UICC World Cancer Congress 2006

CT screening for lung cancer has been performed since 1993 as a research project in the United States (1-3) and integrated into an ongoing screening program using chest radiography in Japan (4,5). Since then, it has spread throughout the world, both in a research and practice setting. Studies have consistently shown that CT is markedly superior to chest radiography in detecting small, early lung cancers (2-7) and it has long been established that resection of early small lung cancers markedly improves the cure rate over that of late stage lung cancer (8, 9).

The Early Lung Cancer Action Project (ELCAP) report on baseline CT screening for lung cancer (2) led to considerable public (10) and professional interest in the practice of CT-based screening for lung cancer. Suddenly, screening for lung cancer became a hot topic with researchers initiating projects to study it, the public demanding it, and medical institutions offering it. The nihilistic North American public policies on lung-cancer screening (11) were suddenly being reconsidered, the American Cancer Society updated its recommendations (12), eventually so did the United States Preventive Services Task Force (13) and others (14). In 2001, the National Cancer Institute organized two conferences to address further evaluation of CT screening for lung cancer (15, 16). In both conferences it was recognized that alternative approaches to randomized trials comparing screening with no screening are useful and should be supported. It had already been recognized that previous randomized studies of lung cancer screening were seriously flawed (17-20) and that such studies do not always provide the correct answer (21-23). In fact, the United States Preventive Services Task Force (13) did not rank any of the prior randomized trials for lung cancer screening as good. Recognition of these problems had led the ELCAP investigators to develop a different approach for their study, one that separates the evaluation of the diagnostic aspect of screening from that of the subsequent treatment (1). This distinction is important as information about the usefulness of the diagnostic process can only be obtained from those who undergo it (24, 25), never from those who do not receive it. Evaluation of early treatment of screen-diagnosed cases of lung cancer follows, and here, timely comparative information about treatment alternatives is needed and randomization is useful.

The demand for information on screening led us to hold the First International Conferences on Screening for Lung Cancer in 1999 to which all those already performing screening or wishing to start it were invited (26). These conferences were an outgrowth of the already extensive role of ELCAP in helping other investigator groups at the University of Muenster in Germany (27), Hadassah Medical Center in Israel (28), University of South Florida in the United States, the Mayo Clinic in the United States (29), the University of Navarra (30) in Spain and Hirslanden Lung Centre (31) in Switzerland to initiate their research projects patterned after the original ELCAP. By 2005, 12 such conferences have been held. Their broadest mission was collective pursuit of avant-garde understanding of the issues surrounding screening for lung cancer and updates of research on and practice of screening for lung cancer.

These conferences led to the formation of the International (I)-ELCAP consortium in 2000. The members have a shared set of principles, common protocol, and centralized management system which allows for pooling of the data from participating institutions. I-ELCAP's goal is to assess the effectiveness of CT screening in preventing deaths from lung cancer. It asserts that to determine the effectiveness of screening, the particular regimen of screening as to how early diagnosis of lung cancer is to be pursued must be specified. The first task of I-ELCAP, thus, was to define a potentially optimal regimen and it was unanimously adopted in 2001 (32). A particularly notable feature of the regimen is the difference between the baseline and repeat screenings in the definition of a positive result and the algorithm for further work-up. In the repeat screenings, the focus is on new nodules, thus growing by definition, as the prior screen is available for comparison. At baseline, by contrast, such prior information is not available. Although the fundamental nature of the regimen of screening has remained stable, it is continually updated based on emerging information (33-35).

