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Background: A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance., Methods: TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0-45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5-12.5 mg/m 2 /day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m 2 /day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients., Discussion: TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms., Trial Registration: EudraCT, 2018-001795-38. Registered 2020-05-15, Clinicaltrials.gov , NCT04307576 . Registered 2020-03-13, https://clinicaltrials.gov/ct2/show/NCT04307576., (© 2022. The Author(s).)

Background: Childhood cancers represent a small proportion of all cancers but are still a major public health problem. The study analysed long-term trends in childhood cancer incidence and survival in Estonia in relation to societal and health care transition., Methods: Data on all malignant tumours, diagnosed in children aged 0-14 during 1970-2016, were derived from the Estonian Cancer Registry. Age-standardised (World standard) incidence rates were calculated by ICCC-3 site groups and joinpoint regression was used to estimate annual percentage change (APC) for incidence trends. Cohort and period approach were used to estimate 5-year survival. Internal age standardisation was applied., Results: A total of 1628 incident cancer cases were diagnosed during the study period and overall incidence increased significantly at a rate of 0.5% per year. Significant increases were seen for neuroblastoma and germ cell tumours, for lymphoid leukemias and some CNS sub-sites. At the same time, decline in incidence was seen in almost all subgroups of unspecified neoplasms. The overall 5-year survival improved from 24% in 1970-1979 to 73% in 2010-2016, with the largest changes occurring in the 1990s and 2000s. For many sites, survival increase thereafter has been marginal., Conclusion: In this first comprehensive population-based study of childhood cancer incidence and survival in Estonia, long-term trends are shown in the context of societal and health care changes. Even though the increasing incidence of some sites may, at least partially, be explained by improved diagnostics reflected in the decreased incidence of unspecified neoplasms, the overall cancer incidence in children seems to be rising. Rapid progress in diagnosis and care have improved childhood cancer survival immensely, but deficit in Estonia persists compared to other European countries. Results of the study accentuate the need for a more in-depth analysis of clinical data, but also for the prioritization of childhood cancer in Estonia, to ensure access to standard care and innovative treatments.