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CT Screening for Lung Cancer: Not Ready for Routine Practice¹

¹ From the Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710 (E.F.P., P.C.G.); and the Department of Radiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.C.B.). Received October 12, 2000; revision requested October 24; revision received November 21; accepted December 9. Address correspondence to E.F.P. (e-mail: patz0002@mc.duke.edu).

	ABSTRACT

TOP ABSTRACT Introduction Biologic Issues in Lung... Principles of Screening Lung Cancer Screening Trials Current CT Screening Trials Summary REFERENCES

 
Lung cancer continues to be a major worldwide health problem. Multiple strategies are being explored in an attempt to reduce lung cancer mortality, including a renewed interest in screening. Multiple low-dose spiral computed tomography (CT) trials have been proposed, as proponents predict that small nodules will represent early-stage disease and detecting them will ultimately translate into improvements in outcomes. At this time, however, only prevalence-screening data are available, and it remains to be seen if CT will truly reduce mortality. The appropriate hypothesis-driven studies still must be performed and the results carefully analyzed before CT screening for lung cancer can be accepted as the standard of care.

Index terms: Computed tomography (CT), utilization • Lung neoplasms, CT, 60.12111, 60.12115 • Lung neoplasms, diagnosis, 60.32 • Lung neoplasms, screening • Lung neoplasms, staging

	Introduction

TOP ABSTRACT Introduction Biologic Issues in Lung... Principles of Screening Lung Cancer Screening Trials Current CT Screening Trials Summary REFERENCES

 
Over 25 years ago, the U.S. government proclaimed a "war" against cancer; unfortunately, however, the disease remains the second leading cause of death in adults, behind heart-related illnesses. Among malignancies, lung cancer is the most common cause of death in men and women in the United States; in fact, more people die each year of lung cancer than of colon, breast, and prostate cancers combined (1).

Because most lung cancer patients present with advanced-stage disease and prognosis is strongly related to stage, screening for lung cancer has had many advocates. The results of prior screening trials with chest radiography (CR) and sputum cytologic analysis, however, did not show a reduction in lung cancer mortality, despite the fact that the disease was often diagnosed before patients were symptomatic. Nevertheless, screening with low-dose spiral computed tomography (CT) is now being proposed because it is more sensitive than CR, and some argue that it may enable detection of lung cancer at a presumably earlier, and more curable, stage (2).

In this article, we will review the biologic characteristics of lung cancer, the basic principles of screening, the results of previous randomized screening trials for lung cancer, and the current data for low-dose spiral CT screening.

	Biologic Issues in Lung Cancer Screening

TOP ABSTRACT Introduction Biologic Issues in Lung... Principles of Screening Lung Cancer Screening Trials Current CT Screening Trials Summary REFERENCES

 
The theoretical advantage of CT for lung cancer screening is its ability to demonstrate smaller cancers, presumably at an earlier stage, than those that can be detected at conventional CR. Although primary tumor size has traditionally been promoted as an important prognostic factor, there currently are no data to show that a 5-mm-diameter lung mass (approximately 10⁸ cells) is associated with a substantially better prognosis than a 10-mm mass (approximately 10⁹ cells) or even a 30-mm mass (approximately 2.7 x 10¹⁰ cells). All of these tumors are well advanced in the biologic history of disease, since patient death typically occurs with a tumor burden of around 10¹² cells (3). In fact, the results of several recent studies raise questions about the correlation of tumor size with outcome. In one report (4) of 510 patients with T1N0M0 disease (tumors 3 cm) at presentation, no significant relationship between small size and survival was found. Patients with 3-cm masses had the same outcome as those with nodules smaller than 1 cm. Why is this the case? More important, what is the relationship between the size of a lesion and the stage at presentation? The answers may lie in the fundamental nature of lung cancer.

There is a growing body of experimental and clinical data to suggest that lung cancer is markedly heterogeneous. At one end of the spectrum, lung cancer can be a systemic disease by the time the primary lesion becomes detectable with radiologic techniques. Some investigators (5–8) have shown that it is possible for metastases to occur at the time of angiogenesis, when lesions are approximately 1-2 mm, and perhaps even earlier as neoplasms can co-opt normal adjacent vessels before angiogenesis begins. Other results (9) have revealed that human tumors grown in nude mouse models shed between 3 and 6 million cells per gram of tissue every 24 hours, a constant potential for metastatic disease.

