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Background Previous randomized controlled trials that used the two-drug chemotherapy regimen of cisplatin and doxorubicin as the conventional arm showed no evidence of benefit from an increase in the number of agents or the length of treatment. It was then proposed that survival could be improved by increasing the planned dose intensity of cisplatin and doxorubicin. Methods Previously untreated patients with nonmetastatic, high-grade, central osteosarcoma of an extremity were randomly assigned to Regimen-C (conventional treatment with six 3-week cycles of cisplatin [100 mg/[m.sup.2] by 24-hour infusion] and doxorubicin [25 mg/[m.sup.2]/day by 4-hour infusion for 3 days]) or to Regimen-DI (intensified treatment with identical total doses of cisplatin and doxorubicin, planned as six 2-week cycles supported by granulocyte colony stimulating factor (G-CSF). Surgery was scheduled for week 6 in both arms. Primary and secondary outcome measures were overall and progression-free survival, respectively. Intention-to-treat analyses were performed using standard survival analysis methods. Landmark analyses were performed in patients with known surgical details and centrally reviewed histologic response. All statistical tests were two-sided. Results Between May 1993 and September 2002, treatment was randomly allocated to 497 eligible patients. Six cycles of chemotherapy were completed by 78% of patients in Regimen-C and 80% of patients in Regimen-DI. The delivered preoperative median dose intensity of cisplatin was 86% in Regimen-C and 111% in Regimen-DI (as the percentage of that planned for the conventional regimen). Postoperative median dose intensity of cisplatin was 82% in Regimen-C and 110% in Regimen-DI (the corresponding figures for doxorubicin dose intensity were similar). Regimen-DI was associated with lower risks of severe leucopenia and neutropenia and higher risks of thrombocytopenia and mucositis. Good histologic response (>90% tumor necrosis) was observed in 36% of Regimen-C patients and 50% of Regimen-DI patients (P = .003, [chi square] test). There was no evidence of a difference in overall survival (hazard ratio [HR] = 0.94, 95% CI = 0.71 to 1.24; P = .64) or progression-free survival (HR = 0.98, 95% CI = 0.77 to 1.24; P = .83). Landmark analyses showed similar results. Conclusions Planned intensification of chemotherapy with cisplatin and doxorubicin increased received dose intensity and resulted in a statistically significant increase in favorable histologic response rate, but not in increased progression-free or overall survival. Our results call into question the use of histologic response as a surrogate outcome measure in trials of this disease.

Anticancer cytotoxic agents go through a process by which their antitumor activity--on the basis of the amount of tumor shrinkage they could generate--has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate. [J Natl Cancer Inst 2000; 92:205-16]