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.

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.

Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?

Few studies have examined human population data for evidence of an association between environmental mutagens and genetic disease. Our objective was to determine whether study of pregnancies and offspring of childhood cancer survivors would show evidence that therapy potentially mutagenic to germ cells is associated with increased risk of miscarriage, serious congenital abnormalities, or altered sex ratio. We analyzed information from patients' general practitioners for 2286 survivors of childhood cancer (1049 females and 1237 males) who were exposed or not exposed to direct irradiation of the abdomen or gonads or treatment with an alkylating agent. In addition, external control data based on the general population were used for some of the comparisons relating to congenital abnormalities and sex ratio. Data on reproductive history were complete for 1037 female survivors, who had 944 completed pregnancies, and 1078 male survivors, who produced 537 offspring. For the female survivors given abdominal or gonadal irradiation, there was an excess of miscarriages for the total number of pregnancies (17%) and for first pregnancies (19%), compared with the proportion for the total number of pregnancies in the females with similar neoplasms who were not exposed to such therapy (9%) and for first pregnancies in these females (8%). These results show re-emergence of an association suggested in our previous report of an increased risk of miscarriage as well as low birth weight among off-spring of female survivors of childhood cancer who received abdominal irradiation. In that study, it was considered unlikely that the association was due to germ cell mutation. Data in the present study do not show an association of exposure to therapy potentially mutagenic to germ cells with sex ratio, or with occurrence of serious congenital abnormalities in the offspring of male or female survivors of such therapy. However, the question of a possible germ cell mutagenic effect of therapy will be adequately addressed only through an international collaborative effort.

Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer.

BACKGROUND: Individuals who had cancer in childhood are at higher risk of developing bone cancer than any other type of second primary cancer. PURPOSE: Using the population-based National Registry of Childhood Tumours in Britain, we investigated the incidence and etiology of second primary bone cancer after childhood cancer in a cohort study and in a case-control study. METHODS: A cohort study of 13,175 3-year survivors of childhood cancer diagnosed in Britain between 1940 and 1983 revealed 55 subsequent bone cancers. A largely nested case-control study comprised 59 case subjects developing second primary bone cancer, and 220 control subjects were selected and matched for sex, type of first cancer, age at first cancer, and interval between diagnosis of first cancer and subsequent bone cancer. Outcome measures were the incidence of bone cancer after childhood cancer, the cumulative dose of radiation received at the site of the second cancer in the case subject and at the corresponding anatomic site in the matched control subjects, and the cumulative dose of alkylating agents and vinca alkaloids received by case and control subjects. RESULTS: The percentage of 3-year survivors developing bone cancer within 20 years did not exceed 0.9%, except following heritable retinoblastoma (7.2%), Ewing's sarcoma (5.4%), and other malignant bone tumors (2.4%). The risk of bone cancer increased substantially with increased cumulative dose of radiation to the bone (P< .001, linear trend). At the highest levels of exposure, however, the risk appeared to decline somewhat (P=.065, nonlinearity). Exposure to less than 10 Gy was at worst, associated with only a small increased relative risk (RR) of bone cancer (RR= 0.7; 95% confidence interval = 0.2-2.2). The risk of bone cancer increased linearly (P= .04, one-tailed test) with increased cumulative dose of alkylating agents. IMPLICATIONS: This population-based study provides grounds for reassurance of the majority of survivors in that their risk of developing bone cancer within 20 years of 3-year survival did not exceed 0.9%. The higher risks found for bone cancer following the other specific rare types of childhood cancer provide a rational basis for surveillance. The RRs reported for bone cancer after specified levels of exposure to radiation should help in making decisions concerning future treatment protocols.

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.

Influence of smoking, weight gain, and pregravid weight for height on intrauterine growth.

Combined effects of pregravid weight, weight gain and smoking on birth weight, length, and head circumference was investigated in uncomplicated, term pregnancies. Each gravida was categorized by height and pregravid weight as underweight, normal, moderately overweight, or massively overweight. Weight gain was grouped: poor, low-normal, high-normal, and excessive. Women who smoked 10 to 20 cigarettes daily were studied. Women who did not smoke were used as controls. Birth weights, lengths, and head circumferences were evaluated. Within each pregravid category and each gain group there was nearly uniform incremental increase in mean birthweight with advancing weight gain in both smoking and nonsmoking women. Infants born to smoking women fell behind nonsmoking counterparts by an entire gain group regardless of the mother's pregravid classification. Similar trends were observed in length and head circumference, although not as pronounced. Encouragement of higher weight gains helps correct the growth retardation observed in infants born to women who smoke.

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.

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).

Second primary tumors following radiotherapy for childhood cancer.

Among a cohort of 9,279 survivors of childhood neoplasms other than retinoblastoma treated in Britain before 1980, the cumulative risk of a second primary tumor (SPT) by 25 years from 3-year survival was 3.7%. This corresponds to about five times the number expected from rates of cancer occurring in the general population. In the absence of both radiotherapy and chemotherapy, there was four times the expected number of subsequent cancers. The risk of an SPT associated with radiotherapy but not chemotherapy and both radiotherapy and chemotherapy were 6 and 9 times that expected, respectively. There is evidence that radiotherapy was involved in the development of many of the SPT's observed. However, case-control investigations are required to examine the relationship between relative risk of an SPT and therapy in detail. Secondary leukemia appears to occur more frequently among more recently diagnosed children with cancer. It is important to continue to monitor the occurrence of SPT's with a view to identifying the least carcinogenic therapies that are consistent with not compromising survival prospects.

