Fact sheet Lung cancer screening for employees exposed to asbestos using CT screening (CTTS)

Version: February 2013 Fact sheet Lung cancer screening for employees exposed to asbestos using CT screening (CTTS) Dr. med. Susanna Stöhr, PD Dr. med. Dr. phil. David Miedinger, Dr. med. Marcel Jost 1. Situation prior to 2011 Asbestos-related changes and diseases - such as lung cancers (bronchial carcinoma) and mesothelioma - are usually associated with macroscopically discernible tissue neoplasms. For screening tests, priority is therefore given to imaging techniques. The screening studies carried out in the 1970s to detect lung cancer among smokers - the main risk group - using the X-ray technology of that time were disappointing as these studies failed to reduce lung cancer mortality. For this reason, no recommendation for lung cancer screening with plain chest ray studies were given over the next two decades. At an international conference on the prevention and early detection of bronchial carcinoma held in Varese in 1998, it was found that the effectiveness of the screening of this common tumor, which is mainly caused by smoking, should be explored with the help of newer imaging techniques, particularly computer tomography (CT). For the diagnosis of bronchial carcinoma, computer tomography of the thoracic organs is superior in terms of sensitivity and specificity to conventional X-rays. The goal of screening is to detect a disease at an early stage. It is known from the literature that surgically treated bronchial carcinoma at stage I have a much better five-year survival than in later stages. The use of CT, in particular using low irradiation-dose and spiral technique, has shown that among older smokers in particular, as well as among people previously exposed to asbestos, lung tumors can be detected more frequently and at earlier stages, which is reflected in an improved five-year survival period. In 2000, Henschke et al. published the first in a series of publications in which it could be shown that bronchial carcinoma can be diagnosed at an early stage among smokers over the age of 60 using low-dose spiral CT technology, i.e. to the extent of 85% in stage I. Among 233 of 1,000 subjects, a total of 559 nodules was found, 28 of which were shown by biopsy to be malignant tumors. An algorithm with phased follow-up investigations together with volume calculations made it possible to limit the number of cases to be clarified by biopsy to a minimum. The investigation carried out in the International Early Lung Cancer Action Program (IELCAP) showed that bronchial carcinoma can be discovered at an early stage (stage I) by spiral CT screening. In this study conducted among more than 30,000 people over the age of 40 and with an increased risk of lung cancer due to smoking, passive smoking and occupational exposure to carcinogenic agents, lung cancer in stage I was found in 85% of the patients

- 2 - affected and the estimated 10-year survival rate was 88% in this subgroup. The study concluded that annual spiral CT screening can recognize lung cancers in a stage in which they can often be cured. A study published in 2007 by Bach et al. showed that while more new bronchial carcinoma can be discovered with CT screening, the number of cases of advanced bronchial carcinoma and mortality resulting from bronchial carcinoma may not be reduced by CT screening. An overview of current and planned randomized controlled studies on low dose- CT screening by the University of Lausanne in 2007 concluded that systematic CT screening should only be considered if controlled, randomized studies show a decrease in mortality due to screening. CT-based screening for the early detection of lung tumors has also been carried out among people previously exposed to asbestos. Tiitola et al. found 111 nodules of > 0.5 cm in size, 6 of which in the end proved to be bronchial carcinoma, among 602 people previously exposed to asbestos (97% of them were smokers). In a CT screening study published in 2007 - also from Finland (Vierikko et al.) - HRCT and CT investigations were used to detect a noncalcified nodule among 86 of 633 former workers exposed to asbestos, which in five cases were histologically proven to be bronchial carcinoma. Two were in stage Ia, three in stage IIIb. In addition, 343 additional findings, of which 46 had to be further clarified, were identified among the total of 277 subjects. A multicenter study from Italy (Fasola et al.) conducted in 2007 among employees previously exposed to asbestos showed that CT screening among people previously exposed to asbestos produces similar results to those among smokers. It was noted that only the randomized controlled investigations show whether a reduction in mortality caused by bronchial carcinoma can be achieved by low-dose CT screening. As part of the Asbestos Surveillance Program Aachen (ASPA), 187 people from a group of over 5,000 former powerplant employees with a particularly high risk of lung cancer due to exposure to asbestos, smoking and old age were studied prospectively (Das M. et al.). Asbestos-related changes of the pleura and the lungs were observed among 43% of the people. Among 8/187 employees, that is to say 4%, lung cancer was detected in the first examination. Within the framework of this screening, a high number of additional nodular changes was observed and only 12% of the subjects had no nodular changes. The high prevalence of lung cancer in the Aachen monitoring program shows that the inclusion criteria for screening were well chosen. Mastrangelo et al. studied 1,119 employees previously exposed to asbestos; in the group studied, the risk of lung cancer was not greater compared to the general population and the screening program was not judged to be cost-effective. Experience with CT screening in Canada was published by Roberts et al. in 2009. An increased sensitivity of chest CT compared with the conventional radiography for the detection of lung cancers was described by Clin et al. in France in 2009. In 2009, a randomized controlled study of 2,472 people was published under the name of the Dante trial. It included men aged between 60 and 75 with a cigarette consumption of 20 or more pack-years. Annual screening with a low spiral CT was compared to an annual medical examination (without chest x-ray). Lung cancer was found in 4.7% of persons using CT screening and 2.8% of the other people; in the group with CT screening, more lung cancer in stage I was observed compared with the controls (54% versus 34%). With a figure of 1.6%, mortality from lung cancer was not significantly lower in the CT screening group compared to the control group at 1.7%. The study authors concluded that lung cancer screening with lowdose spiral CT should not yet be performed outside of studies.

- 3 - The psychological impact of lung cancer screening among employees exposed to asbestos was investigated by Vierikko et al. in Finland; the results were published in 2009. Among 633 employees examined using CT screening, no significant psychological differences (such as increased anxiety regarding their personal health) were observed after one year between employees with normal findings and employees among whom additional tests after CT screening became necessary. These encouraging results were confirmed in another study in Holland and Belgium among participants of the NELSON program. Among participants among whom findings were noted during the first examination and which required further clarification, a slight temporary impairment of quality of life due to uncertainty was, identified. However, further investigation two years later showed that this impairment was no longer measurable. 2. The NLST trial 2011 The largest randomized controlled study investigating whether overall mortality and specific lung cancer mortality can be reduced in persons with an elevated risk of lung cancer by regular screening with low-dose spiral CT is the National Lung Screening Trial (NLST). Itinvestigated more than 53,000 smokers and ex-smokers aged between 55 and 74. Smokers with at least 30 pack-years were included in the study. One group was investigated with low-dose spiral CT and the control group with chest radiographs. A press release issued by the NLST in November 2010 claimed that overall mortality in the group with annual low-dose spiral CT was 7% lower than in the control group and that lung-cancer specific mortality was 20% lower in the group with low-dose spiral CT. In this study, 26,723 participants in a low-dose CT group were investigated using a low-dose spiral CT once a year for 3 years and then monitored for another 3.5 years. In the comparison group, 26,733 participants were examined and observed by a chest x-ray using the same timeframe. All three investigations were carried out among 95% in the CT group and 93% in the X-ray group. In each of the three time points in the investigation, far more positive results, these being about three times as often, were obtained with low-dose spiral CT than in the group with the X-ray examination. However, only 2% to 7% of the radiological findings suggestive of lung cancer actually proved to be malignant tumors. The clarification of positive results was usually handled by consulting former radiological studies and invasive investigations were not often necessary. In those who needed further clarifications, very few complications due to invasive exams had occurred (1.4% in the group receiving low-dose spiral CT). More serious complications after invasive investigations among participants without any resultant lung cancer occurred among 0.06% of the participants in the group receiving low-dose spiral CT. In the group receiving low-dose spiral CT, more lung cancer was observed in a stage IA and IB less advanced lung cancer in stage IV than in the group receiving conventional chest x-ray. Small-cell lung cancer was detected at an early stage neither in the group receiving low-dose spiral CT nor X-ray examination. Lung-cancer specific mortality was lower by 20.0% and total mortality by 6.7 % in the group with low-dose spiral CT. The authors conclude that the efficacy of low-dose spiral CT screening may possibly be even greater than the study suggests. On the one hand, better scanners are used today than at the time of the studies (August 2002 to April 2004). On the other hand, the effect of reducing mortality might be even higher as a result of extending the observation period after the end of the CT screening.

