Lee J S, Lippman S M, Benner S E, Lee J J, Ro J Y, Lukeman J M, Morice R C, Peters E J, Pang A C, Fritsche H A
Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, TX 77030.
J Clin Oncol. 1994 May;12(5):937-45. doi: 10.1200/JCO.1994.12.5.937.
Retinoids have proven chemopreventive efficacy in both preclinical and clinical studies. This trial was designed to confirm the finding of an earlier uncontrolled trial that the synthetic retinoid etretinate had major activity in reversing squamous metaplasia found in the bronchial epithelium of chronic smokers.
We prospectively evaluated 152 smokers with bronchoscopy and obtained biopsies from six sites. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg isotretinoin or placebo daily for 6 months. Of 86 subjects randomized (41 isotretinoin, 45 placebo), 69 were reevaluated at the completion of treatment.
In the group as a whole, the metaplasia index decreased over time from a mean +/- SE of 35.8% +/- 2.7% at baseline to 28.1% +/- 3.3% at the completion of treatment (P = .01) by repeated measures analysis of variance [ANOVA]); a reduction in the metaplasia index (> 8%) was noted in both isotretinoin and placebo groups (19 of 35 [54.3%] and 20 of 34 [58.8%], respectively). Complete reversal of squamous metaplasia was noted in nine subjects from each group. However, the magnitudes of the mean metaplasia index changes did not differ significantly in the two treatment groups. In both groups, smoking cessation resulted in significant declines in the extent of squamous metaplasia, whereas no significant change in metaplasia index was found among those who continued to smoke.
Squamous metaplasia was frequently observed in bronchial biopsy samples from chronic smokers. From this study, we conclude that isotretinoin has no effect on squamous metaplasia, a potential intermediate end point of bronchial carcinogenesis. Although determining the exact role of isotretinoin in lung cancer prevention requires further study, the finding that there was a significant decrease in squamous metaplasia in the placebo group emphasizes the critical importance of a placebo-controlled study design in chemoprevention trials using intermediate end points.
维甲酸在临床前和临床研究中均已证实具有化学预防功效。本试验旨在证实一项早期非对照试验的结果，即合成维甲酸依曲替酯在逆转慢性吸烟者支气管上皮中发现的鳞状化生方面具有主要活性。
我们对152名吸烟者进行了前瞻性支气管镜检查，并从六个部位获取活检样本。发育异常和/或化生指数大于15%的受试者被随机分配，每天接受1mg/kg异维A酸或安慰剂治疗，为期6个月。在随机分组的86名受试者（41名异维A酸组，45名安慰剂组）中，69名在治疗结束时接受了重新评估。
通过重复测量方差分析[ANOVA]），整个组的化生指数随时间从基线时的平均±标准差35.8%±2.7%降至治疗结束时的28.1%±3.3%（P = 0.01）；异维A酸组和安慰剂组均观察到化生指数降低（>8%）（分别为35例中的19例[54.3%]和34例中的20例[58.8%]）。每组有9名受试者的鳞状化生完全逆转。然而，两个治疗组的平均化生指数变化幅度没有显著差异。在两组中，戒烟导致鳞状化生程度显著下降，而继续吸烟者的化生指数没有显著变化。
在慢性吸烟者的支气管活检样本中经常观察到鳞状化生。从这项研究中，我们得出结论，异维A酸对鳞状化生没有影响，鳞状化生是支气管致癌作用的一个潜在中间终点。尽管确定异维A酸在肺癌预防中的确切作用需要进一步研究，但安慰剂组鳞状化生显著减少的发现强调了在使用中间终点的化学预防试验中采用安慰剂对照研究设计的至关重要性。
