一项针对患有支气管发育异常的吸烟者开展的茴香脑二硫酮随机IIb期试验。

A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia.

作者信息

Lam Stephen, MacAulay Calum, Le Riche Jean C, Dyachkova Yulia, Coldman Andy, Guillaud Martial, Hawk Ernest, Christen Marie-Odile, Gazdar Adi F

机构信息

Department of Respiratory Medicine, British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada.

出版信息

J Natl Cancer Inst. 2002 Jul 3;94(13):1001-9. doi: 10.1093/jnci/94.13.1001.

DOI:10.1093/jnci/94.13.1001

PMID:12096085

Abstract

BACKGROUND

Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of ADT in smokers with bronchial dysplasia.

METHODS

One hundred twelve current and former smokers with a smoking history of at least 30 pack-years and at least one site of bronchial dysplasia identified by an autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive placebo or ADT at 25 mg orally thrice daily for 6 months. Each subject then underwent a follow-up bronchoscopy-directed biopsy. We used changes in histopathologic grade and nuclear morphometry index (MI) as the primary and secondary end point biomarkers, respectively. Chi-square tests with continuity correction were used to compare response rates on a lesion- and person-specific basis between the two study groups. All statistical tests were two-sided.

RESULTS

One hundred one subjects had a follow-up bronchoscopy. In the lesion-specific analysis, progression rate of pre-existing dysplastic lesions by two or more grades and/or the appearance of new lesions was statistically significantly lower in the ADT group (8%) than in the placebo group (17%) (P<.001; difference = 9%, 95% confidence interval [CI] = 4% to 15%). In the person-specific analysis, the disease progression rate was statistically significantly lower in the ADT group (32%) than in the placebo group (59%) (P =.013; difference = 27%, 95% CI = 6% to 48%). The two treatment groups did not differ statistically significantly in terms of nuclear MI. Among individuals with an abnormal nuclear MI before treatment (29 in the ADT group and 25 in the placebo group), the progression rate in the ADT group (41%) was substantially lower than that in the placebo group (60%), although the difference was not statistically significant (P =.28; difference = 19%, 95% CI = -11% to 49%). Adverse events were mostly minor gastrointestinal symptoms that resolved with dose reduction or discontinuation of the medication.

CONCLUSION

Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.

摘要

背景

临床前研究结果表明，有机硫化合物茴芹脑二硫酮（ADT）可能是一种有效的肺癌化学预防剂。我们开展了一项IIb期研究，以确定ADT对患有支气管发育异常的吸烟者的影响。

方法

112名有至少30包年吸烟史且经自发荧光支气管镜引导活检确定至少有一处支气管发育异常的现吸烟者和既往吸烟者，被随机分配接受安慰剂或25毫克ADT，每日口服三次，共6个月。然后，每位受试者接受一次随访支气管镜引导活检。我们分别将组织病理学分级变化和核形态计量学指数（MI）作为主要和次要终点生物标志物。采用连续性校正卡方检验，在两个研究组之间按病变和个体特异性比较缓解率。所有统计检验均为双侧检验。

结果

101名受试者接受了随访支气管镜检查。在病变特异性分析中，ADT组（8%）中既往发育异常病变进展两个或更多级别和/或出现新病变的发生率在统计学上显著低于安慰剂组（17%）（P<0.001；差异=9%，95%置信区间[CI]=4%至15%）。在个体特异性分析中，ADT组（32%）的疾病进展率在统计学上显著低于安慰剂组（59%）（P=0.013；差异=27%，95%CI=6%至48%）。两个治疗组在核MI方面无统计学显著差异。在治疗前核MI异常的个体中（ADT组29例，安慰剂组25例）虽然差异无统计学意义（P=0.28；差异=19%，95%CI=-11%至49%），但ADT组（41%）的进展率大幅低于安慰剂组（60%）。不良事件大多为轻微胃肠道症状，并随剂量减少或停药而缓解。