On the road to optimizing long-term survival

To investigate the risk of developing subsequent neoplasms, we used data from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort (1963-2014), including a total of 11,548 survivors. Data on subsequent neoplasms was ascertained through linkages with two nationwide registries: the Netherlands Cancer Registry (NCR)1 and the Dutch Nationwide Pathology Databank (Palga). Chapter 2 describes, to our knowledge, the first study in Europe examining temporal trends in the risk of developing SMNs among five-year childhood cancer survivors and relates these to treatment shifts over the past five decades. Our findings indicate that the risk of developing SMNs among five-year childhood cancer survivors decreased over time (pre-1980, 1980-1989, 1990- 1999, and 2000 onwards). A mediation analysis showed that this decrease was associated with a reduction in the use of radiotherapy. In contrast, changes in the use chemotherapy seems to have the opposite effect, mainly due to the use of anthracyclines and epipodophyllotoxins. This suggests that the temporal decline of SMN risk due to decreased radiotherapy treatments, was counteracted by chemotherapy. Furthermore, this study shows that, although the risk decreased, childhood cancers survivors remain at an increased risk of developing SMNs across all decades, with significantly higher risks for survivors treated with radiotherapy, anthracyclines, and epipodophyllotoxins compared to survivors who did not receive those treatments. In Chapter 3 and 4 we explored the risk of and risk factors for subsequent neoplasms in neuroblastoma survivors. In Chapter 3 we conducted a systematic review and reviewed all literature on this topic. Neuroblastoma survivors were shown to have a 2.8 to 10.4 times elevated risk of developing SMNs compared to the general population. There was limited evidence on risk factors and only a few studies reported on SNMNs. In Chapter 4, we capitalized on this knowledge and analyzed the long-term risk and associated risk factors for developing SMNs and SNMN among the 563 five- year neuroblastoma survivors from the DCCSS-LATER cohort. Our multivariate analyses showed that neuroblastoma survivors treated with Iodine-metaiodobenzylguanidine (131IMIBG) had a significantly higher risk of developing SMNs compared to survivors treated without 131IMIBG, also after adjusting for chemotherapy groups. In Chapter 5 we analyzed the long-term risk of and risk factors for subsequent neoplasms in 3,291 five-year survivors of childhood acute lymphoblastic leukemia (ALL). ALL survivors who were treated with cranial radiotherapy (CRT) had an increased risk of developing SMN, SNMN, and BCC. In multivariable analyses, we found that survivors who were treated with allogenic hematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI) as conditioning regimen had a higher risk of SMN, SNMN, and BCC compared to the survivors treated without HSCT. A significant new insight of this study is that we also observed a higher risk for developing SMNs in HSCT-treated survivors without TBI conditioning, which might be due to the accompanying chemotherapy, but due to the limited number of cases, we were unable to analyze this further.