BACKGROUND: Because survival rates among childhood cancer patients are 
increasing, assessing the risk of second and subsequent malignant neoplasms 
(SMNs) is ever more important. Using the Childhood Cancer Survivor Study cohort, 
we identified the risk of SMNS:
METHODS: A retrospective cohort of 13 581 children diagnosed with common cancers 
before age 21 years and surviving at least 5 years was constructed with the use 
of data from patients treated at 25 U.S. and Canadian institutions. SMNs were 
ascertained through self-administered questionnaires and verified by pathology 
reports. Information on therapeutic exposures was abstracted from medical 
records. The risk of SMN was evaluated by standardized incidence ratios (SIRs) 
and excess absolute risk. Poisson multiple regression models were used to assess 
the impact of host and therapy factors on the risk of developing SMNS: All 
statistical tests were two-sided.
RESULTS: In 298 individuals, 314 SMNs were identified (SIR = 6.38; 95% 
confidence interval [CI] = 5.69 to 7.13). The largest observed excess SMNs were 
bone and breast cancers (SIR = 19.14 [95% CI = 12.72 to 27.67] and SIR = 16.18 
[95% CI = 12.35 to 20.83], respectively). A statistically significant excess of 
SMNs followed all childhood cancers. In multivariate regression models adjusted 
for therapeutic radiation exposure, SMNs of any type were independently 
associated with female sex (P<.001), childhood cancer at a younger age (P for 
trend <.001), childhood Hodgkin's disease or soft-tissue sarcoma (P<.001 and P 
=.01, respectively), and exposure to alkylating agents (P for trend =.02). 
Twenty years after the childhood cancer diagnosis, the cumulative estimated SMN 
incidence was 3.2%. However, only 1.88 excess malignancies occurred per 1000 
years of patient follow-up.
CONCLUSIONS: Success in treating children with cancer should not be overshadowed 
by the incidence of SMNS: However, patients and health-care providers must be 
aware of risk factors for SMNs so that surveillance is focused and early 
prevention strategies are implemented.