Elsebeth Lynge

The Danish National Patient Register

Introduction: The Danish National Patient Register (NPR) was established in 1977, and it is considered to be the finest of its kind internationally. Content: At the onset the register included information on inpatient in somatic wards. The content of the register has gradually been expanded, and since 2007 the register has included information on all patients in Danish hospitals. Validity and coverage: Although the NPR is overall a sound data source, both the content and the definitions of single variables have changed over time. Changes in the organisation and provision of health services may affect both the type and the completeness of registrations. Conclusion: The NPR is a unique data source. Researchers using the data should carefully consider potential fallacies in the data before drawing conclusions.

Occupation and cancer ― follow-up of 15 million people in five Nordic countries

We present up to 45 years of cancer incidence data by occupational category for the Nordic populations. The study covers the 15 million people aged 30–64 years in the 1960, 1970, 1980/1981 and/or 1990 censuses in Denmark, Finland, Iceland, Norway and Sweden, and the 2.8 million incident cancer cases diagnosed in these people in a follow-up until about 2005. The study was undertaken as a cohort study with linkage of individual records based on the personal identity codes used in all the Nordic countries. In the censuses, information on occupation for each person was provided through free text in self-administered questionnaires. The data were centrally coded and computerised in the statistical offices. For the present study, the original occupational codes were reclassified into 53 occupational categories and one group of economically inactive persons. All Nordic countries have a nation-wide registration of incident cancer cases during the entire study period. For the present study the incident cancer cases were classified into 49 primary diagnostic categories. Some categories have been further divided according to sub-site or morphological type. The observed number of cancer cases in each group of persons defined by country, sex, age, period and occupation was compared with the expected number calculated from the stratum specific person years and the incidence rates for the national population. The result was presented as a standardised incidence ratio, SIR, defined as the observed number of cases divided by the expected number. For all cancers combined (excluding non-melanoma skin cancer), the study showed a wide variation among men from an SIR of 0.79 (95% confidence interval 0.66–0.95) in domestic assistants to 1.48 (1.43–1.54) in waiters. The occupations with the highest SIRs also included workers producing beverage and tobacco, seamen and chimney sweeps. Among women, the SIRs varied from 0.58 (0.37–0.87) in seafarers to 1.27 (1.19–1.35) in tobacco workers. Low SIRs were found for farmers, gardeners and teachers. Our study was able to repeat most of the confirmed associations between occupations and cancers. It is known that almost all mesotheliomas are associated with asbestos exposure. Accordingly, plumbers, seamen and mechanics were the occupations with the highest risk in the present study. Mesothelioma was the cancer type showing the largest relative differences between the occupations. Outdoor workers such as fishermen, gardeners and farmers had the highest risk of lip cancer, while the lowest risk was found among indoor workers such as physicians and artistic workers. Studies of nasal cancer have shown increased risks associated with exposure to wood dust, both for those in furniture making and for those exposed exclusively to soft wood like the majority of Nordic woodworkers. We observed an SIR of 1.84 (1.66–2.04) in male and 1.88 (0.90–3.46) in female woodworkers. For nasal adenocarcinoma, the SIR in males was as high as 5.50 (4.60–6.56). Male waiters and tobacco workers had the highest risk of lung cancer, probably attributable to active and passive smoking. Miners and quarry workers also had a high risk, which might be related to their exposure to silica dust and radon daughters. Among women, tobacco workers and engine operators had a more than fourfold risk as compared with the lung cancer risk among farmers, gardeners and teachers. The occupational risk patterns were quite similar in all main histological subtypes of lung cancer. Bladder cancer is considered as one of the cancer types most likely to be related to occupational carcinogens. Waiters had the highest risk of bladder cancer in men and tobacco workers in women, and the low-risk categories were the same ones as for lung cancer. All this can be accounted for by smoking. The second-highest SIRs were among chimney sweeps and hairdressers. Chimney sweeps are exposed to carcinogens such as polycyclic aromatic hydrocarbons from the chimney soot, and hairdressers’ work environment is also rich in chemical agents. Exposure to the known hepatocarcinogens, the Hepatitis B virus and aflatoxin, is rare in the Nordic countries, and a large proportion of primary liver cancers can therefore be attributed to alcohol consumption. The highest risks of liver cancer were seen in occupational categories with easy access to alcohol at the work place or with cultural traditions of high alcohol consumption, such as waiters, cooks, beverage workers, journalists and seamen. The risk of colon cancer has been related to sedentary work. The findings in the present study did not strongly indicate any protective role of physical activity. Colon cancer was one of the cancer types showing the smallest relative variation in incidence between occupational categories. The occupational variation in the risk of female breast cancer (the most common cancer type in the present series, 373 361 cases) was larger, and there was a tendency of physically demanding occupations to show SIRs below unity. Women in occupations which require a high level of education have, on average, a higher age at first child-birth and elevated breast cancer incidence. Women in occupational categories with the highest average number of children had markedly lower incidence. In male breast cancer (2 336 cases), which is not affected by the dominating reproductive factors, there was a suggestion of an increase in risk in occupations characterised by shift work. Night-shift work was recently classified as probably carcinogenic, with human evidence based on breast cancer research. The most common cancer among men in the present cohort was prostate cancer (339 973 cases). Despite the huge number of cases, we were unable to demonstrate any occupation-related risks. The observed small occupational variation could be easily explained by varying PSA test frequency. The Nordic countries are known for equity and free and equal access to health care for all citizens. The present study shows that the risk of cancer, even under these circumstances, is highly dependent on the persons position in the society. Direct occupational hazards seem to explain only a small percentage of the observed variation – but still a large number of cases – while indirect factors such as life style changes related to longer education and decreasing physical activity become more important. This publication is the first one from the extensive Nordic Occupational Cancer (NOCCA) project. Subsequent studies will focus on associations between specific work-related factors and cancer diseases with the aim to identify exposure-response patterns. In addition to the cancer data demonstrated in the present publication, the NOCCA project produced Nordic Job Exposure Matrix (described in separate articles in this issue of Acta Oncologica) that transforms information about occupational title histories to quantitative estimates of specific exposures. The third essential component is methodological development related to analysis and interpretation of results based on averaged information of exposures and co-factors in the occupational categories.

