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

Abstract

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 ( 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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    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.

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    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    ,

    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.

    Source

    MeSH

    Adolescent
    Adult
    Adult Survivors of Child Adverse Events
    Aged
    Antineoplastic Agents
    Bone Neoplasms
    Breast Neoplasms
    Central Nervous System Neoplasms
    Chemoradiotherapy
    Child
    Child, Preschool
    Cyclophosphamide
    Doxorubicin
    Female
    Humans
    Ifosfamide
    Incidence
    Infant
    Infant, Newborn
    Leukemia
    Li-Fraumeni Syndrome
    Lymphoma
    Male
    Middle Aged
    Neoplasms, Second Primary
    Netherlands
    Proportional Hazards Models
    Registries
    Risk Assessment
    Sarcoma
    Soft Tissue Neoplasms
    Time Factors
    Young Adult

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    28530852

    Citation

    Teepen, Jop C., et al. "Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 35, no. 20, 2017, pp. 2288-2298.
    Teepen JC, van Leeuwen FE, Tissing WJ, et al. Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy. J Clin Oncol. 2017;35(20):2288-2298.
    Teepen, J. C., van Leeuwen, F. E., Tissing, W. J., van Dulmen-den Broeder, E., van den Heuvel-Eibrink, M. M., van der Pal, H. J., ... Ronckers, C. M. (2017). Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 35(20), pp. 2288-2298. doi:10.1200/JCO.2016.71.6902.
    Teepen JC, et al. Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy. J Clin Oncol. 2017 Jul 10;35(20):2288-2298. PubMed PMID: 28530852.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy. AU - Teepen,Jop C, AU - van Leeuwen,Flora E, AU - Tissing,Wim J, AU - van Dulmen-den Broeder,Eline, AU - van den Heuvel-Eibrink,Marry M, AU - van der Pal,Helena J, AU - Loonen,Jacqueline J, AU - Bresters,Dorine, AU - Versluys,Birgitta, AU - Neggers,Sebastian J C M M, AU - Jaspers,Monique W M, AU - Hauptmann,Michael, AU - van der Heiden-van der Loo,Margriet, AU - Visser,Otto, AU - Kremer,Leontien C M, AU - Ronckers,Cécile M, AU - ,, Y1 - 2017/05/22/ PY - 2017/5/23/pubmed PY - 2017/8/30/medline PY - 2017/5/23/entrez SP - 2288 EP - 2298 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J. Clin. Oncol. VL - 35 IS - 20 N2 - 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 ( 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. SN - 1527-7755 UR - https://www.unboundmedicine.com/medline/citation/28530852/Long_Term_Risk_of_Subsequent_Malignant_Neoplasms_After_Treatment_of_Childhood_Cancer_in_the_DCOG_LATER_Study_Cohort:_Role_of_Chemotherapy_ L2 - http://ascopubs.org/doi/full/10.1200/JCO.2016.71.6902?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -