The goal of this study was to use dose-intensity analyses of published
Ewing's sarcoma and
osteogenic sarcoma trials to determine which agents were most closely associated with a favorable response. The percentage of patients with more than 90%
tumor necrosis following
neoadjuvant chemotherapy was the end point for analysis of
osteogenic sarcoma trials, and disease-free survival and percentage of patients with distant-only relapse were the end points for analysis of
Ewing's sarcoma trials. The data were analyzed using logistic regression analysis to circumvent the distortion of univariate analysis resulting from the correlation between
doxorubicin dose intensity and the dose intensity of other agents. Our analysis suggests that
doxorubicin dose intensity is an important determinant of favorable outcome for both
Ewing's sarcoma and
osteogenic sarcoma and that the dose intensities of other agents do not contribute as significantly to outcome as does
doxorubicin dose intensity. Increasing
dactinomycin dose intensity was associated with a poorer outcome in treatment of
osteogenic sarcoma and
Ewing's sarcoma, most likely resulting from regimens with a higher
dactinomycin dose intensity having a lower
doxorubicin dose intensity. While our analysis of
osteogenic sarcoma trials is consistent with significant activity for
cisplatin and high-dose
methotrexate (and likely
ifosfamide), a rank ordering of the efficacy of these agents when given with
doxorubicin in multiagent regimens is not possible. Our analysis illustrates the importance of analyzing the contributions of individual agents to
combination chemotherapy regimens. In the design of future clinical trials for
osteogenic sarcoma and
Ewing's sarcoma, careful attention should be given to optimizing
doxorubicin dose intensity in regimens to be tested.