Lung cancer screening: panacea or pipe dream?

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1 Annals of Oncology 16 (Supplement 2): ii215 ii219, 2005 doi: /annonc/mdi723 Lung cancer screening: panacea or pipe dream? A. K. Ganti 1 & J. L. Mulshine 2 1 Division of Hematology-Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE; 2 Intervention Section, Aerodigestive Chemoprevention Faculty, Center for Cancer Research, NIH Clinical Center, National Cancer Institute, National Institutes for Health, Department of Health and Human Services, Bethesda, MD, USA The problem Lung cancer is currently the most common malignancy and also the leading cause of mortality related to cancer in the world. In 1999, worldwide, there were 1.04 million (12.8%) new cases and deaths (17.8%) due to lung cancer [1]. Given the current patterns of smoking, it is projected that this number will continue to rise through the beginning of the 21st century [2]. In the USA alone, the American Cancer Society estimates that there will be new cases of lung cancer and deaths will occur from lung cancer during 2004 [3]. Approximately 87% of cases of lung cancer, including 90% of cases in males and 79% of cases in females, are thought to be attributable to cigarette smoking [4, 5]. In a British study of 3070 lung cancer patients, the authors found that only 2% of patients were life-long non-smokers [6]. Given this indisputable link between cigarette smoking and risk of lung cancer, carcinoma of the lung should be the most preventable of the common forms of cancer. Unfortunately, however, despite advances in tobacco cessation awareness and better techniques to help current smokers quit smoking, 25% of Americans ( 47 million people), continue to smoke [7]. Although the percentage of adult smokers decreased from 50.2% in 1965 to 25% in 1990 [5], there has been no further change since then [8]. Also, in the USA, one in four adults is a former smoker and thus has a persistently elevated risk of lung cancer [9, 10]. Nearly lung cancer deaths occur annually in people who cannot benefit from tobacco cessation [11, 12]. Thus, clearly, measures beyond smoking cessation awareness are required to decrease the mortality from lung cancer at the present time. The 5-year survival of all patients with lung cancer is only 14% [1]. The major reason for these dismal statistics is that the diagnosis of lung cancer is typically at an advanced stage and is hence is unresectable for cure. In contrast, the 5-year survival of stage I lung cancer reaches 70% [13 19], thereby suggesting that if the diagnosis were to be made at an earlier stage, the outcome in these patients could be vastly improved. Rationale for screening for lung cancer Deciding whether a particular disease is suitable for screening requires the consideration of a number of factors. A major q 2005 European Society for Medical Oncology factor is whether the disease is curable at the stage that is likely to be found with screening. Cancer screening can afford both benefits and disadvantages; therefore, evaluation of the effectiveness of screening programs by specifying criteria to meet the program s objectives is important. Finally, the economic costs associated with cancer screening should be evaluated before a cancer screening test is recommended to the public. The estimation of a cost benefit ratio in cancer screening is complicated by the fact that the benefits of the investment occur over many years [20]. An ideal screening tool should satisfy the following conditions [21]. (i) The disease in question should be a major public health problem with a clear understanding of the natural history and an obvious latent phase. (ii) There should be a suitable, safe, sensitive, acceptable, cost-effective method to detect latent disease. (iii) There should be effective treatment available for the early disease so detected. The enormity of the public health problem that is posed by lung cancer is not in question. In addition, it has substantial morbidity and mortality, and effective treatment is possible with early, localized cancer. For long the major issue with lung cancer screening has been the availability of a diagnostic technique that enables us to detect the disease at a time when therapy improves cancer-related mortality. Randomized clinical trials for the screening for lung cancer Chest radiography alone The first study was conducted in the UK in the 1960s, in which over males were randomized to chest X-ray every 6 months for 3 years or to chest X-rays at the beginning of the study and at the completion of the 3-year period. One hundred and thirty-two cancers were detected in the screened group, of which 44% were resected, while 96 cases were detected in the control group, of which only 29% were resected. However, the lung cancer-related mortality was the same in both the groups [22, 23]. The Mayo Clinic initiated the Mayo Lung Project screening trial in They randomized 4618 participants to receive chest X-ray and sputum cytology every 4 months, and 4593 to a control group in which no specific screening was conducted after a baseline chest X-ray and sputum cytology at entry into

