Royal Marsden Hospital, London, UK.
Erasmus MC Cancer Institute, Rotterdam, Netherlands.
Lancet Oncol. 2014 Apr;15(4):415-23. doi: 10.1016/S1470-2045(14)70063-4. Epub 2014 Mar 5.
Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone.
We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18-60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m(2) by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m(2); 25 mg/m(2) per day, days 1-3) plus ifosfamide (10 g/m(2) over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs ≥50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984.
Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31-77) in the doxorubicin only group and 59 months (36-72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12·8 months [95·5% CI 10·5-14·3] in the doxorubicin group vs 14·3 months [12·5-16·5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0·83 [95·5% CI 0·67-1·03]; stratified log-rank test p=0·076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7·4 months [95% CI 6·6-8·3]) than for the doxorubicin group (4·6 months [2·9-5·6]; HR 0·74 [95% CI 0·60-0·90], stratified log-rank test p=0·003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228; p<0·0006). The most common grade 3 and 4 toxic effects-which were all more common with doxorubicin and ifosfamide than with doxorubicin alone-were leucopenia (97 [43%] of 224 patients vs 40 [18%] of 223 patients), neutropenia (93 [42%] vs 83 [37%]), febrile neutropenia (103 (46%) vs 30 [13%]), anaemia (78 [35%] vs 10 [5%]), and thrombocytopenia (75 [33%]) vs one [<1%]).
Our results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumour shrinkage. These findings should help individualise the care of patients with this disease.
Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, Amgen.
对于大多数肉瘤，有效的靶向治疗是不可行的，而多柔比星和异环磷酰胺已经用于治疗软组织肉瘤 30 多年，仍然具有重要作用。单独使用多柔比星还是联合使用多柔比星和异环磷酰胺应该是常规治疗方案，这仍然存在争议。我们评估了与单独使用多柔比星相比，强化多柔比星联合异环磷酰胺治疗晚期软组织肉瘤是否能改善患者的生存。
我们在 10 个国家的 38 家医院进行了这项 3 期随机对照试验（EORTC 62012）。纳入的患者为局部晚期、不可切除或转移性高级软组织肉瘤，年龄在 18-60 岁之间，WHO 体能状态为 0 或 1。他们通过最小化方法以 1:1 的比例随机分配到多柔比星组（静脉推注 75mg/m²，第 1 天或 72 小时连续静脉滴注）或强化多柔比星组（75mg/m²；每天 25mg/m²，第 1-3 天）联合异环磷酰胺（4 天内 10g/m²，并用美司钠和培非格司亭）作为一线治疗。随机分组按中心、体能状态（0 与 1）、年龄（<50 岁与≥50 岁）、肝转移和组织病理学分级（2 与 3）分层。患者每 3 周接受治疗，直至进展或出现不可接受的毒性反应，最多进行 6 个周期。主要终点是意向治疗人群的总生存。该试验在 ClinicalTrials.gov 上注册，编号为 NCT00061984。
在 2003 年 4 月 30 日至 2010 年 5 月 25 日期间，共有 228 例患者被随机分配接受多柔比星治疗，227 例患者接受多柔比星和异环磷酰胺治疗。多柔比星组的中位随访时间为 56 个月（IQR 31-77），联合组为 59 个月（36-72）。两组之间的总生存无显著差异（多柔比星组的中位总生存时间为 12.8 个月[95%CI 10.5-14.3]，联合组为 14.3 个月[12.5-16.5]；危险比[HR]0.83[95%CI 0.67-1.03]；分层对数秩检验 p=0.076）。联合组的无进展生存时间明显高于多柔比星组（7.4 个月[95%CI 6.6-8.3]）（4.6 个月[2.9-5.6]；HR 0.74[95%CI 0.60-0.90]，分层对数秩检验 p=0.003）。与多柔比星组相比，联合组的总缓解率更高（227 例患者中有 60 例[26%]，228 例患者中有 31 例[14%]；p<0.0006）。与单独使用多柔比星相比，联合组更常见的 3 级和 4 级毒性作用是白细胞减少症（224 例患者中有 97 例[43%]，223 例患者中有 40 例[18%]）、中性粒细胞减少症（224 例患者中有 93 例[42%]，223 例患者中有 83 例[37%]）、发热性中性粒细胞减少症（224 例患者中有 103 例[46%]，223 例患者中有 30 例[13%]）、贫血症（224 例患者中有 78 例[35%]，223 例患者中有 10 例[5%]）和血小板减少症（224 例患者中有 75 例[33%]，223 例患者中有 1 例[<1%]）。
我们的结果不支持强化多柔比星联合异环磷酰胺用于晚期软组织肉瘤的姑息治疗，除非特定目标是肿瘤缩小。这些发现应该有助于个体化治疗这种疾病的患者。
英国癌症研究中心、EORTC 慈善信托基金、英国国民健康保险制度、加拿大癌症协会研究所以及安进公司。
