Background

A standardised approach to treatment of paediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), which account for about 4% of childhood cancers, is still lacking. We report the results of the NRSTS 2005 protocol developed specifically by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) to determine a risk-adapted multimodal standard of care for this group of tumours.

Methods

The EpSSG NRSTS 2005 study included two prospective, non-randomised, historically controlled trials (one on localised adult-type NRSTS and the other on localised synovial sarcoma) done at 100 academic centres and hospitals in 14 countries. Patients younger than 21 years with a pathologically proven diagnosis of synovial sarcoma or an adult-type NRSTS, no evidence of metastatic disease, no previous treatment other than primary surgery, and diagnostic specimens available for pathological review were included. Patients were stratified by surgical stage, tumour size, nodal involvement, tumour grade (for adult-type NRSTS), and tumour site (for synovial sarcoma). Patients were then divided into four treatment groups: surgery alone, adjuvant radiotherapy, adjuvant chemotherapy (with or without radiotherapy), or neoadjuvant chemotherapy (with or without radiotherapy). The main chemotherapy regimen was ifosfamide (3·0 g/m² intravenously per day for 3 days) plus doxorubicin (37·5 mg/m² intravenously per day for 2 days); only ifosfamide (3·0 g/m² intravenously per day for 2 days) was given concomitantly with radiotherapy (delivered with three-dimensional conformal external beam technique, using conventional fractionation [1·8 daily fractions, 5 days per week] at a dose of 50·4 Gy or 54·0 Gy, to a maximum of 59·4 Gy). The number of chemotherapy cycles ranged from three to seven depending on the stage of the disease. The primary outcomes were event-free survival and overall survival. This study has been completed, and is registered under EudraCT, 2005-001139-31.

Findings

Between May 31, 2005, and Dec 31, 2016, 1321 patients were enrolled, of whom 569 (206 with synovial sarcoma and 363 with adult-type NRSTS), with a median age of 12·6 years (IQR 8·2–14·9), were included in this analysis. With a median follow-up of 80·0 months (IQR 54·3–111·3) for the 467 patients alive, 5-year event-free survival was 73·7% (95% CI 69·7–77·2) and 5-year overall survival was 83·8% (95% CI 80·3–86·7). 5-year event-free survival was 91·4% (95% CI 87·0–94·4) and 5-year overall survival was 98·1% (95% CI 95·0–99·3) in the surgery alone group (n=250); 75·5% (46·9–90·1) and 88·2% (60·6–96·9) in the adjuvant radiotherapy group (n=17); 65·6% (54·8–74·5) and 75·8% (65·3–83·5) in the adjuvant chemotherapy group (n=93); and 56·4% (49·3–63·0) and 70·4% (63·3–76·4) in the neoadjuvant chemotherapy group (n=209). Reported severe adverse events included one case of generalised seizures (probably related to ifosfamide) and six cases of secondary tumours.

Interpretation

Findings from the EpSSG NRSTS 2005 study help to define the risk-adapted standard of care for this patient population. Adjuvant treatment can be safely omitted in the low-risk population (classified here as the surgery alone group). Improving the outcome for patients with high-risk, initially resected adult-type NRSTS and those with initially unresectable disease remains a major clinical challenge.

Funding

Fondazione Città della Speranza.

中文翻译：

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小儿非横纹肌肉瘤软组织肉瘤：欧洲小儿软组织肉瘤研究组 (EpSSG) 的前瞻性 NRSTS 2005 研究

背景

儿童非横纹肌肉瘤软组织肉瘤 (NRSTS) 约占儿童癌症的 4%，目前仍缺乏标准化的治疗方法。我们报告了由欧洲小儿软组织肉瘤研究小组 (EpSSG) 专门开发的 NRSTS 2005 协议的结果，以确定针对这组肿瘤的风险适应多模式护理标准。

方法

EpSSG NRSTS 2005 研究包括在 14 个国家的 100 个学术中心和医院进行的两项前瞻性、非随机、历史对照试验（一项针对局部成人型 NRSTS，另一项针对局部滑膜肉瘤）。年龄小于 21 岁、经病理证实诊断为滑膜肉瘤或成人型 NRSTS、无转移性疾病证据、既往未接受过除初次手术以外的治疗以及可用于病理检查的诊断标本的患者均被纳入。根据手术分期、肿瘤大小、淋巴结受累、肿瘤分级（成人型 NRSTS）和肿瘤部位（滑膜肉瘤）对患者进行分层。然后将患者分为四个治疗组：单纯手术、辅助放疗、辅助化疗（放疗或不放疗）、或新辅助化疗（有或没有放疗）。主要化疗方案为异环磷酰胺（3·0 g/m²每天静脉注射 3 天）加多柔比星（每天静脉注射 37·5 mg/m ² 2 天）；仅异环磷酰胺（3·0 g/m ²每天静脉注射，持续 2 天）与放疗（使用三维适形外照射技术，使用常规分次 [每天分次 1·8，每周 5 天]）同时给予50·4 Gy 或 54·0 Gy，最大 59·4 Gy）。根据疾病的阶段，化疗周期的数量从三到七个不等。主要结局是无事件生存率和总生存率。这项研究已经完成，并在 EudraCT 下注册，2005-001139-31。

发现

2005年5月31日至2016年12月31日期间，共纳入1321例患者，其中569例（滑膜肉瘤206例，成人型NRSTS 363例），中位年龄12·6岁（IQR 8·2-14） ·9)，被包括在这个分析中。467 名存活患者的中位随访时间为 80·0 个月（IQR 54·3–111·3），5 年无事件生存率为 73·7%（95% CI 69·7-77·2 ) 和 5 年总生存率为 83·8% (95% CI 80·3–86·7)。手术中的 5 年无事件生存率为 91·4%（95% CI 87·0-94·4），5 年总生存率为 98·1%（95% CI 95·0-99·3）单独组（n=250）；辅助放疗组 (n=17) 75·5% (46·9–90·1) 和 88·2% (60·6–96·9)；辅助化疗组（n=93）分别为65·6%（54·8-74·5）和75·8%（65·3-83·5）；新辅助化疗组 (n=209) 分别为 56·4% (49·3-63·0) 和 70·4% (63·3-76·4)。

解释

EpSSG NRSTS 2005 研究的结果有助于为该患者群体定义适应风险的护理标准。在低风险人群中可以安全地省略辅助治疗（这里分类为单独手术组）。改善最初切除的高危成人型 NRSTS 患者和最初无法切除的疾病患者的预后仍然是一项重大的临床挑战。

资金

Fondazione Città della Speranza 基金会。