Screening for non-small cell lung cancer

Lung cancer is the leading cause of cancer mortality and is usually discovered at an advanced stage, when treatment is generally not effective. Many researchers have investigated the value of screening for lung cancer, which would theoretically allow earlier detection and more effective treatment. Unfortunately, no trials of screening strategies for lung cancer have shown a mortality benefit, and as a result, no major medical organization currently recommends screening. Research continues to seek proof of the benefit of screening as new techniques are developed, including low-dose spiral computed tomography (CT), autofluorescence bronchoscopy, and advanced techniques of sputum analysis. Although there are promising data on the sensitivity of these newer screening methods, especially low-dose CT, for detecting early lung cancer, none of the published trials are controlled, and they have not yet proven a decrease in mortality. There are ongoing randomized, controlled trials aiming to demonstrate a mortality benefit. Patients who are interested in being screened for lung cancer should be encouraged to participate in well-designed clinical trials whenever possible.     

Computed tomography screening for the early detection of lung cancer

Although lung cancer is the leading cause of cancer-related death in the world and has an increased chance of cure if detected at an earlier stage, routine lung cancer screening is currently not recommended in the United States. Unfortunately, most patients with lung cancer present only after the onset of symptoms and have advanced disease that cannot be surgically resected. The overall 5-year survival rate for all patients with lung cancer is only 15%. When the cancer is detected at its earliest stage (pathologic stage IA), however, the 5-year survival rate is more than 70%. Although past randomized screening trials evaluating the use of standard chest radiography or sputum cytology have not resulted in lower mortality, recent studies suggest that computed tomography (CT) may have promise as a screening tool. This article summarizes experience over the past decade of using low-dose spiral CT imaging as a screening tool to detect early lung cancers in asymptomatic, high-risk individuals.     

基于社区的早期肺癌低剂量螺旋CT扫描筛查上海实践初探

背景与目的：作为中国最常见的恶性肿瘤,肺癌的发病率及死亡率长期保持在较高水平。而有效改善肺癌预后,关键在于早期诊断和规范治疗。本研究密切结合上海社区医疗服务发展现状,整合各级医疗机构优势资源,探索基于上海社区的早期肺癌低剂量螺旋CT筛查路径模式。方法：2013年8月—2014年8月,针对上海市闵行区部分试点社区,以低剂量螺旋CT作为肺癌初步筛查手段,在高危人群中开展肺癌早期诊断,并结合以微创手术治疗为主的多学科综合治疗模式,构建涵盖肺癌预防、诊断、治疗、康复及随访等医疗服务措施的综合治疗立体网络。结果：筛查总人数为11332人(男性7144人,女性4188人)。其中,明确诊断恶性肿瘤29例,包括原发性肺癌27例、转移性肺癌1例和乳腺癌1例;筛查原发性肺癌发病率为238.26×10-5;0~Ⅰ期肺癌共22例,在原发性肺癌中占81.48%。结论：基于上海社区的早期肺癌低剂量螺旋CT筛查路径模式提高肺癌早期诊断率,具有可行性及有效性,可在有条件的社区及医疗卫生机构推广。     

Mortality outcomes of low-dose computed tomography screening for lung cancer in urban China: a decision analysis and implications for practice

