Clinical Cancer Research Vol. 11, 4988s-4992s, July 1, 2005
© 2005 American Association for Cancer Research
Early Stage Lung Cancer: New Approaches to Evaluation and Treatment |
Limitations of Screening for Lung Cancer with Low-Dose Spiral Computed Tomography
James R. Jett
Authors' Affiliation: Mayo Clinic, Rochester, Minnesota
Requests for reprints: James R. Jett, Thoracic Diseases and Medical Oncology, Mayo Clinic Rochester, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-3764; Fax: 507-266-4372; E-mail: jett.james{at}mayo.edu.
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Abstract
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Past lung cancer screening trials in the United States with chest X-ray and sputum cytology were not able to show any decrease in lung cancer mortality; however, these trials are over 20 years old. Recent follow-up of the Mayo Lung Project showed a better survival from lung cancer in the screened arm, but no difference in overall mortality, suggesting an overdiagnosis of nonfatal cancers. Recent reports of low radiation dose spiral computed tomography (CT) chest screening for lung cancer have shown that CT screening detects cancers at a smaller size than chest X-rays. To date, there have been no randomized trials of CT versus observation or chest radiographs for screening purposes. All data available thus far on CT screening are from phase II proof-of-principle trials. The major limitations of CT screening, discussed here, include (a) a high rate of nodule detection: over 50% of participants will have at least one noncalcified nodule; (b) resulting follow-up CT scans, associated with increased costs; (c) cost and morbidity of biopsy or resection of benign noncalcified nodule (20-25% of such procedures in several trials); and (d) a small, but difficult to quantify, risk of cancer associated with multiple follow-up CT scans.
Lung cancer is the number one cancer killer in North America and in much of the Western world. In 2004, there will be 
174,000 new cases of lung cancer in the United States. The overall 5-year survival for these newly diagnosed patients is 15% (1). Lung cancer alone accounts for more cancer deaths than the next four most commonly fatal cancers combined. The message of the American Cancer Society to the general public is that early detection of cancer is good and desirable, at least for the cancers for which they recommend screening. However, American Cancer Society does not currently recommend routine screening for lung cancer even in high-risk individuals (2). Past screening trials in the United States and elsewhere utilizing chest X-ray and sputum cytology were not able to show any decrease in lung cancer mortality (3, 4). More recently, there have been encouraging preliminary reports of screening for lung cancer with low-dose spiral computed tomography (CT) chest scans (5–10). The purpose of this article is to review the potential limitations of screening for lung cancer with low radiation dose spiral CT.
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High Rate of Noncalcified Nodules
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In 1999, Mayo Clinic investigations initiated a trial of low-dose spiral CT screening for lung cancer. High-risk individuals of 50 years of age or more and 20 pack-years of smoking or more were enrolled in the trial. Low-dose spiral CT scanning was done with a multidetector scanner (four detectors) using 5 mm collimation (thickness of CT slice) with 3.75 mm reconstruction. Low-dose radiation in our trial was approximately one-ninth the dose of radiation with a normal CT chest (0.6 versus 5.8 mSv). On the baseline CT scan, 780 of 1,520 (51%) participants had at least one noncalcified nodule detected (10). A total of more than 1,600 noncalcified nodules were detected in 780 participants. The rate of new nodule detection on the annual screening CT scan from 2000 through 2003 ranged from 9.3% to 13.5% of participants. After five annual CT scans, 73.5% of participants had at least one noncalcified nodule. A total of 3,356 noncalcified nodules were detected in these 1,118 individuals. Table 1 shows the distribution by size of all of these nodules; 61% of the nodules were less than 4 mm in size, and only 6% of all nodules were 8 mm or larger in size.