The I-ELCAP regimen starts with the initial low-dose CT, and if the result is positive, other testing follows along a well-thought out algorithm which eventually leads to a (rule-in) diagnosis of lung cancer (33). Assessment of growth has remained a critical part of the regimen (36-39). Ultimately, the diagnosis of lung cancer derives from a biopsy of the suspicious nodule, ideally by fine-needle aspiration, followed by the specimen's cytologic reading and interpretation. Growth and biopsy are important components of the regimen as they serve to limit unnecessary biopsy and surgery and also serve to limit the number of potentially ‘overdiagnosis' cases of lung cancer, defined as slow-growing cancers which to not lead to death if not treated. Given the critical role of pathology, a separate pathology protocol was developed (40, 41). Following this protocol, all submitted slides were examined by a 5-member panel of pulmonary experts to determine their consensus diagnosis according to the latest World Health Organization criteria (42).

As of December 2005, more than 32,000 people have had baseline screenings and they have had more than 23,000 repeat screenings at 38 institutions participating in I-ELCAP throughout the world, including the original ELCAP and its continued screenings and its extension throughout New York State (NY-ELCAP).

Diagnostic performance The I-ELCAP regimen starts with the initial low-dose CT, and if the result is positive, other testing follows along a well-thought out algorithm which eventually leads to a (rule-in) diagnosis of lung cancer. Assessment of growth has remained a critical part of the regimen (36-39). Ultimately, the diagnosis of lung cancer derives from a biopsy of the suspicious nodule followed by the specimen's reading and interpretation. Growth and minimally-invasive (i.e., percutaneous fine-needle aspiration) biopsy are important components of the regimen as they serve to limit unnecessary open surgical biopsy and also serve to limit resction of slow-growing cancers which would not lead to death if left untreated. Given the critical (and ultimate) role of pathology in making the diagnosis, a separate pathology protocol was developed (40, 41). Following this protocol, all submitted slides were examined by a 5-member panel of pulmonary experts to determine their consensus diagnosis according to the latest World Health Organization criteria (42).

The regimen provides recommendations for the work-up, but the actual decision is left to each screenee and his/her referring physician. In the I-ELCAP approach, this does not compromise the validity of the study as long as actions, results of the tests, and interventions are documented for each screenee. Adherence to the regimen, however, does affect the performance of the regimen as it determines the frequency of unnecessary biopsy or surgery and the timeliness of the diagnosis which ultimately determines how early (e.g., resectability, stage) the cancer is diagnosed. Thus, for adequate performance of any screening regimen, adherence to it by the screenees and their referring physicians is important and should be stressed in physician and lay-community education.

Comparison of two regimens is provided by comparing the respective diagnostic distributions by stage and size. Two different initial diagnostic tests (e.g., CT and chest radiography) can be compared by giving both tests to all participants as illustrated by the original ELCAP of 1,000 screenees (2). The ELCAP study (2) as well as the Japanese study (6) clearly demonstrated the marked superiority of CT (computed tomography) imaging over chest radiography in identifying early lung cancer as 85% of the earliest-stage cancers were missed on the chest radiography. Based on this, chest radiography was no longer performed in the subsequent non-randomized studies.

Performance measures are useful when comparing different regimens of screening. Such measures should not depend on the risk indicators of the participants (e.g., age, smoking history) but on the regimen itself and we provide several such measures below and have illustrated them in greater detail in a previous publication (43).

1. Proportion having a positive result of the initial CT test Using the updated definition of a positive result (33), it occurred in less than 15% of screenees on baseline and less than 6% on annual repeat screening.

2. Proportion of screen-diagnosed cases Screen-diagnosed cases are classified as baseline or annual repeat cancers according to the screening cycle in which the nodule is first identified, regardless of when the diagnosis is actually made. A screening cycle starts with the performance of the initial test including any diagnostic work-up and ends before the next routinely scheduled rescreening. Any case of cancer diagnosed outside the regimen is called an interim-diagnosed cancer and is attributed to the cycle of screening during which it is diagnosed. The proportion of screen-diagnosed cases was more than 95% in the baseline cycle and 98% in repeat cycles of screening.

