The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected fusion-negative disease arising at an unfavourable site or non-metastatic fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy. ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic -positive rhabdomyosarcoma or unresected -negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had -negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV -negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with () and is complete. Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0–11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were negative in the VAC/VI group, and 108 (73%) of 149 were negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8–4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5–74·1] in the VAC/VI group 66·8% [57·5–76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58–1·26]; log-rank p=0·44). The most common grade 3–4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified. Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population. The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).

中文翻译：

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在患有中危横纹肌肉瘤的儿童、青少年和年轻人的化疗中添加替西罗莫司 (ARST1431)：儿童肿瘤学组的一项随机、开放标签 3 期试验


儿童肿瘤学组将中危横纹肌肉瘤定义为在不利部位发生的未切除的融合阴性疾病或非转移性融合阳性疾病。替西罗莫司联合化疗在复发或难治性横纹肌肉瘤患者中显示出有希望的活性。我们的目的是比较长春新碱、放线菌素和环磷酰胺交替治疗与长春新碱和伊立替康 (VAC/VI) 联合替西罗莫司随后维持治疗与单独 VAC/VI 联合维持治疗治疗的中危横纹肌肉瘤患者的无事件生存期。 ARST1431 是一项随机、开放标签的 3 期试验，在澳大利亚、加拿大、新西兰和美国的 210 个机构中进行。符合条件的患者是年龄在40岁或以下、患有非转移性阳性横纹肌肉瘤或来自不利部位的未切除阴性横纹肌肉瘤疾病的患者。另外两组患者也符合资格：那些在有利部位（不包括眼眶）患有阴性疾病且未切除的患者；年龄小于 10 岁、患有 IV 期阴性疾病且有远处转移的患者。符合条件的患者，如果年龄不超过 16 岁，兰斯基体能状态评分必须达到 50 分或更高；如果年龄超过 16 岁，卡诺夫斯基体能状态评分必须达到 50 分或更高；所有患者之前均未接受治疗。患者被随机分为四组（1:1），并按组织学、分期和组进行分层。患者接受静脉 VAC/VI 化疗，环磷酰胺剂量为每个周期每剂 1·2 g/m，有或没有每周静脉注射替西罗莫司减少剂量，起始剂量为每剂 15 mg/m 或 0·5 mg/kg。重量不到10公斤。 所有患者的总治疗时间为 42 周，随后接受 6 个月的口服环磷酰胺加静脉注射长春瑞滨的维持治疗。放疗期间和任何重大手术前两周停用替西罗莫司。主要终点是 3 年无事件生存率。采用修订后的意向治疗方法分析数据。该研究已在 () 处注册并已完成。 2016年5月23日至2022年1月1日期间，共有325名患者入组。在 297 名可评估患者中（148 名分配至单独 VAC/VI 组，149 名分配至 VAC/VI 联合替西罗莫司组），中位年龄为 6·3 岁（IQR 3·0–11·3）； 33 名（11%）患者年龄在 18 岁或以上； 297 人中有 179 人（60%）是男性。 VAC/VI 组 148 名患者中有 113 名（77%）呈阴性，VAC/VI 联合替西罗莫司组 149 名患者中有 108 名（73%）呈阴性。中位随访时间为 3·6 年 (IQR 2·8–4·5)，两组之间的 3 年无事件生存率没有显着差异 (64·8% [95% CI 55·5– VAC/VI 组中为 74·1] VAC/VI 加替西罗莫司组中为 66·8% [57·5–76·2]（风险比 0·86 [95% CI 0·58–1·26]；对数秩 p=0·44）最常见的 3-4 级不良事件是贫血（VAC/VI 组 148 名患者中 60 名 [41%] 发生 62 次事件，149 名患者中 87 名 [58%] 发生 89 次事件。 VAC/VI 联合替西罗莫司组）、淋巴细胞减少（65 例 [44%] 中的 83 例事件、71 例 [48%] 中的 99 例事件）、中性粒细胞减少症（99 例 [67%] 中的 160 例事件、105 例 [70%] 中的 164 例事件）、和白细胞减少症（86 例 [58%] 中 121 例，93 例 [62%] 中 132 例），VAC/VI 组中有 1 例与治疗相关的死亡，分类为未另行指定。 在 VAC/VI 中添加替西罗莫司并不能改善根据易位状态和临床因素定义的中危横纹肌肉瘤患者的无事件生存期。需要新的基于生物学的策略来改善该人群的治疗结果。儿童肿瘤学小组（由美国国家癌症研究所、美国国立卫生研究院支持）。