Table 2 summarizes seven studies published in peer-reviewed journals in which the rate of noncalcified nodule detection varied from 17% to 51%. The four studies using 10 mm collimations on the screening CT scan reported the lowest number of noncalcified nodule, ranging from 17% to 27% (5, 6, 11, 12). The three studies that used a smaller collimation of 5 mm or less, including the Mayo study by Swensen et al. (10), a study from Germany (9), and one from Vancouver, Canada (13), reported the highest rate of noncalcified nodule, between 43% and 51%. Based on these data and other reports in the literature, it is clear that the number of noncalcified nodules depends on the thickness of the collimation of the CT chest scan used in the screening trial. Studies with thinner sections will detect higher numbers of noncalcified nodule, although the majority of these will be small micronodules of <3 to 4 mm in size. The number of nodules detected is not a reflection of the geographic location where the study was done because a high rate of nodules was seen in three studies from the United States, Canada, and Germany (9, 10, 13).
Midthun et al. (14) did a 3-year follow-up evaluation of all of the noncalcified nodules detected at baseline in the Mayo Clinic spiral CT study. After 3 years of follow-up, a total of 26 prevalence (baseline) non–small-cell lung cancers had been detected by the CT. Thus, 26 of 1,600 noncalcified nodules were proven with follow-up to be lung cancer, with a malignancy rate of <2% for all noncalcified nodules. When the rate of malignancy was evaluated based on nodule size, <1% of the noncalcified nodule 
7 mm subsequently proved to be malignant. The frequency of malignancy in nodules 8 to 20 mm in size was 21%. There were only eight nodules larger than 20 mm, and four of them were malignant.
We concluded that the vast majority of noncalcified nodules detected on screening CT scans are benign; however, due to the uncertainty as to which ones are malignant when first detected, all of them require periodic follow-up scans to watch for evidence of growth.
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Thoracic Surgery and/or Biopsies for Benign Disease
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Crestanello et al. (15) reviewed the number of thoracic surgery procedures done in the Mayo spiral CT screening trial. At the time of analysis, 55 participants had had a total of 60 thoracic surgical operations; all five with repeat operations were for cancer. Of the 55 participants, 10 (18%) had surgery done for benign disease: nine for benign pulmonary nodules and one for spontaneous pneumothorax that required bleb resection and pleurodesis. Of the nine individuals with benign pulmonary nodules, eight had limited resection and one participant with a central nodule required a lobectomy. These operations were done via thoracotomy in six cases and video-assisted thoracoscopic surgery in three. There was no operative mortality in the individuals with benign disease. One of the patients undergoing a lung cancer resection died within 30 days of the operation due to a cerebrovascular event.
A pilot randomized screening trial compared low-dose spiral CT versus chest radiograph in 3,300 high-risk individuals (16). Of the 1,660 participants enrolled in the CT screening arm, 20.5% had an abnormal screen that required further studies. In comparison, for the 1,658 participants in the chest X-ray screening arm, 9.8% of participants had a positive screen. Abnormalities detected by either screening modality required additional follow-up testing, including bronchoscopy, lung biopsy, or resection. Seventeen percent of the positive screening abnormalities detected on the spiral CT arm of the trial required an invasive procedure, whereas 10% of the positive screening chest X-rays required a subsequent invasive procedure. In a review article, Diederich and Wormanns (17) summarized the rate of the invasive procedures for benign lesions detected by CT screening. Invasive procedures were done in 22% to 55% of participants with abnormal CT findings (Table 3).
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Cost-Effectiveness
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Estimates of the cost-effectiveness of CT screening have varied tremendously, ranging from as little as $2,500 per year of life saved to a high of $2,300,000 (18–20). The case-based analysis by Wisnivesky et al. (18) resulted in the lowest estimate of cost-effectiveness of screening. The other two studies were estimates based on various case evaluations. Given the tremendous variation in these estimates, it is probably safe to say that we really do not have definite knowledge as to whether or not spiral CT screening will prove to be cost-effective. Cost-effectiveness studies are being done as part of the National Lung Cancer Screening Trial on a subset of individuals enrolled in that study. These results will be based on actual costs encountered in the spiral CT screening study and will give a better estimate as to cost-effectiveness.
