Journal of Carcinogenesis Lung Cancer Screening Update

Journal of Carcinogenesis Special issue on Lung Cancer Review Article Lung cancer screening update

Samjot Singh Dhillon, Gregory Loewen1, Vijayvel Jayaprakash2, Mary E. Reid3*

Departments of Medicine Pulmonology, 2Dental and Maxilofacial Prosthetics and 3Medicine, Elm and Carlton Streets, Roswell Park Cancer Institute, Buffalo, New York, 1Providence Regional Cancer Center, 105 W 8th Ave. Suite 170, Spokane, WA 99204, USA

E‑mail: [email protected] *Corresponding author

Published: 31 January, 2013 Received: 03 August, 2012 Journal of Carcinogenesis 2012, 11:2 Accepted: 31 December, 2012 This article is available from: http://www.carcinogenesis.com/content/11/1/2 © 2012 Dhillon

Abstract Lung cancer is the leading cause of cancer‑related mortality globally and the American cancer society estimates approximately 226,160 new cases and 160,340 deaths from lung cancer in the USA in the year 2012. The majority of lung cancers are diagnosed in the later stages which impacts the overall survival. The 5‑year survival rate for pathological st age IA lung cancer is 73% but drops to only 13% for stage IV. Thus, early detection through screening and prevention are the keys to reduce the global burden of lung cancer. This article discusses the current state of lung cancer screening, including the results of the National Lung Cancer Screening Trial, the consideration of implementing computed tomography screening, and a brief overview of the role of bronchoscopy in early detection and potential biomarkers that may aid in the early diagnosis of lung cancer. Keywords: Early detection, lung cancer, screening

INTRODUCTION Compounding the sheer numbers of lung cancer, despite advances in the treatment strategies, the overall 5‑year Lung cancer is the leading cause of cancer‑related mortality survival of lung cancer remains dismal at 16%.[1] One of globally and the American cancer society estimates the reasons for this poor survival is that only 15% of cases approximately 226,160 new cases and 160,340 deaths from are diagnosed in the early localized stages[1] where there is lung cancer in the USA in the year 2012.[1] Almost 90% of the highest chance of survival. The 5‑year survival rate for lung cancers are attributed to smoking and unfortunately even pathological stage IA lung cancer is 73% but drops to only the latest trend shows that 19.3% (45.3 million) of US adults 13% for stage IV.[3] Thus, early detection and prevention are continue to be active smokers.[2] Former smokers continue the keys to succeeding in the global fight against lung cancer. to be at elevated risk for lung cancer, constituting 50% of all newly diagnosed lung cancer cases. Estimates suggest that This article discusses the current state of lung cancer approximately 90 million people in the USA are at risk of a screening, including the results of the National lung smoking‑related lung cancer. This will continue to remain a cancer screening trial (NLST), the consideration of substantial public health problem for years to come. implementing CT screening, and a brief overview of the role of bronchoscopy in early detection and potential biomarkers that may aid in the early diagnosis of lung cancer. Access this article online Quick Response Code: Website: OVERVIEW OF CONCEPTS FOR CANCER www.carcinogenesis.com SCREENING

DOI: The aim of screening for a disease is to detect disease in the 10.4103/1477-3163.106681 early asymptomatic stage when treatment has high chance of success. An effective screening test should be highly

