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MS 10 - Management of Screening Detected Lung Cancer (ID 28)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 7
- Moderators:N. Ikeda, B. Park, P. Goldstraw, L.E. Raez
- Coordinates: 9/07/2015, 14:15 - 15:45, Mile High Ballroom 2c-3c
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MS10.01 - Epidemiology of Lung Cancer and Smoking (ID 1889)
14:20 - 14:30 | Author(s): P. Yang
- Abstract
- Presentation
Abstract:
As of 2014, use of low-dose computed tomography (LDCT) screening for lung cancer was recommended by the U.S. Preventive Services Task Force (USPSTF), i.e., to annually screen people aged 55-80 years of age who have smoked 30 or more pack-years of cigarettes and are either current smokers or have quit within 15 years recommend. From the perspective of epidemiology of lung cancer and smoking, the USPSTF criteria target precisely on the population at the highest risk: peak age range and the heaviest cumulative exposure to cigarette smoking. On the other hand, through closely following the dynamic trends of tobacco smoking and lung cancer incidence and mortality, updating and improving the eligibility criteria for lung cancer screening should be a continuing effort. Reported in 2015 from the Global Adult Tobacco Survey (GATS), current tobacco use prevalence ranges from 43% in Bangladesh to 6% in Panama and Nigeria. Based on a WHO 2015 report, lung cancer remains as the most common cancer in men worldwide with the highest estimated age-standardized incidence rates in Central and Eastern Europe and Eastern Asia (>50.4 per 100,000); in women, the highest estimated rates are in Northern America (33.8) and Northern Europe (23.7). In United States, during 2005-2012, the proportion of heavy smokers who smoked ≥30 cigarettes per day declined significantly, from 12.6% to 7.0%. With the declining percentage of the population who smoke, lung cancer incidence and mortality have been decreasing among men in the past three decades, and only recently, has shown decrease among women. A similar trend has been observed in Olmsted County population, Minnesota (Figure). Meanwhile, former cigarette smokers remain at a high risk for lung cancer although at lower risk than they would have been had they continued smoking. As a consequence, more people with lung cancers are now identified in former smokers rather than in current smokers. Specifically, less than 18% of United States adults are current smokers and more than 30% are former smokers. Intriguingly, our recent report showed that approximately two thirds of newly diagnosed lung cancer patients would not have met the current USPSTF high-risk criteria for LDCT screening. Particularly, we found a 24% offal in screening-eligibility (from 57% in 1984-1990 to 43% in 2005-2011) which exceeded the 17% decline in incidence in lung cancer (from 53 to 44/1000000) over the same time intervals. We have conducted further investigations to delineate the high-risk subpopulations based on evidence from two prospective lung cancer patient cohorts and a retrospective community cohort. Our goal was to improve the identification of individuals at high-risk for lung cancer by (1) demonstrating the chronological patterns of patients who would have been the beneficiaries or missed-outs under USPSTF criteria for lung cancer screening in two contrasting cohorts, and (2) provide strong evidence of a new subpopulation that should be added to the definition of high risk and the public health impact of this subgroup on smoking cessation effort. Two prospective cohorts are primary lung cancer patients diagnosed between 1997-2011 from referral patients (Hospital) and defined-community residents (Community); the retrospective cohort is the Olmsted County population (Minnesota, USA) followed for 28 years (1984-2011). Hospital and Community cohorts include 5988 and 850 patients, respectively; the Olmsted County population is approximately 140,000. Between 1997 and 2011, former smokers with 15-30 quit-years age 55-80 formed the largest subgroup not meeting current USPSTF screening criteria. This subgroup constituted 12% of the hospital cohort and 17% of community cohort of patients with lung cancer. Between 1984 and 2011, using current screening criteria, the age- and sex-adjusted lung cancer incidence rates in Olmsted County decreased significantly from 1.5/1000 to 0.6/1000 person-years; when adding former smoker cases with 15-30 quit-years to the high risk group, the incidence rate was doubled by 2011. Evidence from both Community and Hospital cohorts in this study suggest that former smokers with 30+ pack-years and 15-30 quit-years of cigarettes remain at high risk and should be considered as eligible for lung cancer screening. These individuals may perceive the USPSTF’s requirement to stop screening after 15 years as an indication they are no longer at high risk for lung cancer or as a pass not to quit smoking. These results may impact smoking cessation and optimize the effectiveness of screening program, and demand more effective criteria to define high-risk for lung cancer. Individuals who are under 81 years, had 30 or more pack-year smoking history, and had quit for 15-30 years should also be considered as eligible for lung cancer screening. Figure 1 References: 1. Moyer VA, US Preventive Services Task Force. Screening for Lung Cancer: USPSTF Recommendation Statement. Ann Intern Med. Mar 4 2014;160(5):330-338. 2. The GATS Atlas. Global Adult Tobacco Survey. Global Tobacco Surveillance System. Published by CDC 2015. 3. GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance. July 23, 2015 4. Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System Prevalence and Trends Data, 2013. Atlanta: U.S. DHHS, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2013 [accessed January 2015]. 5. Lung Cancer Incidence Trends in U.S.A. SEER Program: http://surveillance.cancer.gov/. April 2015. 6. St Sauver JL, Grossardt BR, Yawn BP, et al. Data resource profile: the Rochester Epidemiology Project medical records-linkage system. Int J Epidemiol. Dec 2012;41(6):1614-1624. 7. Wang Y, Midthun DE, Wampfler JA, Deng B, Stoddard SM, Zhang S, Yang P. Trends in the proportion of patients with lung cancer meeting screening criteria. JAMA. 2015; 313(8):853-5. 8. Yang P, Allen MS, Aubry MC, et al. Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest. Jul 2005;128(1):452-462.
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MS10.02 - Positive Lung Cancer Screens - Which Ones are Lung Cancer? (ID 1890)
14:30 - 14:40 | Author(s): M. Tammemägi
- Abstract
- Presentation
Abstract not provided
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MS10.03 - What Is the Ideal Method of Diagnosis for Screening Detected Lung Nodules? (ID 1891)
14:40 - 14:50 | Author(s): D. Minnich
- Abstract
Abstract not provided
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MS10.04 - When to Intervene on Screening Detected Lung Nodules (ID 1892)
14:50 - 15:00 | Author(s): G. Veronesi
- Abstract
- Presentation
Abstract:
The National Lung Screening Trial (1) largely resolved the dispute as to whether low-dose computed tomography (LDCT) screening can reduce lung cancer mortality. However the trial was characterized by a high recall rate and high rate of benign disease at surgery, probably because a diagnostic and management protocol for indeterminate nodules was not in place. Screening has improved the stage distribution of lung cancer at diagnosis and greatly increased the cure rate (2). It has also increased numbers of overdiagnosed cancers and of potentially harmful diagnostic procedures carried out for benign disease. It is therefore critical to establish quality criteria for screening programs to reduce the risks of these occurrences. Recommendations from the surgeon team at the 2011 WCLC workshop, Amsterdam (3) were that: (i) A formal diagnostic and surgical management protocol should be part of any screening program; surgeons should be involved drawing up protocols along with other members of the multidisciplinary team. (ii) A false positive rate of less than 15% should be aimed at. (iii) Screening should only be performed at centres with access to a full minimally invasive surgical program (VATS or robotic anatomical resection). (iv) For pure ground-glass or partially-solid LDCT-detected lung cancers below 2 cm, anatomical segmentectomy is adequate treatment provided intraoperative frozen section examination shows that lymph nodes at hilar and mediastinal stations are negative. The diagnostic algorithm of COSMOS (4) was non-invasive, with no routine CT-guided transthoracic biopsy, and indication for surgery based on nodule size, volume doubling time (VDT), and SUV on PET-CT. After 5 years, only 14% of surgical biopsies were for benign disease, one of the lowest in the literature. Around half the biopsied benign nodules had a VDT generally