3. Proportion of cases by relevant prognostic indicators

The frequency distribution of the cases by relevant prognostic factors (e.g., stage, size, histology) are important performance measures. In terms of stage, the critical determination as to treatment depends on the pre-surgical stage, typically based on CT and PET results, so it is the proportion of pre-surgical Stage I diagnoses that is of particular interest. We found that more than 80% of all lung-cancer diagnoses, interim cases included, were of pre-surgical Stage I on baseline and annual repeat screening. Also, as expected, the median tumor size was larger at baseline than on annual repeat.

4. Proportion of cases resulting in a diagnosis of malignancy after biopsy Among the recommended biopsies according to the regimen of screening in the ELCAP (43) and NY-ELCAP studies, over 90% resulted in a diagnosis of malignancy. No lobectomies were performed for benign disease. Thus the screening regimen turned out to be quite successful as to avoidance of undue invasive procedures, complications, and cost. On the other hand, none of the biopsies performed outside of the regimen's recommendation resulted in diagnosis of lung cancer.

5. Summary of diagnostic performance The diagnostic performance of the I-ELCAP regimen of screening demonstrated that further work-up can be limited to a reasonable percentage of the cases and result in 80% or more being of pre-surgical Stage I. By following the regimen of screening, 94% of the recommended biopsies resulted in a malignant diagnosis. A key performance parameter of the screening regimen is the proportion of Stage I diagnoses, and this proportion may be as high as 90% depending on the adherence to the regimen of screening.

We also demonstrated that among cases of lung cancer diagnosed in asymptomatic persons by CT screening, there is a strong relationship between tumor size and lymph-node status (44).

Genuineness of diagnoses When a person with a screen-diagnosed case of lung cancer dies of some other cause before having clinical manifestations of lung cancer, the case is said to be an ‘overdiagnosed' case of lung cancer; and so is a screen-diagnosed case that actually is so slow-growing that it, even if left untreated, would not pose a risk for survival. While both are important topics to be addressed in the context of screening, only the latter represents overdiagnosis for us, the former being an issue of competing causes of death. We address both topics, first the proportion of screen-diagnosed cancers that are genuine, that is, leading to death if not treated, and secondly the issue of competing causes of death.

Potentially detracting from the apparent benefit of CT screening is the possibility that a proportion of the screen-diagnosed cases of lung cancer are free of manifest metastases because they are growing so slowly as to not lead to death if not resected. Protection against this was built into the regimen by requiring assessment of growth prior to biopsy of nodules less than 15 mm in diameter and by pathologic review by a panel of expert pulmonary pathologists. To supplement this, we also determined the proportion of genuine pre-surgical Stage I cases diagnosed as a result of baseline screening as these are the most suspect for being slow-growing. Among the cases presenting as solid nodules, all had doubling times of less than 400 days, except for a carcinoid tumor. For the cases presenting as part-solid nodules and nonsolid nodules, the percentage of those with doubling times of less than 400 days was 90% and 67%, respectively (45). It should be noted, however, that a cancer of 10 mm with a doubling time of 400 days would lead to death from it in approximately 10 years, so even such a cancer should not be ignored. In the repeat cycles, the cancers are typically aggressive ones as growth since the previous screen is integral in the concept of positive result. For example, a newly-seen nodule of 3 mm means that it has grown since the prior screen when it was not visible. Assuming it had a diameter just under the visibility threshold of 2 mm on the prior screen, its slowest doubling time would be 200 days. As newly seen nodules on repeat screening are typically 3 mm or larger in diameter when first identified, this means that these cancers are rapidly growing, aggressive, genuine cancers.

Further evidence was provided by the Pathology Review Panel who reviewed the pathologic specimens and confirmed that all diagnoses were genuine lung cancers. Ultimately, evidence against overdiagnosis is provided by the untreated cases of lung cancer (46-48) or those in whom the recommended biopsy and/or treatment was delayed. To date, all those cases for which treatment was delayed, progressed and those which were not treated, all died.