Journal of Carcinogenesis 1 A peer reviewed journal in the field of Carcinogenesis and Carcinoprevention Journal of Carcinogenesis 2012, 11:2 http://www.carcinogenesis.com/content/11/1/2 sensitive and specific with low false‑positive rate and it should tool for lung cancer because it could detect small lung be cost‑effective, safe, accessible, reproducible, and above nodules using multi‑detector technology with thin cuts all, it should reduce the disease‑specific mortality.[4] The and a lower dose of radiation. Several clinical screening disease should have a preclinical phase that is long enough trials were initiated in 1990s to evaluate the utility of this that it can be detected by screening and effective treatment test.[11] Evidence from a prospective single‑arm cohort trial for screen‑detected disease should be available. However, suggested that LDCT resulted in the detection of earlier stage there are some important concepts that must be considered lung cancers with an improved survival rate.[12] However, before embarking on screening. The standard against which questions remained about the influence of overdiagnosis the effectiveness of a screening test is judged changes in the on the results.[4] A meta‑analysis of six randomized clinical disease‑specific mortality or the number of deaths from the trials of lung cancer screening with LDCT was published in disease with number of individual screened as denominator.[4] 2010 and indicated that although a higher proportion of early A lack of improvement in mortality from the disease may stage lung cancers were detected, the rate of false‑positive result from simply an earlier diagnosis of the disease without benign lesions was very high.[13] For every 1,000 individuals a change in the outcome (lead time bias), the extension of screened with LDCT, nine cases of stage 1 non‑small‑cell the time from diagnosis to death without a change in the cancer were identified. At the same time, 235 benign mortality rate (length time bias), or the diagnosis of disease nodules were identified that resulted in four unnecessary that is not likely to become deadly (overdiagnosis bias). No thoracotomies.[13] In addition, concerns of overdiagnosis and matter how effective a screening test is, there will always be other biases persisted.[14,15] Above all, none of these studies interval cancers. Because we really do not know the natural showed a lung cancer‑specific mortality benefit because history of early lung cancers, we cannot estimate the rates of they were not adequately powered and had an insufficient interval lung cancers across multiple risk groups until there duration of follow‑up. The NLST, the largest trial of lung is more experience with detecting this disease early and cancer screening ever designed, was powered to answer screening over long periods of time. several of these key questions and it now serves as the basis of several guidelines and future public policy decisions for Lung cancer screening with chest radiograph lung cancer screening. Lung cancer has a long preclinical phase and generally starts as a nodule with a volume doubling time of typically THE NATIONAL LUNG CANCER 160‑180 days[5] that raised the possibility of detecting it in SCREENING TRIAL early stages by imaging. Several large trials of lung cancer screening with chest radiographs and some with sputum The NLST was a NCI sponsored large multi‑institutional evaluation were conducted in 1970s when central squamous trial (33 centers in the USA) comparing annual LDCT with cell histology was leading type of lung cancer (vs. the current annual chest radiographs for 3 years.[8,16,17] The trial recruited trends in the USA where adenocarcinoma is the predominant patients from August 2002 until April 2004 and subjects histology) including three large National Cancer Institute were followed‑up until December 2009 (median: Follow‑up sponsored trials in the USA (Mayo Clinic, John Hopkins, and 6.5 years). A total of 53,454 patients in the ages between Memorial‑Sloan Kettering) and one in Czechoslovakia.[6‑8] 55 and 74 with a smoking history of at least 30 pack years Unfortunately these trials, along with the results of recently were enrolled. Former smokers must have quit within the reported prostate, lung, colorectal and ovarian cancer preceding 15 years to be enrolled. Exclusion criteria included screening (PLCO) trial, did not show any reduction of history of lung cancer and the use of home oxygen support. disease‑specific mortality, although a higher fraction of The approximate radiation dose for each chest radiograph and resectable early stage disease was found.[7,9] These data are LDCT was 0.02 mSv and 1.5 mSv, respectively (as compared likely due in part to high false‑positive rates and sub‑optimal to conventional chest CT dose of 8 mSv).[8] Adherence to detection of small lung nodules by chest radiographs. In the protocol was >90% in both groups. The findings of a addition, the results suggest that lead time, length time, nodule >4 mm, adenopathy, or effusions were considered to and overdiagnosis bias also had substantial influence.[10] In be suspicious and deemed to be a positive finding. Overall, conclusion, the chest radiograph as a tool for lung cancer 24.2% of LDCT and 6.9% of chest radiographs were positive screening is no longer recommended. over three screens and 96.4% and 94% of these nodules were deemed false positive, respectively. Further diagnostic Lung cancer screening with chest computed work‑up involved mainly imaging modalities while invasive tomography tests were infrequent (invasive procedure performed on only The low‑dose computed tomography (LDCT) of the chest 11.4% in LDCT group including 4% undergoing surgery). without contrast was considered a promising screening The rate of at least one complication from diagnostic tests was

2 Journal of Carcinogenesis A peer reviewed journal in the field of Carcinogenesis and Carcinoprevention Journal of Carcinogenesis 2012,11:00** http://www.carcinogenesis.com/content/11/1/2 low at 1.4% in LDCT group and 1.6% in chest radiograph assessment of nodules to reduce false positives.[22] This trial group. is expected to complete in 2015.