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Interval Lung Cancers
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In the Mayo spiral CT screening trial, a total of 68 lung cancers have been detected in 66 patients (21). Three of those patients with lung cancer presented with symptoms in between their annual CT scans (i.e., interval cancers); one had stage IV undifferentiated non–small lung cancer with bony metastasis and the other two individuals had limited stage small-cell lung cancer. Diederich et al. (22) reported the results of their incidence screening. They observed 10 screen-detected or incidence cancers after an initial baseline screen. Additionally, they observed five interval cancers in patients who presented with symptoms. Five of the screening trials have reported a total of 117 incidence cancers detected by CT and an additional 12 interval lung cancers (a 10% increase) that presented in between the yearly scans (17). The vast majority of interval cancers are symptomatic. Symptomatic lung cancer is generally advanced disease and associated with poor prognosis. Thus, interval cancers are one major limitation of effective screening.
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Small-Cell Lung Cancer
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Recent estimates from the Surveillance, Epidemiology, and End Results database have observed that 14% of all new lung cancers in the United States are of small cell histology. Small-cell lung cancer has a rapid doubling time, and it is not generally believed that screening is likely to be beneficial in patients with small-cell lung cancers. In the Mayo screening trial, 8 of 68 cancers have been of the small cell histology (12%; ref. 21). In the screening trial from Germany, three small-cell lung cancers have been detected from a total of 26 (12%) lung cancers (22).
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Deaths from Lung Cancer in Computed Tomography Screening Trials
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To date, we have observed a total of 49 deaths in participants enrolled in the Mayo spiral CT screening trial, of which 12 were due to lung cancer (21): 3 from prevalence cancers, 8 from incidence cancers, and 1 from an interval cancer. Thus, 12 (18%) lung cancer deaths have occurred to date among 66 patients with lung cancer detected in our study. Similarly, the Germany CT screening trial reported a total of 6 deaths (26%) in 23 patients with lung cancer (22). Additionally, two patients had metastatic lung cancer at the time of the study report and will most likely die of their disease. Other screening trials have not been as rigorous in reporting the number of deaths in their follow-up results. Several of the screening trials reported to date suffer from significant numbers of participants lost to follow-up (7, 22, 23). Accordingly, it is impossible to know in these trials how many more cases of lung cancer would have occurred and how many deaths due to lung cancer were missed.
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Overdiagnosis of Lung Cancer
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Overdiagnosis is defined as a lung cancer that would not lead to an individual's death because of slow growth rate and competing age-related risks for death. In the original Mayo lung screening project, Fontana et al. (3) showed a significantly better 5-year survival for the screened group as compared with the control group; however, there was no difference in lung cancer mortality between the two groups. Their study observed 206 lung cancers in the screened group but only 160 cancers in the control group. Accordingly, 46 additional cancers (29% more) were diagnosed in the screened group as compared with the control group, without producing an impact on lung cancer death rates. Long-term follow-up studies by Marcus et al. (24) have continued to show a survival benefit for the intensely screened group as compared with the control group, but no difference in mortality. The generally accepted reason for this difference is overdiagnosis of lung cancer. For a more in-depth discussion of the differences between survival and mortality, the reader is referred to Marcus et al. (24).
A number of studies have reported the average lung cancer doubling times. Most reports show doubling times in the range of 100 to 300 days for non–small-cell lung cancer. In a report by Usuda et al. (25), 86 adenocarcinomas had a geometric mean doubling time of 163 days. In an analysis of data from the Mayo Clinic and Memorial Sloan Kettering Cancer Center screening trials, Yankelevitz et al. (26) noted a mean doubling time of 101 days in the Mayo study and 144 days in the Memorial study. Only 4 of 87 cancers in those two trials had doubling times of more than 400 days. With a doubling time of 400 days, it would take 7.7 years for a 3 mm lesion to increase in size to a diameter of 15 mm. The authors opined that doubling times of >400 days would be consistent with overdiagnosis.
