J.W.W. Coebergh

The rise in incidence of lymphomas in Europe 1985–1992

A collaborative study was carried out of the descriptive epidemiology of the lymphomas from seven countries across Europe in the period 1985-1992. Careful attention was paid to sources of information and the data quality in close collaboration with expert histopathologists. The data were classified as non-Hodgkins lymphoma (NHL) and Hodgkins disease (HD). An attempt was made to put the data into a modified version of the Revised European American Lymphoma (REAL) classification. We observed an overall rise in total NHL throughout the time period in all European countries but no such trend in HD. The increase in NHL overall being 4.2% per annum, representing an increase of 4.8% in males and 3.4% in females per annum, was only marked in middle and old age. Such increases were observed in all participating areas except in Burgundy. Different countries, however, have different base rates, the rates being highest in Scandinavia and the Netherlands. The analysis by subcategory classification suggested that the increase in NHL was confined to the follicle centre cell type, extranodal B-cell, nodal T-cell and nodal lymphomas not otherwise specified, categories. These new observations present a picture of real increase in case incidence with no obvious explanation. The increases in NHL do not appear to be due solely to better diagnoses. Pending other explanations or refutation, these present a compelling picture of an inexorable rise in incidence of this disease.

A systematic review of health-related quality of life in cutaneous melanoma.

Melanoma can be considered an emerging chronic disease that may considerably affect patients’ lives. The authors systematically reviewed the available literature on health-related quality of life (HRQOL) and melanoma. Of reviews and the selected studies, reference lists were hand-searched. The quality of the eligible studies was appraised based on 14 previously published criteria. Of the 158 abstracts, 44 articles were appraised, resulting in 13 selected studies written in English (published between 2001 and 2008). Most studies assessed patients from specialised centres with varying, but relatively advanced, disease stages. The most commonly used instruments were the SF-36 and EORTC QLQ-C30. Recently, a melanoma-specific HRQOL questionnaire [FACT-Melanoma (FACT-M)] was introduced for clinical trial purposes. It showed that approximately one-third of melanoma patients experienced considerable levels of distress, mostly at the time of diagnosis and following treatment. Systemic therapies affected HRQOL negatively in the short term, but to a lesser extent in the long term. Health status and patients’ psychological characteristics are associated with higher levels of HRQOL impairment. The authors found that the impact of melanoma on patients’ HRQOL is comparable to that of other cancers. Accurately assessing HRQOL impairment in melanoma patients is pivotal, as it may affect disease management, including therapy and additional counselling, future preventive behaviour and perhaps even prognosis.

Improved survival of patients with rectal cancer since 1980: a population-based study

The treatment of rectal cancer has changed over the last two decades as far as surgical techniques and radiotherapy are concerned. We studied the changes in patterns of care for patients with rectal cancer and the effect on prognosis. All patients with cancer of the rectum or rectosigmoid in South-east Netherlands, diagnosed in the period of 1980-2000, were included in our analyses (n=3635). The use of surgery as the only treatment decreased from 62% in the period of 1980-1989 to 42% in the period of 1995-2000, whereas the combination of surgery and radiotherapy increased from 26 to 40%. The use of postoperative radiotherapy decreased from 25 to 4%, while preoperative radiotherapy increased from 1 to 35%. Patients aged 75 years or older were less likely to receive radiotherapy. After adjustment for age, gender, tumour stage and tumour site, significant improvements in the relative risk of death were observed between the periods of 1995-2000 and 1980-1989 for patients under 60 years of age (Relative Risk (RR)=0.45; 95% Confidence Interval (CI)=0.35-0.58) and those 60-74 years old (RR=0.62; 95% CI 0.53-0.72). No improvement in the risk of death was found for patients aged 75 years and over. No improvements in the distribution of tumour stage were observed, making it very likely that the continuing increase in population-based survival among patients aged <75 years results from the shift from postoperative to preoperative radiotherapy, the development of the total mesorectal excision technique and the related tendency to subspecialisation of surgeons in colorectal cancer surgery.

Spatial clustering of childhood leukaemia: summary results from the EUROCLUS project.

The interpretation of reports of clusters of childhood leukaemia is difficult, first because little is known about the causes of the disease, and second because there is insufficient information on whether cases show a generalized tendency to cluster geographically. The EUROCLUS project is a European collaborative study whose primary objective is to determine whether the residence locations of cases at diagnosis show a general tendency towards spatial clustering. The second objective is to interpret any patterns observed and, in particular, to see if clustering can be explained in terms of either infectious agents or environmental hazards as aetiological agents. The spatial distribution of 13351 cases of childhood leukaemia diagnosed in 17 countries between 1980 and 1989 has been analysed using the Potthoff-Whittinghill method. The overall results show statistically significant evidence of clustering of total childhood leukaemia within small census areas (P=0.03) but the magnitude of the clustering is small (extra-Poisson component of variance (%) = 1.7 with 90% confidence interval 0.2-3.1). The clustering is most marked in areas that have intermediate population density (150-499 persons km[-2]). It cannot be attributed to any specific age group at diagnosis or cell type and involves spatial aggregation of cases of different ages and cell types. The results indicate that intense clusters are a rare phenomenon that merit careful investigation, although aetiological insights are more likely to come from investigation of large numbers of cases. We present a method for detecting clustering that is simple and readily available to cancer registries and similar groups.

