A Methodological Issue in the Analysis of Second-Primary Cancer Incidence in Long-Term Survivors of Childhood Cancers.
Yasui, Yutaka 1; Liu, Yan 1; Neglia, Joseph P. 2; Friedman, Debra L. 1,3; Bhatia, Smita 4; Meadows, Anna T. 5; Diller, Lisa R. 6; Mertens, Ann C. 2; Whitton, John 1; Robison, Leslie L. 2
[Miscellaneous Article] American Journal of Epidemiology. 158(11):1108-1113, December 1, 2003.

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Survival of childhood cancer patients has increased remarkably in the last several decades due to therapeutic improvements. Associated with this progress is the emerging need to accurately assess/minimize late effects of cancer therapy in long-term survivors. This paper considers a methodological issue in assessing the risk of second-primary malignant neoplasms, a major late effect of concern, using second-primary female breast cancer as an example. In the assessment of second-primary malignant neoplasm risk, attained age is a critical factor that must be taken into account. Even with follow-up of decades, childhood-cancer survivors are still at relatively young ages for developing adult-onset diseases. Attained ages at follow-up, however, modify cancer risk considerably; for example, in the general population, women aged 40 years have about fivefold increased breast cancer risk compared with women aged 30 years. A failure to account for the natural age-associated increase of risk could alter, or even reverse, analytical conclusions. This problem was studied empirically by both descriptive and regression analyses of two major studies of long-term childhood-cancer survivors, the Childhood Cancer Survivor Study (1975-1999) and the Late Effects Study Group (1955-1994). These showed appreciable differences in the analytical results by not accounting for the natural age-associated increase of risk, illustrating a significant impact of this methodological issue on study conclusions.

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