Clinical results (10–13) support the concept of early spread, since patients with small primary tumors can have malignant cells in normal-appearing lymph nodes or distant sites. Other investigators (14–16) have found tumor cells in the peripheral blood and bone marrow of patients with all sizes and stages of lung cancer. More important, the authors of a recent clinical study (17) could find no correlation between the size of a small (3-cm) lesion and the stage of neoplasm at presentation. The probability for disseminated disease and the stage distribution were not significantly different whether the primary lesion was smaller than 1 cm or was 2–3 cm. With newer more sensitive detection methods, sites of isolated tumor cells and early micrometastases may now become even more apparent, although at this time the true clinical importance remains to be determined (18).

There also is evidence that some lung cancers are extremely indolent. In one large study (19), about one-sixth of lung cancers found at autopsy were clinically unrecognized and unrelated to the subject’s death. In addition, CT is far more sensitive than autopsy for detection of small lung nodules, some of which appear to be undiagnosed lung cancers (20). Thus, it is not unreasonable to expect that some of the cases detectable at CT would be clinically unimportant. Further evidence suggesting that at least some tumors detected at screening may be indolent is provided in one of the Japanese CT trials (21), in which the prevalence–screening rate of lung cancer was the same in smokers and nonsmokers. If all of these lung cancers detected at screening were truly clinically important, then in clinical practice there should be just as many lung cancer cases diagnosed in smokers as in nonsmokers. This is clearly not the case, and smokers have a substantially higher risk of dying of this disease.

The marked heterogeneity of lung cancer raises the critically important questions that were elegantly posed by Whitmore (22) in the setting of prostate cancer: "Is cure necessary in those in whom it may be possible? Is cure possible in those in whom it may be necessary?" In the context of lung cancer screening, these questions can only be answered reliably with properly designed studies.

	Principles of Screening

TOP ABSTRACT Introduction Biologic Issues in Lung... Principles of Screening Lung Cancer Screening Trials Current CT Screening Trials Summary REFERENCES

 
The purpose of screening is to prevent or delay, by means of earlier detection, the development of advanced disease and its adverse effects (23,24). By definition, screening entails the evaluation of individuals who are asymptomatic but at risk to develop advanced forms of the target disease. Those with positive screening results can undergo further evaluation to determine if they actually have the disease.

Effective screening must meet at least three conditions. First, screening must be able to help diagnose disease before the patient becomes symptomatic. Second, earlier treatment must be more effective than later treatment. Third, the benefits of earlier treatment (usually applied to a small number of screened individuals) must outweigh the harm of the screening process (which applies to all screened patients). In the case of lung cancer screening, the first condition is relatively easy to assess. The second and third conditions, however, are difficult to assess and are subject to several sources of bias.

The most widespread biases are introduced if survival (ratio of number of patients alive after diagnosis of the disease relative to that of all patients with a diagnosis of the disease) is inappropriately used as an end point for a diagnostic screening trial. Lead-time bias results from the failure to control for the timing of diagnosis (Fig 1). Screening-detected cases are diagnosed earlier, and the patients live longer from the time of diagnosis, even if death is ultimately not delayed as compared with time of death in an unscreened population. Length-time bias results from the failure to control for the rate of disease progression. The probability that a case will be detected with screening is directly proportional to the length of the asymptomatic interval (the detectable preclinical phase) (Fig 2). Therefore, cases detected at screening tend to be less aggressive and progress more slowly than those that are not detected at screening and ultimately manifest clinically. Finally, overdiagnosis bias results from the failure to control for the detection of pseudodisease, or preclinical disease that would not have produced any signs or symptoms before the individual would have died of other causes (Fig 3). Pseudodisease dilutes the subset of screening-detected cases with cases that are effectively disease free, and this can have a large effect on survival and cure rates.

View larger version (42K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Schematic illustrates lead-time bias. Considering two comparable cases of lung cancer, the case in the screened group is diagnosed earlier than the case in the control group. Therefore, the screening-detected case must survive longer from the time of diagnosis, even if death is not delayed by earlier detection. Note that both patients develop metastatic disease (indicated by symbols over the lower extremities).

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Schematic illustrates length-time bias. Rapidly growing tumors have a short potential screening period (interval between detection and symptoms), while more indolent (slowly growing) tumors have a longer detectable preclinical phase. Therefore, cases detected at screening tend to progress more slowly than those that are not detected at screening and manifest clinically. Consequently, screening-detected cases tend to progress less rapidly than interval cases. Tumor onset is shown in the "patient" on the left, detectable tumor is shown in the middle, and symptomatic tumor is shown on the right.

