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. doi: 10.1200/JCO.2016.71.6902. Epub 2017 May 22.
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 < .001) and breast cancer ( P < .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 = .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( P = .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.
儿童癌症幸存者（CCS）发生后续恶性肿瘤（SMN）的风险增加。我们评估了一组特征明确的 5 年 CCS 队列中 SMN 的长期风险，特别关注个体化疗药物和实体癌风险。
荷兰儿童癌症肿瘤学组-儿童癌症后长期效应队列纳入了 1963 年至 2001 年期间在荷兰诊断的 6165 例 5 年 CCS。通过与荷兰癌症登记处、荷兰病理学登记处和病历审查进行链接，确定 SMN。我们计算了标准化发病比、超额绝对风险和累积发病率。多变量 Cox 比例风险回归分析用于评估乳腺癌、肉瘤和所有实体癌的治疗相关风险。
中位随访时间为首次诊断后 20.7 年（范围，5.0 至 49.8 年），在 261 例 CCS 中确定了 291 例 SMN（标准化发病比，5.2；95%CI，4.6 至 5.8；超额绝对风险，20.3/10000 人年）。首次诊断后 25 年的累积 SMN 发生率为 3.9%（95%CI，3.4%至 4.6%），90 年代治疗的 CCS 与早期治疗的 CCS 相比，未见明显变化。我们发现阿霉素相关剂量依赖性所有实体癌（P<0.001）和乳腺癌（P<0.001）风险增加。李-佛美尼综合征相关儿童癌症（白血病、CNS 和非尤文肉瘤）幸存者与其他癌症幸存者（P=0.008）相比，阿霉素-乳腺癌剂量反应更强。此外，环磷酰胺发现与肉瘤风险呈剂量依赖性增加（P=0.01）。
结果强烈表明，CCS 中阿霉素暴露增加了后续实体癌和乳腺癌的风险，而环磷酰胺暴露增加了后续肉瘤的风险。这些结果可能为未来的儿童癌症治疗方案和 CCS 的 SMN 监测指南提供信息。