A total of 1,060 lung cancers were diagnosed in LDCT arm CURRENT RECOMMENDATIONS and 941 in chest radiograph arm (645 and 572 per 100,000 REGARDING LUNG CANCER SCREENING person‑years, respectively). Of the 1060 cancers in LDCT WITH LOW‑DOSE COMPUTED group, 649 (61%) were detected by screening, 44 (4%) were TOMOGRAPHY interval cancers, and 367 (35%) were found in participants who missed the screening or were still in follow‑up after In the wake of NLST results, several professional organizations the 3rd year of screening was done. In the LDCT arm, have developed guidelines for lung cancer screening.[4,23‑26] 356 patients died of lung cancer, whereas 443 participants Most agree that screening should include patients who meet died of lung cancer in the chest radiograph arm. These the NLST inclusion criteria. The national comprehensive numbers correspond to 247 and 309 deaths per 100,000 cancer network (NCCN) and american thoracic society person‑years, respectively. The LDCT group had a 20% (ATS) additionally recommend LDCT screening for patients relative reduction in lung cancer‑specific mortality (95% CI, who are 50 years or older with 20 pack years or more smoking 6.8‑26.7; P = 0.004) and 6.7% reduction in all‑cause mortality history and who have an additional lung cancer risk factor, like (95% CI, 1.2‑13.6; P = 0.02). This was the first randomized environmental exposure or family history.[26] The American trial of lung cancer screening using LDCT that showed a Association of Thoracic Surgery recommends increasing the significant decrease in lung cancer‑specific mortality. These upper age limit of screening to 79 because the peak incidence data show that in this population, 320 subjects needed to be of lung cancer is at 70 years in the USA and with the average screened with annual LDCT for 3 years to prevent one lung life expectancy is 79 years, at least half of Americans are cancer death. The mortality benefit may be even higher in expected to live until the age of 80‑89 years.[25] Aggressive real practice as chest radiographs are not customarily done smoking cessation and performing screening in a center with for lung cancer screening and the new generations of LDCT a multi‑disciplinary team, similar to NLST institutions, are scanners are superior (though this may also transcribe into also recommended by most organizations. A brief summary even higher false‑positive rate). Due to logistic and economic of these guidelines is shown in Table 1. issues, this study was not able to determine survival benefits of LDCT screening over a longer duration. In the LDCT SCREENING FOR LUNG CANCER WITH arm, 40% of the lung cancers were detected in stage IA and BRONCHOSCOPY 21.7% in stage IV compared to 21% of cancers being stage IA and 36% being stage IV in chest radiograph arm. This Several published studies have utilized bronchoscopy, coupled suggests that as LDCT is used more widely for lung cancer with LDCT, for the detection of early central premalignant screening, there may be persistent changes in the rates of lesions that are typically precursors for squamous cell early lung cancers diagnosed, offering more patients surgical carcinoma.[27‑32] Although none of the national professional options for treatment. organizations have recommended the use of bronchoscopy for lung cancer screening, there are several programs, both ONGOING TRIALS OF LOW‑DOSE research and clinical, based at large tertiary care centers that COMPUTED TOMOGRAPHY SCREENING utilize bronchoscopy in patients at high risk for lung cancer. The majority of these programs also use devices that combine Several European trials of lung cancer screening with LDCT white light and autofluorescence imaging during the procedure, are ongoing including DANTE trial in Italy,[18] Danish which has been shown to increase the detection of dysplasia.[33,34] randomized lung cancer CT screening trial,[19] and the Dutch Belgian randomized lung cancer screening trial (http://www. Access to the airway through bronchoscopy, while not likely trialregister.nl/trialreg/admin/rctview.asp?TC = 636) (Dutch to be applied as a standard screening exam in the immediate acronym: NELSON) that has routine care and not a chest future, provides important sampling opportunities of the radiograph in control arm.[20‑22] This trial is the only trial central lung field that can impact our understanding of that may have a sufficient sample size to possibly detect a biomarkers of lung field damage and early carcinogenesis. mortality difference, as other trials are small. The trial is Although the majority of lung cancers now develop as different as it also enrolls 5‑year lung cancer survivors who are adenocarcinoma in the distal segments of the lung that are at very high risk of lung cancer, has a detailed assessment of not accessible by bronchoscopy, identifying biomarkers of smoking cessation in context of screening program, and looks field damage that may help to improve defining lung cancer into cost‑effectiveness, quality of life as well as volumetric risk, risk of recurrence, or risk of nodules that harbor cancer

