• Jop C Teepen, Flora E van Leeuwen, Wim J Tissing, Eline van Dulmen-den Broeder, Marry M van den Heuvel-Eibrink, Helena J van der Pal, Jacqueline J Loonen, Dorine Bresters, Birgitta Versluys, Neggers Sebastian J C M M SJCMM Jop C. Teepen, Leontien C.M. Kremer, and Cécile M. Ronckers, Emma Children's Hospital/Academic Medical Center; Flora E. van Leeuwen and Mi, Jaspers Monique W M MWM Jop C. Teepen, Leontien C.M. Kremer, and Cécile M. Ronckers, Emma Children's Hospital/Academic Medical Center; Flora E. van Leeuwen and Michael Ha, Michael Hauptmann, Margriet van der Heiden-van der Loo, Otto Visser, Kremer Leontien C M LCM Jop C. Teepen, Leontien C.M. Kremer, and Cécile M. Ronckers, Emma Children's Hospital/Academic Medical Center; Flora E. van Leeuwen and Michael Ha, Cécile M Ronckers, and DCOG LATER Study Group.
• Jop C. Teepen, Leontien C.M. Kremer, and Cécile M. Ronckers, Emma Children's Hospital/Academic Medical Center; Flora E. van Leeuwen and Michael Hauptmann, Netherlands Cancer Institute; Eline van Dulmen-den Broeder, VU University Medical Center; Helena J. van der Pal and Monique W.M. Jaspers, Academic Medical Center, Amsterdam; Wim J. Tissing, Beatrix Children's Hospital/University of Groningen/University Medical Center Groningen, Groningen; Marry M. van den Heuvel-Eibrink, Sophia Children's Hospital/Erasmus Medical Center, Rotterdam; Princess Maxima Center for Pediatric Oncology; Jacqueline J. Loonen, Radboud University Medical Center, Nijmegen; Dorine Bresters, Willem-Alexander Children's Hospital/Leiden University Medical Center, Leiden; Birgitta Versluys, Wilhelmina Children's Hospital/University Medical Center Utrecht; Otto Visser, Netherlands Comprehensive Cancer Organisation, Utrecht; Sebastian J.C.M.M. Neggers, Erasmus Medical Center, Rotterdam; and Margriet van der Heiden-van der Loo, Dutch Childhood Oncology Group, The Hague, the Netherlands.
• J. Clin. Oncol. 2017 Jul 10; 35 (20): 2288-2298.

AbstractPurpose Childhood cancer survivors (CCSs) are at increased risk for subsequent malignant neoplasms (SMNs). We evaluated the long-term risk of SMNs in a well-characterized cohort of 5-year CCSs, with a particular focus on individual chemotherapeutic agents and solid cancer risk. Methods The Dutch Childhood Cancer Oncology Group-Long-Term Effects After Childhood Cancer cohort includes 6,165 5-year CCSs diagnosed between 1963 and 2001 in the Netherlands. SMNs were identified by linkages with the Netherlands Cancer Registry, the Dutch Pathology Registry, and medical chart review. We calculated standardized incidence ratios, excess absolute risks, and cumulative incidences. Multivariable Cox proportional hazard regression analyses were used to evaluate treatment-associated risks for breast cancer, sarcoma, and all solid cancers. Results After a median follow-up of 20.7 years (range, 5.0 to 49.8 years) since first diagnosis, 291 SMNs were ascertained in 261 CCSs (standardized incidence ratio, 5.2; 95% CI, 4.6 to 5.8; excess absolute risk, 20.3/10,000 person-years). Cumulative SMN incidence at 25 years after first diagnosis was 3.9% (95% CI, 3.4% to 4.6%) and did not change noticeably among CCSs treated in the 1990s compared with those treated earlier. We found dose-dependent doxorubicin-related increased risks of all solid cancers ( Ptrend < .001) and breast cancer ( Ptrend < .001). The doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers (leukemia, CNS, and non-Ewing sarcoma) versus survivors of other cancers ( Pdifference = .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( Ptrend = .01). Conclusion The results strongly suggest that doxorubicin exposure in CCSs increases the risk of subsequent solid cancers and breast cancer, whereas cyclophosphamide exposure increases the risk of subsequent sarcomas. These results may inform future childhood cancer treatment protocols and SMN surveillance guidelines for CCSs.

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