Background:Mortality outcomes in trials of low-dose computed tomography (CT) screening for lung cancer are inconsistent.This study aimed to evaluate whether CT screening in urban areas of China could reduce lung cancer mortality and to investigate the factors that associate with the screening effect.Methods:A decision tree model with three scenarios (low-dose CT screening,chest X-ray screening,and no screening) was developed to compare screening results in a simulated Chinese urban cohort (100,000 smokers aged 45-80 years).Data of participant characteristics were obtained from national registries and epidemiological surveys for estimating lung cancer prevalence.The selection of other tree variables such as sensitivities and specificities of low-dose CT and chest X-ray screening were based on literature research.Differences in lung cancer mortality (primary outcome),false diagnoses,and deaths due to false diagnosis were calculated.Sensitivity analyses were performed to identify the factors that associate with the screening results and to ascertain worst and optimal screening effects considering possible ranges of the variables.Results:Among the 100,000 subjects,there were 448,541,and 591 lung cancer deaths in the low-dose CT,chest X-ray,and no screening scenarios,respectively (17.2％ reduction in low-dose CT screening over chest X-ray screening and 24.2％ over no screening).The costs of the two screening scenarios were 9387 and 2497 false diagnoses and 7 and 2 deaths due to false diagnosis among the 100,000 persons,respectively.The factors that most influenced death reduction with low-dose CT screening over no screening were lung cancer prevalence in the screened cohort,low dose CT sensitivity,and proportion of early-stage cancers among low-dose CT detected lung cancers.Considering all possibilities,reduction in deaths (relative numbers) with low-dose CT screening in the worst and optimal cases were 16 (5.4％) and 288 (40.2％) over no screening,respectively.Conclusions:In terms of mortality outcomes,our findings favor conducting low-dose CT screening in urban China.However,approaches to reducing false diagnoses and optimizing important screening conditions such as enrollment criteria for screening are highly needed.     

Lung cancer screening

Lung cancer is the primary cause of cancer mortality in developed countries. First diagnosis only when disease has already reached the metastatic phase is the main reason for failure in treatment. To this regard, although low-dose spiral computed tomography (CT) has proven to be effective in the early detection of lung cancer (providing both higher resectability and higher long-term survival rates), the capacity of annual CT screening to reduce lung cancer mortality in heavy smokers has yet to be demonstrated. Numerous ongoing large-scale randomised trials are under way in high-risk individuals with different study designs. The initial results should be available within the next 2 years.     

Finding needles in a haystack: annual low-dose computed tomography screening reduces lung cancer mortality in a high-risk group

Lung cancer is a global health issue. Compared with other common malignancies, the prognosis is poor as many patients present with advanced disease. The National Lung Screening Trial (NLST) aimed to identify and treat early lung cancers using annual low-dose computed tomography (CT) screening in a high-risk group. When compared with chest x-ray screening, low-dose CT screening reduced lung cancer mortality by 20%; the NLST is the first lung cancer screening trial to demonstrate such a mortality benefit. However, we must wait for cost-effectiveness data from the NLST, as well as the results of ongoing European studies comparing low-dose CT with observation alone, before firm conclusions can be drawn regarding the overall benefits of introducing a CT screening program to clinical practice.     

Finding needles in a haystack: annual low-dose computed tomography screening reduces lung cancer mortality in a high-risk group

Evaluation of: Aberle DR, Adams AM, Berg CD et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365(5), 395–409 (2011).

Lung cancer is a global health issue. Compared with other common malignancies, the prognosis is poor as many patients present with advanced disease. The National Lung Screening Trial (NLST) aimed to identify and treat early lung cancers using annual low-dose computed tomography (CT) screening in a high-risk group. When compared with chest x-ray screening, low-dose CT screening reduced lung cancer mortality by 20%; the NLST is the first lung cancer screening trial to demonstrate such a mortality benefit. However, we must wait for cost–effectiveness data from the NLST, as well as the results of ongoing European studies comparing low-dose CT with observation alone, before firm conclusions can be drawn regarding the overall benefits of introducing a CT screening program to clinical practice.     

Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project.

PURPOSE: Because efficacy of lung cancer screening using chest x-ray is controversial and insufficient, other screening modalities need to be developed. To provide data on screening performance of low-dose helical computed tomography (CT) scanning and its efficacy in terms of survival, a one-arm longitudinal screening project was conducted. PATIENTS AND METHODS: A total of 1,611 asymptomatic patients aged 40 to 79 years, 86% with smoking history, were screened by low-dose helical CT scan, chest x-ray, and 3-day pooled sputum cytology with a 6-month interval. RESULTS: At initial screening, the proportions of positive tests were 11.5%, 3.4%, and 0.8% with low-dose helical CT scan, chest x-ray, and sputum cytology, respectively. In 1,611 participants, 14 (0.87%) cases of lung cancer were detected, with 71% being stage IA disease and a mean tumor diameter of 19.8 mm. At repeated screening, the proportions of positive tests were 9.1%, 2.6%, and 0.7% with low-dose helical CT, chest x-ray, and sputum cytology, respectively. In 7,891 examinations, 22 (0.28%) cases of lung cancer were detected, with 82% being stage IA disease and a mean tumor diameter of 14.6 mm. The 5-year survival rate for screen-detected lung cancer was 76.2% and 64.9% for initial and repeated screening, respectively. CONCLUSION: Screening with low-dose helical CT has potential to improve screening efficacy in terms of reducing lung cancer mortality. An evaluation of efficacy using appropriate methods is urgently required.     

