Cardiovascular and pulmonary disorders

- a large population-based patient cohort from Denmark, Finland, Iceland, Norway and SwedenUsing the unique population-based registries in the Nordic countries with long-term and virtually complete follow-up, we will investigate whether survivors of childhood cancer are at increased risk for cardiovascular- and pulmonary diseases compared to the general population. Furthermore, we will investigate the effect of different treatment modalities and doses on the development of these late outcomes.

Since beginning of nation-wide cancer registration in the Nordic countries more than 55 000 children and adolescents, aged 0-19 years, have been diagnosed with cancer (referred to as childhood cancer) (1). In the 1940s and 1950s only few survived the disease (23%) (2). Due to multimodal chemotherapy, the survival has improved substantially now reaching over 80 percent (1;3;4). However, the improved survival comes at a price (5;6).
Cancer treatment for children and adolescents has a variety of different complications. With improved survival these morbidities become more apparent and survivors may acquire other yet not fully described chronic diseases as they age. Research within this field is still in its early phase since large population of survivors followed for a substantial part of their life is required to yield reliable estimates of relative and absolute risks.


Late effects of cancer treatment can occur in all organ systems including the cardiovascular- and pulmonary systems. Previous studies, primarily questionnaire-based, indicate that childhood cancer survivors have an eight-fold excess risk of a severe chronic health condition compared to that of their siblings (7). That includes a 10.4 times higher risk of coronary artery disease, 15.1 times of congestive heart failure (CHF) and 9.3 times of cerebrovascular accidents (7).

Research have also shown that survivors have an almost eleven-fold increased risk of death compared to the general population (standardized mortality ratio [SMR], 10.8; 95% CI, 10.3 to 11.5)(8). The leading non-malignant cause of death among survivors was cardiac and the risk was seven-fold higher than that of the general population ([SMR], 7.0; 95% CI, 5.9 to 8.2) (7;9;10).
Reports from an American study on childhood cancer survivors (the CCSS) described a significant higher incidence of self-reported cardiovascular- and pulmonary disease. Survivors were significantly more likely to report cardiac outcomes such as myocardial infarction (hazard ratio [HR] 5.0, 95% confidence interval [CI] 2.3 to 10.4; P<0.001) and congestive heart failure (CHF) (HR 5.9, 95% CI 3.4 to 9.6; P<0.001)(10). Statistically significant associations were found for lung fibrosis following chest irradiation (relative risk [RR] 4.3; P = 0,001) (11). The cumulative incidence of pulmonary fibrosis continued to increase 15 to 25 years after diagnosis for survivors receiving chest irradiation with or without pulmonary-toxic chemotherapeutic agents and reached 3.5% 20 years after diagnosis for survivors who only received chest irradiation (11).


Although results of previous studies have given an idea of the health-related late effects that childhood cancer survivors may encounter, the exact scale of the problem and verification is needed since no nation-wide studies have yet been completed. None of the previous studies have described late effects in survivors aged >40 years. Consequently the lifelong risk of late complications related to previous cancer and its treatment remains to be explored. The excess risk, prevalence and severity of cardiovascular and pulmonary diseases need to be fully investigated. To improve both late follow-up care and current cancer treatments, linking the different complications to the causing treatment modality and doses is necessary.


A two-step approach will be used in this Ph.D. project. This will be a part of the large Nordic study “Adult Life after Childhood Cancer in Scandinavia” (AliCCS) (, which includes an inter-Nordic childhood cancer cohort (n = 55 000) and a population comparison cohort consisting of a randomly selected sample of the general Nordic populations (n = 275 000).


The first objective, 1st phase, will be to establish a complete, population-based series of children and adolescents in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) in whom cancer was diagnosed during the period 1943 to 2008; and to follow them up individually to the present in a multi-national retrospective cohort study using various health-related national registers, such as National Cancer Registries and National Hospital Registries, in order to investigate cardiovascular and pulmonary diseases as late complications. This will comprise the largest group of persons affected by cancer in childhood ever followed-up for late complications.
Using a cohort design, we will assess the relative and absolute risk for all cardiovascular and pulmonary diseases among adult childhood cancer survivors.


