Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy

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, Sebastian J. C. M. M. Neggers, Monique W. M. Jaspers, Michael Hauptmann, Margriet van der Heiden-van der Loo, Otto Visser, Leontien C. M. Kremer, Cecile M. Ronckers, DCOG LATER Study Grp

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

85 Citaten (Scopus)


Purpose: 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 (P-trend <.001) and breast cancer (P-trend <.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 (P-difference = .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner (P-trend = .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.

Originele taal-2English
Pagina's (van-tot)2288-2298
Aantal pagina's18
TijdschriftJournal of Clinical Oncology
Nummer van het tijdschrift20
StatusPublished - 10-jul-2017

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