient lipid clinics in the UK from 1980 to 1998 and was followed for 22,992 person-years. The standardised mortality ratio (SMR) was calculated from the ratio of the number of deaths observed to the number expected in the general population of England and Wales. RESULTS: There were 169 deaths, including 102 (60.4%) from CHD, and 32 (18.9%) from cancer. The SMR for CHD was 2.5-fold higher than in the general population (95% CI 2.1, 3.1), but the all-cause SMR was not increased (1.1, 95% CI 0.9, 1.3) and non-coronary mortality was significantly lower in men (0.5, 95% CI 0.3, 0.7) and women (0.6, 95% CI 0.4, 0.9). The SMR for all cancers was significantly reduced (0.6, 95% CI 0.4, 0.8) with an 80% reduction in fatal cancers of the respiratory and intra-thoracic organs and a non-significant reduction in fatal cancers of the genitourinary and digestive organs. CONCLUSIONS: Although the study cannot exclude the possibility that statins have anti-cancer activity, the results strongly suggest that giving advice to consume a healthy diet, increase physical activity and stop smoking is associated with a substantial reduction in mortality from cancer.

Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain.

In a population-based, retrospective cohort study of 16 541 3-year survivors of childhood cancer treated in Britain up to the end of 1987, 278 second malignant neoplasms (SMNs) were identified against 39.4 expected giving a standardised incidence ratio (SIR) of 6.2. The overall cumulative risk of an SMN by 25 years from 3-year survival from childhood cancer was 4.2%. Analysis of the cohort of nonretinoblastoma childhood cancers combined revealed a significant decline in SIR of SMN with increasing duration of follow-up. There was a greater risk of developing a SMN, particularly secondary acute myeloid leukaemia, in those diagnosed with childhood cancer from 1980 onwards. However, on multivariate modeling, this was not an independent risk factor. There was significant heterogeneity (P<0.001) in SIR of SMN across different treatment groups, the greatest risk observed in the group exposed to both radiotherapy and chemotherapy. The risks of SMN observed were comparable with those in other population-based studies. While the decline in SIR with duration of follow-up and the small excess numbers of cancers observed over later decades after diagnosis are reassuring, the high excess risk, particularly of leukaemia, associated with recent more intense therapy is of concern.

Comparison of the risk of fatal coronary heart disease in treated xanthomatous and non-xanthomatous heterozygous familial hypercholesterolaemia: a prospective registry study.

BACKGROUND: A clinical diagnosis of familial hypercholesterolaemia (FH) is often made in the absence of tendon xanthomata (TX), which are not usually present before the fourth decade of life. The prognosis of treated non-xanthomatous (TX-) FH is uncertain and the objective of this study was to compare mortality from coronary heart disease (CHD) in patients with treated TX+ (definite) and TX- (possible) heterozygous FH. METHODS: A diagnosis of definite or possible FH was based on raised cholesterol levels (>7.5 mmol/l) and a family history of premature CHD or hypercholesterolaemia. Patients were recruited from 21 outpatient lipid clinics in the UK from 1980 to 1998. The cohort of 1569 patients with TX+ FH were followed for 12754 person years and the cohort of 1302 patients with TX- FH for 10238 person years. The standardised mortality ratio (SMR) was calculated from the ratio of the number of deaths observed to the number expected in the general population of England and Wales (SMR=100 for reference population). FINDINGS AND DISCUSSION: CHD accounted for 64 (63%) of the 102 deaths in the TX+ cohort and 38 (57%) of the 67 deaths in the TX- cohort with the SMR for a fatal coronary event being, respectively, 294 (95% confidence interval 228, 380, P<0.00001) and 205 (95% CI 145, 282, P=0.0001). The similarly elevated CHD mortality risk suggests that, in adulthood, both groups of patients should be treated equally aggressively with HMG Co A reductase inhibitors (statins).

The risk and outcome of cerebral oedema developing during diabetic ketoacidosis.

BACKGROUND: Cerebral oedema is a major cause of morbidity and mortality in children with insulin dependent diabetes. AIMS: To determine the risk and outcome of cerebral oedema complicating diabetic ketoacidosis (DKA). METHODS: All cases of cerebral oedema in England, Scotland, and Wales were reported through the British Paediatric Surveillance Unit between October 1995 and September 1998. All episodes of DKA were reported by 225 paediatricians identified as involved in the care of children with diabetes through a separate reporting system between March 1996 and February 1998. Further information about presentation, management, and outcome was requested about the cases of cerebral oedema. The risk of cerebral oedema was investigated in relation to age, sex, seasonality, and whether diabetes was newly or previously diagnosed. RESULTS: A total of 34 cases of cerebral oedema and 2940 episodes of DKA were identified. The calculated risk of developing cerebral oedema was 6.8 per 1000 episodes of DKA. This was higher in new (11.9 per 1000 episodes) as opposed to established (3.8 per 1000) diabetes. There was no sex or age difference. Cerebral oedema was associated with a significant mortality (24%) and morbidity (35% of survivors). CONCLUSIONS: This first large population based study of cerebral oedema complicating DKA has produced risk estimates which are more reliable and less susceptible to bias than those from previous studies. Our study indicates that cerebral oedema remains an important complication of DKA during childhood and is associated with significant morbidity and mortality. Little is known of the aetiology of cerebral oedema in this condition and we are currently undertaking a case control study to address this issue.

