硫代硫酸钠对顺铂所致听力损失的保护作用

摘要(中文译文)

顺铂化疗和手术是标准风险肝母细胞瘤患儿的有效治疗方法，但可能导致相当程度且不可逆的听力损失。本试验比较了单用顺铂与顺铂联合延迟给予硫代硫酸钠的方案，旨在降低顺铂相关耳毒性反应的发生率和严重程度，同时不损害总生存期和无事件生存期。我们将年龄大于1个月且小于18岁、患有标准风险肝母细胞瘤（累及≤3个肝段，无转移性疾病，甲胎蛋白水平>100 ng/mL）的儿童随机分配接受单用顺铂（剂量为80 mg/m²体表面积，持续6小时给药）或顺铂联合硫代硫酸钠（剂量为20 g/m²，在停用顺铂6小时后，经15分钟静脉给药），术前4个疗程、术后2个疗程。主要终点为最小年龄3.5岁时通过纯音测听法测得的绝对听阈。听力损失根据Brock分级进行评估（分级范围0至4级，级别越高表示听力损失越严重）。主要次要终点为3年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联合硫代硫酸钠（57名儿童）或单用顺铂（52名儿童），并可进行评估。硫代硫酸钠与少数高级别毒性反应相关。对101名儿童进行了绝对听阈评估。顺铂-硫代硫酸钠组55名儿童中有18名（33%）发生1级或以上听力损失，而单用顺铂组46名中有29名（63%），表明顺铂-硫代硫酸钠组听力损失发生率降低48%（相对危险度，0.52；95%置信区间[CI]，0.33至0.81；P=0.002）。在中位随访52个月时，顺铂-硫代硫酸钠组的3年无事件生存率为82%（95% CI，69至90），单用顺铂组为79%（95% CI，65至88）；3年总生存率分别为98%（95% CI，88至100）和92%（95% CI，81至97）。在顺铂化疗后6小时加用硫代硫酸钠，可降低标准风险肝母细胞瘤患儿顺铂诱导的听力损失发生率，且不损害总生存期或无事件生存期。（由英国癌症研究中心及其他机构资助；SIOPEL 6 ClinicalTrials.gov注册号，NCT00652132；EudraCT编号，2007-002402-21。）

Abstract

Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk 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 .).

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