- 4 - However, the publication of the NLST in summer 2011 cannot yet answer some important questions such as the question as to how long a CT screening is to be performed, whether a CT screening with larger intervals is also effective and to what extent people with lower risks than those represented by the NLST inclusion criteria can benefit from a CT screening. While complications resulting from clarifications, particularly severe complications, were rarely observed in the NLST, the question of the association between low-dose spiral CT screening and the incidence of radiation-induced malignancies cannot be answered by the study. It is also worth mentioning in this context that the medical centers participating had a wealth of experience regarding the clarification and treatment of bronchial tumors and that results in another medical context (non-university clinics, pulmonologists in private practices) are still missing. The NLST will publish further evaluations regarding the costs/benefits of low-dose spiral CT screening and the effect on participants quality of life. Other issues such as the effectiveness of prolonged CT screening programs will only be definitely answered after the publication of further controlled randomized trials in Europe and their evaluations in meta-analyses. The authors of the NLST come to the conclusion that, before the decision to initiate a low-dose spiral CT screening on a large scale, we must wait for the analyses of costs and benefits and the reduction in lung cancer-specific mortality compared with the side-effects of CT screening. They also note that the costs/benefits of low-dose CT screening must be seen in the context of other interventions, particularly smoking cessation. In the relevant editorial in the New England Journal of Medicine in the summer of 2011, H.C. Sox basically also supports the opinion that Policy makers should wait for cost-effectiveness analyses of the NLST data, further follow-up data to determine the amount of overdiagnosis in the NLST, and perhaps, identification of biologic markers of cancers that do not progress. He also notes: Systematic reviews that include other, smaller lung-cancer screening trials will provide an overview of the entire body of evidence. The results of the NLST have led to recommendations from organizations such as the National Comprehensive Cancer Network NCCN and the American Association for Thoracic Surgery. The NCCN guidelines on lung cancer prevention note that "The NCCN Lung Cancer Screening panel recommends spiral LDCT screening for select patients at high risk for lung cancer based on the NLST results, non-randomized studies, and observational data". Criteria for the inclusion of lung-cancer screening are described by the NCCN. In these guidelines, it is emphasized that smokers should always be encouraged to give up smoking. The American Association for Thoracic Surgery also published guidelines for CT lung cancer screening among people with high risks in 2012. 3. Lung cancer prevention among employees exposed to asbestos by means of CTscreening (CTTS) 3.1 Conclusions drawn from the NLST study for occupational health screening Until 2011, effective occupational health screening for employees with exposure to asbestos was only possible for the detection and monitoring of benign asbestos occupational diseases and their consequences; effective occupational healthcare for the reduction of mortality caused by mesothelioma, i.e. by particularly malignant tumors of the pleura and peritoneum, is still not possible today.

- 5 - Because of the NLST study, the risk of mortality for people with a significantly increased risk of lung cancer can be reduced with the use of low-dose spiral CT by being able to detect lung cancer at an earlier stage in which there are effective treatment options as well as the prospect of a complete cure. However, compared to a typical X-ray image, computer tomography involves a higher radiation dose. This exposure to radiation, which is higher than a conventional X-ray image, appears to be justified given the option of better and earlier identification of pathological findings. Due to the greater sensitivity of CT over conventional radiography, however, it is also possible to obtain findings that, while they are not morbid, nevertheless require clarification; these false-positive findings due to the further clarification are the most frequent to be expected especially during the earliest investigations. For lung cancer prevention among workers exposed to asbestos using CT screening (CTTS), it must be noted that the results of the NLST apply to high, relative risks for lung cancer (more than 30 pack-years nicotine consumption) and the age category of 55 to 75. Based on scientific evidence, a CTTS can thus be performed in line with the risk, which means that the tests are recommended to persons among whom similarly high risks such as the increased cancer risk in the NLST study can be assumed due to asbestos exposure and smoking. Here, the super-additive