Register-based studies on childhood cancer : relapsed childhood acute lymphoblastic leukemia and skeletal adverse events in childhood cancer survivors in the Nordic countries

Background: Although cancer is a rare disease in children, it is the leading disease-related cause of death in children and adolescents in developed countries. Currently 80% of patients become long-time survivors but if a relapse occurs the outcome for most patients is still poor. Childhood cancer survivors are also at increased risk of chronic health conditions caused by the cancer treatment. The skeletal system is vulnerable to the toxic effects of cancer treatment during childhood and adolescence. Skeletal adverse events are not life- threatening events but may have a large impact on the quality of life and daily functions of childhood cancer survivors.

Aims: The overall aim of this thesis is to explore the use of the unique Nordic registry data to find ways to improve outcomes in childhood cancer. In studies I and II we identified a cohort of patients with relapsed acute lymphoblastic leukemia (ALL) within the NOPHO ALL registry and searched for factors associated with overall survival and treatment-related mortality (TRM). In studies III and IV, we used both the Nordic public health data registries and arthroplasty quality registries to explore the life-time pattern of skeletal late adverse events in a large cohort of childhood cancer survivors and to identify vulnerable subgroups.

Results: In study I, we observed an improvement in the 5-year overall survival after relapse of ALL between 1992-2001 and 2002-2011. We identified risk factors independently associated with death: short duration in first remission, bone marrow relapse, age ≥10 years at primary diagnosis, unfavorable cytogenetics and Down syndrome. Our findings indicate that the currently used risk stratification underestimates the risk of second relapses in patients with combined B-precursor relapses. In study II, we identified 52 patients who met criteria for TRM but we did not observe a reduction of TRM over time. Infections, predominantly bacterial infections, were the most common cause of death. Factors associated with TRM were high-risk stratification at relapse, unfavorable cytogenetics and allogeneic HSCT. In study III, we observed a 35% increased hospitalization risk for skeletal adverse events among childhood cancer survivors compared to population comparison subjects. For most of the skeletal adverse events the risk was highest in the years close to the treatment, but an excess risk extended for decades for some of the events. The relative risk was particularly high for osteonecrosis, especially among patients with hematological malignancies and patients diagnosed with cancer between 10-19 years of age. In study IV, we observed an increased risk for hip arthroplasties among survivors of leukemia and lymphoma and for knee arthroplasties among survivors of malignant bone tumors. The rate of arthroplasty operations was highest in early adulthood.

Conclusions: Finding ways to balance the treatment intention of inducing and maintaining long-term remission against the potential risk of life-threatening or long-term treatment complications is becoming more difficult. Individualized treatment approaches and novel strategies are therefore needed both to increase survival and improve health in patients with childhood cancer. Despite different study designs and end-points, studies I-IV provide evidence that the Nordic registry data can be used as excellent research tools to increase our knowledge on childhood cancer. The Nordic countries are in a unique position to conduct registry studies on childhood cancer by combining data from public health registries and different quality registries. The design of the registries and the regulatory framework should aim to facilitate research using this valuable source of information.

List of scientific papers

I. Oskarsson T, Söderhäll S, Arvidson J, Forestier E, Montgomery S, Bottai M, Lausen B, Carlsen N, Hellebostad M, Lähteenmäki P, Pihkala U, Jonsson OG, Heyman M. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries – prognostic factors, treatment and outcome. Haematologica. 2016; 101: 68-76.
https://doi.org/10.3324/haematol.2015.131680

II. Oskarsson T, Söderhäll S, Arvidson J, Forestier E, Frandsen TL, Hellebostad M, Lähteenmäki P, Jónsson ÓG, Myrberg IH, Heyman M. Treatment-related death in relpased childhood acute lymphoblastic leukemia. Pediatric Blood and Cancer. 2018; 65(4): e26909.
https://doi.org/10.1002/pbc.26909

III. Oskarsson T, Duun-Henriksen AK, Bautz A, Boschini C, Montgomery S, Harila-Saari A, Petersen C, Niinimäki R, Madanat- Harjuoja L, Tryggvadóttir L, Holmqvist AS, Hasle H, Heyman M*, Falck Winther J*. Skeletal adverse events in childhood cancer survivors: An Adult Life after Childhood Cancer in Scandinavia (ALiCCS) cohort study. International Journal of Cancer. 2021;149 (11); 1863-1876. *Shared last authorship.
https://doi.org/10.1002/ijc.33741

IV. Oskarsson T, Dehlendorff C, Krøyer A, Montgomery S, Harila-Saari A, Petersen C, Niinimäki R, Madanat-Harjuoja L, Wesenberg F, Garellick G, Dale H, Holmqvist AS, Hasle H, Falck Winther J, Heyman M. Total hip and knee arthroplasties in childhood cancer survivors – a population-based cohort study. [Manuscript]