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Screening and early diagnosis in lung cancer Expert Rev. Anticancer Ther. 8(10), 1529–1531 (2008)
Pieter E Postmus, MD, PhD Department of Pulmonary Diseases, De Boelelaan 1117 4A50, 1081HV Amsterdam, The Netherlands Tel.: +31 204 444 782 Fax: +31 204 444 328
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“If the theory of a difference between the outcome of screen-detected tumors and clinically found tumors is correct, this may result in a negative outcome of the randomized screening studies.” Lung cancer was a rare disease at the beginning of the 20th century. Despite this, the rapid increase in tobacco use resulted in 100 million tobacco-related deaths in the 20th century, in large part owing to lung cancer. This dramatic spin-off of an apparently very dangerous addiction initiated effective antitobacco campaigns and antitobacco legislation in the so-called developed world. However, the reduction in this part of the world will be far less than the expected increase in smoking-related death in developing countries. Here, the epidemic spread of smoking-related disease started recently and already 1 billion deaths are expected in the 21st century, a third of which will be due to lung cancer. The direct gain of antismoking campaigns and legislation is a reduction of cardiovascular disease, whereas the increased risk of developing lung cancer persists for many years after stopping smoking [1] . Owing partly to this, lung cancer is and will be the world’s leading cause of cancer death [2] for a very long time; enhanced by the fact that it is usually diagnosed at a regionally advanced or metastatic stage, when incurable [3] . Furthermore, smoking is increasing among young people [4] and women in Western countries. Lung cancer can be broadly subdivided into two groups: small-cell and non-smallcell lung cancer. The latter is further subdivided based on histology in adenocarcinoma, large-cell cancer and squamous cell cancer. A different subdivision could be on the site of origin in the lung parenchyma or airways: central or peripheral. Lung cancer detected at a stage prior to spread to regional lymph nodes or distant sites has the best chance for cure if treated radically, most commonly by resection although stereotactic radiotherapy might
10.1586/14737140.8.10.1529
be a promising, and possibly as effective, approach [5] . The highest cure rates can be achieved in small tumors without lymphatic involvement: stage IA (T1N0M0). By definition, these are the lesions that are surrounded by air-containing tissue and beyond the proximal parts of the bronchial tree. Adenocarcinoma, and to some extent large-cell tumors, are found in this area. More central tumors have a higher stage and as such a poorer prognosis, these are especially small-cell lung cancer and squamous cell cancer. Improving outcome for the lung cancer patient should be an important part of the public health response to this tobaccorelated disease. As lower stages have a better prognosis, one may hope that earlier detection of lung cancers, especially in high-risk current or former heavy smokers, might be a way to detect lung cancer at a still curable stage. Screening might therefore be an effective way to improve the overall dismal outcome of lung cancer: a 5-year survival rate of less than 15%. The idea of screening for lung cancer goes back to the 1950s and the Philadelphia Pulmonary Neoplasm Research Project, which performed periodic fluoroscopic screening on more than 6000 male volunteers [6] . Although survival was slightly better in the screening-detected cancers than in the symptom-detected cancers, no difference was seen in the outcome [6] . In the 1970s and 1980s, several randomized controlled trials of chest radiography were performed with similar results. Despite finding more early-stage cancers in the screened group and performing more surgical procedures, there was no difference in lung cancer-specific mortality, leading to the conclusion that screening by chest x-ray was not helpful in reducing lung cancer mortality [7,8] .
© 2008 Expert Reviews Ltd
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Postmus
The reports of high rates of early-stage cancers found on computed tomography (CT) screening [9–13] renewed the interest in screening in the mid to late 1990s. CT is definitely a better technique for detecting early-stage lung cancer than chest x-ray. Current CT methods of screening, almost by definition and related to the technique, improves the detection of small tumors surrounded by air-containing tissue especially. Early-stage centrally located lung cancer may be found by CT but this needs a different CT approach and setting [14,15] .
