Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.
Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.
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DOI：
10.1016/s1470-2045(10)70071-1
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发表时间：
2010-06
期刊：
影响因子：
51.1
通讯作者：
Hohenberger, Peter
中科院分区：
文献类型：
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作者：
Issels, Rolf D.;Lindner, Lars H.;Verweij, Jaap;Wust, Peter;Reichardt, Peter;Schem, Baard-Christian;Abdel-Rahman, Sultan;Daugaard, Soeren;Salat, Christoph;Wendtner, Clemens-Martin;Vujaskovic, Zeljko;Wessalowski, Ruediger;Jauch, Karl-Walter;Duerr, Hans Roland;Ploner, Ferdinand;Baur-Melnyk, Andrea;Mansmann, Ulrich;Hiddemann, Wolfgang;Blay, Jean-Yves;Hohenberger, Peter
成人高危软组织肉瘤(STS)的最佳治疗方法尚不清楚。区域热疗将化疗的作用集中在肿瘤受热区域。第二阶段的研究表明，与单独化疗相比，区域加温化疗可以改善局部控制。我们设计了一项平行组随机对照试验，以评估区域热疗联合化疗的安全性和有效性。1997年7月21日至2006年11月30日期间，在欧洲和北美的9个中心招募了患者参加试验。局部高危STS(≥5 cm，国家癌症防治中心2级或3级，深至筋膜)的患者被随机分配到接受新辅助化疗(包括依托泊苷、异环磷酰胺和阿霉素)，或在局部治疗的基础上联合区域热疗(EIA+区域热疗)。局部无进展生存期(LPFS)是主要终点。按意向处理进行疗效分析。这项试验在ClinicalTrials.gov注册，编号nct 00003052。341例患者入选，169例随机分为EIA加局部热疗组和172例单纯EIA组。所有患者都被纳入主要终点分析，332名接受至少一个周期化疗的患者被纳入安全性分析。平均随访34个月(IQR20-67)，132例患者局部进展(EIA加局部热疗56例，EIA 76例)。与EIA加局部热疗组相比，单纯EIA组患者发生局部进展或死亡的可能性更大(相对危险度0.58，95%CI0.41~0.83；p=0.003)，两年后LPFS的绝对差异为15%(95%可信区间6~26；76%EIA加局部热疗vs 61%EIA)。在无病生存方面，局部热疗加局部热疗与单纯热疗相比，相对危险度为0.70(95%CI0.54-0.92，p=0.011)。局部热疗组有效率为28.8%，单纯化疗组有效率为12.7%(p=0.002)。在一项预先指定的按方案进行的分析中，与仅完成环境影响评估的患者相比，完成环境影响评估加区域热疗诱导治疗的患者的总体存活率更好(HR0.66，95%CI0.45-0.98，p=0.038)。白细胞减少(3级或4级)在EIA加局部热疗组比单纯EIA组更常见(128/165比106/167，p=0.005)。与热疗相关的不良反应是疼痛、团注压力和皮肤灼伤，分别为66例(40.5%)、43例(26.4%)和29例(17.8%)，其中7例(4.3%)、8例(4.9%)和1例(0.6%)为重度。两例死亡归因于联合治疗组的治疗，一例死亡归因于单独EIA组的治疗。据我们所知，这是第一个显示区域热疗增加化疗益处的随机3期试验。在化疗的基础上加用局部热疗是治疗高危STS的一种新的有效治疗策略，包括腹部或腹膜后部位的STS。Deutsche Krebshilfe、Helmholtz协会(HGF)、欧洲癌症研究和治疗组织(EORTC)、欧洲热疗肿瘤学会(ESHO)和美国国立卫生研究所(NIH)。
The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. Patients were recruited to the trial between July 21, 1997, and November 30, 2006, at nine centres in Europe and North America. Patients with localised high-risk STS (≥5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00003052. 341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone. All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20–67), 132 patients had local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0.58, 95% CI 0.41–0.83; p=0.003), with an absolute difference in LPFS at 2 years of 15% (95% CI 6–26; 76% EIA plus regional hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0.70 (95% CI 0.54–0.92, p=0.011) for EIA plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional hyperthermia was 28.8%, compared with 12.7% in the group who received chemotherapy alone (p=0.002). In a pre-specified per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0.66, 95% CI 0.45–0.98, p=0.038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0.005). Hyperthermia-related adverse events were pain, bolus pressure, and skin burn, which were mild to moderate in 66 (40.5%), 43 (26.4%), and 29 patients (17.8%), and severe in seven (4.3%), eight (4.9%), and one patient (0.6%), respectively. Two deaths were attributable to treatment in the combined treatment group, and one death was attributable to treatment in the EIA-alone group. To our knowledge, this is the first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective treatment strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location. Deutsche Krebshilfe, Helmholtz Association (HGF), European Organisation of Research and Treatment of Cancer (EORTC), European Society for Hyperthermic Oncology (ESHO), and US National Institute of Health (NIH).