View larger version (43K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Schematic illustrates overdiagnosis bias. Consider two screening-detected cases of lung cancer (top) and two comparable cases in the control group (bottom). Only one of the two cases in the control group is diagnosed because the other one remains asymptomatic until the patient dies of causes other than lung cancer. In this example, lung cancer survival is 50% (one of two survives) in the screened group but 0% (the one patient with a diagnosis) in control group, although in each group only one patient dies of lung cancer (ie, mortality is the same). Note that in the control group, one patient dies with undiagnosed lung cancer, which did not affect the individual’s natural lifespan. An indolent cancer is designated by a black circle, while an aggressive cancer is designated by a "sun" symbol.

Of course, the type of investigation used to study screening may be subject to other biases, including selection bias, which results from differences in the population that is screened and that which is not screened. The study design that most effectively removes such differences and minimizes selection bias is the RCT. Additionally, this design is straightforward: Subjects are randomly assigned to two (or more) groups at time zero, and deaths (or adverse events) due to the target disease are counted during the time between randomization and some predetermined end of the study.

But even RCTs are not immune to all forms of bias. Study subjects may not comply with randomization; subjects randomly assigned to screening may fail to undergo screening, or subjects randomly assigned to a control group may undergo screening (noncompliance in the control group is often referred to as contamination). Lack of compliance in either group always causes the effectiveness to be underestimated. Other major limitations of screening RCTs are the requirement for a large number of subjects (usually >5,000) and a long observation period (usually >5 years). This is a strong argument for using decision modeling to help generalize the results of an RCT to populations or conditions that may differ from those in the original study. Decision modeling can also be used to help weigh the benefits, harms, and costs of screening for policy formulation and informed consent.

	Lung Cancer Screening Trials

TOP ABSTRACT Introduction Biologic Issues in Lung... Principles of Screening Lung Cancer Screening Trials Current CT Screening Trials Summary REFERENCES

 
In the early 1970s, four RCTs of lung cancer screening were performed (2), three of them sponsored by the National Cancer Institute. In the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Project, screening with CR and sputum cytologic analysis every 4 months was compared with screening with CR alone, while in the Mayo Lung Project screening with CR and sputum cytology every 4 months was compared with usual care, which entailed some, but much less intensive, screening. In the fourth RCT, which was conducted in Czechoslovakia, CR screening was compared with no screening at all. These four RCTs combined enrolled approximately 37,000 "high-risk" male smokers over 45 years of age (25–31).

Investigators in each trial found an increased incidence of earlier stage lung cancers, more resectable cancers, and improved 5-year survival rates in the screened groups, as compared with these parameters in the control groups (35% vs 15%) (32). However, in no trial was a statistically significant decrease in lung cancer mortality found (32). In other words, more subjects were diagnosed with lung cancer and more were apparently cured in the screened groups than in the control groups, but, ultimately, equal numbers of patients in the two groups died of the disease. Most if not all of the discrepancy between the improved survival and mortality can be explained by some combination of lead-time, length-time, and overdiagnosis bias.

In addition, in a substantial proportion of patients who developed lung cancer in all trials, the diagnosis was established because of clinical signs and symptoms that developed in the 4 months between a negative CR screening and the next scheduled CR screening. In fact, in the Johns Hopkins Lung Project trial, about half of all lung cancer cases that were diagnosed were "interval" cases. Also, some of the patients with small primary lesions had already developed metastases. These findings indicate that a substantial proportion of lung cancers grow very rapidly or metastasize very early and thus would not be affected by CR screening or even possibly by CT. Finally, while the combined data from the trials showed an expected increase in the number of early lung cancer cases in the screened versus control groups (240 vs 212 cases), they did not find the expected concomitant reduction in the number of cases of advanced-stage disease (303 vs 304 cases). This suggests that many of the early lung cancers that were detected at screening may not have become clinically important.

The Mayo Lung Project, which is the RCT most relevant to CR screening, has been criticized for insufficient duration of follow-up, lack of compliance (in both arms), misclassification of the cause of death, and faulty randomization. However, all of these criticisms have recently been answered in an extended follow-up and reanalysis of the Mayo Lung Project findings. This showed a slight excess (not significant) in both lung cancer and non–lung cancer deaths, suggesting that there were some fatal complications of treatment that were unrecognized (33). In a screening RCT, deaths due to treatment should be counted as deaths due to the target disease.