2 ii216 the study. The latter group of patients were however, advised to obtain annual chest radiographs and sputum cytology for screening. After 6 years, 206 cases (4.5%) of lung cancer were detected in the screened group and 160 (3.5%) in the control group. The proportion of early stage cancers and resectable lesions was higher in the screened group. The actuarial 5-year survival among those found to have lung cancer was 33% in the study group as compared with 15% in the control group [24, 25]. There was a statistically significant improvement in the lung cancer fatality rate (the percentage of patients with lung cancer who died from the cancer) among those randomized to screening (59% versus 72%; P = 0.016) [26]. Despite advantages in stage distribution, resectability and survival, there were 122 lung cancer deaths in the screened group and 115 among the controls. The final result of the study was that there was no statistically significant mortality advantage favoring the control group. However, there were serious methodological flaws in the study design that could affect the validity of these results. The initial prevalence screen done for both arms found 91 cancers. These patients were followed separately and were excluded from the analysis and the impact of these cases on the overall mortality data could not be determined. Another factor confounding the results of this study was the fact that 50% of the controls received annual chest X-rays and 33% of cancers in this group were found on screening chest X-rays. Also, contamination of the study was unexpectedly high, as 73% of the controls obtained a chest X-ray during the last 2 years of the trial. This potentially undermined the power of the study in evaluating the screening benefit of chest radiography. More recent analyses of this experience have concluded that because of the serious methodological problems, the negative conclusions obtained in this trial should not constitute a basis for current health-care policy. A randomized prospective study conducted in Czechoslovakia randomized 6364 high-risk men to screening with chest X-ray and sputum cytology either every 6 months or 3 years, or to no screening. After 3 years all the subjects were entered into a follow-up phase where they received chest X-rays annually. In this study, 84 cases of lung cancer were identified, of which 31% were stage I and 17% were stage II. Complete resections were possible in 27% of cases, and 5-year survival of these patients was 23% [27]. Cases detected by screening were identified at an earlier stage, were more often resectable, and had a significantly better survival than cases diagnosed mainly because of symptoms. A comparison of the groups, however, showed a higher incidence of lung cancer in the intervention group, despite the follow-up period when both groups received annual examinations, thereby suggesting the possibility of overdiagnosis. In addition, they did not find any significant difference in mortality between the groups. They found no impact on the frequency of screening on the overall survival from lung cancer [28]. Chest radiography and sputum cytology In 1974, the Memorial Sloan-Kettering Cancer Center initiated a study to evaluate the utility of sputum cytology as a supplement to annual chest radiography for early detection and diagnosis of lung cancer. Over adult, male cigarette smokers were randomly assigned to receive an annual chest X-ray examination only or an annual chest X-ray combined with evaluation of sputum cytology every 4 months. There were 288 lung cancers detected in this study, of which, over 40% were in stage I. The 5-year survival in these patients was 76%, compared with an overall 5-year survival for all cases of 35%. Although individuals who received dual screening had early cancer detection, there was no difference in the number of malignancies eventually detected, survival and mortality among the two groups [29], suggesting no benefit to screening sputum cytology. Similarly, the Johns Hopkins Lung Project randomized men to the dual screening or annual chest X-rays alone. This study also found no differences in outcome among the two groups [30]. Patients who were diagnosed with lung cancer had a 8-year survival of only 20%, irrespective of the group to which they were assigned. These two screening trials were primarily designed to assess the benefit of sputum cytology rather than chest X-rays. The 5-year survival rate in the screened groups was 35% as compared with 15% in the control groups. Despite this, equal numbers of patients in both groups eventually died from their disease. However, selection and other screening biases (e.g. lead-time bias