New developments in lung cancer screening.

Lung cancer is the most lethal cancer in our society. Late diagnosis of this disease is a major problem and so recent favorable reports with spiral computed tomography screening of high-risk populations have rekindled interest in improving early lung cancer detections. The process of lung cancer screening is a complicated process that involves many component activities. Interest to date has heavily focused on the initial case identification, but more recent reports have suggested that the issues with case work-up and surgical management also bear closer consideration. Given the dynamic nature of spiral computed tomography scan development and the remarkable improvements in imaging resolution over the last decade, there is an urgent need for research to establish optimal clinical management of early lung cancer detected in a screening setting.     

Computed tomography screening for lung cancer: review of screening principles and update on current status

Screening for lung cancer with low-dose computed tomography (CT) is controversial. In favor of screening, lung cancer is the leading cause of cancer death in the United States, and those at greatest risk are identified readily on the basis of age and smoking history. In addition, it is well established that CT is far more sensitive than chest radiography in detecting lung cancer when it is small and asymptomatic. Furthermore, very high rates of survival were reported recently for screen-detected lung cancers in a large, multinational, single-arm observational study. However, a reduction in lung cancer mortality has not been demonstrated to date, and a recent longitudinal study with a simulated control group suggested little or no mortality reduction. In addition, there are important harms from CT screening, including false-positive test results and overdiagnosis. Furthermore, healthcare resources are finite. Therefore, even if the benefits do outweigh the harms, the cost-effectiveness of CT screening for lung cancer still will need to be considered in the context of competing healthcare alternatives. The objectives of this article were 3-fold: 1) to review the basic principles of screening and study designs related to cancer screening, 2) to summarize the results of the observational and analytical studies of CT screening that have been reported to date, and 3) to describe the design of the 2 ongoing, randomized controlled trials of CT screening and what may be learned from these studies in the near future.     

血清自身抗体联合低剂量螺旋CT在肺癌早期筛查中的价值

目的 探讨血清自身抗体检测联合低剂量螺旋CT（LDCT）在肺癌早期筛查中的可行性。方法 收集武汉大学人民医院体检中心体检人群12 568例体检资料,男7 453例、女5 115例,筛选出肺癌高危人群1 324例纳入本研究,该人群均进行胸部X线检查。随机选取443例患者采用低剂量螺旋CT检测;488例患者采用血清自身抗体进行检测;393例患者采用血清自身抗体联合低剂量螺旋CT检测。均随访一年,比较不同筛查方法对肺结节初筛阳性率及肺癌确诊率,早期肺癌筛查的敏感度及特异性。结果 血清自身抗体联合低剂量螺旋CT检测对于发现肺结节的初筛率、肺癌的确诊率及不同直径肺结节的检出率均明显高于低剂量螺旋CT组及血清自身抗体检测组（P<0.001）。血清自身抗体联合低剂量螺旋CT检测的特异性为89.1%,敏感度为88.4%,AUC为0.863。结论 血清自身抗体检测联合低剂量螺旋CT可明显提高高危人群早期肺癌筛查的确诊率,为寻找肺癌筛查路径提供理论依据。     

Lung cancer screening: the way forward

To take lung cancer screening into national programmes, we first have to answer the question whether low-dose computed tomography (LDCT) screening and treatment of early lesions will decrease lung cancer mortality compared with a control group, to accurately estimate the balance of benefits and harms, and to determine the cost-effectiveness of the intervention.     