Journal of Carcinogenesis 3 A peer reviewed journal in the field of Carcinogenesis and Carcinoprevention Journal of Carcinogenesis 2012, 11:2 http://www.carcinogenesis.com/content/11/1/2

Table 1: Recommendations of various organizations for lung cancer screening Name of society Year Recommendation National comprehensive 2012 Screen: Age 55‑74, ≥30 pack years, smoking cessation within previous 15 year (category 1) cancer network (NCCN) Screen: Age ≥50‑74, ≥20 pack years, and one additional risk factor other than second hand smoke (category 2B). Risk factors including exposure to radon and occupational contaminants, cancer history, family history, COPD, pulmonary fibrosis Do not screen moderate or low risk subjects American association for 2012 Screen: Age 55‑79, ≥30 pack years (tier 1) thoracic surgery (AATS) Screen: Age≥50, ≥20 pack years and ≥5% risk of developing lung cancer in 5 years (category 2). Risk factors including COPD with FEV1<70%, environmental/occupational exposures, prior cancer/thoracic radiation, genetic/family history Screen: Lung cancer survivors having completed 4 years of surveillance without recurrence as long as they can tolerate potential treatment for lung cancer. (tier 2) American cancer 2012 Follow NLST enrollment criteria society (ACS)‑interim Make shared informed decision with physician guidelines Participate in an institution with multidisciplinary team and expertize in LDCT interpretation Vigorous smoking cessation American lung 2012 Follow NLST enrollment criteria association (ALA) Encourage smoking cessation No chest radiograph for screening Screening centers should develop ethical practices for advertising and promoting screening Screening should be linked to best access multi‑disciplinary teams American college of 2012 Screen the subjects who meet NLST enrollment criteria chest physicians (ACCP) Screening should be done only in the setting that can provide comprehensive care similar to what the NLST and american society of participants received (grade 2B) clinical oncology (ASCO) No screening if: Age <55 or >74, smoking cessations >15 years ago, co‑morbidities that preclude curative treatment of lung cancer, limited life expectancy (grade 2C) NCCN Category 1: Based upon high‑level of evidence, uniform NCCN consensus, Category 2A/2B: Lower level of evidence, uniform NCCN consensus that intervention is appropriate, Category 3: Any level of evidence with major disagreement that intervention is appropriate. AATS Tier 1: Subjects at highest risk with level 1 evidence: Supported by randomized prospective trial data; AATS Tier 2: Subject with level 2 evidence: Case control or non‑randomized trial data or level3 evidence: Consensus opinion and sufficient evidence, COPD: Chronic obstructive pulmonary disease, FEV: Forced expiratory volume, NLST: National lung cancer screening trial, LDCT; Low‑dose CT is an important step to conquering lung cancer. resections, serum, plasma and whole blood, sputum, and exhaled breath concentrate. The most promising markers THE STATE OF THE ART OF BIOMARKERS under investigation range from specific mutations in the FOR LUNG CANCER DETECTION DNA from tumors, DNA methylation, mRNA expression arrays, miRNA signatures, proteins and proteomic signatures, With the advent of lung cancer screening recommendations autoantibodies, volatile organic compounds, and circulating for high‑risk subjects, the need for biomarkers to aid tumor cells. The breadth of both the tissue types and the in the identification of lung cancer risk and early stage marker technologies demonstrates the need for methods disease becomes even more important.[35] Ideally, validated to identify the populations at highest risk of lung cancer, to biomarkers of early lung cancer would serve to supplement develop earlier interventions and more effective, targeted LDCT findings and identify the indiscriminant lung nodules treatments. that carry the highest probability of harboring cancer. Validated markers could guide the use of interventional CONSIDERATIONS FOR IMPLEMENTING diagnostic testing and better classify the state of the lung field LOW‑DOSE COMPUTED TOMOGRAPHY in characterizing lung cancer risk. There are many biomarkers SCREENING currently under development that use several state‑of‑the‑art technologies and utilize several different biospecimens. The Although the NLST has ushered a new era in lung cancer key to this strategy is to identify either changes in the lung screening, a few questions remain unanswered and several field or early lesions that will signal potential risk of lung concerns have been raised about generalizing these results cancer in the detected nodule or in the future. into the routine general practice: • The NLST participants were comparatively younger, better There have been several recent reviews of the ongoing educated, and less likely to be current smokers as compared potential biomarkers for lung cancer.[36‑39] A recent to general population based on US Census Survey,[16] a comprehensive review by Hassanein et al.,[40] documents phenomenon also described as the “healthy volunteer” effect the published candidate biomarkers and the spectrum of and also noted in the large PLCO trial. The average age at biospecimens that are being used. The tissue types include diagnosis of lung cancer in the USA is 70 and only 8.8% of bronchial biopsies and brushes of normal and abnormal participants of NLST were in age group of 70‑74 years. areas, tumor and adjacent normal tissue from surgical • The smokers as a high‑risk group may be difficult to