effect of smoking and asbestos must be taken into account. The results of the NLST study are based on three investigation cycles on an annual basis and a subsequent observation period of three and a half years. This does not permit any statement to be made on the value of further investigation cycles that go beyond the three years. The issue of CT screening over several years must therefore be reassessed at a later time based on further results of randomized controlled trials on a CT screening and the experience of lung cancer screening in Switzerland and abroad. The Helsinki criteria are the determining factors for the recognition of lung cancer after exposure to asbestos, (q.v. fact sheet issued by Suva s Department of Occupational Medicine Asbestos-related diseases ). Recognition of lung cancer after asbestos exposure as an occupational disease is not dependent on whether CT screening is recommended and implemented. When lung cancer is diagnosed in the context of CT screening, the causality is thus assessed as in other situations based on the Helsinki criteria, which means that not every lung cancer detected by CT screening can be recognized as an occupational disease. The question of using a low-dose spiral CT within the framework of the occupational health screening of employees exposed to asbestos has to take into consideration a context that is different from the question of whether a CT screening is to be offered to heavy smokers in the general population. Compared to the large group of heavy smokers in the general population, the group of employees relevantly exposed to asbestos is significantly smaller; for those with previous exposure to asbestos, stopping smoking is only a part of risk reduction. While the wait for the results of further controlled randomized trials and their meta-analyses for many years is an option for the question of the introduction of CT screening among smokers, in the case of asbestos-related malignant neoplasms, the peak of the number of patients affected by malignant neoplasms is expected between 2015 and 2020 - the effectiveness of CT screening is thus best in the years ahead. With regard to the question of the introduction of CT screening in the case of people exposed to asbestos, ethical issues or society's responsibility for the increased risk for malignant neoplasms should be included in the consideration. After all, employees exposed to asbestos not only continue to undergo radiological investigation for the

- 6 - early detection of lung cancer, but also with regard to the incidence of other benign and malignant illnesses. In this regard, we refer to the overview of the subsequent investigations of employees after exposure to asbestos by A. Massardier-Pilonchery and A. Bergeret and the work of T.Vierikko et al. 2010. 3.2 Lung cancer screening at Suva Through the medium of a personal letter, Suva recommends people aged between 55 and 75 to have a CT screening either as part of occupational healthcare or with asbestos-related occupational diseases if - as a result of exposure to asbestos alone or as a result of exposure to asbestos and smoking together - there is an increased risk of lung cancer that corresponds to smoking 30 pack-years, i.e. the inclusion criteria of the NLST. In the event of exposure to asbestos alone, i.e. among non-smokers, a CT screening is also recommended if lung cancer were recognized as an occupational disease, i.e. in the presence of the Helsinki criteria (see asbestos fact sheet). Due to the super-additive effect of asbestos exposure and smoking, a CT screening is also recommended if a higher lung cancer risk in the range of the NLST s risk is present without the Helsinki criteria being met. Within the framework of occupational healthcare, Suva informs employees and people with asbestos-related occupational diseases by newsletter on the offer of a CT screening. The examination with computer tomography recommended by Suva is voluntary for these people. Employees have an opportunity to discuss their situation with a pulmonologist in the department of occupational medicine. As part of occupational healthcare for employees, a CT scan is performed annually, analyzed by an X-ray specialist and, in the presence of findings requiring clarification, discussed with a lung specialist. The doctors responsible (GPs, occupational healthcare physicians and pulmonary specialists) are informed of the findings by the X-ray department. As before, the medical history is obtained, a clinical exam of the heart and lungs, and a lung function test are carried out every two years by the doctor for a medical prophylactic examination. In the case of people with asbestos-related occupational diseases, Suva usually demands to perform medical history taking, a clinical examination of the heart and lungs as well as lung function tests by the family doctor or a pulmonary specialist every year. In addition, a CT scan is performed each year. The procedure for information corresponds to the one for occupational health screening.