and overdiagnosis bias) may confound the validity of these comparisons involving different populations of patients. Also, in the Johns Hopkins study, almost 50% of patients who developed lung cancer had negative findings on the screening studies and became symptomatic before the next follow-up study, suggesting the limitations of chest X-ray as a tool to find early lung cancer. Low-dose spiral computed tomography One of the major drawbacks of these older studies was the relative insensitivity of the chest radiograph in detecting early lung cancer. In the above studies, despite annual or more frequent chest X-rays, less than half of the screened diagnosed cancers were stage I (Table 1). With the development of the computed tomography (CT) scan and the improvement in the quality of the images, the focus has since shifted to using lowdose CT scan to screen for early lung cancer. Low-dose CT scanning allows a low resolution image of the entire thorax to be obtained with a low radiation exposure and within a single breath hold. Kaneko et al. [31] compared the efficacy of low-dose spiral CT with radiography of the chest for the screening and detection of small peripheral lung cancers in a high-risk population. They obtained chest X-rays and low-dose CT scans in 1369 individuals every 6 months for 3 years. Peripheral lung cancer was detected in 15 individuals. Among the 15 cases, the results of chest radiography were abnormal only in four subjects (27%), and the tumors were detected only at low-dose

3 ii217 Table 1. Characteristics of lung cancer detected by screening with chest X-rays Study Intervention Early stage [n (%)] Late stage [n (%)] London CXR every 6 months 44 (43) 57 (57) Mayo Clinic CXR and sputum cytology every 4 months 99 (48) 107 (52) Czechoslovakia CXR and sputum cytology every 6 months 20 (51) 19 (49) MSKCC CXR annually ± sputum cytology every 4 months 108 (46) 127 (54) Johns Hopkins CXR annually ± sputum cytology every 4 months 139 (37) 240 (63) CXR, chest X-ray; MSKCC, Memorial Sloan-Kettering Cancer Center. spiral CT in 11 instances (73%). Fourteen (93%) of the 15 tumors were stage I. In another study of low-dose CT scan in lung cancer screening, Sone et al. [32, 33] screened 5483 individuals, who had undergone annual chest radiography and cytological assessment of sputum, with a low-dose spiral CT scan of the thorax. At the end of 3 years they had performed CT scans and diagnosed 60 cases of lung cancer, of which 55 (88%) were stage I. The tumor size was <_ 10 mm in 21 cases, mm in 23 cases, mm in 13 cases and >20 mm in three cases. The Early Lung Cancer Action Project (ELCAP) was initiated in 1993 and has screened more than 1000 asymptomatic, high-risk men and women with baseline and annual helical CT scans and chest X-rays [34]. This study addressed the frequency with which malignancy is found in screendetected nodules and the frequency with which malignant nodules are curable, as well as the dependence of the curability rates on the size of the resected malignant nodules. In their initial report, non-calcified nodules were detected three times as often (23% versus 7%), malignancies four times as often (2.7% versus 0.7%) and stage I malignancies six times as often as no screening based on historical controls (2.3% versus 0.4%). Of the 27 CT-detected cancers, 96% (26/27) were resectable, 85% (23/27) were stage I and 83% (19 of the 23) of the stage I tumors were not seen on chest radiography [35]. Thus, screening by low-dose CT scans in this study led to detection of lung cancer more often and at an earlier, presumably more resectable, stage. In a recent update of the International Early Lung Cancer Action Project presented in November 2004, baseline screening had been performed on men and women and subsequent annual screenings had been performed. Of the 376 (313+63) screen-diagnosed lung cancers, 82% were stage I. Of these, 303 had been resected, and the 8-year lung cancer case-fatality rate in this group of screened subjects was 4% [36]. A Mayo Clinic study [37] of 1520 men and women smokers who had a baseline spiral CT scan and sputum cytology found 25 cases of lung cancer, of which 22 underwent curative resection. Twelve (57%) of the 21 non-small-cell cancers detected by CT scan were stage IA at diagnosis. Another Japanese study screened 1611 individuals with a low-dose CT scan, chest X-ray and 3-day pooled sputum cytology every 6 months [38]. At initial screening, 14 (0.87%) cases of lung cancer were detected, with 71% being stage IA disease and a mean tumor diameter of 19.8 mm. At repeated screening, after 7981 examinations, a total of 22 (0.28%) cases of lung cancer were detected, with 82% being stage IA disease and a mean tumor diameter of 14.6 mm. The 5-year survival rate for screen-detected lung cancer was 76.2% and 64.9% for initial and repeated screening, respectively. In an Italian study, Pastorino et al. [39] enrolled 1035 