Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup.
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/m2 by 24-hour infusion] and doxorubicin [25 mg/m2/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, chi2 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.
Lewis
Ian J
IJ
Paediatric Oncology and Haematology, St James University Hospital, Leeds, UK. bo06@ctu.mrc.ac.uk
Nooij
Marianne A
MA
Whelan
Jeremy
J
Sydes
Matthew R
MR
Grimer
Robert
R
Hogendoorn
Pancras C W
PC
Memon
Muhammad A
MA
Weeden
Simon
S
Uscinska
Barbara M
BM
van Glabbeke
Martine
M
Kirkpatrick
Anne
A
Hauben
Esther I
EI
Craft
Alan W
AW
Taminiau
Antonie H M
AH
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D009503:Neutropenia / Q000139:chemically induced; D016017:Odds Ratio; D012516:Osteosarcoma / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology* / Q000601:surgery; D012107:Research Design; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
D004317:Doxorubicin; D002945:Cisplatin