Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.
Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.
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DOI：
10.1056/nejmoa1801109
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发表时间：
2018-06-21
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影响因子：
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通讯作者：
Neuwelt EA
中科院分区：
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作者：
Brock PR;Maibach R;Childs M;Rajput K;Roebuck D;Sullivan MJ;Laithier V;Ronghe M;Dall'Igna P;Hiyama E;Brichard B;Skeen J;Mateos ME;Capra M;Rangaswami AA;Ansari M;Rechnitzer C;Veal GJ;Covezzoli A;Brugières L;Perilongo G;Czauderna P;Morland B;Neuwelt EA
顺铂化疗和手术是标准风险肝母细胞瘤儿童的有效治疗方法，但可能会导致严重和不可逆转的听力损失。这项试验比较了顺铂和顺铂加延迟给药硫代硫酸钠，目的是在不危及总体和无事件生存的情况下减少顺铂相关耳毒性反应的发生率和严重程度。我们随机将年龄在1个月以上、18岁以下的患有标准风险肝母细胞瘤(⩾3累及肝脏，无转移，甲胎蛋白水平为100 ng/毫升)的儿童分配到单独接受顺铂(剂量为每平方米体表面积80毫克，持续6小时)或顺铂加硫代硫酸钠(顺铂剂量为每平方米20克，在顺铂停药后6小时内静脉注射)四个术前和两个疗程。主要终点是最小年龄3.5岁时用纯音测听法测量的绝对听力阈值。听力损失根据Brock分级(从0到4，级别越高表示听力损失越大)进行评估。主要的次要终点是3年的总生存率和无事件生存率。共有109名儿童被随机分配接受顺铂加硫代硫酸钠(57名儿童)或仅接受顺铂(52名)治疗，并可进行评估。硫代硫酸钠几乎没有严重的毒性作用。对101名儿童的绝对听力阈值进行了评估。顺铂联合硫代硫酸钠治疗组55例中听力损失1级以上18例(33%)，单纯顺铂治疗组46例中听力损失29例(63%)，两组听力损失发生率降低48%(相对危险度0.52；95%可信区间0.33~0.81；P=0.002)。中位随访52个月，顺铂组和单纯顺铂组3年无事件生存率分别为82%(95%CI，69~90)和79%(95%CI，65~88)，3年总生存率分别为98%(95%CI，88~100)和92%(95%CI，81~97)。在顺铂化疗后6小时给予硫代硫酸钠，在标准风险肝母细胞瘤儿童中，顺铂引起的听力损失的发生率较低，而不会危及总体或无事件生存。(由英国癌症研究和其他机构资助；SIOPEL 6 ClinicalTrials.gov编号，NCT00652132；EudraCT编号，2007-002402-21。)
Cisplatin chemotherapy and surgery are effective treatments for children with standardrisk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (⩾3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132; EudraCT number, 2007–002402-21.)