Any decision about screening for a cancer needs to consider the person's risk of dying from causes other than lung cancer. This is particularly relevant for lung-cancer screening as smokers and former smokers are also at higher risk of death from other, competing causes, cardiovascular diseases in particular. To shed some light on the frequency of death from a ‘competing' cause among persons who enter into CT screening for lung cancer, we determined the 5- and 10-year rates of death from causes other than lung cancer in a high-risk older cohort of 2,141 smokers and former smokers who had enrolled for CT screening for lung cancer in 1993-2004 (49); they were aged 60-75 years and had a history of 30-100 pack-years of cigarette smoking. Using Kaplan-Meier analysis, we found that the 5- and 10-year survival rates conditional on not dying from lung cancer were 96% (95% CI: 95-97%) and 91% (95% CI: 88-93%), respectively. Based on this analysis, older, high-risk smokers and former smokers seeking and receiving CT screening for lung cancer have quite a low 10-year risk of dying from causes other than lung cancer, and early treatment of screen-diagnosed cancer thus has a good opportunity to be life-saving.

Prognostic performance The proportion of deaths that can be prevented by CT screening can be estimated by the (proportion of pre-surgical Stage I cases) x (cure rate of genuine Stage I cases). This is a conservative estimate as it assumes that all screen-diagnosed cases of higher stage die. The estimated cure rate of genuine Stage I cases of lung cancer is 95% and 96%, respectively for baseline and repeat screening. Thus, the estimated deaths that can be prevented are 87% x 95% = 83% and 85% x 96% = 82%, respectively for baseline and annual repeat screening (50). Using, very conservatively, the lower 95% confidence limits for both of these two proportions, the corresponding estimates for the probability of preventing an otherwise fatal outcome of cancer for baseline and annual repeat cycles are 76% and 68%, respectively – still high when contrasted with the 5% (1-163,510/172,570) or so (51) in the absence of screening.

Indication for screening We performed a traditional cost-effectiveness analysis using the actual hospital costs of the original ELCAP baseline screening and subsequent work-up, it was found that CT screening is highly cost-effective, around $2,500 per life-year saved, for smokers and former smokers 60 years and older with a history of at least 10 pack-years of smoking (52). Others using actual data have found similar results (53-55), except for one model-based analysis (56) using unrealistic assumptions (e.g., a very high rate of overdiagnosis).

The decision about screening is really an individual decision and thus should be based on the benefit and risks to a specific person for a particular round of screening. Once this benefit and risks is known, the individual then has to weigh the cost of the screening (typically $300) with its benefit in potentially not dying of lung cancer.

The survival benefit of any contemplated round of screening is determined by the product of the following four probabilities: the probability P1 that the round of screening will result in the diagnosis of lung cancer, the probability P2 that of not dying from some other cause in a sufficiently long period of time, the probability P3 that the diagnosed case, should there be one, would be genuine and of Stage I at the time of diagnosis and, finally, the probability P4 that such a genuine case of lung cancer would be curable by early treatment. The first of these probabilities are specific to the individual at the time while the last two depend on the regimen of screening, rather than the individual's characteristics. Using the I-ELCAP database, we are estimating these probabilities (50).

Staging issues Staging is problematic when no lymph node metastases are detected but more than one cancer was diagnosed, either in the same lobe or in different lobes. Typically in the screening context, the additional malignancies are tiny and not visible on CT prior to surgery. Current staging criteria require that when the cell-types of cancers are the same, the classification is supposed not to be T1-2N0M0 but T4N0M0 or T1-2N0M1, respectively, depending whether the lesions are in the same or in different lobes; and only if the cell-types are different are the lesions supposed to be classified as separate primary cancers. However, adenocarcinoma is a very frequent type of lung cancer so the likelihood of finding the same cell-type is high even with separate primaries. For this reason, cases of multiple adenocarcinoma without lymph node metastases are classified as T and M status indeterminate and it was recommended that in the context of screening these be treated as Stage I cases until long-term follow-up is available.

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