Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: A randomized phase III trial of the European Osteosarcoma Intergroup
Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: A randomized phase III trial of the European Osteosarcoma Intergroup
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DOI：
10.1093/jnci/djk015
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发表时间：
2007-01-17
影响因子：
10.3
通讯作者：
Taminiau, Antonie H. M.
中科院分区：
文献类型：
--
作者：
Lewis, Ian J.;Nooij, Marianne A.;Taminiau, Antonie H. M.
背景以前使用顺铂和阿霉素两种药物化疗方案作为常规组的随机对照试验显示，没有证据表明药物数量或治疗时间的增加会带来益处。方法将四肢非转移性、高级别、中央型骨肉瘤患者随机分为两组，C组采用顺铂[100 mg/m(2)，24小时静脉滴注]6个3周周期，阿霉素[25 mg/m(2)/d，4h静脉滴注，连续3天]，DI方案采用等量顺铂和阿霉素强化治疗，每组6个2周周期，粒细胞集落刺激因子支持。手术原定在第6周进行，手术时间为双臂。主要和次要结果分别是总体生存率和无进展生存率。采用标准生存分析方法进行意向处理分析。对已知手术细节和中央回顾的组织学反应的患者进行里程碑式的分析。结果在1993年5月至2002年9月期间，497例符合条件的患者被随机分配治疗。方案C和方案DI分别有78%和80%的患者完成了6个周期的化疗。顺铂的术前给药中位剂量强度C方案为86%，DI方案为111%(按常规方案计划的百分比)。术后顺铂的中位剂量强度C方案为82%，DI方案为110%(相应的阿霉素剂量强度数据相似)。DI方案发生严重白细胞减少和中性粒细胞减少的风险较低，而发生血小板减少和粘膜炎的风险较高。C方案和DI方案分别有36%和50%的患者观察到良好的组织学反应(>；90%的肿瘤坏死)(P=0.003，x(2)检验)。总生存期(危险比[HR]=0.94，95%CI=0.71~1.24；P=.64)和无进展生存率(HR=0.98，95%CI=0.77~1.24；P=.83)的差异无统计学意义。标志性分析显示相似的结果。结论顺铂和阿霉素的计划强化化疗增加了接受剂量强度，导致良好的组织学应答率在统计学上显著增加，但没有增加无进展或总体生存率。我们的结果质疑在这种疾病的试验中使用组织学反应作为替代结果的方法。
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(2) by 24-hour infusion] and doxorubicin [25 mg/m(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(2) test). There was no evidence of a difference in overall survival (hazard ratio [HR] = 0.94, 95% Cl = 0.71 to 1.24; P = .64) or progression-free survival (HR = 0.98, 95% Cl = 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.