Freyer David R, Chen Lu, Krailo Mark D, Knight Kristin, Villaluna Doojduen, Bliss Bonnie, Pollock Brad H, Ramdas Jagadeesh, Lange Beverly, Van Hoff David, VanSoelen Michele L, Wiernikowski John, Neuwelt Edward A, Sung Lillian
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA; Departments of Pediatrics and Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Children's Oncology Group, Monrovia, CA, USA.
Lancet Oncol. 2017 Jan;18(1):63-74. doi: 10.1016/S1470-2045(16)30625-8. Epub 2016 Dec 1.
Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without compromising the antitumour efficacy of cisplatin. The primary aim of this study was to assess sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents.
ACCL0431 was a multicentre, randomised, open-label, phase 3 trial that enrolled participants at 38 participating Children's Oncology Group hospitals in the USA and Canada. Eligible participants aged 1-18 years with newly diagnosed cancer and normal audiometry were randomly assigned (1:1) to receive sodium thiosulfate or observation (control group) in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of four. Randomisation was initially stratified by age and duration of cisplatin infusion. Stratification by previous cranial irradiation was added later as a protocol amendment. The allocation sequence was computer-generated centrally and concealed to all personnel. Participants received sodium thiosulfate 16 g/m intravenously 6 h after each cisplatin dose or observation. The primary endpoint was incidence of hearing loss 4 weeks after final cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria but treatment was not masked for participants or clinicians. Analysis of the primary endpoint was by modified intention to treat, which included all randomly assigned patients irrespective of treatment received but restricted to those assessable for hearing loss. Enrolment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976.
Between June 23, 2008, and Sept 28, 2012, 125 eligible participants were randomly assigned to either sodium thiosulfate (n=61) or observation (n=64). Of these, 104 participants were assessable for the primary endpoint (sodium thiosulfate, n=49; control, n=55). Hearing loss was identified in 14 (28·6%; 95% CI 16·6-43·3) participants in the sodium thiosulfate group compared with 31 (56·4%; 42·3-69·7) in the control group (p=0·00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the sodium thiosulfate group compared with the control group (odds ratio 0·31, 95% CI 0·13-0·73; p=0·0036). The most common grade 3-4 haematological adverse events reported, irrespective of attribution, were neutropenia (117 [66%] of 177 participant cycles in the sodium thiosulfate group vs 145 [65%] of 223 in the control group), whereas the most common non-haematological adverse event was hypokalaemia (25 [17%] of 147 vs 22 [12%] of 187). Of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were deemed probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count: 26 episodes in 14 participants.
Sodium thiosulfate protects against cisplatin-induced hearing loss in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for sodium thiosulfate among emerging otoprotection strategies.
US National Cancer Institute.
硫代硫酸钠是一种抗氧化剂，动物临床前研究表明，在顺铂给药后定时给予硫代硫酸钠可预防顺铂所致的听力损失，且不影响顺铂的抗肿瘤疗效。本研究的主要目的是评估硫代硫酸钠预防儿童和青少年顺铂所致听力损失的效果。
ACCL0431是一项多中心、随机、开放标签的3期试验，在美国和加拿大的38家参与研究的儿童肿瘤学组医院招募参与者。年龄在1 - 18岁、新诊断为癌症且听力测试正常的符合条件的参与者，除接受含顺铂的化疗方案外，还使用4个一组的置换区组随机分配（1:1）接受硫代硫酸钠或观察（对照组）。随机分组最初按年龄和顺铂输注时间分层。后来作为方案修正案增加了既往颅脑照射分层。分配序列由中央计算机生成并对所有人员保密。参与者在每次顺铂剂量给药6小时后静脉注射16 g/m²硫代硫酸钠或进行观察。主要终点是最后一剂顺铂给药4周后的听力损失发生率。使用标准听力测试测量听力，并由听力学家集中审核，听力学家对分配情况不知情，采用美国言语 - 语言 - 听力协会标准，但参与者或临床医生对治疗情况不设盲。主要终点的分析采用改良意向性分析，包括所有随机分配的患者，无论接受何种治疗，但仅限于可评估听力损失的患者。入组已完成，本报告代表最终分析。本试验已在ClinicalTrials.gov注册，编号为NCT00716976。
在2008年6月23日至2012年9月28日期间，125名符合条件的参与者被随机分配至硫代硫酸钠组（n = 61）或观察组（n = 64）。其中，104名参与者可评估主要终点（硫代硫酸钠组，n = 49；对照组，n = 55）。硫代硫酸钠组有14名（28.6%；95%CI 16.6 - 43.3）参与者出现听力损失，而对照组有31名（56.4%；42.3 - 69.7）（p = 0.00022）。经分层变量调整后，硫代硫酸钠组听力损失的可能性显著低于对照组（优势比0.31，95%CI 0.13 - 0.73；p = 0.0036）。无论归因如何，报告的最常见3 - 4级血液学不良事件是中性粒细胞减少（硫代硫酸钠组177个参与者周期中有117例[66%]，对照组223个周期中有145例[65%]），而最常见的非血液学不良事件是低钾血症（147例中有25例[17%]，187例中有22例[12%]）。在接受硫代硫酸钠治疗的26名参与者报告的194例严重不良事件中，无一例被认为可能或肯定与硫代硫酸钠有关；最常见的严重不良事件是中性粒细胞计数减少：14名参与者出现26次。
硫代硫酸钠可预防儿童顺铂所致的听力损失，且与因使用该药导致的严重不良事件无关。需要进一步研究以明确硫代硫酸钠在新兴耳保护策略中的适当作用。
美国国立癌症研究所。