Spatial temporal patterns in childhood leukaemia: Further evidence for an infectious origin

The EUROCLUS project included information on residence at diagnosis for 13351 cases of childhood leukaemia diagnosed in the period 1980-89 in defined geographical regions in 17 countries. A formal algorithm permits identification of small census areas as containing case excesses. The present analysis examines spatial-temporal patterns of the cases (n = 970) within these clustered areas. The objectives were, first, to compare these results with those from an analysis conducted for UK data for the period 1966-83, and, second, to extend them to consider infant leukaemias. A modification of the Knox test investigates, within the small areas, temporal overlap between cases in a subgroup of interest at a putative critical time and all other cases at any time between birth and diagnosis. Critical times were specified in advance as follows: for cases of acute lymphoblastic leukaemia aged 2-4 years, the 18-month period preceding diagnosis; for cases of total leukaemia aged 5-14 years, 1 year before to 1 year after birth; and for infant cases (diagnosed < 1 year), 1 year before to 6 months after birth. Each of the analyses found evidence of excess space-time overlap compared with that expected; these were 10% (P = 0.005), 15% (P= 0.0002) and 26% (P= 0.03) respectively. The results are interpreted in terms of an infectious origin of childhood leukaemia.

Cancer incidence and mortality patterns in South Eastern Europe in the last decade: Gaps persist compared with the rest of Europe☆

INTRODUCTION Cancer registration coverage and cancer control programmes in South Eastern (SE) Europe, embracing about six new EU member states, remain thin, despite a relatively high incidence and mortality burden from avoidable cancers, particularly in males. We assembled the most recent cancer registry data to estimate the burden of the 17 most common cancers in the region, from Slovenia to Cyprus and Malta. METHODS Data were made available for analysis from Bulgaria, Croatia, Cyprus, Malta, Romania (Cluj County), Serbia, Slovenia and Turkey (Antalya and Izmir provinces). We analysed incidence and mortality of the 17 most common cancers (counts and age-standardised rates, for the most recent year available and for the period 1999-2008). We used Joinpoint regression to quantify recent trends. FINDINGS For much of SE Europe, there were no marked declines in overall cancer mortality rates during 1999-2008. In men, lung cancer incidence and mortality rates were high compared to other European countries (age-standardised rates (ASRW) of incidence being 50-60/100,000 in most of the countries), and still increasing in Bulgaria, Serbia and Turkey. Prostate cancer incidence rapidly increased throughout the region by 3-12% annually, largely without any clear declines in mortality. Colorectal cancer incidence increased throughout the region, as did mortality especially in Croatia, Serbia and Bulgaria (average annual percentage change (AAPC) 1.5-2%). In women, breast cancer mortality significantly declined in Slovenia, Croatia and Malta (Average Annual Percentage of Change [AAPC] -2%, -1% and -5%, respectively), but not elsewhere. Cervical cancer incidence rates remained very high in Romania, Serbia and Bulgaria (ASRW>20/100,000). INTERPRETATION Our data confirmed the North West to South East Europe gradient of increasing incidence and mortality rates of tobacco-related cancers, as well as increasing mortality rates of screen-detectable cancers. The lack of decline in overall cancer mortality also indicates suboptimal levels of cancer control in the region.

No increased risk of non-Hodgkin's lymphoma with steroids, estrogens and psychotropics (Netherlands)

Objective: Earlier studies with data on drug use from interview suggested that corticosteroids, estrogens and psychotropics may increase the risk of non-Hodgkins lymphoma (NHL). The objective of this case–control study with complete pharmacy records was to investigate whether these results could be reproduced. Methods: Cases were all subjects aged 20 years and older in a population of approximately 300,000 residents in the Netherlands who were registered with an incident primary discharge diagnosis of NHL between January 1, 1991 and December 31, 1998. Controls were matched to cases on sex, year of birth, community pharmacy, calendar period and total duration of medication history. Conditional logistic regression was used to evaluate the association between categories of cumulative drug use in days and the risk of NHL. Results: 997 controls were matched to 251 cases of NHL that occurred during the study period. In multivariate analyses, there was no statistically significant risk increase of NHL after exposure to corticosteroids, estrogens or psychotropics. Moreover, long-term use of benzodiazepines showed an unexpected statistically significant protective effect (OR 0.34; 95% confidence interval 0.18–0.64). Conclusions: In our population-based study, corticosteroids, estrogens and psychotropics were not associated with an increased risk of NHL.