“Despite finding more early-stage cancers in the screened group … there was no difference in lung cancer-specific mortality…” Ultimately, to show the effectiveness of screening, not only do more early-stage cancers need to be found in the screened group, but there must also be fewer late-stage cancers (i.e., a stage shift) [16] . Since these early trials did not contain a control group, they were also insufficient to determine whether CT screening could decrease the lung cancer mortality rate. These promising results led to the funding of the National Lung Screening Trial (NLST) by the National Cancer Institute in the USA [17] . The NLST is a randomized controlled trial comparing CT screening with chest radiography, with lung cancer mortality as the end point. More than 50,000 participants were enrolled across the USA. Screening ended in 2006 and subjects are currently in follow-up, with final results expected in approximately 2010. A second randomized trial of CT screening, the NELSON trial, has no screening as the comparison arm and has accrued 20,000 participants in The Netherlands, Belgium and Denmark [18] . Screening trials suffer from several biases
Lead-time bias results from the earlier detection of a disease, which leads to an earlier diagnosis and an apparent survival advantage but does not truly affect the date of death. In other words, survival increases without an effect on disease-specific mortality [16] . Length-time bias relates to the relative aggressiveness of tumors. In a screened group, more indolent tumors are more likely to be detected, whereas aggressive tumors are more likely to be detected by symptoms, an example of this is small-cell lung cancer. This disproportionally assigns more indolent disease to the intervention group and results in the appearance of a survival benefit. Overdiagnosis bias, the most extreme form of length-time bias occurs when the disease is detected and thought to be ‘cured’. However, if the disease had not been detected at all, it would never have caused symptoms. These tumors provide the illusion of a cure where none was needed. The extent to which overdiagnosis exists in any screening test can profoundly influence the apparent success of screening. Crossover bias: in each case, participants are followed up for a number of years after the intervention, with reduction in disease-specific mortality as the end point of the following period. Although randomization should lead to both arms of the trial containing similar populations, voluntary crossover of patients 1530
from the control arm to the intervention arm (e.g., in the NLST, a subject in the radiography arm undergoes CT outside the trial) can confound the results, potentially reducing the disease-specific mortality of the control arm. This may occur more easily in a situation where the population is more or less stimulated by advertisements to undergo screening by CT or MRI, and might even be enhanced by easy access to CT facilities open to the public. The feasibility trial for the NLST showed a 0.9% crossover rate after the prevalence screening and 1.3% after 1 year [19] . The NLST is empowered to account for contamination of the chest radio graphy (control) arm. In a healthcare system with more restrictions on these facilities crossover is potentially a lesser problem. This, together with a control arm without any active screening, makes the NELSON study a very promising approach. Two other biases are inherent in randomized controlled trials that may influence study outcome: ‘sticky diagnosis’ and ‘slippery linkage’ [20] . Sticky diagnosis refers to the increased likelihood of disease detection in the screened population. This means that the target disease has a higher likelihood of being listed as the cause of death even if it is not truly related. Thus, the apparent diseasespecific mortality of the screened disease will be increased artificially. Slippery linkage refers to the possibility that the downstream results of screening may lead to mortality without being attributed to the target disease itself. For example, a screeningdetected nodule undergoes wedge resection and ultimately proves to be benign. If the subject died from complications related to the procedure, the death would not be attributed to lung cancer although the screening process contributed directly to death. As death is not assigned to the target disease, the value of screening may be overestimated. For this reason, a corollary end point to disease-specific mortality is all-cause mortality [20] .
“The extent to which overdiagnosis exists in any screening test can profoundly influence the apparent success of screening.” Based on the currently available information, it is questionable whether screening will have a major impact on survival of lung cancer patients. Together with all potential biases of screening studies as discussed previously, the screening technique itself will only be able to find those early tumors that are within the ‘field of view’ that is screened. In other words, it is very unlikely that centrally located tumors, such as small-cell lung cancer and squamous cell cancer, will be found at an early stage comparable with the less than 1 cm peripheral adenocarcinomas. As squamous and small-cell cancer comprise more than 50% of all lung cancers, the benefit achieved by early detection needs to be very large to result in substantial improvement of long-term survival for the whole population. Whether screening studies will also result in the detection of tumors that are beyond surgery but still potentially curable by combined modality approaches (stage II and III) is a question that is not mentioned in the ongoing debate on screening. Publication of two major scientific papers that reached vastly different conclusions [21,22] resulted in a heated debate in the medical literature and two policy briefs taking a more philosophic Expert Rev. Anticancer Ther. 8(10), (2008)
Screening & early diagnosis in lung cancer
view of screening in the context of social responsibility [23,24] . Apparently the heated debate has not affected the general public and did not induce an extensive request for screening [25] . Recently, the natural history assumptions of the disease were questioned; it is not certain that lung cancer develops along the supposed pathways from small tumors to disseminated disease. This may imply that the screen-detected small tumors are not the early stages of – if left untreated – disseminated incurable tumors that are often found at the time of diagnosis in many lung cancer patients. If the theory of a difference between the outcome of screen-detected tumors and clinically found tumors is correct, References 1
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Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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this may result in a negative outcome of the randomized screening studies. [26] . At this stage it is too early to advise CT screening as routine, the outcomes of trials may give the answer [27,28] .
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van Iersel CA, de Koning HJ, Draisma G et al. Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the Dutch–Belgian randomized lung cancer multi-slice CT screening trial (NELSON). Int. J. Cancer 120, 868–874 (2007). Gohagan JK, Marcus PM, Fagerstrom RM, et al. Final results of the Lung Screening Study, a randomized feasibility study of
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