Overdiagnosis in mammographic screening for breast cancer in Europe: A literature review

Objectives Overdiagnosis, the detection through screening of a breast cancer that would never have been identified in the lifetime of the woman, is an adverse outcome of screening. We aimed to determine an estimate range for overdiagnosis of breast cancer in European mammographic service screening programmes. Methods We conducted a literature review of observational studies that provided estimates of breast cancer overdiagnosis in European population-based mammographic screening programmes. Studies were classified according to the presence and the type of adjustment for breast cancer risk (data, model and covariates used), and for lead time (statistical adjustment or compensatory drop). We expressed estimates of overdiagnosis from each study as a percentage of the expected incidence in the absence of screening, even if the variability in the age range of the denominator could not be removed. Estimates including carcinoma in situ were considered when available. Results There were 13 primary studies reporting 16 estimates of overdiagnosis in seven European countries (the Netherlands, Italy, Norway, Sweden, Denmark, UK and Spain). Unadjusted estimates ranged from 0% to 54%. Reported estimates adjusted for breast cancer risk and lead time were 2.8% in the Netherlands, 4.6% and 1.0% in Italy, 7.0% in Denmark and 10% and 3.3% in England and Wales. Conclusions The most plausible estimates of overdiagnosis range from 1% to 10%. Substantially higher estimates of overdiagnosis reported in the literature are due to the lack of adjustment for breast cancer risk and/or lead time.

Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols.

Epidemiological studies have revealed an increased risk of cancer, notably soft-tissue sarcomas and non-Hodgkins lymphomas, in people occupationally exposed to chlorophenoxy herbicides, including those contaminated by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). We report here a historical cohort study of mortality in an international register of 18,910 production workers or sprayers from ten countries. Exposure was reconstructed through questionnaires, factory or spraying records, and job histories. Cause-specific national death rates were used as reference. No excess was observed in all-cause mortality, for all neoplasms, for the most common epithelial cancers, or for lymphomas. A statistically non-significant two-fold excess risk, based on 4 observed deaths, was noted for soft-tissue sarcoma with a standardised mortality ratio (SMR) of 196 and 95% confidence interval (Cl) 53-502; this was concentrated as a six-fold statistically significant excess, occurring 10-19 years from first exposure in the cohort as a whole (SMR = 606 [165-1552]) and, for the same time period, as a nine-fold excess among sprayers (SMR = 882 [182-2579]). Risks appeared to be increased for cancers of the testicle, thyroid, other endocrine glands, and nose and nasal cavity, based on small numbers of deaths. The excess of soft-tissue sarcomas among sprayers is compatible with a causal role of chlorophenoxy herbicides but the excess does not seem to be specifically associated with those herbicides probably contaminated by TCDD.