Healthy pregnancy program in a national managed care organization: evaluation of satisfaction and health behavior outcomes.

OBJECTIVE: To evaluate satisfaction with the Healthy Pregnancy Program (HPP), which was developed to educate and coordinate the care of pregnant women in a managed care setting. STUDY DESIGN: Telephone survey. PATIENTS AND METHODS: A random sample of program participants at 3 large health plans were contacted by telephone to evaluate their satisfaction with the program overall and with its components, including an educational booklet and telephone contact with a HPP nurse as needed. Women also were asked about changes in health behaviors (smoking, alcohol use, diet, and stress) resulting directly from participation in the HPP. Of 1155 eligible women participating in HPP who delivered a baby from April 1997 through March 1998, 684 completed the survey. The response rate was 59%. RESULTS: Overall satisfaction with the HPP was reported by 96% of the women, and 76% reported the 2 highest ratings of satisfaction (completely or very satisfied). Reports of satisfaction were more likely for women who entered the program early in pregnancy, who read the booklet, and who had more telephone contacts. In general, at least half of the women in each behavior category reported improving their behavior, especially if they were younger, identified as high risk, or having their first child. Verbatim comments supported the high satisfaction levels. CONCLUSIONS: The HPP is an example of a program that was developed to improve healthcare delivery in a managed care setting and, when evaluated, was found to result in highly satisfied mothers likely to improve their health behaviors.

Phase I/IIa study of concurrent paclitaxel and cisplatin with radiation therapy in locally advanced non-small cell lung cancer: analysis of early and late pulmonary morbidity.

Recent efforts to improve survival outcome in patients with locally advanced non-small cell lung cancer have focused on the use of chemoradiotherapy regimens containing vinblastine/cisplatin or etoposide/cisplatin. However, the overall treatment outcome with these regimens remains poor, emphasizing the need for new therapeutic options. Based on the activity of paclitaxel in advanced non-small cell lung cancer, its additive cytotoxicity with cisplatin, and the radiation-sensitizing effect of both agents, a phase I/IIa study was designed to examine the feasibility of paclitaxel/cisplatin concurrently with conventional thoracic irradiation in patients with locally advanced tumors. One major concern regarding combined modality therapy has been the enhancement of pulmonary toxicity. This report describes the incidence and severity of pulmonary toxicities observed in this trial according to the Radiation Therapy Oncology Group scoring criteria. A literature-based review was performed in an attempt to determine the impact of paclitaxel-based versus non-paclitaxel-based chemoradiotherapy regimens on the early and late pulmonary morbidity. Twenty-four evaluable patients died and 14 (37%) are still alive without evidence of disease. The 1- and 2-year survival rates are 62% and 40%, respectively, with a median survival of 17 months. Pulmonary toxicity >/=grade 2 was more frequently manifested as late toxicity in approximately 70% of the patients. In most, prompt symptomatic and radiologic improvement was observed with the early administration of corticosteroids. There were three late grade 5 toxicities characterized by diffuse (bilateral) rapidly progressive interstitial infiltrates. Protracted lymphocytopenia was noted in the great majority of patients, and its role in the pathogenesis of this complication remains to be determined. There were minor changes in pulmonary function parameters, except in the forced vital capacity and diffusion capacity to carbon monoxide. In a univariate analysis, no relationship was noted between paclitaxel dose level, degree of lymphocytopenia, changes in pulmonary function indices, and incidence of pulmonary toxicity. However, there was a significant dose-volume relationship (using conventional dose-volume histograms) with late pulmonary toxicity at radiation doses between 15 Gy and 30 Gy. Based on a literature review, paclitaxel-based chemotherapy regimens seem to be associated with a slightly higher risk of pulmonary toxicity; however, comparison of such toxicity between trials has many limitations that require that the conclusion reached be viewed with caution.

Variations with time and age in the risks of solid cancer incidence after radiation exposure in childhood.

The Japanese atomic bomb survivor incidence data set and data on five other groups exposed to ionizing radiation in childhood are analysed and evidence found for a reduction in the radiation-induced relative risk of cancers other than leukaemia with increasing time since exposure. Overall, reductions of 5.7-6.1 per cent per year of time since exposure are indicated, depending on the time at which the reduction is presumed to start, and all the reductions are statistically significant at the 5 per cent level. There is no significant heterogeneity in the speed of the reductions in relative risk with time by cohort, by cancer type, sex, or age at exposure group. There is a significant reduction of relative risk with increasing age at exposure, but adjustment for age at exposure does not markedly affect the time trends of relative risk. For all of the groups considered, there is a statistically significant increase in the excess absolute risk with increasing time since exposure. However, by contrast with the relative homogeneity of the time trends of relative risk, there is statistically significant heterogeneity by cancer type within the Japanese cohort (P = 0.05) and between the cohorts (P < 0.0001) in the speed of increase of the excess absolute risk with time since exposure.