Abstract：
BACKGROUND: The Children\'s Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 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.
METHODS: 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 FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-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/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 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 ClinicalTrials.gov (NCT02567435) and is complete.
RESULTS: 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 FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 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 vs 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 vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified.
CONCLUSIONS: Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.
BACKGROUND: The Children\'s Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).
METHODS: 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 FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-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/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 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 ClinicalTrials.gov (NCT02567435) and is complete.
RESULTS: 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 FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 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 vs 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 vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified.
CONCLUSIONS: Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.
BACKGROUND: The Children\'s Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).
摘要：
背景：儿童肿瘤学小组将中危横纹肌肉瘤定义为出现在不利部位的未切除FOXO1融合阴性疾病或非转移性FOXO1融合阳性疾病。坦西罗莫司联合化疗在复发性或难治性横纹肌肉瘤患者中显示出有希望的活性。我们旨在比较接受长春新碱治疗的中危横纹肌肉瘤患者的无事件生存率。放线菌素,环磷酰胺与长春新碱和伊立替康（VAC/VI）交替联合替西罗莫司，然后进行维持治疗，而VAC/VI单独进行维持治疗。
方法：ARST1431是随机的，开放标签，在澳大利亚的210个机构中进行的第三阶段试验，加拿大,新西兰,和美国。符合条件的患者是年龄在40岁或以下，患有非转移性FOXO1阳性横纹肌肉瘤或来自不利部位的未切除FOXO1阴性横纹肌肉瘤疾病的患者。另外两组患者也符合资格：在未切除的有利部位（不包括眼眶）患有FOXO1阴性疾病的患者；以及年龄小于10岁的IV期FOXO1阴性疾病伴远处转移的患者。如果16岁或以下，符合条件的患者必须具有50或更高的Lansky表现状态评分，如果16岁以上，则Karnofsky表现状态评分必须为50或更高；所有患者先前均未接受治疗。患者被随机(1:1)分为4个组，并按组织学分层，舞台,和团体。患者接受静脉VAC/VI化疗，每个周期的环磷酰胺剂量为1·2g/m2，有或没有减少剂量的每周静脉坦西罗莫司，从15mg/m2或0·5mg/kg开始体重小于10kg。所有患者的治疗总持续时间为42周，然后口服环磷酰胺加静脉注射长春瑞滨维持治疗6个月。在放疗期间和任何重大外科手术前2周内，坦西罗莫司被停用。主要终点是3年无事件生存期。采用修订后的意向治疗方法分析数据。该研究已在ClinicalTrials.gov（NCT02567435）注册，并且已完成。
结果：2016年5月23日至2022年1月1日，共纳入325例患者。在297名可评估患者中（148名仅接受VAC/VI治疗，149名接受替西罗莫司治疗的VAC/VI治疗），中位年龄为6·3岁(IQR3·0-11·3);33例(11%)患者年龄在18岁或以上;297人中有179例(60%)为男性.在VAC/VI组中,148例患者中有113例(77%)FOXO1阴性,在替罗莫司组的VAC/VI中，149例中的108例（73％）为FOXO1阴性。中位随访时间为3·6年（IQR2·8-4·5），两组之间的3年无事件生存率没有显着差异（VAC/VI组的64·8％[95％CI55·5-74·1]与66·8％[57·5-76·2]在VAC/VI加替西罗莫司组（风险比0·86[95％CI0·58-1·26]；log-rankp=0·44）。最常见的3-4级不良事件是贫血（VAC/VI组148例患者中有62例发生[41%]，VAC/VI组149例患者中有89例发生[58%]，淋巴细胞减少（65例[44%]中的83例事件与71例[48%]中的99例事件），中性粒细胞减少症（99例[67%]中的160例事件与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与替西罗莫司组发生1例治疗相关死亡，归类为未指定。
结论：在VAC/VI中添加替西罗莫司并不能改善由FOXO1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率。需要新的基于生物学的策略来改善该人群的结果。
背景：儿童肿瘤学小组（由美国国家癌症研究所支持，美国国立卫生研究院）。
方法：ARST1431是随机的，开放标签，在澳大利亚的210个机构中进行的第三阶段试验，加拿大,新西兰,和美国。符合条件的患者是年龄在40岁或以下，患有非转移性FOXO1阳性横纹肌肉瘤或来自不利部位的未切除FOXO1阴性横纹肌肉瘤疾病的患者。另外两组患者也符合资格：在未切除的有利部位（不包括眼眶）患有FOXO1阴性疾病的患者；以及年龄小于10岁的IV期FOXO1阴性疾病伴远处转移的患者。如果16岁或以下，符合条件的患者必须具有50或更高的Lansky表现状态评分，如果16岁以上，则Karnofsky表现状态评分必须为50或更高；所有患者先前均未接受治疗。患者被随机(1:1)分为4个组，并按组织学分层，舞台,和团体。患者接受静脉VAC/VI化疗，每个周期的环磷酰胺剂量为1·2g/m2，有或没有减少剂量的每周静脉坦西罗莫司，从15mg/m2或0·5mg/kg开始体重小于10kg。所有患者的治疗总持续时间为42周，然后口服环磷酰胺加静脉注射长春瑞滨维持治疗6个月。在放疗期间和任何重大外科手术前2周内，坦西罗莫司被停用。主要终点是3年无事件生存期。采用修订后的意向治疗方法分析数据。该研究已在ClinicalTrials.gov（NCT02567435）注册，并且已完成。
结果：2016年5月23日至2022年1月1日，共纳入325例患者。在297名可评估患者中（148名仅接受VAC/VI治疗，149名接受替西罗莫司治疗的VAC/VI治疗），中位年龄为6·3岁(IQR3·0-11·3);33例(11%)患者年龄在18岁或以上;297人中有179例(60%)为男性.在VAC/VI组中,148例患者中有113例(77%)FOXO1阴性,在替罗莫司组的VAC/VI中，149例中的108例（73％）为FOXO1阴性。中位随访时间为3·6年（IQR2·8-4·5），两组之间的3年无事件生存率没有显着差异（VAC/VI组的64·8％[95％CI55·5-74·1]与66·8％[57·5-76·2]在VAC/VI加替西罗莫司组（风险比0·86[95％CI0·58-1·26]；log-rankp=0·44）。最常见的3-4级不良事件是贫血（VAC/VI组148例患者中有62例发生[41%]，VAC/VI组149例患者中有89例发生[58%]，淋巴细胞减少（65例[44%]中的83例事件与71例[48%]中的99例事件），中性粒细胞减少症（99例[67%]中的160例事件与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与替西罗莫司组发生1例治疗相关死亡，归类为未指定。
结论：在VAC/VI中添加替西罗莫司并不能改善由FOXO1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率。需要新的基于生物学的策略来改善该人群的结果。
背景：儿童肿瘤学小组（由美国国家癌症研究所支持，美国国立卫生研究院）。