4 Journal of Carcinogenesis A peer reviewed journal in the field of Carcinogenesis and Carcinoprevention Journal of Carcinogenesis 2012,11:00** http://www.carcinogenesis.com/content/11/1/2

target in the community because as a group they have is recommended for the broader community. higher chance of being poor, less well educated, have • The issue of cost‑effectiveness of screening needs to less access to screening and preventive services, such be analyzed further. Based on current NLST enrolling as smoking cessation. They are also more likely to less criteria, around 7 million people in the USA will qualify likely to participate in screening or pay for it.[41,42] and there are around 94 million current and former • The compliance rate with screening in NLST was very smokers at risk of lung cancer.[8] Concern has been high at >90% which may be difficult to replicate in raised that the absolute number of deaths prevented by standard practice settings. LDCT was low. The cost‑effectiveness needs to take • The NLST was conducted in high volume urban tertiary into account the rising cost of management of lung care hospitals and the morality rate associated with surgical cancer in the era of aggressive surveillance and targeted resections was very low at 1% as compared 3‑6% rate therapy. Cost‑effectiveness can improve and the number reported in US general population.[43] It has been shown of patients (320) needed to be screened to find one lung that survival after lung cancer resection is directly related cancer can decrease if the population screened has a to volume of surgeries performed at the institution and greater risk than the participants enrolled in NLST. the use of thoracic surgeons over general surgeons.[43,44] • The NLST recruited patients who had only smoking as a The practice patterns of invasive diagnostic procedures risk factor. The role of screening in patients with additional may also vary and a recent report demonstrated an risk factors such as radon exposure, pulmonary fibrosis, almost two‑fold variation among geographical regions asbestosis, and genetic factors/family history needs to in the utilization of CT‑guided biopsy.[45] Therefore, the be answered. Degree of lung function impairment and extremely low rate of complications and low mortality co‑morbidities were not evaluated Developing risk may not be replicable in all settings. prediction models that take into account the other risk • The NLST utilized rigorous quality control to factors may be helpful to decide about eligibility for standardize the radiology equipment and LDCT screening. interpretation. Only NLST approved expert • The risk of radiation exposure from LDCT and any radiologists, utilizing standardized protocols, reviewed further radiological tests to evaluate positive findings the scans. Even with the precautions, variations in have not been directly studied and data extrapolated LDCT interpretation existed even between radiologists from atomic bomb survivors are generally used. Brenner in high volume NLST study centers. These issues will estimated that a 50‑year‑old smoker who undergoes only be compounded when screening is implemented annual LDCT until age 75 is at 0.85% risk of lung cancer in multiple centers and community practices.[46] from smoking in addition to 17% risk already incurred • The NLST did not offer insight into the optimal from smoking.[48] The Radiological Society of North duration of screening. A longer follow‑up period America and The American College of radiology (http:// would have clarified whether long‑term screening had www.radiologyinfo.org) classify the additional lifetime additional survival benefits and the potential role of risk of cancer from a LDCT as very low (1 per 10,000 to 1 overdiagnosis bias. The LDCT arm saw 120 more lung per 100,000 persons). However, the cumulative radiation cancers than chest radiograph arm, suggesting that some exposure from multiple tests can be a cause for concern overdiagnosis may have occurred. and needs to be evaluated and the current goal for • The rate of false‑positive findings seen in NLST is very radiation exposure should remain “As low as possible.” high and the cost of the work‑up can be prohibitive. In • Prevention is better than cure.” Since smoking cessation addition, as per the NLST protocol, the work‑up and is a much less expensive and safer alternative to lung management of positive findings were determined by the cancer screening, it should be the first public policy goal. individual healthcare providers. Thus, at the end of the Coordinating a smoking cessation intervention at the trial, it is difficult to formulate standardized guidelines time of screening may be an optimal time to motivate for management of abnormal findings on LDCT. The more people to quit. However, there is concern that lung nodule guidelines by Fleishner society and recent negative LDCT test results may provide smokers with a guidelines on ground glass opacities are steps in right rationale to continue to smoke. Educating patients on the direction.[5,47] Volumetric growth rate assessment of CT risk of lung cancer and other smoking‑related diseases lesions was incorporated into the NELSON trial which will be an important component to these efforts. The may also help to reduce false positives.[22] Again, this ongoing randomized NELSON trial is looking at these approach is costly, personnel intensive, and requires a issues and early results suggest that screening may be a certain level of expertise and must be evaluated before it valuable teachable moment for smoking cessation.[49]

