Risk factors for lung cancer and for intervention effects in CARET, the beta-carotene and retinol efficacy trial
Risk factors for lung cancer and for intervention effects in CARET, the beta-carotene and retinol efficacy trial
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DOI：
10.1093/jnci/88.21.1550
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发表时间：
1996-11-06
期刊：
影响因子：
--
通讯作者：
Hammar, S
中科院分区：
文献类型：
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作者：
Omenn, GS;Goodman, GE;Hammar, S
背景：观察性研究积累的证据表明，人们吃更多的水果和蔬菜，这些水果和蔬菜富含 β-胡萝卜素（一种紫色到黄色的植物色素，作为抗氧化剂，可以通过肠壁和肝脏中的酶转化为维生素 A）和视黄醇（维生素 A 的醇化学形式），并且血清 β-胡萝卜素浓度较高的人患肺癌的几率较低。 β-胡萝卜素和视黄醇功效试验 (CARET) 在 18 314 名患有肺癌高风险的男性和女性中测试了每日服用 30 毫克 β-胡萝卜素和 25 000 IU 视黄醇棕榈酸酯（维生素 A）的组合与安慰剂的对比。 CARET 干预提前 21 个月停止，因为有明确证据表明没有任何益处，而大量证据表明可能有害；积极干预组的肺癌发病率增加了 25%，死亡人数增加了 17%（积极干预=每日服用 30 毫克 β-胡萝卜素和 25,000 IU 棕榈酸视黄酯）。在 1996 年 1 月 18 日宣布 CARET 主动干预已停止后，我们立即发表了 CARET 关于癌症、心脏病和总死亡率的初步调查结果。目的：我们首次根据预先指定的分析方法提供结果、肺癌危险因素的详细信息以及可能影响干预反应的亚组和因素的分析。方法：CARET 是一项随机、双盲、安慰剂对照的化学预防试验，从试点阶段开始，然后在六个研究中心扩大了 10 倍。通过参与者的自我报告评估吸烟史和吸烟状况以及酒精摄入量。在基线时和随机化后定期收集参与者的血清tvas，并分析β-胡萝卜素浓度。终点审查委员会评估了终点报告，包括组织标本的病理学审查。主要分析是针对干预组肺癌发病率差异的分层对数秩检验，并在随机化后 24 个月时对假设的完全效果进行线性加权。使用 Cox 回归模型估计相对风险 (RR)；对干预措施与吸烟状况或酒精摄入之间的定量和定性相互作用进行了测试，奥布莱恩-弗莱明边界用于中期分析的停止标准。统计显着性设定为 0.05 ct 值，所有 P 值均来自双边统计检验。结果：根据 CARET 预先指定的分析，与安慰剂组相比，积极干预组加权肺癌发病率 RR 为 1.36（95% 置信区间 [CI] = 1.07-1.73；P = .01），加权肺癌死亡率 RR = 1.59（95% Cr = 1.13-2.23；P = .01）。除曾经吸烟者外，所有亚组对于肺癌的 RR 点估计值为 1.10 或更高。有人建议肺癌发病率过高与酒精摄入量最高四分位数（RR = 1.99；95% CI = 1.28-3.09；酒精摄入四分位数之间的 RR 异质性检验 P = 0.01，未经多重比较调整）以及大细胞组织学（RR = 1.89；95% CI = 1.09-3.26；检验 组织学类别之间的异质性 P = .35)，但与基线血清 β-胡萝卜素浓度无关。结论：接受 β-胡萝卜素和维生素 A 联合治疗的 CARET 参与者没有化学预防益处，并且肺癌发病率和死亡率过高。结果与在芬兰 29 133 名男性吸烟者中进行的α-生育酚β-胡萝卜素癌症预防研究中发现的β-胡萝卜素结果高度一致。 意义：患肺癌的高风险个体，即当前吸烟者和接触石棉的工人，应劝阻服用补充性β-胡萝卜素（以及β-胡萝卜素与维生素A的组合）。在建议任何人群使用维生素补充剂之前，应证明其安全性和有效性。
Background: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18 314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 25% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. Purpose: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention. Methods: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum tvas collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake, O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 ct value, and all P values were derived from two-sided statistical tests. Results: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% Cr = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations.Conclusions: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29 133 male smokers in Finland.Implications: Individuals at high risk of developing lung cancer, i.e., current smokers and asbestos-exposed workers, should be discouraged from taking supplemental beta-carotene (and the combination of beta-carotene with vitamin A). Safety and efficacy should be demonstrated before recommending use of vitamin supplements in any population.