Diabetes Mellitus

AIMS

The aim of this work is to investigate whether survivors of childhood cancer have a higher prevalence of diabetes mellitus compared to the general population and to study possible risk factors for these survivors to develop diabetes mellitus. The first study of diabetes mellitus will clarify if diabetes mellitus is a late complication after childhood cancer and will constitute the base for the second study identifying risk factors for survivors to develop diabetes mellitus. This and similar studies are important for the planning of future treatment protocols minimizing late complications and contribute to the development of preventive intervention strategies, improving the basis for patient counselling and optimal follow-up care.

BACKGROUND

Since the introduction of multimodal therapies in the early 1970s, the survival rates for most children with cancer have improved dramatically. Today, almost 80% of children with cancer treated in the Nordic countries survive more than five years (1, 2). These high survival rates have resulted in a rapidly growing population of childhood cancer survivors, and currently a steeply increasing number of survivors reach mid-life, where the incidence of most chronic diseases starts to increase in the general population.

Previous studies have shown that survivors of childhood cancer have a greater number of chronic health conditions than the general population (3-5). These chronic health conditions include cardiovascular, pulmonary, endocrine, musculoskeletal and neurological conditions, as well as infertility. Survivors are also at an increased risk of secondary neoplasm and late mortality (6-9).

Diabetes mellitus is one of the major chronic diseases in the Nordic countries. The prevalence of diabetes mellitus increases with age and reaches about 10% by the age of 60 years in most populations. The prevalence has risen in all age groups during the past 20 years and WHO has estimated that the number of individuals with diabetes mellitus worldwide will double within the next 20 years (10). In January 2007, the Danish National Diabetes Register reported an overall prevalence of 4,2% in Denmark (11).

In a recent report from the Childhood Cancer Survivor Study (CCSS), childhood cancer survivors were nearly two times more likely than their siblings to report diabetes mellitus (12). The increased risk of diabetes mellitus was associated with total body irradiation, abdominal irradiation, alkylating agents and younger age at diagnosis. In addition, there are studies suggesting that cancer survivors whose treatment included bone marrow transplantation may have an increased prevalence of diabetes mellitus, particularly those who were treated with total body irradiation (13-16). Furthermore, a study by Link et al. (17) showed increased insulin resistance among survivors of acute lymphoblastic leukemia treated with cranial irradiation, compared with controls.

The two studies of diabetes mellitus as a late complication after childhood cancer are part ALiCCS (Adult Life after Childhood Cancer in Scandinavia), a large, retrospective study of late complications after treatment for childhood cancer in the five Nordic countries. In this large population-based study using information from nationwide, high-quality registers in the Nordic countries and population-based comparisons, we investigate the risk of diabetes mellitus in childhood cancer survivors and risk factors within given cancer treatment to develop diabetes mellitus.

METHODS

ALiCCS is a population-based study of a cohort of all individuals who have been diagnosed with cancer under the age of 20, from the start of cancer registration (in Denmark 1943, in Sweden 1958) to 2008 in Denmark, Finland, Iceland, Norway and Sweden (n?55 000). The morbidity-specific incidence and cause-specific mortality of this cohort will be compared with those of a sample of the general populations of the Nordic countries (n?275 000). These comparisons will be based on a broad range of outcome data available from high-quality, nationwide health and disease registers. ALiCCS will also include several case–control studies nested in the childhood cancer cohort, in order to investigate associations, including dose-response, between specific treatment regimens and selected outcomes.

In the two studies of diabetes mellitus as a late complication, we identified 25 635 patients from the Danish, Icelandic and Swedish Cancer Registries, in whom cancer was diagnosed before the age of 20, between 1943 in Denmark, 1955 in Iceland and 1958 in Sweden, when the Cancer Registries were established, and 2008. The end of follow-up was 31 December 2009.

Information of cancer diagnosis and year of diagnosis was collected from the Cancer Registries of the three countries. The patients were grouped according to the first malignant neoplasm diagnosed before the age of 20 years to one of the 12 main diagnostic groups of the International Classification Scheme for Childhood Cancer, proposed by the International Agency for Research on Cancer (IARC).

A randomly sampled control cohort of 125 850 controls (5 controls per case) was identified in the Central Population Registry of the three countries. The controls were matched by sex, year of birth and country of residence in the year of diagnosis of the corresponding case.

Information of diabetes mellitus of cases and controls was collected from the National Hospital Registries (NHR) of the three countries. The Danish NHR register includes information on all hospital admissions in Denmark since 1977. Each admission record includes the date of admission and discharge, the treating department and up to 20 discharge diagnoses coded according to the 8th revision of the International Classification of Diseases (ICD-8) in 1977-1993 and thereafter according to the 10th revision (ICD-10). Data from out-patient visits to somatic hospital departments and emergency room visits are included since 1995. The Icelandic NHR contains the corresponding data since 1999 and the discharge diagnoses are coded according to ICD-10. The Swedish NHR includes the same information on all in-patient care for parts of the country since 1964 and for the entire country since 1987. From 2001, the registry also includes all outpatient visits to hospitals. The discharge diagnoses are coded according to ICD-7 1964-1968, ICD-8 1969-1986, ICD-9 1987-1996 and according to ICD-10 from 1997 and onwards. The diagnoses of DM included in this study were E10 and E11 in ICD-10, 250 in ICD-9, 249 and 250 in ICD-8 and 260 in ICD-7.

In the second study, survivors found to have diabetes mellitus in the first study will be compared to survivors without diabetes mellitus, concerning type of cancer and type of cancer treatment given. These comparisons will be based on detailed treatment data, containing cumulative dose of radiotherapy and that of different types of chemotherapy, as well as time of treatment, extracted from medical records.

REFERENCES

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