Journal of Carcinogenesis 5 A peer reviewed journal in the field of Carcinogenesis and Carcinoprevention Journal of Carcinogenesis 2012, 11:2 http://www.carcinogenesis.com/content/11/1/2

In summary, at this time, it is appropriate to offer lung cancer Black WC, Church TR, Fagerstrom RM, et al. The National Lung Screening Trial: Overview and study design. Radiology 2011;258:243‑53. screening with LDCT to high‑risk individuals after a discussion 18. Infante M, Lutman FR, Cavuto S, Brambilla G, Chiesa G, Passera E, et al. Lung of the pros and cons of screening. It also seems critical that cancer screening with spiral CT: Baseline results of the randomized DANTE screening programs be highly integrated with smoking trial. Lung Cancer 2008;59:355‑63. 19. Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Toennesen P, et al. The cessation programs. Screening programs should only be Danish randomized lung cancer CT screening trial – Overall design and administered by well‑equipped centers with multi‑disciplinary results of the prevalence round. J Thorac Oncol 2009;4:608‑14. teams that can evaluate and treat all abnormal findings and 20. van Iersel CA, de Koning HJ, Draisma G, Mali WP, Scholten ET, Nackaerts K, et al. Risk‑based selection from the general population in a screening provide consistent ongoing follow‑up, similar to those involved trial: Selection criteria, recruitment and power for the Dutch‑Belgian in the NLST centers. As the utility of bronchoscopy as a randomised lung cancer multi‑slice CT screening trial (NELSON). Int J secondary screening tool is defined in high‑risk populations, Cancer 2007;120:868‑74. 21. Ru Zhao Y, Xie X, de Koning HJ, Mali WP, Vliegenthart R, Oudkerk M. it may also be added to the screening program. In the future, NELSON lung cancer screening study. Cancer Imaging 2011;11:S79‑84. the incorporation of validated biomarkers into lung cancer 22. van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, screening will improve the assessment of lung cancer risk, Vernhout R, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009;361:2221‑9. direct interventional diagnostic procedures, and may provide 23. Fontham ET, Wender R. American Cancer Society Interim Guidance on identifiable targets for chemoprevention and treatment. Lung Cancer Screening, 2012. Available from: http://www.cancer.org/acs/ groups/content/@editorial/documents/document/acspc‑030879.pdf. [Last accessed: January 29, 2013]. REFERENCES 24. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, et al. Benefits and harms of CT screening for lung cancer: A systematic review. 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin JAMA 2012;307:2418‑29. 2012;62:10‑29. 25. Jaklitsch MT, Jacobson FL, Austin JH, Field JK, Jett JR, Keshavjee S, et al. The 2. Centers for Disease Control and Prevention (CDC). Vital signs: Current American Association for Thoracic Surgery guidelines for lung cancer cigarette smoking among adults aged ≥8 years – United States, 2005‑2010. screening using low‑dose computed tomography scans for lung cancer MMWR Morb Mortal Wkly Rep 2011;60:1207‑12. survivors and other high‑risk groups. J Thorac Cardiovasc Surg 2012;144:33‑8. 3. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami‑Porta R, 26. Providing Guidance on Lung Cancer Screening To Patients and Physicians, et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of 2012. Available from: http://www.lung.org/lung‑disease/lung‑cancer/lung- the TNM stage groupings in the forthcoming (seventh) edition of the TNM cancer-screening‑guidelines/lung‑cancer‑screening.pdf. [Last accessed: Classification of malignant tumours. J Thorac Oncol 2007;2:706‑14. January 29, 2013]. 4. Wood DE, et al. Lung cancer screening. J Natl Compr Canc Netw 27. McWilliams A, Mayo J, MacDonald S, leRiche JC, Palcic B, Szabo E, et al. 2012;10:240‑65. Lung cancer screening: A different paradigm. Am J Respir Crit Care Med 5. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, et al. 2003;168:1167‑73. Guidelines for management of small pulmonary nodules detected on CT 28. Lam S, MacAulay C, Le Riche JC, Dyachkova Y, Coldman A, Guillaud M, et al. scans: A statement from the Fleischner Society. Radiology 2005;237:395‑400. A randomized phase IIb trial of anethole dithiolethione in smokers with 6. Holin SM, Dwork RE, Glaser S, Rikli AE, Stocklen JB. Solitary pulmonary bronchial dysplasia. J Natl Cancer Inst 2002;94:1001‑9. nodules found in a community‑wide chest roentgenographic survey; a 29. Merrick DT, Kittelson J, Winterhalder R, Kotantoulas G, Ingeberg S, Keith RL, five‑year follow‑up study. Am Rev Tuberc 1959;79:427‑39. et al. Analysis of c‑ErbB1/epidermal growth factor receptor and c‑ErbB2/ 7. Eddy DM. Screening for lung cancer. Ann Intern Med 1989;111:232‑7. HER‑2 expression in bronchial dysplasia: Evaluation of potential targets for 8. National Lung Screening Trial Research Team, Aberle DR, Adams AM, chemoprevention of lung cancer. Clin Cancer Res 2006;12:2281‑8. Berg CD, Black WC, Clapp JD, et al. Reduced lung‑cancer mortality with 30. Keith RL, Blatchford PJ, Kittelson J, Minna JD, Kelly K, Massion PP, et al. Oral low‑dose computed tomographic screening. N Engl J Med 2011;365:395‑409. iloprost improves endobronchial dysplasia in former smokers. Cancer Prev 9. Oken MM, Hocking WG, Kvale PA, Andriole GL, Buys SS, Church TR, et al. Res (Phila) 2011;4:793‑802. Screening by chest radiograph and lung cancer mortality: The Prostate, Lung, 31. Loewen G, Natarajan N, Tan D, Nava E, Klippenstein D, Mahoney M, et al. Colorectal, and Ovarian (PLCO) randomized trial. JAMA 2011;306:1865‑73. Autofluorescence bronchoscopy for lung cancer surveillance based on risk 10. Patz EF Jr, Goodman PC, Bepler G. Screening for lung cancer. N Engl J Med assessment. Thorax 2007;62:335‑40. 2000;343:1627‑33. 32. Loewen GM, et al. Detection of premalignant bronchial epithelial 11. Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, abnormalities in high‑risk patients. Proc ASCO 2002;21:447. Miettinen OS, et al. Early Lung Cancer Action Project: Overall design and 33. Lam S, Palcic B. Re: Autofluorescence bronchoscopy in the detection of findings from baseline screening. Lancet 1999;354:99‑105. squamous metaplasia and dysplasia in current and former smokers. J Natl 12. International Early Lung Cancer Action Program Investigators, Henschke CI, Cancer Inst 1999;91:561‑2. Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, et al. Survival of 34. Edell E, Lam S, Pass H, Miller YE, Sutedja T, Kennedy T, et al. Detection patients with stage I lung cancer detected on CT screening. N Engl J Med and localization of intraepithelial neoplasia and invasive carcinoma using 2006;355:1763‑71. fluorescence‑reflectance bronchoscopy: An international, multicenter 13. Gopal M, Abdullah SE, Grady JJ, Goodwin JS. Screening for lung cancer with clinical trial. J Thorac Oncol 2009;4:49‑54. low‑dose computed tomography: A systematic review and meta‑analysis 35. Massion PP, Carbone DP. The molecular basis of lung cancer: Molecular of the baseline findings of randomized controlled trials. J Thorac Oncol abnormalities and therapeutic implications. Respir Res 2003;4:12. 2010;5:1233‑9. 36. Gomperts BN, Spira A, Elashoff DE, Dubinett SM. Lung cancer biomarkers: 14. Reich JM. A critical appraisal of overdiagnosis: Estimates of its magnitude and FISHing in the sputum for risk assessment and early detection. Cancer Prev implications for lung cancer screening. Thorax 2008;63:377‑83. Res (Phila) 2010;3:420‑3. 15. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 37. Perdomo C, Spira A, Schembri F. MiRNAs as regulators of the response 2010;102:605‑13. to inhaled environmental toxins and airway carcinogenesis. Mutat Res 16. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, 2011;717:32‑7. Clapp JD, Clingan KL, et al. Baseline characteristics of participants in the 38. Malerba M, Ragnoli B, Corradi M. Non‑invasive methods to assess randomized national lung screening trial. J Natl Cancer Inst 2010;102:1771‑9. biomarkers of exposure and early stage of pulmonary disease in smoking 17. National Lung Screening Trial Research Team, Aberle DR, Berg CD, subjects. Monaldi Arch Chest Dis 2008;69:128‑33.

