Background

Adolescent and young adult patients with rhabdomyosarcoma often have poorer outcomes than do children. We aimed to compare the findings of adolescent and young adult patients with children enrolled in two prospective clinical protocols.

Methods

This retrospective observational analysis was based on data from the European paediatric Soft tissue sarcoma Study Group (EpSSG) rhabdomyosarcoma 2005 trial (phase 3 randomised trial for localised rhabdomyosarcoma, open from April, 2006, to December, 2016) and the EpSSG MTS 2008 protocol (prospective, observational, single-arm study for metastatic rhabdomyosarcoma, open from June, 2010, to December, 2016), which involved 108 centres from 14 different countries in total. For this analysis, patients were categorised according to their age into children (age 0–14 years) and adolescents and young adults (age 15–21 years). For the analysis of adherence to treatment and toxicity, only patients with high-risk localised rhabdomyosarcoma included in the randomised part of the rhabdomyosarcoma 2005 study were considered. The primary outcome of event-free survival (assessed in all participants) was defined as the time from diagnosis to the first event (eg, tumour progression, relapse) or to the latest follow-up. Secondary outcomes were overall survival, response to chemotherapy, and toxicity.

Findings

Our analysis included 1977 patients, 1720 children (median age 4·7 years; IQR 2·6–8·4) and 257 adolescents and young adults (16·6 years; 15·8–18·0). 1719 patients were from the EpSSG rhabdomyosarcoma 2005 study (1523 aged <15 years and 196 aged 15–21 years) and 258 patients were from the EPSSG MTS 2008 study (197 aged <15 years and 61 aged 15–21 years). Adolescent and young adult patients were more likely than were children to have metastatic tumours (61 [23·7%] of 257 vs 197 [11·5%] of 1720; p<0·0001), unfavourable histological subtypes (119 [46·3%] vs 451 [26·2%]; p<0·0001), tumours larger than 5 cm (177 [68·9%] vs 891 [51·8%]; p<0·0001), and regional lymph node involvement (109 [42·4%] vs 339 [19·7%]; p<0·0001). Adolescent and young adult patients had lower 5-year event-free survival (52·6% [95% CI 46·3–58·6] vs 67·8% [65·5–70·0]; p<0·0001) and lower 5-year overall survival (57·1% [50·4–63·1] vs 77·9% [75·8–79·8]; p<0·0001) than did children. The multivariable analysis confirmed the inferior prognosis of patients aged 15–21 years (hazard ratios 1·48 [95% CI 1·20–1·83; p=0·0002] for poorer event-free survival and 1·73 [1·37–2·19; p<0·0001] for poorer overall survival). Modifications of administered chemotherapy occurred in 13 (15·3%) of 85 adolescents and young adults, and in 161 (21·4%) of 754 children. Grade 3–4 haematological toxicity and infection were observed more frequently in children than in adolescent and young adult patients.

Interpretation

This study found better outcomes for adolescent and young adult patients than those reported in epidemiological studies (eg, the EUROCARE-5 study reported 5-year overall survival of 39·6% for patients aged 15–19 years in the 2000–07 study period), suggesting that adolescent and young adult patients, at least up to age 21 years, can be treated with intensive paediatric therapies with no major tolerability issues and should be included in paediatric rhabdomyosarcoma trials. However, the inferior outcomes in adolescent and young adult patients compared with those in children, despite receiving similar therapy, suggest that a tailored and intensive treatment strategy might be warranted for these patients.

Funding

Fondazione Città della Speranza.

中文翻译：

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在欧洲小儿软组织肉瘤研究组 (EpSSG) 方案中治疗的患有横纹肌肉瘤的青少年和年轻人：一项队列研究

背景

患有横纹肌肉瘤的青少年和年轻成人患者的预后通常比儿童差。我们旨在比较参加两项前瞻性临床方案的青少年和年轻成人患者与儿童的研究结果。

方法

这项回顾性观察分析基于欧洲小儿软组织肉瘤研究组 (EpSSG) 横纹肌肉瘤 2005 试验（局部横纹肌肉瘤 3 期随机试验，于 2006 年 4 月至 2016 年 12 月开放）和 EpSSG MTS 2008 方案的数据（转移性横纹肌肉瘤的前瞻性、观察性、单臂研究，开放时间为 2010 年 6 月至 2016 年 12 月），共涉及来自 14 个不同国家的 108 个中心。在这项分析中，患者根据年龄分为儿童（0-14 岁）和青少年（15-21 岁）。为了分析治疗依从性和毒性，仅考虑纳入 2005 年横纹肌肉瘤研究随机部分的高危局限性横纹肌肉瘤患者。无事件生存（在所有参与者中评估）的主要结果定义为从诊断到第一次事件（例如，肿瘤进展、复发）或到最近一次随访的时间。次要结局是总生存期、对化疗的反应和毒性。

发现

我们的分析包括 1977 名患者、1720 名儿童（中位年龄 4·7 岁；IQR 2·6-8·4）和 257 名青少年和年轻人（16·6 岁；15·8-18·0）。1719 名患者来自 EpSSG 横纹肌肉瘤 2005 研究（1523 名年龄 <15 岁和 196 名年龄在 15-21 岁），258 名患者来自 EPSSG MTS 2008 研究（197 名年龄 <15 岁和 61 名年龄在 15-21 岁）。与儿童相比，青少年和年轻成人患者更可能发生转移性肿瘤（257 人中的 61 [23·7%] vs 1720 人中的 197 [11·5%]；p<0·0001），不利的组织学亚型（119 [46 ·3%] vs 451 [26·2%]；p<0·0001)，大于 5 cm 的肿瘤（177 [68·9%] vs 891 [51·8%]；p<0·0001），和区域淋巴结受累（109 [42·4%] vs339 [19·7%]；p<0·0001)。青少年和青年患者的 5 年无事件生存率较低（52·6% [95% CI 46·3–58·6] vs 67·8% [65·5–70·0]；p<0· 0001）和低于儿童的 5 年总生存率（57·1% [50·4–63·1] vs 77·9% [75·8–79·8]；p<0·0001）。多变量分析证实 15-21 岁患者的预后较差（风险比为 1·48 [95% CI 1·20-1·83；p=0·0002]，无事件生存期较差，1·73 [1 ·37–2·19；p<0·0001] 表示总生存率较差）。85 名青少年和年轻人中的 13 名 (15·3%) 和 754 名儿童中的 161 名 (21·4%) 发生了化疗的修改。与青少年和年轻成人患者相比，在儿童中观察到 3-4 级血液学毒性和感染的频率更高。

解释

该研究发现，青少年和年轻成人患者的结局优于流行病学研究报告的结果（例如，EUROCARE-5 研究报告，在 2000-07 年研究期间，15-19 岁患者的 5 年总生存率为 39·6% )，这表明至少 21 岁以下的青少年和年轻成人患者可以接受强化儿科治疗而没有重大的耐受性问题，应纳入儿科横纹肌肉瘤试验。然而，尽管接受了类似的治疗，但与儿童相比，青少年和年轻成人患者的结局较差，这表明可能需要对这些患者进行量身定制的强化治疗策略。

资金

Fondazione Città della Speranza。