The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: A report from the childhood cancer survivor study

Abstract

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.

Breast Cancer Risk in Childhood Cancer Survivors Without a History of Chest Radiotherapy: A Report From the Childhood Cancer Survivor Study

“…Relative SIRs (rSIRs) and 95% CIs are presented. A multivariate model was constructed including the main risk factors of interest, cumulative anthracycline dose, cyclophosphamide equivalent dose (CED), 22,23 and age at primary cancer diagnosis, adjusting for race/ethnicity (white, non-Hispanic, and other) and attained age. We explored inclusion of the primary cancer diagnosis (sarcoma/leukemia v other cancers); including it was not significant and did not meaningfully change the results.…”

Subsequent Malignant Neoplasms in a Population-Based Cohort of Pediatric Cancer Patients: A Focus on the First 5 Years

“…All anthracycline doses were converted to doxorubicin equivalents using factors of 0.83, 0.67, 5.0, and 4.0 for daunorubicin, epirubicin, idarubicin, and mitoxantrone, respectively (21). Alkylators were converted to a cyclophosphamide equivalent dose using the methods of Green and colleagues and were categorized into a 4-level variable based on total dose: 0, >0-<4,000, 4,000-<8,000, 8,000 (22). Dose scores for anthracyclines, epipodophyllotoxins, and platinum agents were determined following the methods proposed by Tucker and colleagues (23) and modified by Friedman and colleagues (8) where the total dose for each agent within a chemotherapy class was determined for each patient and then the tertile for each agent was generated from these distributions where 0 represented no exposure to that agent and 1, 2, and 3 represented the lower, middle, and upper range of the distribution.…”

Intestinal Obstruction in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

“…In addition, an alkylating agent score (cyclophosphamide equivalent dose) and a platinum agent score were calculated based on previously published formulas, which estimate cumulative exposure to these agents. [7][8][9] Radiotherapy data were collected and analyzed in collaboration with the Radiation Physics Center at The University of Texas MD Anderson Cancer Center. 10 Radiotherapy directed to the abdomen and/or pelvis occurring within 5 years of childhood cancer diagnosis was assessed as both a binary variable (did or did not receive radiotherapy directed to the abdomen and/or pelvis) and as a continuous variable (maximum total dose).…”