6 Journal of Carcinogenesis A peer reviewed journal in the field of Carcinogenesis and Carcinoprevention Journal of Carcinogenesis 2012,11:00** http://www.carcinogenesis.com/content/11/1/2

39. Jiang YW, Chen LA. microRNAs as tumor inhibitors, oncogenes, biomarkers An analysis of discharge records. Ann Intern Med 2011;155:137‑44. for drug efficacy and outcome predictors in lung cancer (review). Mol Med 46. Gierada DS, Pilgram TK, Ford M, Fagerstrom RM, Church TR, Nath H, et al. Report 2012;5:890‑4. Lung cancer: Inter observer agreement on interpretation of pulmonary 40. Hassanein M, Callison JC, Callaway‑Lane C, Aldrich MC, Grogan EL, findings at low‑dose CT screening. Radiology 2008;246:265‑72. Massion PP. The state of molecular biomarkers for the early detection of 47. Godoy MC, Naidich DP. Subsolid pulmonary nodules and the spectrum of lung cancer. Cancer Prev Res (Phila) 2012;5:992‑1006. peripheral adenocarcinomas of the lung: Recommended interim guidelines 41. Silvestri GA. Screening for lung cancer: It works, but does it really work? for assessment and management. Radiology 2009;253:606‑22. Ann Intern Med 2011;155:537‑9. 42. Silvestri GA, Nietert PJ, Zoller J, Carter C, Bradford D. Attitudes towards 48. Brenner DJ. Radiation risks potentially associated with low‑dose CT screening for lung cancer among smokers and their non‑smoking screening of adult smokers for lung cancer. Radiology 2004;231:440‑5. counterparts. Thorax 2007;62:126‑30. 49. van der Aalst CM, van Klaveren RJ, van den Bergh KA, Willemsen MC, de 43. Bach PB, Cramer LD, Schrag D, Downey RJ, Gelfand SE, Begg CB. The Koning HJ. The impact of a lung cancer computed tomography screening influence of hospital volume on survival after resection for lung cancer. result on smoking abstinence. Eur Respir J 2011;37:1466‑73. N Engl J Med 2001;345:181‑8. 44. Silvestri GA, Handy J, Lackland D, Corley E, Reed CE. Specialists achieve better outcomes than generalists for lung cancer surgery. Chest How to cite this article: Dhillon SS, Loewen G, Jayaprakash V, 1998;114:675‑80. Reid ME. Lung cancer screening update. J Carcinog 2013;12:2. 45. Wiener RS, Schwartz LM, Woloshin S, Welch HG. Population‑based risk for Source and Support: Nil. Conflict of Interest:None declared. complications after transthoracic needle lung biopsy of a pulmonary nodule:

AUTHOR’S PROFILE Journal of Carcinogenesis is published for Dr. Samjot Singh Dhillon, Roswell Park Cancer Institute, Buffalo, New York, Carcinogenesis Press by Medknow Publications USA and Media Pvt. Ltd. Manuscripts submitted to the journal are peer reviewed and Dr. Gregory Loewen, Providence Regional Cancer Center, Spokane, WA, USA published immediately upon acceptance, cited in PubMed and archived on PubMed Central. Your research papers Dr. Vijayvel Jayaprakash, Roswell Park Cancer Institute, Buffalo, New York, will be available free of charge to the entire biomedical USA community. Submit your next manuscript to Journal of Carcinogenesis. Dr. Mary E. Reid, Roswell Park Cancer Institute, Buffalo, New York, USA www.journalonweb.com/jcar/

Journal of Carcinogenesis 7 A peer reviewed journal in the field of Carcinogenesis and Carcinoprevention Copyright of Journal of Carcinogenesis is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.