Fitting the Armitage-Doll model to radiation-exposed cohorts and implications for population cancer risks.

The Armitage-Doll model of carcinogenesis is fitted to Japanese bomb survivors with the DS86 dosimetry and to three other radiation-exposed cohorts. The model is found to provide an adequate description of solid cancer incidence and also, to a lesser extent, of that of leukemia as a function of radiation dose when up to two radiation-affected stages are assumed. For non-leukemias the optimal model is one in which there are two radiation-affected stages separated by two additional stages. In the case of leukemia one radiation-affected stage or two adjacent stages provide suitable fits. There appear to be significant differences between the optimal models fitted to each cohort, although there is no heterogeneity within the Japanese data set by sex, by cancer type, or by age at exposure. Low-dose and low-dose-rate population risks for a population having the cancer and overall mortality rates of the current UK population are calculated on the basis of the optimal models fitted to the Japanese data to be about 8.3 x 10(-2) excess cancer deaths person-1 Sv-1, 10.1 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 1.40 years of life lost person-1 Sv-1. Risks for a population having the mortality rates of the current Japanese population are about 6.5 x 10(-2) excess cancer deaths person-1 Sv-1, 7.8 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 0.89 years of life lost person-1 Sv-1. It is a feature of the Armitage-Doll model, and other multistage models of carcinogenesis, that if radiation acts at more than one stage then (inverse) dose-rate effects may arise as a result of interactions between the effects of a protracted dose at the various radiation-affected stages. However, it is shown in this paper that these three measures of cancer risk in general display fairly slight dependence on administered dose in the range 0.001 to 1.0 Sv and on the length of the time over which the dose is administered in the range 1 to 100 years. Dose-rate effects resulting from the protraction of a radiation exposure over many years acting on (the same) cells at various stages of a multistep process of carcinogenesis are therefore expected to be slight. Dose-rate effects which have been observed in epidemiological studies and cellular radiobiology may thus find their explanation in other phenomena such as short-term intracellular repair.

Time variations in the risk of cancer following irradiation in childhood.

The Japanese atomic bomb survivors and three other cohorts of children exposed to radiation are analyzed, and evidence is found for a reduction in the radiation-induced relative risk of cancers other than leukemia with time following exposure. Multiplicative adjustments to the excess risk either of the form exp[-delta.(time since exposure)] or of the form [time since exposure] gamma give equivalent goodness of fit. Using the former type of adjustment an annual overall reduction of 6.9-8.6% in excess relative risk is indicated (depending on the year after which this reduction might take effect). Using the second type of multiplier an adjustment to the excess relative risk varying between [time after exposure]-2.0 and [time after exposure]-3.2 fits best overall. All these reductions are statistically significant at the 5% level. There is no significant variation by cohort, by sex, by cancer type, or by age at exposure group in the degree of annual reduction in excess relative risk. Although time-adjusted relative and absolute risk models give equivalently good fits within each cohort, there is significant variation between cohorts in the degree of increase of risk with time in the absolute risk formulation, in contrast to the lack of such heterogeneity for the relative risk formulation. It is shown that if the range of observed reductions in relative risk is assumed to operate 40 or more years after exposure in the youngest age groups, the calculated UK population risks would be reduced by 30-45% compared to those based on a constant relative risk model.

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.

Late deaths and survival after childhood cancer: implications for cure.

OBJECTIVES: To investigate causes of death and survival in subjects who had survived at least five years after diagnosis of childhood cancer; to compare observed mortality with that expected in the general population; and to compare results with a corresponding cohort diagnosed earlier. DESIGN: Retrospective cohort study. SETTING: Population based National Register of Childhood Tumours. SUBJECTS: 9080 five year survivors of childhood cancer diagnosed in Britain during 1971-85, of whom 793 had died. Comparison with corresponding cohort diagnosed during 1940-70. MAIN OUTCOME MEASURES: Cause of death established from all available sources of information (including hospital and general practitioner records and postmortem reports) and underlying cause of death coded on death certificate. RESULTS: Of the 781 deaths for which sufficient information was available, death was attributed to recurrent tumour in 578 (74%) cases, treatment related effect in 121 (15%), second primary tumour in 52 (7%), and other causes in 30 (4%). Comparison of observed mortality with that expected in the general population indicated a fourfold excess of deaths from non-neoplastic causes. The risk of dying of recurrent tumour in the next 10 years after surviving five years from diagnosis during 1940-70 and 1971-85 fell from 12% to 8%. The risk of dying from a treatment related effect increased slightly from 1% to 2%. CONCLUSION: Improvements in five year survival after childhood cancer have been accompanied by a reduction in risk of dying from recurrent tumour during the subsequent 10 years and by a slight increase in risk of dying from treatment related effects. The results provide information relevant to decisions concerning balance between effective treatments and their potentially harmful effects.

Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

OBJECTIVE: To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN: Cohort study and a case-control study. SETTING: Britain and population based National Register of Childhood Tumours. SUBJECTS: Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES: Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS: Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS: Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer.