高危吸烟者从肺癌CT筛查中获益最大

《新英格兰医学杂志》(New England Journal of Medicine)7月18日在线发表的一份研究报告称，对于5年内死于肺癌风险最高的吸烟者，小剂量CT筛查可以避免的死亡人数最多，而对于风险最低的人群，CT筛查只能使很少人避免死亡。

目前，筛查指南均建议符合NLST(美国全国肺筛查试验)纳入标准的所有患者都接受小剂量CT筛查，但有专家认为还有必要进一步完善筛查标准。于是，美国国立癌症研究所的Stephanie A. Kovalchik博士及其同事对NLST受试者筛查前的肺癌死亡风险进行了分层，以确定小剂量CT扫描对于不同风险患者的效益和危害是否存在差异。研究者采用的是一个经验证的预测模型，确定了患者在入组时的风险层次。该模型涉及的危险因素有年龄、体重指数、肺癌家族史、吸烟年包数、戒烟至今的时间(对于已经戒烟的患者)、是否存在肺气肿、性别和种族。

NLST是一项大规模随机临床试验，在53,454例年龄介于55~74岁且吸烟年包数至少达到30年包的吸烟者中比较了小剂量CT与胸部摄片的筛查效果。在这项研究中，Kovalchik博士及其同事评估了NLST试验的意向性治疗人群中26,604例接受了3次年度CT扫描以及26,554例接受了3次年度胸片检查的受试者的结局。

主要终点是在5.5年的中位随访期内患者死于肺癌的发生率。CT组共有354例受试者达到了这一终点，而胸片组有442例。在接受CT筛查的受试者中，肺癌死亡的发生率为24.6/10,000人-年，而在接受胸片筛查的受试者中，发生率为30.9/10,000人-年。研究者报告称，这表明小剂量CT筛查可以使肺癌死亡风险相对降低20%(N. Engl. J. Med. 2013 July 18 [doi: 10.1056/NEJMoa1301851])。

研究者针对肺癌死亡率制作了一个绝对风险预测模型，通过结合肺癌死亡和其他竞争死因的Cox比例风险模型考虑了受试者的特定风险特征和预期寿命。采用Lasso回归分析从一组之前确立的肺癌人口统计学和临床危险因素(包括吸烟史)中选取了肺癌死亡的预测因素。然后，基于PLCO(前列腺、肺、结直肠和卵巢)癌症筛查试验中胸片组纳入的15,114例符合NLST标准和22,649例不符合NLST标准(年龄均介于55~74岁)的吸烟者的结局数据，对该预测模型进行了外部验证。根据肺癌死亡的5年预测风险，将受试者分为5个风险层次。

研究者报告称：“肺癌死亡风险最高的受试者不成比例地占据了小剂量CT筛查的大部分效益。例如，CT预防的88例肺癌死亡中有77例(88%)都发生于60%的肺癌死亡5年风险≥0.85%的受试者，而CT预防的肺癌死亡中仅有1%发生于20%的风险最低者。”

与整个CT组相比，60%的5年内肺癌死亡风险最高(大于0.85%)的受试者占到了88%的CT可预防肺癌死亡，将预防1例肺癌死亡所需的筛查人数从302降至161，将每例CT预防的肺癌死亡的假阳性结果数从108降至65。相比之下，在CT预防的肺癌死亡病例中几乎未见那20%的肺癌死亡风险最低者。

研究者总结道，在风险最高组中，小剂量CT预防1例肺癌死亡所需的筛查人数为161人；而在风险最低组中，预防1例肺癌死亡所需的筛查人数高达5,276人。医学界一直试图识别出哪些患者可以从目标人群筛查中获益最大，即小剂量CT筛查的效益明显大于相对频繁的假阳性结果所产生的危害，上述结果为此提供了相关的经验证据。

“上述观察结果支持采用肺癌死亡的个性化风险评估模型而非NLST纳入标准，这样可以提高小剂量CT的筛查效率。……根据患者的肺癌死亡预测风险来个性化定制小剂量CT筛查可以缩小符合NLST标准的人群范围，同时也不会降低筛查的潜在公共卫生效益，也不会使潜在危害不成比例地增加。”

Kovalchik博士及其同事指出，在一个重要的吸烟者亚组中，该筛查技术的效果有限：合并肺部疾病的患者。因此，尚需进一步评估小剂量CT筛查用于这类患者的效益和危害。

这项研究由美国国家癌症研究院资助。作者声明无相关经济利益冲突。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Low-dose computed tomography screening for lung cancer prevents the greatest number of deaths if it is reserved for smokers at highest risk of dying from the disease within 5 years, and it prevents very few deaths among those at lowest risk, according to a report published online July 18 in the New England Journal of Medicine.

When smokers were stratified into quintiles based on 5-year risk of death, 161 patients in the highest-risk quintile would need to be screened using low-dose CT to prevent 1 lung cancer death. In contrast, among the smokers in the lowest-risk quintile, 5,276 would need to be screened to prevent 1 lung cancer death, said Stephanie A. Kovalchik, Ph.D., of the National Cancer Institute and her associates.

These findings provide the empirical evidence that the medical community has been seeking to identify patients who would reap the most benefit from targeted screening – a benefit that would clearly outweigh the harm of the relatively frequent false-positive results with low-dose CT screening.

At present, screening guidelines all recommend low-dose CT screening for patients who meet the NLST (National Lung Screening Trial) entry criteria, but some experts argue that further refinement of screening criteria would be appropriate. The observations in this study "argue for the use of individualized risk assessment of lung cancer death instead of the NLST entry criteria, to increase the efficiency of low-dose CT screening," the investigators said.

Dr. Kovalchik and her colleagues examined whether the benefits and harms of low-dose CT scanning in the NLST differed according to the study subjects’ prescreening risk of lung cancer death, which was determined at enrollment using a validated prediction model. Risk factors included in this model were age, body mass index, family history of lung cancer, pack-years of smoking, years since smoking cessation (among patients who had quit), presence or absence of emphysema, sex, and race.

The NLST was a large randomized clinical trial that compared the efficacy of this screening technique against that of chest radiography in 53,454 smokers aged 55-74 years who had a minimum of 30 pack-years of smoking.

For their study, Dr. Kovalchik and her associates assessed outcomes in 26,604 NLST participants who had undergone three annual CT scans and 26,554 who had undergone three annual radiographs in the trial’s intention-to-treat population.

The primary end point was the rate of death from lung cancer during a median of 5.5 years of follow-up. This end point was reached by 354 subjects in the CT group, compared with 442 in the radiography group.

The rate of lung cancer deaths was 24.6 per 10,000 person-years among subjects screened by CT, compared with 30.9 per 10,000 person-years among those screened by radiography. This reflects a 20% relative reduction in lung cancer deaths with low-dose CT screening, the investigators reported (N. Engl. J. Med. 2013 July 18 [doi: 10.1056/NEJMoa1301851]).

The researchers developed an absolute risk-prediction model for lung-cancer mortality that accounted for a participant’s specific risk characteristics and life expectancy by incorporating Cox proportional-hazards models of death from lung cancer and competing causes of death. Predictors of lung-cancer death were selected from a set of previously identified demographic and clinical risk factors for lung cancer (including smoking history) using Lasso regression. The prediction model was externally validated with outcome data from 15,114 NLST-eligible and 22,649 NLST-ineligible smokers aged 55-74 years who were enrolled in the radiography group of the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial. The participants were stratified into five quintiles for the predicted 5-year risk of death from lung cancer.

"Participants at highest risk for lung cancer death accounted for a disproportionate share of the benefits of low-dose CT screening. For example, 77 of 88 CT-prevented lung cancer deaths (88%) occurred among the 60% of participants with a 5-year risk of lung-cancer death of 0.85% or more, whereas only 1% of prevented lung-cancer deaths occurred among the 20% of participants at lowest risk," the researchers said.

Restricting screening to the 60% of participants at highest risk for death from lung cancer within 5 years (more than 0.85%), as compared with the entire CT group, captured 88% of CT-preventable lung-cancer deaths, reduced the number of participants who would need to be screened to prevent one lung-cancer death from 302 to 161, and reduced the number of false-positive results per CT-prevented lung cancer death from 108 to 65. In contrast, the 20% of participants at lowest risk for lung cancer death accounted for almost none of the CT-prevented lung cancer deaths, the researchers said.

"These observations argue for the use of individualized risk assessment of lung cancer death instead of the NLST entry criteria to increase the efficiency of low-dose CT screening. ... [T]ailoring of low-dose CT screening to a patient’s predicted risk of lung cancer death could narrow the NLST-eligible population without a loss in the potential public health benefits of screening or a disproportionate increase in the potential harms," they wrote.

Dr. Kovalchik and her colleagues noted that this screening technique was of limited efficacy in one important subgroup of smokers: those who had coexisting pulmonary disorders. Further study of the benefits and harms of low-dose CT screening in such patients is needed.

This study was funded by the National Cancer Institute. No relevant financial conflicts of interest were reported.