The Cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: A report from the childhood cancer Survivor Study

Daniel M. Green, Vikki G. Nolan, Pamela J. Goodman, John A. Whitton, Deo Kumar Srivastava, Wendy M. Leisenring, Joseph P. Neglia, Charles A. Sklar, Sue C. Kaste, Melissa M.M. Hudson, Lisa R. Diller, Marilyn Stovall, Sarah S. Donaldson, Leslie L. Robison

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Background. Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses. Methods. We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS) outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike's Information Criterion (AIC). Results. The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure. Conclusion. The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure.

Original languageEnglish (US)
Pages (from-to)53-67
Number of pages15
JournalPediatric Blood and Cancer
Issue number1
StatePublished - Jan 2014



  • Alkylating agent
  • Alkylating agent dose score
  • Chemotherapy
  • Cyclophosphamide
  • Late effects of cancer treatment
  • Long-term survival

Cite this

Green, D. M., Nolan, V. G., Goodman, P. J., Whitton, J. A., Srivastava, D. K., Leisenring, W. M., Neglia, J. P., Sklar, C. A., Kaste, S. C., Hudson, M. M. M., Diller, L. R., Stovall, M., Donaldson, S. S., & Robison, L. L. (2014). The Cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: A report from the childhood cancer Survivor Study. Pediatric Blood and Cancer, 61(1), 53-67.