	Current CT Screening Trials

TOP ABSTRACT Introduction Biologic Issues in Lung... Principles of Screening Lung Cancer Screening Trials Current CT Screening Trials Summary REFERENCES

 
Recent advances in technology have prompted new early-detection trials of low-dose spiral CT (34–36). The first two trials initiated were nonrandomized screening studies from Japan. Both used a combination of CR and CT; one was performed in smokers and the other in both smokers and nonsmokers (21,37). There are two additional trials in the United States being performed by the Early Lung Cancer Action Project group and the Mayo Clinic (38). Both enrolled "high-risk" patients (smokers over the age of 60 years), in a nonrandomized trial design with low-dose CT, with the addition of CR in one of the studies (38).

Prevalence-screening data from all of these trials confirmed the well-accepted and previously published premise that CT is more sensitive than conventional CR for the detection of lung nodules and that some of these nodules represent lung cancer. A comparison of data between the recent prevalence trials and the prior screening trials reveals that there will be more lung cancer cases found (27 per 1,000 vs 9.1–7.6 per 1,000) and that more patients will have resectable early-stage disease at CT screening. These findings are similar to those from decades earlier, when CR-screened and nonscreened populations were compared. As previously discussed, the clinical importance of some of these "additional" small tumors now found at CT screening is uncertain. In addition, there are other features of CT trials that must be addressed. Lead-time bias will be much greater than with CR, since CT demonstrates lung cancers when they are much smaller. For example, in one study (39) of small (<3-cm) surgically resected peripheral adenocarcinomas, tumor volume doubling times ranged from 42 to 1,486 days. With a 1-year doubling time, it takes nearly 8 years for a tumor to increase in diameter from 5 mm to 3 cm. With longer doubling times, it may take 30 years for a tumor to grow this much. Thus, length-time bias, not surprisingly, will clearly be a factor in the distribution of tumors detected at CT screening. There will be overrepresentation of slowly growing tumors and underrepresentation of rapidly growing ones.

If CT screening were harmless, it could be argued that at-risk populations should be screened without evidence of effectiveness, because of the likelihood that at least a few individuals would benefit. However, there are two serious harms that must be weighed against any potential benefit. The more familiar harm is the false-positive test result, which may lead to excess worry and further, perhaps invasive, procedures to confirm the diagnosis. In one recent CT screening trial, at least one indeterminate nodule was found in up to 50% of all screened cases (Swenson S, unpublished data, 2000). Statistically, the majority of nodules should be benign, but they will necessitate evaluation that may entail percutaneous needle biopsy or thoracotomy. A less familiar but more serious harm is overdiagnosis, in which screening results in a diagnosis of cancer and leads to definitive treatment, such as a lobectomy (40).

It must also be recognized that even if CT screening for lung cancer could provide a net benefit at an acceptable cost, it would probably do so only under certain exacting conditions. These would include targeting the right population, screening with the right frequency, correctly interpreting the screening CT and follow-up findings, and delivering the appropriate treatment. We still have a long way to go in identifying all of these conditions and ensuring that they will be met.

	Summary

TOP ABSTRACT Introduction Biologic Issues in Lung... Principles of Screening Lung Cancer Screening Trials Current CT Screening Trials Summary REFERENCES

 
Screening for lung cancer is a complex, confusing, and controversial topic. Clinical and experimental data do not clearly support the assumption that by simply detecting smaller sized tumors with today’s screening tools, including CT and CR, there will be a meaningful reduction in lung cancer mortality. It cannot be assumed that improved anatomic imaging resolution will parallel the biologic behavior of lung cancer.

Although public and medical pressure to improve lung cancer outcomes by means of mass screening is understandable, there can be no compromise or short cuts in the rigorous scientific process needed to determine if screening for lung cancer is justified (41,42). We cannot set guidelines or standards for mass screening before the appropriately designed trials address and answer this fundamental question: Does screening with low-dose spiral CT reduce lung cancer mortality?

	FOOTNOTES

 
See also the Viewpoint (pp 592–596 ) and Commentary (pp 598–599 ) by Miettinen and Henschke in this issue.

	REFERENCES

TOP ABSTRACT Introduction Biologic Issues in Lung... Principles of Screening Lung Cancer Screening Trials Current CT Screening Trials Summary REFERENCES

 

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This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2213001643v1 221/3/587    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Patz, E. F. Articles by Goodman, P. C. Search for Related Content PubMed PubMed Citation Articles by Patz, E. F., Jr Articles by Goodman, P. C.