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ARTICLE |
Improvement in Histologic Response But Not Survival in Osteosarcoma Patients Treated With Intensified Chemotherapy: A Randomized Phase III Trial of the European Osteosarcoma Intergroup
On behalf of MRC BO06 and EORTC 80931 collaborators and European Osteosarcoma Intergroup
Affiliations of authors: Paediatric Oncology and Haematology, St James University Hospital, Leeds, U.K. (IJL); Departments of Clinical Oncology (MN), Orthopaedic Surgery (AHMT), and Pathology (PCWH, EIH), Leiden University Medical Center, The Netherlands; Department of Oncology, University College Hospital, London, U.K. (JW); Cancer Group, Medical Research Council Clinical Trials Unit, London, U.K. (MRS, SW, BMU); School of Clinical Medical Sciences, University of Newcastle, Newcastle, U.K. (AWC); European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium (MvG, AK); Royal Orthopaedic Hospital, Birmingham, U.K. (RG); Department of Oncology, King Faisal Hospital, Saudi Arabia (MM); Laboratory for Pathology, University of Antwerp, Eindhoven, The Netherlands (EIH)
Correspondence to: Ian J. Lewis, MB, ChB, FRCP, FRCPCH, BO06 Trial, Cancer Group, Medical Research Council Clinical Trials Unit, London NW1 2DA, U.K. (e-mail: bo06{at}ctu.mrc.ac.uk).
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, 
2 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.
| CONTEXT AND CAVEATS Prior knowledge Chemotherapy has improved outcomes for patients with osteosarcoma such that 50%–70% of them are alive 5 years after diagnosis. However, in recent trials, treatments in which the number of chemotherapeutic agents or the duration of chemotherapy was increased did not improve patient survival compared to conventional chemotherapy. Study design This is a randomized clinical trial comparing two treatment regimens with overall and progression-free survival as the clinical endpoints. Contribution This trial investigated whether increasing the planned dose intensity of the chemotherapeutic agents cisplatin and doxorubicin would improve outcomes compared to conventional treatment with these drugs. The investigators found that increased dose intensity, while improving histologic response, did not prolong patient survival. Implications Testing of additional therapeutic strategies will be required to improve survival of patients with osteosarcoma, and histologic response may not be a valid surrogate outcome in osteosarcoma trials. Limitations Due to the rarity of osteosarcoma, this trial took a long time to recruit and mature, and it involved many countries with different standard approaches to chemotherapy and surgery.
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Editorial about this Article
- Response Rate as an Endpoint in Clinical Trials
- Stephen L. George
J Natl Cancer Inst 2007 99: 98-99.[Extract] [Full Text] [PDF]
Related Article in JNCI
- Press Release: No Benefit to Increasing Dose Intensity of Chemotherapy in Osteosarcoma, Study Finds
- Andrea Widener
J Natl Cancer Inst 2007 99: 97.[Extract] [Full Text]
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