- 7 - Further reading Anonymous: Official statement of the Varese Conference on Prevention and Early Diagnosis of Lung Cancer. Lung Cancer Frontiers (1999); 5 (Newsletter) Ashraf H. et al.: Effect of CT screening on smoking habits at 1-year follow-up in the Danish Lung Cancer Screening Trial (DLCST). Thorax 2009; 64: 388-392 Bach P.B. et al.: Computed tomography screening and lung cancer outcomes. JAMA 2007; 297: 953-961 Black W.C., Baron J.A.: CT Screening for Lung Cancer: Spiraling Into Confusion? JAMA (2007): 297: 995-97 Clin B. et al.: Performance of chest radiograph and CT scan for lung cancer screening in asbestos-exposed workers. Occup Environ Med 2009: 66: 529-534 Das M. et al.: Asbestos Surveillance Program Aachen (ASPA): initial results from baseline screening for lung cancer in asbestosexposed high-risk individuals using low-dose multidetector-row CT. Eur Radiol 2007: 17: 1193-1199 Fasola G. et al.: Low-Dose Computed Tomography Screening for Lung Cancer and Pleural Mesothelioma in an Asbestos-Exposed Population: Baseline Results of a Prospective, Nonrandomized Feasibility Trial. The Oncologist (2007): 12: 1215-24 Gohagan J. et al.: Baseline findings of a randomized feasibility trial of lung cancer screening with spiral CT scan versus chest radiograph: the Lung Screening Study of the National Cancer Institute. Chest (2004); 126: 114-21 Guessous I., Cornuz J.,Paccaud F.,: Lung cancer screening: current situation and perspective. Swiss Medical Weekly (2007); 137: 304-311 Hagemeyer O. et al.: Krebsfrüherkennung verspricht bessere Heilungschancen. IPA-Journal 2012; 02: 12-16 Henschke C.I.: Early Lung Cancer Action Project. Cancer (2000); Supplement 89: 2474-82 Heyneman L.E. et al.: Stage distribution in patients with a small (< or = 3cm) primary nonsmall cell lung carcinoma. Implication for lung carcinoma screening. Cancer (2001); 92: 3051-55 Infante M. et al.: A Randomized Study of Lung Cancer Screening with Spiral Computed Tomography. Am J Respir Crit Care Med 2009; 180:445-453 Jaklitsch M.T. et al.: The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg 2012; 144: 33-38 Lopes Pegna A. et al.: Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. Lung Cancer 2009; 64: 34-40 Massardier-Pilonchery A., Bergeret A.: Suivi après exposition professionnelle à l'amiante: modalitiés et dispositifs étrangers. Revue des Maladies Respiratoires 2011; 28: 556-564

- 8 - Mastrangelo G. et al.: Feasibility of a screening programme for lung cancer in former asbestos workers. Occupational Medicine 2008: 58: 175-180 Mc Mahon P.M. et al.: Estimating long-term Effectiveness of Lung Cancer Screening in the Mayo CT Screening Study Radiology 2008;10:1148 ff National Comprehensive Cancer Network NCCN: Lung Cancer Screening. www.nccn.org Patz E.F. et al.: Correlation of tumor size and survival in patients with stage IA non-small cell lung cancer. Chest (2000); 117: 1568-71 Roberts H.C. et al.: Screening for Malignant Pleural Mesothelioma and Lung Cancer in Individuals with a History of Asbestos Exposure. J Thorac Oncol 2009; 4: 620-628 Sox H.C.: Better Evidence about Screening for Lung Cancer. N Engl J Med; 365:5, 455-457 Strauss G.M. et al.: Como International Conference Position Statement. Chest (2005); 127: 1146-51 The National Lung Screening Trial Research Team Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. N Engl J Med 2011; 365:395-409 Tiitola M. et al.: Computed tomography screening for lung cancer in asbestos-exposed workers. Lung Cancer (2002); 35: 17-22 The International Early Lung Cancer Action Programm Investigators: Survival of Patients with Stage I Lung Cancer Detected on CT Screening. N Engl J Med (2006): 35: 1763-71 Van den Bergh K.A.M. et al.: Long-term effects of lung cancer computed tomography screening on health related quality of life: the NELSON trial. Eur Respir J 2011; 38: 154-161 Van Iersel C.A. et al.: Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the Dutch-Belgian randomised lung cancer multi-slice CT screening trial (NELSON). Int J Cancer 2007; 120: 868-874 Vierikko T. et al.: Chest CT screening of asbestos-exposed workers: lung lesions and incidental findings. Eur Resp J 2007; 29: 78-84 Vierikko T. et al.: Psychological impact of computed tomography screening for lung cancer and occupational pulmonary disease among asbestos-exposed workers. European Journal of Cancer Prevention 2009; 18: 203-206 Vierikko T. et al.: Clinical and HRCT screening of heavily asbestos-exposed workers. Int Arch Occup Environ Health 2010; 83: 47-54