Occupation and bladder cancer among men in Western Europe

Objectives: We examined which occupations and industries are currently at high risk for bladder cancer in men. Methods: We combined data from 11 case–control studies conducted between 1976–1996 in six European countries. The study comprised 3346 incident cases and 6840 controls, aged 30–79 years. Lifetime occupational and smoking histories were examined using common coding. Results: Odds ratios for eight a priori defined high-risk occupations were low, and with the exception of metal workers and machinists (OR = 1.16, 95% CI = 1.02–1.32), were not statistically significant. Higher risks were observed for specific categories of painters, metal, textile and electrical workers, for miners, transport operators, excavating-machine operators, and also for non-industrial workers such as concierges and janitors. Industries entailing a high risk included salt mining, manufacture of carpets, paints, plastics and industrial chemicals. An increased risk was found for exposure to PAHs (OR for highest exposure tertile = 1.23, 95% CI = 1.07–1.4). The risk attributable to occupation ranged from 4.2 to 7.4%, with an estimated 4.3% for exposure to PAHs. Conclusions: Metal workers, machinists, transport equipment operators and miners are among the major occupations contributing to occupational bladder cancer in men in Western Europe. In this population one in 10 to one in 20 cancers of the bladder can be attributed to occupation.

The impact of mammographic screening on breast cancer mortality in Europe: a review of observational studies

Objectives To assess the impact of population-based mammographic screening on breast cancer mortality in Europe, considering different methodologies and limitations of the data. Methods We conducted a systematic literature review of European trend studies (n = 17), incidence-based mortality (IBM) studies (n = 20) and case-control (CC) studies (n = 8). Estimates of the reduction in breast cancer mortality for women invited versus not invited and/or for women screened versus not screened were obtained. The results of IBM studies and CC studies were each pooled using a random effects meta-analysis. Results Twelve of the 17 trend studies quantified the impact of population-based screening on breast cancer mortality. The estimated breast cancer mortality reductions ranged from 1% to 9% per year in studies reporting an annual percentage change, and from 28% to 36% in those comparing post- and prescreening periods. In the IBM studies, the pooled mortality reduction was 25% (relative risk [RR] 0.75, 95% confidence interval [CI] 0.69–0.81) among invited women and 38% (RR 0.62, 95% CI 0.56–0.69) among those actually screened. The corresponding pooled estimates from the CC studies were 31% (odds ratio [OR] 0.69, 95% CI 0.57–0.83), and 48% (OR 0.52, 95% CI 0.42–0.65) adjusted for self-selection. Conclusions Valid observational designs are those where sufficient longitudinal individual data are available, directly linking a womans screening history to her cause of death. From such studies, the best ‘European’ estimate of breast cancer mortality reduction is 25–31% for women invited for screening, and 38–48% for women actually screened. Much of the current controversy on breast cancer screening is due to the use of inappropriate methodological approaches that are unable to capture the true effect of mammographic screening.

Breast cancer mortality in Copenhagen after introduction of mammography screening: cohort study

Abstract Objectives To evaluate the effect on breast cancer mortality during the first 10 years of the mammography service screening programme that was introduced in Copenhagen in 1991. Design Cohort study. Setting The mammography service screening programme in Copenhagen, Denmark. Participants All women ever invited to mammography screening in the first 10 years of the programme. Historical, national, and historical national control groups were used. Main outcome measures The main outcome measure was breast cancer mortality. We compared breast cancer mortality in the study group with rates in the control groups, adjusting for age, time period, and region. Results Breast cancer mortality in the screening period was reduced by 25% (relative risk 0.75, 95% confidence interval 0.63 to 0.89) compared with what we would expect in the absence of screening. For women actually participating in screening, breast cancer mortality was reduced by 37%. Conclusions In the Copenhagen programme, breast cancer mortality was reduced without severe negative side effects for the participants.