considered to indicate malignancy, and the other half were PET positive. Thus addition always of reducing false positives are needed and molecular markers appear promising in this respect. The false negative rate is a good indicator of screening program quality. In COSMOS we defined false negatives as stage II-IV cancers present on a previous annual scan but not considered to merit further workup: 16 of the 190 cancers (8%) were false negatives, similar to the I-ELCAP figure of 9%. Most false negatives were centrally located, rapidly-growing nodules, but a few were misinterpreted by radiologists. The role of PET-CT in the workup algorithm was investigated on 378 COSMOS volunteers with indeterminate nodules (5). PET-CT was found highly sensitive for nodules detected at baseline, nodules ≥15 mm, and solid nodules. Sensitivity was lower for partially solid and nonsolid nodules, and those discovered after baseline, for which other methods, e.g. VDT, should be used. The Danish Lung Cancer Screening Trial investigated both PET-CT and VDT, finding that the best predictor of malignant nodules was PET-CT and VDT combined (6). NELSON trial investigators were the first to introduce VDT as main the component of the diagnostic algorithm (7). As regards overdiagnosis, in a retrospective analysis of 175 COSMOS patients VDT was suggested as a marker of aggressiveness that could be used to estimate overdiagnosis and tailor treatment [8]. We divided nodules into: fast-growing (VDT <400 days) days), slow-growing (VDT 400-599 days), and indolent (VDT >600 days). Median VDT was significantly faster in new cancers than slow-growing and indolent cancers (52, 223 and 545 days, respectively). Median VDT (303 days) was significantly longer in adenocarcinomas than squamous cell carcinomas (77 days) and small cell cancers (70 days). The authors concluded that slow-growing nonsolid nodules, many of which are likely to be overdiagnosed, could be safely treated with minimally invasive (sublobar) surgery. If centrally located, stereotactic ablative body radiotherapy (SABR) should be considered and discussed with the patient. The recent paper of Yankelevitz et al. (9) focused on the frequency, treatment and prognosis of nonsolid nodules encountered the large I-ELCAP screening cohort. Nonsolid nodules were rare, being identified in 2392 (4.2%) of 57,496 baseline screenings, with new nonsolid nodules identified in 485 (0.7%) of 64,677 repeat screenings. All 84 lung cancers identified were stage I adenocarcinomas and survival was 100% a median of 78 months (IQR, 45–122). after diagnosis. The authors concluded that nonsolid nodules of any size could be safely followed at 12-month intervals and that transition to part-solid should prompt a pathologic diagnosis. The authors suggested the nonsolid nodules should be renamed ‘indolent lesions of epithelial origin,’ in part to counter the fear that the word cancer evokes; in part because they behave much like benign lesions. In the COSMOS study, nonsolid lesions constituted 17% of all cancers detected, probably more than in I-ELCAP (although an updated breakdown is not available). This may be because COSMOS investigators removed these nodules if they increased in size or were PET-CT positive. As regards the question of lymph node dissection for early lung cancers, 193 consecutive patients with non-screening detected clinically N0 lung cancers, were studied (10). It emerged that 42/43 cases had negative PET-CT (usually SUVmax <2.0) or nodule ≤10 mm were pN0, suggesting that, for cancers with these characteristics, node dissection can be avoided because the risk of nodal involvement is minimal. To conclude, the results of the National Lung Screening Trial (1) shifted the debate from whether to how screening should be performed. Various diagnostic algorithms have been proposed, most with good results in terms of safety and number of resections for benign disease, however there is still room for improvement. The role of molecular markers, alone or in combination with VDT and PET positivity (FDG uptake), is under evaluation. Nonsolid nodules can be safely monitored at yearly intervals until the appearance of a solid component. Large scale implementation of screening in Europe is now a priority: although many investigators still have reservations, LDCT screening, with an appropriate diagnostic and surgical management protocol, is now good enough to save many lives with limited risks. References 1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. doi: 10.1056/NEJMoa1102873. 2. Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006; 355: 1763–1771. 3. Field JK, Smith RA, Aberle DR, et al. IASLC CT Screening Workshop 2011 Participants. International Association for the Study of Lung Cancer. Computed Tomography Screening Workshop 2011 report. J Thorac Oncol. 2012;7(1):10-9. doi: 10.1097/JTO.0b013e31823c58ab. 4. Veronesi G, Maisonneuve P, Spaggiari L, et al. Diagnostic performance of low-dose computed tomography screening for lung cancer over five years. J Thorac Oncol. 2014;9(7):935-9. doi: 10.1097/JTO.0000000000000200. 5. Veronesi G, Travaini LL, Maisonneuve P, et al. Positron emission tomography in the diagnostic work-up of screening-detected lung nodules. Eur Respir J. 2015;45(2):501-10. doi: 10.1183/09031936.00066514. 6. Ashraf H, Dirksen A, Loft A, et al. Combined use of positron emission tomography and volume doubling time in lung cancer screening with low-dose CT scanning. Thorax. 2011;66(4):315-9. doi: 10.1136/thx.2010.136747. 7. Horeweg N, van der Aalst CM, Vliegenthart R, et al. Volumetric computer tomography screening for lung cancer: three rounds of the NELSON trial. Eur Respir J 2013; 42: 1659–1667. 8. Veronesi G, Maisonneuve P, Bellomi M, et al. Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med 2012; 157: 776–784 9. Yankelevitz DF, Yip R, Smith JP, et al. As the Writing Committee for The International Early Lung Cancer Action Program Investigators Group. CT Screening for lung cancer: nonsolid nodules in baseline and annual repeat rounds. Radiology. 2015:142554. 10. Veronesi G, Maisonneuve P, Pelosi G, et al. Screening-detected lung cancers: is systematic nodal dissection always essential? J Thorac Oncol. 2011;6(3):525-30. doi: 10.1097/JTO.0b013e318206dbcc.
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MS10.05 - Rationale for Sublobar Resection for Early Cancer (ID 1893)
15:00 - 15:10 | Author(s): H. Asamura
- Abstract
- Presentation
Abstract:
THE oncological appropriateness of the limited, sublobar resection (segmentectomy or wide wedge resection) for lung cancer has been again discussed in the thoracic surgical community, although the previous randomized trial definitively showed the prognostic advantage of the lobectomy over sublobar, limited resection. Generally, the operative modes used for pulmonary parenchymal resection have been classified into pneumonectomy, bi-lobectomy, lobectomy, segmentectomy, and wedge resection according to the volume of the resected lung parenchyma. From a technical viewpoint, these can be divided into non-anatomic (wedge resection) and anatomic (all the others) resections. In anatomic resections, all vessels and bronchi are divided at the hilum to ensure the resection of the whole lung area related to the divided bronchus. The term, “limited resection”, is also used as opposed to “standard resection”, which is essentially at least lobectomy with hilar and mediastinal lymph node sampling/dissection as of now. Therefore, the present-day “limited” resection inevitably indicates “sublobar” resections. There are several important landmark articles in the surgical evolution for lung cancer. In 1930s, Churchill and Belsey originally introduced segmentectomy for the treatment of bronchiectasis of the lingular segment, and it was termed as “segmental pneumonectomy” [1]. In 1970’s, Jensik reported a 5-year survival rate at 56% and local recurrence rate at 10% after segmentectomy for T1 lung cancer. He suggested that anatomic segmentectomy could be effectively applied to small primary lung cancers when the surgical margins were sufficient [2]. After these, many non-randomized, case series came out, and suggested the prognostic equivalence between lobectomy and segmentectomy for T1 lung cancer. To definitively answer the question regarding the prognoses after lobectomy and limited resection, a prospective, randomized trial was conducted by the North American Lung Cancer Study Group (LCSG) [3]. Segmentectomy and wide wedge resection were compared with lobectomy for stage IA lung cancer with regard to the postoperative prognosis and pulmonary function. A three-fold increase in local recurrence rate and 30% increase in overall death rate were shown for limited resection, and therefore, this study solidified lobectomy as the procedure of choice for the treatment of T1N0 lung cancer. This is still the only completed, randomized