The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study.
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.


CONCLUSIONS
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.
Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.
Daniel M
DM
Green
Vikki G
VG
Nolan
Pamela J
PJ
Goodman
John A
JA
Whitton
DeoKumar
D
Srivastava
Wendy M
WM
Leisenring
Joseph P
JP
Neglia
Charles A
CA
Sklar
Sue C
SC
Kaste
Melissa M
MM
Hudson
Lisa R
LR
Diller
Marilyn
M
Stovall
Sarah S
SS
Donaldson
Leslie L
LL
Robison
D000465:Algorithms; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D019540:Area Under Curve; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D010600:Pharmacology / Q000379:methods*; D011247:Pregnancy; D012372:ROC Curve; D017741:Survivors
D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide
Alkylating Agent Dose score; alkylating agent; chemotherapy; cyclophosphamide; late effects of cancer treatment; long-term survival