Validity of self-reported smoking status among participants in a lung cancer screening trial.

Lung cancer remains a devastating disease associated with substantial morbidity and mortality. Recent research has suggested that lung cancer screening with spiral computed tomography scans might reduce lung cancer mortality. Studies of lung cancer screening have also suggested that significant numbers of participants quit smoking after screening. However, most have relied solely on self-reported smoking behavior, which may be less accurate among participants in lung cancer screening. To assess the validity of self-reported smoking status among participants in a lung cancer screening trial, this study compared self-reported smoking status against urinary cotinine levels. The sample included 55 consecutive participants enrolled in a randomized clinical trial comparing annual spiral computed tomography and chest X-ray for lung cancer screening. Participants were a mean of 59 years of age and predominantly Caucasian (96%) and male (55%). Self-reported smoking status was assessed before and after participants learned of the purpose of the biochemical verification study. Using urinary cotinine as the "gold standard," the sensitivity and specificity of self-reported smoking status were 91% and 95%, respectively (kappa = 0.85, P < 0.001, 95% confidence interval = 0.71-0.99). Total misclassification rate was 7%. However, three of the four misclassified participants reported concurrent use of nicotine replacement strategies. Eliminating these cases from the analysis revealed sensitivity of 100% and specificity of 95% (kappa = 0.96, P < 0.001, 95% confidence interval = 0.88-1.00). In conclusion, self-reported smoking status among participants in a lung cancer screening trial was highly consistent with urinary cotinine test results.     

肺癌筛查方法现状

肺癌是目前恶性肿瘤死亡的首要原因,早期诊断对肺癌的预后至关重要。研究显示低剂量计算机断层扫描（computed tomography, CT）筛查可以使肺癌的死亡率下降。但其存在的问题不可忽视,如过高的假阳性率、过度诊断、辐射效应等。作为一种肿瘤无创筛查方法,血液相关肿瘤标志物的检测,在肺癌早期诊断中显示出良好的敏感性和特异性。如何利用现有的筛查手段,建立肺癌筛查综合模式,需要更多大规模的临床研究。     

肺内磨玻璃影的分子生物学研究进展

近年来,低剂量CT广泛应用于早期肺癌的筛查,肺内磨玻璃影(ground-glass opacity,GGO)的检出率逐渐升高。多数学者认为它与早期肺腺癌密切相关,其定性诊断和早期治疗对于提高早期肺癌患者的诊断率与生存率具有重要意义。关于GGO的影像学诊断、定位方法及手术方式进展国内外已有许多报道,现重点将近年来与其分子生物学方面相关的研究进展综述如下。     

Lung cancer screening with low-dose computed tomography

Lung cancer is the most common cause of cancer death in the world, with most patients having a dismal prognosis. As many as 40?% of lung cancers are diagnosed in stage IV, with current 5-year survival rates well below 20?%. Conventional chest radiography has been historically derided as a valid screening tool for this dreaded disease. A recent National Cancer Institute-sponsored study known as the Prostate, Lung, Colorectal, and Ovarian cancer screening trial found no benefit from such screening in patients at risk. In recent years, low-dose computed tomography (LDCT) of the chest has emerged as a promising screening tool. Recent evidence from the National Lung Screening Trial (NLST) demonstrated a 20?% reduction in mortality from lung cancer in patients undergoing three rounds of LDCT screening. Opponents of lung cancer screening favor its limited use in the setting of well-designed trials claiming excessive false-positive findings, overdiagnosis, and morbidity and mortality associated with invasive testing. That notwithstanding, leading medical societies such as ASCO and ATS have positioned themselves recently in favor of screening subjects meeting the NLST criteria.     

Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial

The efficacy and cost-effectiveness of low-dose spiral computed tomography (LDCT) screening in heavy smokers is currently under evaluation worldwide. Our screening program started with a pilot study on 1035 volunteers in Milan in 2000 and was followed up in 2005 by a randomized trial comparing annual or biennial LDCT with observation, named Multicentric Italian Lung Detection. This included 4099 participants, 1723 randomized to the control group, 1186 to biennial LDCT screening, and 1190 to annual LDCT screening. Follow-up was stopped in November 2011, with 9901 person-years for the pilot study and 17 621 person-years for Multicentric Italian Lung Detection. Forty-nine lung cancers were detected by LDCT (20 in biennial and 29 in the annual arm), of which 17 were identified at baseline examination; 63% were of stage I and 84% were surgically resectable. Stage distribution and resection rates were similar in the two LDCT arms. The cumulative 5-year lung cancer incidence rate was 311/100 000 in the control group, 457 in the biennial, and 620 in the annual LDCT group (P=0.036); lung cancer mortality rates were 109, 109, and 216/100 000 (P=0.21), and total mortality rates were 310, 363, and 558/100 000, respectively (P=0.13). Total mortality in the pilot study was similar to that observed in the annual LDCT arm at 5 years. There was no evidence of a protective effect of annual or biennial LDCT screening. Furthermore, a meta-analysis of the four published randomized trials showed similar overall mortality in the LDCT arms compared with the control arm.     

Impact of low-dose CT on lung cancer screening

Despite advances in therapy, the prognosis of lung cancer remains dismal due to the fact that most cases of lung cancer are diagnosed at advanced stages, when the chance of cure is poor. In cases detected at early stages prognosis is better. Unfortunately, early lung cancer usually causes no symptoms and is, consequently, rarely diagnosed. Therefore, screening for early asymptomatic lung cancer with diagnostic procedures appears promising particularly as risk factors for lung cancer are well known (cigarette smoking, occupational asbestos exposure and others) and screening could, therefore, focus on these risk groups. In the past, screening trials using analysis of sputum cytology and to some extent chest radiography have failed to demonstrate a reduction in lung-cancer mortality with screening, probably due to insufficient sensitivity of these tests for early lung cancer. During the last decade the introduction of spiral computed tomography (CT) has provided a technique with a much higher sensitivity for small lung cancers. Feasibility studies using low-radiation-dose CT demonstrated a high proportion of non-small-cell lung cancer at the initial examination (prevalence) with decreasing numbers of detected cancers at follow-up (incidence). The proportion of early-stage tumors was high both at prevalence and incidence examinations. The rate of invasive procedures for benign lesions was low; most indeterminate lesions could be classified with non-invasive diagnostic approaches. The proportion of interval cancers (cancers diagnosed by symptoms between two screening CT scans) was low. As, however, these one-arm feasibility trials are not appropriate to assess a potential mortality reduction through CT screening, prospective randomised multicenter trials were recently initiated in several countries to analyse the effect of CT screening on lung-cancer mortality.     

非高危人群的肺癌筛查策略

低剂量螺旋计算机断层扫描（low-dose spiral computed tomography，LDCT）筛查肺癌可以将高危人群的死亡率降低20.0％。但是现行的高危人群筛查标准存在局限性，并不能覆盖非高危人群，因此需要有新的具体的筛查策略应对非高危人群的肺癌筛查。现在有些单位把肺癌CT筛查当作员工福利，不分年龄、基线CT结果和其他因素，每年都做1次，不但浪费医疗资源，而且对员工的身心健康亦有害。我们建议将第1次基线LDCT的时间提前至30岁附近，并根据基线CT的发现结果，结合不同年龄段和其他危险因素将随访间隔延长2~10年。针对非高危人群应当采取折中的筛查策略，不但能早期发现肺癌，还能减少CT的辐射暴露。     

Management of Progressive Pulmonary Nodules Found during and outside of CT Lung Cancer Screening Studies

Although the effectiveness of screening for lung cancer remains controversial, it is a fact that most lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, albeit with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them is the open question of how enlarging pulmonary nodules detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches and the potential therapeutic options for enlarging pulmonary nodules, followed by a meeting report including consensus statements of an interdisciplinary expert panel that discussed the potential of the different therapeutic options.