《柳叶刀肿瘤学》提出软组织肉瘤药物治疗新见解

　　

生物通报道：软组织肉瘤（STS）是一类起源于软组织及内脏器官的间质组织恶性肿瘤，来源广泛、组织学表现各异。目前软组织肉瘤临床上分为：成人软组织肉瘤（占成人恶性肿瘤的1%）、尤文家族肿瘤、横纹肌肉瘤（恶性度极高的小圆细胞肿瘤，儿童患者多见）以及其他少见的肉瘤。软组织肉瘤的发展是一个由局部期逐渐蔓延至全身的过程，主要表现为软组织肿胀和(或)深部肿块。发生于成人及部分儿童患者的肉瘤局部期持续时间较长。最常见的转移部位首先是肺,其次为骨、肝脏等器官，区域淋巴结较少累及。关于儿童横纹肌肉瘤治疗曾经有过报道：Cancer Cell：基因测序发现治疗儿童肿瘤的药物。

最近发表在《柳叶刀肿瘤学》（The Lancet Oncology）的一项EORTC（欧洲癌症研究组织）研究，不支持使用多柔比星（doxorubicin）和异环磷酰胺（ifosfamide）的强化治疗来缓解晚期软组织肉瘤，除非目的是为了缩小肿瘤。

伦敦皇家马斯登医院的Ian Judson博士指出：“我们的临床试验，旨在对多柔比星和异环磷酰胺联合疗法与单用多柔比星疗法进行比较，结果表明，联合疗法并不能提高总存活率。所以，如果治疗的目的是控制病情，那么仅服用多柔比星就是合适的。另一方面，如果我们的目标是在另一项干预之前缩小肿瘤或缓解症状，那么联合疗法是比较合理的。所观察到的总体存活率缺乏表明，还需要对这类疾病患者进行更好的治疗。”

近30年来，软组织肉瘤患者一直都是采用多柔比星和异环磷酰胺治疗，但很少有研究直接评估多柔比星是否应该单独给药或与异环磷酰胺联合用药。这项EORTC试验62012评估了与单独服用多柔比星相比，在多柔比星中添加异环磷酰胺是否会提高晚期软组织肉瘤患者的存活率。

在2003年四月和2010年五月之间，研究人员在10个国家的38家医院进行了这项3期随机对照试验（EORTC 62012）。研究随机选择了455位年龄在18岁至60之间、具有不可切除的局部晚期或转移性高级软组织肉瘤患者，把他们按最小化方法随机分配（1:1），让其中228名患者单独接受多柔比星用药，另外227名患者使用强化的多柔比星联合异环磷酰胺作为一线治疗。

对单药多柔比星组的中位随访期为56个月，联合治疗组的中位随访期为59个月。两组的总存活期无显著差异，单用多柔比星组的中位总存活期为12.8个月，而联合疗法组的中位总存活期为14.3个月。联合疗法组的平均无进展生存期明显高于单药多柔比星组。联合疗法组中有更多的患者具有总体反应。最常见的3级和4级毒性有：血细胞减少、中性粒细胞减少症、发热性中性粒细胞减少、贫血和血小板减少，这些毒性反应在多柔比星联合异环磷酰胺组全中，比单药多柔比星组更加常见。

研究人员指出，这项研究结果并不支持将多柔比星和异环磷酰胺的强化治疗用于缓解晚期软组织肉瘤，除非目的是缩小肿瘤。这些发现将有助于这类疾病患者的个体化治疗。（生物通：王英）

生物通推荐原文摘要：
Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial
Summary
Background
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.
Methods
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/m2 by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m2; 25 mg/m2 per day, days 1—3) plus ifosfamide (10 g/m2 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.
Findings
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%]).
Interpretation
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.