trial that directly compared limited resection with lobectomy, and therefore, the gold standard for lung cancer still remains as lobectomy as of now. However, there has been a surge of the interest in the sublobar resection among thoracic surgeons recently, since many earlier, smaller cases are being found owing to the improved technology in CT image and the introduction of the CT screening programs. [4] Among the lesions that are specifically found in this context, the non-solid lesion that is referred to as ground glass opacity (GGO) is a newly established clinical entity that may be a candidate for limited pulmonary resection. The understandings of pathobiological nature of such earlier lesions have progressed [5]. New proposal for the classification of adenocarcinoma was also promulgated, in which the earlier forms of adenocarcinoma were newly defined as AIS (adenocarcinoma in situ) or MIA (minimally invasive adenocarcinoma) [6]. In the face of this situation, it is not surprising that questions have arisen as to whether it might be possible to manage smaller, earlier lung cancers by sublobar resections. Moreover, it has been more than 20 years since the LCSG randomized clinical trial was conducted in the 1980s. Given this situation, randomized clinical trials with peripheral lung cancers no more than 2 cm in diameter as the target lesions were begun in the United States (CALGB 140503) and Japan (JCOG 0802) at almost the same time [7]. JCOG0802/WJOG4607L trial is a prospective, randomized, multi-institutional study which intends to compare the prognosis and postoperative pulmonary function between patients with non-small lung cancer 2 cm or less in diameter undergoing either lobectomy or segmentectomy. The target number of patient accrual is 1,100, and as of the end of June, 2015, accrual is over in full and the data maturation is awaited. The important fact is that the candidate lesions of this trial are supposed to be invasive adenocarcinomas pathologically with solid part in ground glass opacity (GGO) on the CT images. As a selection criterion, a consolidation/tumor ratio has been employed as 25 to 100% to define invasive adenocarcinomas preoperatively. This study is coupled with JCOG0804/WJOG4507L trial, which deals with the non-invasive or minimally invasive adenocarcinomas (adenocarcinoma in situ, AIS/minimally invasive adenocarcinoma, MIA) with CT images as pure GGO with/without minimal solid part. They are treated with limited, sublobar resection (segmentectomy or wide wedge resection). This study is a prospective, but non-randomized, single-arm study because no death is expected for these tumors despite surgical modes. Target accrual is 330, and the registration was already closed, waiting for data maturation. The present-day selection of the surgical mode for lung cancer should be based upon the solid data which demonstrate the overt advantage over the standard mode of resection (lobectomy). We need another some years until getting the definitive conclusion as to the appropriateness of sublobar resection for early stage lung cancer. Until then, surgeons should be prudent in performing a sublobar resection as a radical resection for lung cancer.[8] Figure 1 SEGMENTECTOMY OF THE ANTERIOR SEGMENT OF THE RIGHT UPPER LOBE (from "Asamura's Operative Thoracic Surgery") [References] 1. Churchill ED, Belsey R. Segmental pneumonectomy in bronchiectasis: the lingular segment of the left of the left upper lobe. Ann Surg 1939;109:481-99 2. Jensik RJ. Faber LP, Milloy FJ, Monson DO. Segmental resection for lung cancer. A fifteen-year experience. J Thorac Cardiovasc Surg 1973;66:563-72 3. Lung Cancer Study Group, Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1N0 non-small cell lung cancer. Ann Thorac Surg 1995;60:615-23 4. El-Sherif A, Gooding WE, Santos R, et al. Outcome of sublobar resection versus lobectomy for stage I non-small cell lung cancer: a 13-year analysis. Ann Thorac Surg 2006;82:408-16 5. Asamura H, Hishida T, Suzuki K, et al. Japan Clinical Oncology Group Lung Cancer Surgical Study Group. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201. J Thorac Cardiovasc Surg 2013;146:24-30 6. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85 7. Nakamura K, Saji H, Nakajima R, et al.. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271-4 8. Asamura H. Role of limited sublobar resection for early-stage lung cancer: steady progress. J Clin Oncol. 2014;32(23):2403-4.