individuals aged 50 years or older who had smoked for 20 packyears or more. All subjects underwent annual low-dose CT scan, with or without positron emission tomography (PET), for 5 years. At the end of 2 years they identified 22 cancers, with a mean tumor size of 18 mm. Of these 22 cases, 21 (95%) were resected completely, and 17 (77%) were stage I, pathologically. In order to evaluate the cost-effectiveness of a single baseline low-dose CT scan for lung cancer screening in high-risk individuals, Wisnivesky et al. [40] incorporated data from ELCAP into a decision analysis model comparing low-dose CT scan screening of high-risk individuals (i.e. those >60 years with at least 10 pack-years of cigarette smoking and no other malignancies) with observation without screening. They found that the incremental cost-effectiveness ratio of a single baseline low-dose CT scan was $2500/year of life saved. This cost-effectiveness ratio was relatively insensitive to estimates of the potential lead-time bias. The role of low-dose CT scan in the screening of lung cancer is a subject of intense debate. Some argue that the data from these studies are so impressive that we can conclude that screening for lung cancer with low-dose CT scans will lead to an improvement in lung cancer-related mortality. However, a drawback of all these studies is that they have been observational studies of volunteer cohorts and the findings may represent the impact of bias rather than a true effect. Critics of this approach also argue about the possibility of overdiagnosis of lung cancer, as although up to 85% of tumors detected by CT were stage I disease (Table 2), there was in fact no stage shift. Given the rapid emergence of this technology, it is still too early to expect to see mature mortality data using lowdose CT scans for lung cancer screening [41 43]. To address the debate about the efficacy of screening with low-dose CT scans in decreasing lung cancer-related mortality, the National Cancer Institute has sponsored a large randomized controlled trial involving individuals.

4 ii218 Table 2. Characteristics of lung cancer detected by screening with lowdose CT scans Institution % cancer Mean/median % stage I size (mm) Matsumoto Research Center, Japan Prevalence / Incidence /<11 86 Cornell University Prevalence 2.7 <14/<_ Incidence /8 71 Mayo Clinic Prevalence /14 67 Incidence /8 60 National Cancer Prevalence /20 79 Center, Japan Incidence /20 82 Milan Prevalence /NA 55 Incidence /NA 100 NA, not available. The individuals were randomized to either an annual low-dose CT scan or a chest X-ray. The study was closed to accrual in February 2004 and the subjects will be followed until In a pilot trial designed to address the feasibility of this study, 1660 subjects were randomized to the low-dose CT arm and 1658 to the chest X-ray arm [44]. Forty lung cancers were diagnosed in the low-dose CT arm and 20 in the chest X-ray arm. Forty-eight per cent of cancers diagnosed in the low-dose CT arm were stage I compared with 40% in the chest X-ray arm. Clearly, the rapid evolution of CT technology and image processing tools is challenging the nature of our clinical trial process. In the time from the implementation of the National Lung Screening Trial to now, spiral CT had moved through three to four distinct generations of capability [45]. An oftenstated concern is that by the time the final results of this trial are available, the technology for obtaining low-dose CT scan images as we know it today may no longer be in use. With this rapid progress in technology, by the time the trial is completed in 5 years, the CT scanners available will be more accurate in determining which lesion detected on the scan represents a potential cancer than they are today. Also, the role of PET in lung screening is currently unclear, and will be the focus of intense research in the next few years. The opportunity to devise a process to embrace these rapid refinements in imaging capability is a major challenge, but clearly holds the potential to achieve improved outcomes in this most lethal cancer. From that perspective, this area merits urgent consideration. Summary The role of screening in lung cancer is as controversial today as it was in the 1980s. Large randomized controlled trials have conclusively demonstrated that chest X-rays and sputum cytology are too insensitive to make any impact on lung cancer-related mortality. Despite the impressive results of the studies using low-dose CT scan to screen for early lung cancer, there is no consensus regarding its application to the general population. The role of newer modalities like PET is yet to be elucidated. Further research to realize the potential of these powerful imaging modalities in routine public health application is necessary to efficiently, safely and reliably identify and manage early lung cancer. References 1. 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