A Japanese study detected 82 lung cancers over a 3-year period with spiral CT screening. They had serial CT scans on 61 cases and were able to estimate the doubling time (27). Cancers were classified into three different types: (a) cancers that appeared as ground-glass opacities had a median doubling time of 813 ± 375 days; (b) cancers that were partially ground glass and partially solid had a doubling time of 457 ± 260 days; and (c) solid lesions that had a doubling time of 149 ± 125 days (more typical of lung cancers detected during the chest radiograph screening trials; ref. 27). Of these 61 cancers detected in the CT screening trial, Hasegawa et al. noted that 31 (50%) had a mean doubling time of >340 days. Specifically, 27 adenocarcinomas had a doubling time of >450 days, and 12 of these 27 had a volume doubling time of >730 days. If a doubling time of more than 400 days equals overdiagnosis, as opined by Yankelevitz et al. (26), then at least 27 of 82 cancers (33%) in the report by Hasegawa et al. would be considered to be overdiagnosed. In the Mayo spiral CT screening trial, we have observed several cases of grade 1 bronchoalveolar cell carcinomas that have minimally changed in size, based on CT evaluation, over a period of 3.5 to 4.5 years. These lesions were the ground-glass opacity type of lesions on thin-section CT examination. Based on current knowledge, it is questionable as to the benefit of resecting a small (1.5 cm) ground-glass opacity lesion that histologically proves to be bronchoalveolar cell carcinoma. More data on these types of lesions are needed.
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Risk of Cancer from X-rays
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An area of considerable debate is the risk of cancer associated with diagnostic X-rays (28, 29). The risk estimates of inducing malignancy through ionizing radiation have been gathered from high levels of exposure from the atomic bomb blasts in Japan. It is not absolutely certain whether the risk of small doses of radiation (diagnostic X-rays) is higher or lower than those estimates derived from extrapolation of the radiation exposure data from Japan. A recent report from Oxford, United Kingdom, has estimated that the attributable risk percentage of cancers due to diagnostic X-rays ranges from 0.6% to 1.8% of all cancers in most developed countries (30). They estimated that diagnostic X-rays contributed to 3.2% of all cancers in Japan (Table 4). Radiation from CT scans were responsible for the largest number of cases of the nine listed cancers in that trial. This is an area that continues to be a topic of debate, and one on which additional data are needed.
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Conclusion
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In summary, there is a great deal of preliminary information available concerning CT screening for early stage lung cancers. Several of the reports, including the Mayo Clinic trial, have observed that 60% to 85% of lung cancers detected are stage I. This is markedly better than the current state of practice where only 15% to 20% of all newly diagnosed lung cancers are stage I. However, CT screening is associated with a number of problems and limitations as outlined above. None of the trials reported today have been randomized controlled trials. The National Lung Cancer Screening Trial was launched in the fall of 2002 (31). By February 2004, 50,000 high-risk participants from North America were enrolled in this randomized trial, which compares low-dose spiral CT screening to digital chest radiograph. The plan is to obtain three yearly screening tests and then to follow the participants for survival. The study is powered to detect as little as a 20% improvement in lung cancer mortality. No results of the National Lung Cancer Screening Trial have been reported to date because many participants are still in their final year of screening. Final results of the study may not be available for another 5 years. Additional randomized screening trials are currently under way in The Netherlands (NELSON Trial) and France (Depiscan). Those two trials are currently accruing patients on study. Realistically, we anticipate a great deal of additional information with regard to CT chest screening trials in the near future.
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Open Discussion
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Dr. Malcolm DeCamp: In discussing overdiagnosis in older series, to say that we are dealing with the same biology now is a little bit misleading. There are differences in the histology of the cancers that were detected 30 or 40 years ago when we didn't have accurate fine needle aspiration. Surgery is also not as morbid in 2004 as it was in the 1970s. So I think we are doing a bit of a disservice to stand on the Mayo Lung Project and the other randomized projects.
Dr. Thomas Lynch: Dr. Jett has advocated the lung cancer screening study which is currently ongoing. The best trial design may be to randomize people to treatment or no treatment once you screen and diagnose cancer. What do people think about those trial designs?
Dr. Claudia Henschke: We find a fair number of stage I tumors. I think you are not going to randomize a 3 cm lesion cancer into no treatment, but a nonsolid nodule can be followed, and a certain number of them can go to biopsy and, depending on the results, continue to be followed. You could take certain solid lesions under 1 cm and randomize them to lobectomy and limited resections. There are a number of things that you can do, including chemoprevention trials within such a randomized trial. You just have to determine what you are really looking at. We are not talking about taking all lung cancers and randomizing them into intervention or nonintervention. We don't really know what to do. Maybe we have to resect the larger ones, and the smaller ones we give chemoprevention or chemotherapy. There are lot of interesting trials that can be done in North America.