In the 2nd phase, at least two case-cohort studies within the cohort of childhood cancer patients will be set up, in which cases will be defined on the basis of selected serious outcomes within the cardiovascular and pulmonary systems. Specific outcomes among 5-year survivors, such as myocardial infarction, congestive heart failure, cardiomyopathy, pericardial diseases, cerebrovascular incidents and pulmonary fibrosis are considered to be investigated in a case-cohort study designed to investigate damaging late effects of specific treatment regimens and doses. Information on the primary cancer treatment will be retrieved from medical records and collected for both cases and the sub-cohort. Using an abstraction form, information will be collected on the cancer diagnosis and treatment. Dose-response analyses will be conducted based on such detailed treatment information.

This Ph.D. project will add new and more in-depth information on the risk, prevalence and nature of cardiovascular and pulmonary late complications that childhood cancer survivors may encounter in adult life.

The Nordic countries are ideal study areas for this type of epidemiological research, as a broad range of outcome data is available with complete follow-up from high-quality, nation-wide health and population registers including cancer registers, dating back to 1943 and covering all incident cases of childhood cancer as well as National Hospital Registries including hospitalization histories and diagnostic codes carried out by medical doctors at discharge. In the case-cohort study discharge diagnoses will be validated against medical records. The long follow-up period for diseases will allow precise risk estimates in the age group >40 years. This long era of follow-up will also make it possible to evaluate treatments practiced over time in the Nordic countries.

As the population of survivors is ever increasing, now constituting almost 0.1% of the national populations, it is highly relevant to investigate the multiple complications that childhood cancer survivors possibly have or will encounter. The ultimate goals are to improve treatment protocols, with fewer late effects and to contribute to the identification and characterization of high-risk populations. This information is critical for making evidence-based recommendations and improving long-term follow-up of survivors of childhood cancer.

At the moment we are applying for further funds to start up yet another PhD student to cover this comprehensive research area.


Thorgerdur Gudmundsdottir, MD, PhD student
Danish Cancer Society Research Center
Survivorship Unit
Telephone: +45 3525 7648


Jørgen H. Olsen, Director, DMSc, Danish Cancer Society Research Center, Copenhagen
Jeanette Falck Winther, MD, Senior researcher, Danish Cancer Society Research Center, Copenhagen
Henrik Hasle, Professor, MD, PhD, Department of Pediatrics, Aarhus University Hospital, Skejby


(1) Olsen JH, Moller T, Anderson H, Langmark F, Sankila R, Tryggvadottir L, et al. Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries. J Natl Cancer Inst 2009 Jun 3;101(11):806-13.

(2) de Nully BP, Olsen JH, Hertz H, Carstensen B, Bautz A. Trends in survival after childhood cancer in Denmark, 1943-87: a population-based study. Acta Paediatr 1995 Mar;84(3):316-24.

(3) Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010 Sep;60(5):277-300.

(4) Ries LAG. Childhood cancer mortality. In: Ries L.A.G., Smith MA, Gurney JG, et al., editors. Cancer incidence and survival among chiildren and adolescents: Unitet States SEER Program, 1975-1995, National Cancer Institute, SEER Program.Bethesda (MD): National Institutes of Health, National Cancer Institute; 199 NIH Pub. No. 99-4649.; 1999. p. 165-70.

(5) Sklar CA. Overview of the effects of cancer therapies: the nature, scale and breadth of the problem. Acta Paediatr Suppl 1999 Dec;88(433):1-4.

(6) Robison LL, Armstrong GT, Boice JD, Chow EJ, Davies SM, Donaldson SS, et al. The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research. J Clin Oncol 2009 May 10;27(14):2308-18.

(7) Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006 Oct 12;35(15):1572-82.

(8) Moller TR, Garwicz S, Barlow L, Falck WJ, Glattre E, Olafsdottir G, et al. Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries. J Clin Oncol 2001 Jul 1;19(13):3173-81.

(9) Diller L, Chow EJ, Gurney JG, Hudson MM, Kadin-Lottick NS, Kawashima TI, et al. Chronic disease in the Childhood Cancer Survivor Study cohort: a review of published findings. J Clin Oncol 2009 May 10;27(14):2339-55.

(10) Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Stovall M, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009;339:b4606.

(11) Mertens AC, Yasui Y, Liu Y, Stovall M, Hutchinson R, Ginsberg J, et al. Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer 2002 Dec 1;95(11):2431-41.