Late Renal and Gastrointestinal Effects and Their Prevention in Childhood Cancer Survivors

Since the beginning of cancer registration in the Nordic countries, cancer has been diagnosed in approximately 55000 children and adolescents (1). In the 1940s and 1950s, few children survived their disease (2). At the beginning of the 1960s, new therapies were developed, and this led to a significant increase in patients experiencing sustained remission and cure. Today, 80% of affected children can be expected to be longterm survivors. As a result of this success, there is now a fast growing population of persons who have been cured of childhood cancer and have survived for decades since their initial treatment. Since most of these survivors received intensive exposure to radiation and highly toxic compounds during a period of their life characterized by organ growth and maturation, they now face significant, often uncharacterized sequelae (3) - referred to as late effects.

Accurate investigation of the late effects of treatment for childhood cancer requires large groups of survivors who have been followed for a substantial part of their life. Previously, two comprehensive patient cohorts have been established in North America and in the United Kingdom (4, 5). The North American study showed a considerable increase in the prevalence of severe or lifethreatening, disabling chronic illnesses, as well as an increase in secondary cancers, among survivors.

Late effects after cancer treatment occur in all organ systems, including the gastrointestinal and renal systems. The late effects can be non-malignant, as well as malignant, and include intestinal obstruction, asplenia, hepatitis, cirrhosis, glomerular and/or tubular nephropathy, kidney failure/dialysis, recurrent kidney/bladder infections, hematuria, dysfunctional voiding, and
secondary neoplasms of the liver, colon and rectum, kidney, and/or bladder (6).

Aims of this PhD project

A two-step approach will be used in this PhD project. In the first part we will examine whether the survivors of childhood cancer are at greater risk of a wide variety of renal and gastrointestinal disorders compared to that in the general population.
In the second part we will investigate the effect of different treatment regiments on the development of a number of selected serious outcomes.

Methods

Cohort study

The first objective will be to establish a large, retrospective, inter-Nordic childhood cancer cohort (n=55000) and a control cohort consisting of a sample of the general populations of the Nordic countries (n=275000) randomly selected from the Central Population Registries and matched by country, gender and age. In the cohort of childhood cancer survivors diagnosed during the period 1943 to 2008 we will investigate whether childhood cancer survivors have an increased risk of renal and gastrointestinal late effects using National Cancer Registries and National Hospital Registries.

Case-cohort study

In the second part of the study a case- cohort study will be set up based on selected serious outcomes within the renal and gastrointestinal system investigating the effects of specific treatment regimens.

Information regarding the primary cancer treatment will be retrieved from medical records for both cases and the sub-cohort. Dose-respons analyses will be conducted based on detailed treatment information using an abstraction form.

The combined dataset will constitute a new, comprehensive, powerful surveillance instrument for estimating relative and absolute risks for chronic health conditions in childhood cancer survivors.

The ultimate goals are to allow better planning of treatment protocols for childhood cancer, with fewer late effects, to contribute to preventive intervention strategies, and to improve the basis for patient counseling and optimal follow-up care.

References
1) Olsen JH, Möller T, Anderson H, Langmark F, Sankila R, Tryggvadottir L, Winther JF, Rechnitzer C, Jonmundsson G, Christensen J, Garwicz S. Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries. J Natl Cancer Inst 2009; 101: 806-13.

2) Brown PdeN, Olsen JH, Hertz H, Carstensen B, Boutz A. Trends in survival after childhood cancer in Denmark, 1943-87: a population-based study. Acta Paeiatr 1995; 84: 316-24.

3) Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, Schwartz CL, Leisenring W, Robison LL. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355: 1572–82.

4) Robison LL, Armstrong GT, Boice JD, Chow EJ, Davies SM, Donaldson SS, Green DM, Hammond S, Meadows AT, Mertens AC, Mulvihill JJ, Nathan PC, Neglia JP, Packer RJ, Rajaraman P, Sklar CA, Stovall M, Strong LC, Yasui Y, Zelter LK. The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research. J Clin Oncol 2009; 27: 2308–18.

5) Hawkins MM, Lancashire ER, Winter DL, Frobisher C, Reulen RC, Taylor AJ, Stevens MCG, Jenney M. The British Childhood Cancer Survivor Study: objectives, methods, population structure, response rates and initial descriptive information. Pediatr Blood Cancer 2008; 50: 1018–25.

6) Dickerman JD. The Late Effects of Childhood Cancer Therapy. Pediatrics 2007; 119: 554-68.