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MS10.06 - Is There a Role for SBRT in Screening Detected Non-Diagnosed Lung Nodules? (ID 1894)
15:10 - 15:20 | Author(s): D.A. Palma
- Abstract
- Presentation
Abstract:
With the results of the National Lung Screening Trial (NLST) demonstrating improved overall survival with low-dose CT screening in high-risk patients,[1] the management of screen-detected lung nodules has taken on increased clinical importance. In the NLST, low-dose CT scans showing any non-calcified mass or nodule were classified as ‘positive’, but with this definition, fewer than 4% of ‘positive’ results were ultimately shown to be lung cancer. Ongoing randomized trials of lung cancer screening use alternative definitions of a positive result, which may improve the specificity of CT screening. However, despite this high rate of false-positives, validated models are available to allow for accurate prediction of malignancy risk. One such model, developed from the Pan-Canadian Early Detection of Lung Cancer Study and validated, achieved excellent discrimination and calibration, with AUC values in excess of 0.90.[2 ]The availability of such tools should substantially reduce the risk of patients undergoing unnecessary investigations or treatments for benign disease. For patients with a high probability of malignancy, surgical resection has been the historic treatment of choice. Surgical interventions provide a pathologic diagnosis and also allow for lymph node sampling, but can be associated with significant morbidity and mortality. Although surgical morbidity in the NLST was low,[1] such results from specialized centers may not be widely generalizable. Population data have shown higher rates of complications than data from specialized centers, both in terms of complications for CT-guided biopsies, and also for surgical morbidity and mortality.[3,4] Stereotactic ablative radiotherapy (SABR), also called stereotactic body radiation therapy (SBRT), is a non-invasive treatment often delivered in 1-8 fractions on an outpatient basis. For T1-T2N0 NSCLC, SABR achieves high-rates of local control, and with results comparable to surgery in many well-controlled studies. Randomized data, not specific to screen-detected lesions, suggests that SABR may achieve better overall survival than surgical resection.[5] A major advantage of SABR appears to be a reduced risk of serious toxicity in high-risk patients: for example, a systematic review of outcomes for patients with T1-T2 NSCLC and severe COPD (GOLD III/IV) indicated a 30-day mortality rate of 10% with surgical resection and 0% with SABR.[6] Modeling studies comparing surgical resection and SABR suggest that as operative mortality rises, SABR is preferred. This presentation will discuss the relative merits and limitations in the use of SABR for screen-detected lung nodules, including evidence-based thresholds for treating without a definite pathologic diagnosis, issues pertaining to treatment delivery for small targets, toxicity of SABR for small lesions, and ongoing follow-up after SABR. References 1. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409. 2. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, Yasufuku K, Martel S, Laberge F, Gingras M, Atkar-Khattra S, Berg CD, Evans K, Finley R, Yee J, English J, Nasute P, Goffin J, Puksa S, Stewart L, Tsai S, Johnston MR, Manos D, Nicholas G, Goss GD, Seely JM, Amjadi K, Tremblay A, Burrowes P, MacEachern P, Bhatia R, Tsao MS, Lam S. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med. 2013 Sep 5 3. RS Wiener, LM Schwartz, S Woloshin, HG Welch. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med, 155 (2011), pp. 137–144 4. D LaPar, C Bhamidipati, C Lau, D Jones, B Kozower. The Society of Thoracic Surgeons General Thoracic Surgery Database: establishing generalisability to national lung cancer resection outcomes. Ann Thorac Surg, 94 (2012), pp. 216–221 5. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, Groen HJ, McRae SE, Widder J, Feng L, van den Borne BE, Munsell MF, Hurkmans C, Berry DA, van Werkhoven E, Kresl JJ, Dingemans AM, Dawood O, Haasbeek CJ, Carpenter LS, De Jaeger K, Komaki R, Slotman BJ, Smit EF, Roth JA. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015 Jun;16(6):630-7. 6. Palma D, Lagerwaard F, Rodrigues G, Haasbeek C, Senan S. Curative treatment of Stage I non-small-cell lung cancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review. Int J Radiat Oncol Biol Phys. 2012 Mar 1;82(3):1149-56. 7. Louie AV, Rodrigues G, Hannouf M, Zaric GS, Palma DA, Cao JQ, Yaremko BP, Malthaner R, Mocanu JD. Stereotactic body radiotherapy versus surgery for medically operable Stage I non-small-cell lung cancer: a Markov model-based decision analysis. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):964-73
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MS10.07 - Biomarkers: Current Status and Future Direction (ID 1895)
15:20 - 15:30 | Author(s): R. Young
- Abstract