Organic solvents and cancer

Epidemiologic evidence on the relationship between organic solvents and cancer is reviewed. In the 1980s, more than a million persons were potentially exposed to some specific solvents in the United States; in Canada, 40 percent of male cancer patients in Montreal had experienced exposure to solvents; in the Finnish population, one percent was regularly exposed. There is evidence for increased risks of cancer following exposure to: trichloroethylene (for the liver and biliary tract and for non-Hodgkins lymphomas); tetrachloroethylene (for the esophagus and cervix - although confounding by smoking, alcohol, and sexual habits cannot be excluded - and non-Hodgkins lymphoma); and carbon tetrachloride (lymphohematopoietic malignancies). An excess risk of liver and biliary tract cancers was suggested in the cohort with the high exposure to methylene chloride, but not found in the other cohorts where an excess risk of pancreatic cancer was suggested. 1,1,1-trichloroethane has been used widely, but only a few studies have been done suggesting a risk of multiple myeloma. A causal association between exposure to benzene and an increased risk of leukemia is well-established, as well as a suggested risk of lung and nasopharynx cancer in a Chinese cohort. Increased risks of various gastrointestinal cancers have been suggested following exposure to toluene. Two informative studies indicated an increased risk of lung cancer, not supported by other studies. Increased risks of lymphohematopoietic malignancies have been reported in some studies of persons exposed to toluene or xylene, but not in the two most informative studies on toluene. Occupation as a painter has consistently been associated with a 40 percent increased risk of lung cancer. (With the mixed exposures, however, it is not possible to identify the specific causative agent[s].) A large number of studies of workers exposed to styrene have evidenced no consistent excess risk of all lymphohematopoietic malignancies, although the most sensitive study suggested an excess risk of leukemia among workers with a high exposure.

Leukaemia and reproductive outcome among nurses handling antineoplastic drugs.

During the past decades conclusive evidence has accumulated that alkylating antineoplastic drugs (ADs) can cause cancer, most notably acute non-lymphocytic leukaemia, and that most ADs are reprotoxic. Studies on health workers handling ADs have shown significantly increased risks for miscarriages (two studies) and malformations (two studies). The present study monitored the risk for cancer and adverse reproductive outcome among Danish nurses handling ADs. No increased risks were found for miscarriages, malformations, low birth weight, or preterm birth among the offspring of nurses handling ADs during pregnancy. The sex ratio was normal. The relative risk (RR) for leukaemia was significantly increased (10.65) but based on only two cases, one of acute myeloblastic and one of chronic myeloid leukaemia. From the available exposure data occupational exposures to ADs were apparently higher in the studies that have reported increased risks for miscarriages and malformations than in the present one. Regarding reproductive outcome the study gives some confidence that the safety measures which were implemented in the oncology departments around 1980 can protect the health personnel against adverse effects of ADs on reproduction. As the study is as yet the only negative one in a well protected setting, it should be followed up by other studies of well protected health personnel handling ADs. The findings concerning the leukaemia risk, although based on small numbers, encourage larger studies.

Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe.

Epidemiologic studies have shown an increased risk of breast cancer following hormone replacement therapy (HRT). The aim of this study was to investigate whether different treatment regimens or the androgenecity of progestins influence the risk of breast cancer differently. The Danish Nurse Cohort was established in 1993, where all female nurses aged 45 years and above received a mailed questionnaire (n = 23,178). A total of 19,898 women returned the questionnaire (86%). The questionnaire included information on HRT types and regimens, reproductive history and lifestyle‐related factors. Breast cancer cases were ascertained using nationwide registries. The follow‐up ended on 31 December 1999. Women with former cancer diagnoses, women with missing information on HRT, surgical menopause, premenopausal, as well as hysterectomized women were excluded, leaving 10,874 for analyses. Statistical analyses were performed using Cox proportional hazards model. A total of 244 women developed breast cancer during follow‐up. After adjustment for confounding factors, an increased risk of breast cancer was found for the current use of estrogen only (RR = 1.96; 95% CI = 1.16–3.35), for the combined use of estrogen and progestin (RR = 2.70; 95% CI = 1.96–3.73) and for current users of tibolone (RR = 4.27; 95% CI = 1.74–10.51) compared to the never use of HRT. In current users of combined HRT with testosterone‐like progestins, the continuous combined regimens were associated with a statistically significant higher risk of breast cancer than the cyclical combined regimens (RR = 4.16, 95% CI = 2.56–6.75, and RR = 1.94, 95% CI = 1.26–3.00, respectively). An increased risk of breast cancer was noted with longer durations of use for the continuous combined regimens (p for trend = 0.048). The European traditional HRT regimens were associated with an increased risk of breast cancer. The highest risk was found for the use of continuous combined estrogen and progestin.