Bladder cancer incidence and survival in the south-eastern part of the Netherlands, 1975-1989

Trends in cancer occurrence and survival may reflect changing risks and prognosis, respectively, but may also be caused by changes in detection, classification and registration. Changed classification of low-stage papillary carcinomas may have a material effect on observed trends in the occurrence of bladder cancer. We studied the effect of the implementation of the WHO grading system and the third edition of the TNM staging system on bladder cancer incidence in the south-eastern part of the Netherlands. Data on superficial and invasive bladder cancer incidence between 1975 and 1989 were derived from the population-based Eindhoven cancer registry. Data on survival of patients with stages I-IV bladder cancer were derived from the municipal population registers. Age-adjusted bladder cancer incidence per 100,000 person-years rose from 25.9 to 40.7 in males and from 3.1 to 8.5 in females. This increasing trend was caused almost entirely by non-invasive pTa papillary carcinoma. A considerable shift was observed towards lower disease stages, which was less evident within the group of invasive tumours. The relative 5-year survival of patients with stages I-IV invasive bladder cancer was 59% in 1975-1977 and 70% in 1984-1986. After stratification by stage, however, no striking improvement was observed in the prognosis. We conclude that the increasing trend of bladder cancer occurrence in the Netherlands since 1975 has largely been caused by changed classification systems and reporting procedures for pTa tumours (formerly classified as papillomas).

Population density and childhood leukaemia: results of the EUROCLUS study

The EUROCLUS study assembled incidence data for 13,551 cases of childhood leukaemia (CL) diagnosed between 1980 and 1989 in 17 countries (or regions of countries). These were referenced by location at diagnosis to small census areas of which there were 25,723 in the study area. Population counts, surface area and, hence, population density were available for all these small areas. Previous analyses have shown limited extra-Poisson variation (EPV) of case counts within small areas; this is most pronounced in areas of intermediate population density (150-499 persons/km2). In this study, the data set was examined in more detail for evidence that variations in incidence and EPV of CL are associated with population density. Incidence showed a curvilinear association with population density and was highest in areas which were somewhat more densely populated (500-750 persons/km2), where the incidence rate ratio relative to areas having > or = 1000 persons/km2 was 1.16 (95% confidence interval 1.07-1.26) and the P value for quadratic trend across eight strata of population density was 0.02. Incidence in these areas is uniformly elevated and showed no evidence of heterogeneity (i.e. EPV). Statistically significant evidence of EPV was evident amongst some of the areas previously classified as intermediate density areas (specifically, those with a density of 250-499 persons/km2, P < 0.001 for CL). These results were interpreted in terms of the current aetiological hypotheses for CL which propose that exposure to localised epidemics of one or more common infectious agent may contribute to the development of leukaemia. They suggest that such epidemics arise regularly in moderately densely populated areas and also sporadically in areas which are somewhat less densely populated. Although other interpretations are possible, these results may assist in the identification of characteristics which infectious agents must possess if direct or indirect causes of CL.

Verapamil is associated with an increased risk of cancer in the elderly: the Rotterdam study.

The association between the use of calcium channel blockers (CCB) and cancer has received ample attention, but is still controversial. In this study, we have tested the hypothesis that the observed association between CCB and cancer in earlier studies could be explained by residual confounding or by misclassification of exposure because of the use of cross-sectional data on drug use. Data from the Rotterdam Study, a prospective population-based cohort study in the municipal area Ommoord, were used. The study population consisted of a cohort of 3204 participants aged 71 years or older who were followed from a baseline interview in the period 1991-1993 for the occurrence of incident cancer. Data on drug use were gathered at baseline and through the seven community pharmacies which served the Ommoord region during the study period between 1 January 1991 and 1 January 1999. Incident cancer events were gathered from a nationwide registry of hospitalisation data and from a specialised cancer centre in the Rotterdam region. We performed three analyses. First, we followed the method, and adjusted for the same risk factors, as in the earlier studies. In the second analysis, we included all risk factors that were univariately associated with cancer in the Rotterdam Study. In the third analysis, we included exposure to CCBs as time-varying co-variates, while adjusting for potential confounders. The relative risk (RR) of cancer associated with CCB was 1.4 (95% Confidence Interval (CI): 0.9-2.0) in the first analysis and lowered to 1.2 (95% CI: 0.8-1.8) upon adjustment for the different co-variates in the second. In both analyses, however, verapamil was significantly associated with cancer with RRs of 2.1 (95% CI: 1.1-4.0) and 2.0 (1.01-3.9), respectively, whereas no associations were found with the other CCB in this study, i.e. diltiazem and nifedipine. A significantly increased risk of cancer was found for intermediate daily doses of verapamil and diltiazem. Intake of other antihypertensives such as beta-blocking agents, diuretics and ACE-inhibitors was not associated with cancer. In the third analysis with exposure to CCB as time-varying co-variates, the risk increase was non-significant for use of 2 years or less, 1.0 (95% CI: 0.7-1.5), and for use for a cumulative period of more than 2 years, 1.3 (95% CI: 0.8-2.0). However, in all models the hazard ratio was statistically significantly increased for verapamil, but not for diltiazem and nifedipine. On the basis of these analyses, we found no increase in cancer in users of diltiazem and nifedipine, nor in users of other antihypertensives. In line with earlier studies, however, we found an increased risk of cancer in users of verapamil. At variance with the conclusions from several other studies, we think that it is too early to conclude that CCB are not associated with cancer.