- Presentation
Abstract:
The need for biomarkers Yearly low-dose computed tomography (CT) screening for lung cancer is now widely recommended in the United States.[1] Published articles reviewing the benefits versus harms of lung cancer screening have highlighted the potential harms from radiation exposure, unnecessary invasive workup and overdiagnosis.[2] While cost-effectiveness analysis has suggested that CT screening for lung cancer is comparable to other existing cancer screening programs, this analysis makes a number of assumptions based on the NLST findings which may not translate to the wider community. These issues highlight the need for identifying biomarkers that may improve patient selection, maximise lung cancer detection, minimizing overdiagnosis and the treatment of indolent disease.[2] The eligibility criteria for the NLST were specifically designed to maximize the number of cancers that could be identified during screening within a relatively high risk group. However, it has been shown that age and pack years alone have only limited utility in identifying those smokers at greatest risk.[3-5] It was never intended that screening eligibility should be based solely on the NLST criteria. The first problem is the NLST screening criteria include low risk individuals for whom the risk of screening far outweighs the benefit.[3-5] The second problem is that between 40-60% of lung cancer cases are currently ineligible for lung cancer screening due to restrictions on age and smoking history.[6,7] The former group is estimated to represent about 30-40% of those currently eligible for screening based on the NLST and can be identified using multivariate risk models incorporating several clinical risk variables such as age, detailed smoking history, past diagnosis of COPD, BMI, occupation and ethnicity.[4] Lung Function and related tests of COPD There have been several studies that show lung function testing adds considerable predictive utility to clinical multivariate models. This approach stratifies smokers with normal lung function (no airflow limitation and/or DLCO reduction) into a low risk group, where it has been shown their lung cancer incidence is only a quarter of that observed in those with COPD.[8] Emphysema identified on CT has also been shown to identify high risk smokers for lung cancer where airflow limitation is absent.[9] These studies confirm past epidemiology identifying that co-existing COPD, characterized by reductions in forced expiratory volume (and its ratio with forced vital capacity) are significant risk factors for lung cancer. Genetic Markers A limited number of studies have found that genetic markers, primarily single nucleotide polymorphic (SNP) variants, add to the predictive utility of clinically-based risk tests.[10 ]These SNP markers reside in genes encoding several important proteins, including epithelial based receptors, involved in mediating smoking-related inflammation in the lungs.[10 ]The value of identifying these genetic markers lies in their predictive utility to recognize high risk individuals long before the clinical manifestations of smoking damage (airflow limitation or emphysema) are clinically evident. The addition of SNP modestly increases the sensitivity and specificity of the risk models which use clinical variables alone. More importantly, the addition of these markers improves the correct assignment of risk in up to 25-30% of people participating in lung cancer screening trials. Other Molecular Biomarkers Other molecular markers for lung cancer currently under investigation are protein markers, antibody assays and expression (RNA) profiles.[11-14] These types of assay are potentially subject to biological interference from smoking status (eg. current vs ex-smokers) or co-existing COPD, where drug therapies (eg. inhaled corticosteroids or antibiotics) and bacterial colonisation of the lung (eg. effects from the lung microbiome) are present. The “noise” from these co-existing conditions may cause confounding or mediating effects that reduce the predictive utility of the assay of interest. One of the more promising of these biological assays involves the analysis of exhaled volatile compounds from the lung which can now be measured with more accurate devices.[14] These molecular assays are currently being validated in large prospective clinical trials. Biomarkers in CT screening – risk assessment While the utility of these assays in the context of CT screening remains to be established, they all have the potential to improve the current risk-benefit ratio of CT screening. First, this might involve identifying low risk individuals currently eligible for screening based on the age and pack year criteria (“NLST approach”) but who gain little benefit from screening. Alternatively, wider risk assessment would help identify those smokers who are at high risk despite not meeting the NLST criteria (“NCCN approach”). In this setting, markers related to a predisposition to COPD, such as airflow limitation based on spirometry, reduced DLCO (as a marker of emphysema and interstitial lung disease) or CT-based emphysema, are particularly relevant. Genetic (SNP) markers associated with an increased predisposition to COPD or lung cancer may also help in this regard.