Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial
Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial
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DOI：
10.1016/s2468-1253(20)30290-9
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发表时间：
2021-01-01
影响因子：
35.7
通讯作者：
Rolland, Yan
中科院分区：
文献类型：
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作者：
Garin, Etienne;Tselikas, Lambros;Rolland, Yan
背景迄今为止，所有关于晚期肝细胞癌选择性内照射治疗的随机3期研究均报告了阴性结果。然而，这些研究没有使用个性化的剂量测定。我们的目的是比较个性化与标准的剂量测定方法的选择性内部放射治疗与钇-90-加载玻璃微球在hepatocellular carcinoma.Methods患者DOSISPHERE-01是一个随机的，多中心的，开放标签的2期试验在法国的4个医疗中心。如果患者年龄≥ 18岁，患有不可切除的局部晚期肝细胞癌，至少有一处可测量病灶大小≥ 7 cm，选择性内部放射治疗后肝脏储备至少为30%，无肝外扩散（除肝门淋巴结外，病灶≥ 205戈伊靶向指示病灶;个体化剂量测定组），则患者合格。研究者、患者和研究工作人员对治疗不设盲。主要终点是根据欧洲肝脏研究协会标准，在改良的意向治疗人群中选择性内放疗后3个月时，由放射治疗师评估的索引病变的客观缓解率。在所有接受至少一次选择性内部放射治疗注射的患者中评估安全性，并根据实际接受的治疗（通过中心剂量测定评估定义）进行分析。该试验在ClinicalTrials.gov注册，NCT 02582034，并已完成。结果2015年12月5日至2018年1月4日，93名患者接受了合格性评估。在这些患者中，60例被随机分配：31例被分配到个性化剂量测定组，29例被分配到标准剂量测定组（意向治疗人群）。56例（93%）患者（每组28例）接受了治疗（改良的意向治疗人群）。在改良的意向治疗人群中，个性化剂量测定组28例患者中有20例（71% [950% CI 51-87]）和标准剂量测定组28例患者中有10例（36% [19-56]）出现客观缓解（p=0.0074）。在安全性分析人群中，接受个性化剂量测定的35例患者中有7例（20%）报告了至少1起严重不良事件，接受标准剂量测定的21例患者中有7例（33%）报告了至少1起严重不良事件。最常见的（即发生在>5%的患者中）3级或更高级别的不良事件是腹水（1例[3%]接受个性化剂量测定的患者vs 2例[10%]接受标准剂量测定的患者），肝衰竭（2例[6%] vs无）、淋巴细胞减少症（12例[34%] vs 9例[43]1）、天冬氨酸转氨酶浓度升高（3例[9%] vs 2例[10%]）、丙氨酸氨基转移酶浓度升高（3例[9%] vs无）、贫血（2例[6%] vs 1例[5%]）、胃肠道出血（无vs 2例[10%]）和黄疸（无vs 2例[10%]）。解释与标准剂量测定相比，个性化剂量测定显著提高了局部晚期肝细胞癌患者的客观反应率。这项研究的结果表明，个性化的剂量测定可能会改善临床实践中的结果，并应在未来的选择性内放射治疗试验中使用。版权所有（C）2020爱思唯尔有限公司保留所有权利。
Background All randomised phase 3 studies of selective internal radiation therapy for advanced hepatocellular carcinoma published to date have reported negative results. However, these studies did not use personalised dosimetry. We aimed to compare the efficacy of a personalised versus standard dosimetry approach of selective internal radiation therapy with yttrium-90-loaded glass microspheres in patients with hepatocellular carcinoma.Methods DOSISPHERE-01 was a randomised, multicentre, open-label phase 2 trial done at four health-care centres in France. Patients were eligible if they were aged 18 years or older and had unresectable locally advanced hepatocellular carcinoma, at least one measurable lesion 7 cm or more in size, a hepatic reserve of at least 30% after selective internal radiation therapy, no extrahepatic spread (other than to the lymph nodes of the hilum, with a lesion = 205 Gy targeted to the index lesion; personalised dosimetry group). Investigators, patients, and study staff were not masked to treatment. The primary endpoint was the investigator-assessed objective response rate in the index lesion, according to European Association for the Study of the Liver criteria, at 3 months after selective internal radiation therapy iii the modified intention-to-treat population. Safety was assessed in all patients who received at least one selective internal radiation therapy injection, and analysed on the basis of the treatment actually received (defined by central dosimetry assessment). The trial is registered with ClinicalTrials.gov, NCT02582034, and has been completed.Findings Between Dec 5, 2015, and Jan 4, 2018, 93 patients were assessed for eligibility. Of these patients, 60 were randomly assigned: 31 to the personalised dosimetry group and 29 to the standard dosimetry group (intention-to-treat population). 56 (93%) patients (28 in each group) were treated (modified intention-to-treat population). In the modified intention-to-treat population, 20 (71% [950% CI 51-87]) of 28 patients in the personalised dosimetry group and ten (36% [19-56]) of 28 patients in the standard dosimetry group had an objective response (p=0.0074). In the safety analysis population, a least one serious adverse event was reported in seven (20%) of the 35 patients who received personalised dosimetry, and in seven (33%) of the 21 patients who received standard dositnetry. The most frequent (ie, occurring in >5% of patients) grade 3 or higher adverse events were ascites (one [3%] patient who received personalised dosimetry vs two [10%] patients who received standard dosimetry), hepatic failure (two [6%] vs none), lymphopenia (12 [34%) vs nine [43]1), increased aspartate aminotransferase concentrations (three [9%] vs two [10%]), increased alanine aminotransferase concentrations (three [9%] vs none), anaemia (two [6%] vs one [5%]), gastrointestinal haemorrhage (none vs two [10%]), and icterus (none vs two [10%]). One treatment-related death occurred in each group.Interpretation Compared with standard dosimetry, personalised dosimetry significantly improved the objective response rate in patients with locally advanced hepatocellular carcinoma. The results of this study suggest that personalised dosimetry is likely to improve outcomes in clinical practice and should be used in future trials of selective internal radiation therapy. Copyright (C) 2020 Elsevier Ltd. All rights reserved.