Dr. James Mulshine: The screening trial design issues have been discussed at about ten international meetings. The assumption that allows a randomized trial to be responsive is that you have a standard of care that has worked, which you are going to test against, and then you ask your question on a timely basis and get an answer. The challenge of applying the randomized trial structure to screening is exemplified by the HIP study of mammography. That study took 26 years, and during those 26 years mammography was the standard of care. In the time since the National Lung Cancer Screening Trial started, we have already gone through three generations of CT technology. Frankly, I think to suggest that we just stand by for decades while the National Lung Cancer Screening Trial is ongoing, and while over a million people die of lung cancer, is really irresponsible. There are many areas in which research to improve the safety of screen-detected lung cancer could be done now and to wait for the completion of the National Lung Cancer Screening Trial before we begin that research does not seem prudent. I would point out that the U.S. Preventive Service Task Force does not state against screening. They state that screening is a complex issue. The evidence is insufficient to rule against and it is insufficient to rule for it.
Dr. Jett: I believe I listed the organizations that do not advocate routine screening. You are right about the Task Force position. I reviewed the paper.
Dr. Thierry Le Chevalier: Would you recommend screening for a friend who has a 50 pack-year history?
Dr. Jett: I would tell him the rate of nodule detection, and that some of those people have gone to surgery and had benign nodules. I would say that some people have had a lot of anxiety related to a nodule in the chest, but if you think you want to have that information, absolutely, go ahead. I will screen, but I will get an informed consent. Remember, my topic was to point out the warts in screening, which I tried to do. I actually am an advocate. I like screening. I hope it works. I certainly recognize that there are going to be limitations. We are not going to see a 50% mortality reduction; we may see a 20% mortality reduction. I think we have to do the trial.
Dr. Lynch: I think everyone feels that way. I think there is not a person who takes care of lung cancer patients who doesn't hope it works. We see more than 60% of people with mediastinal nodes at presentation. The question is: What do we need to do to get to the point where we know we are doing more good than harm with screening? Prof. Thatcher, can you give us the British perspective on screening? Where do you stand right now?
Prof. Nick Thatcher: Our issue is really not to argue that it will improve the survival, as we all know it will. Does it actually reduce mortality, that is the big end point that we were interested in. Given the size of the trial required to show that, the amount of money to be invested is 10 million pounds, which was felt to be an unreasonable amount of money. The point was then, even if it worked, what would be the health economics of it? So, despite being a good idea, it is not going forward. We are hoping that other methods, such as molecular labeling, might be of help.
Dr. Douglas Wood: It is disappointing that a cost of 10 million pounds prevented that trial in Great Britain because a country with nationalized health insurance is the only place that can do this type of randomized trial and get a real answer. We can't do it in the United States because we have to control the randomized trial with standard of care.
Dr. Henschke: I would agree with that. Many participants, once they are randomized to the chest X-ray arm, go somewhere else and get a CT. So, I think that the National Lung Cancer Screening Trial randomized trial is not going to come up with an answer. It is going to show no difference.
Dr. Giorgio Scagliotti: You know the data of Ugo Pastorino. At the same time, my institution did a similar study using exactly the same criteria. The detection of nodules more than 5 mm was five times higher in our series, even in the second and third years. To me, that means the expertise of the radiologists is making a huge difference from one series to another. The ability of each center to detect nodules will be different, and this is something that we need to address.
Dr. Henschke: Having trained and dual read scans from 35 different institutions, I absolutely agree. First of all, you should start slowly and you need to have the community understand what small cancers look like. You can put in effective training for radiologists, but there is a large variability, and you see it in some of the early trials.
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Footnotes
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Presented at the International Conference on Early-Stage Lung Cancer: New Approaches to Evaluation and Treatment, October 1-2, 2004, Cambridge, Massachusetts.
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Abstract
High Rate of Noncalcified...