[10] Second, expression-based markers may be helpful in distinguishing benign from malignant nodules. With time, greater refinement of these techniques for identifying and validating novel biomarkers will provide greater confidence in their use in conjunction with serial CT screening. This approach might augment existing risk models based on clinical parameters. However, these biomarkers are competing with serial CT -based volumetric analyses which appears on initial studies to considerably reduce the false positive rate (discriminate benign from malignant based on growth rate). These novel biomarkers would be combined with multivariate risk models to reduce the treatment of indolent nodules, reducing overdiagnosis and minimize harm. In a recent post-hoc analysis of the NLST-ACRIN data, we found that airflow limitation based on pre-bronchodilator spirometry is associated with little if any overdiagnosis. This finding is consistent with the results of others showing COPD to be associated with more aggressive lung cancer. Other biomarkers may have a similar utility. Biomarkers in CT screening – smoking cessation Smoking cessation is the only proven lifestyle modification that reduces the risk of lung cancer. Little thought is given to the use of biomarkers in smoking cessation. In a limited number of studies it has been shown that risk assessment tools have some contribution to make to smoking cessation.[15] Inconsistency of findings with respect to the effects of lung function testing and CT nodule identification on quit rates means there is more work to be done here. The basic psychology of smoking suggests that challenging some smokers with personal biodata enhances their perception of smoking-related risks. In particular, showing a smoker they are at greater risk than the average smoker based on personal data increases their interest in quitting.[15] This is believed to occur because personal biodata increases motivational tension and undermines the smoker’s denial which maintains their smoking habit. This aspect of CT screening programmes is not one that has received as much attention as it warrants. However CT screening programmes, with routine use of personalised risk appraisal, are uniquely positioned to reinforce existing public health strategies aimed at reducing smoking rates. Summary While there remains much to do to confirm the utility of biomarkers in the CT screening process , existing data suggests that significant gains may be made by their use in improving risk-benefit appraisal of screening participants, better management of nodules and perhaps significant gains in reducing smoking rates among high risk smokers. References 1. 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. JAMA 2012; 307(22):2418-29. 2. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive Services Task Force recommendation. Ann Int Med 2013; 159(6):411-20. 3. Bach PB, Gould MK. When the average applies to no one: personalized decision making about potential benefits of lung cancer screening. Ann Int Med 2012, August 14. 4. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung cancer death. N Eng J Med 2013; 369: 245-254 5. Young RP, Hopkins RJ, MidthunDE. Benefits and harms of CT screening for lung cancer: A systematic review – Letter. JAMA 2012; 308: 1320-1321. 6. Young RP, Hopkins RJ. Lung cancer risk prediction to select smokers for screening. Cancer Prev Res 2012; 5: 697-698. 7. Wang Y, MidthunDE, Wampfler JA, et al. Trends in the proportion of patients with lung cancer meeting screening criteria. JAMA 2015; 313: 853-855. 8. Young RP, Hopkins RJ. Diagnosing COPD and targeting lung cancer screening. Eur Respir J 2012; 140: 1063-1064. 9. Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med 2008; 178: 738-744. 10. Young RP, Hopkins RJ, Whittington CF, Hay BA, Epton MJ, Gamble GD. Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD. Plos One 2011; 6: e16476. 11. Silvetsri GA, Vachani A, Whitney, D, et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N Eng J Med 2015; May 17. 12. Hassanein M, Rahman JSM, Chaurand P, Massion P. Advances in proteomic strategies towards the early detection of lung cancer. Proc Am Thorac Soc 2011; 8: 183-188. 13. Healey GF, Lam S, Boyle P, et al. Signal stratification of autoantibody levels in serum samples and its applications to the early detection of lung cancer. J Thorac Dis 2013; 5: 618-625. 14. Dent AG, Sutedja, Zimmerman PV. Exhaled breath analysis for lung cancer. J Thorac Dis 2013; 5: S540-S550. 15. Young RP, Hopkins RJ. Genetic susceptibility testing to lung cancer and outcomes in smokers. Tob Control 2012; 21: 347-354.
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