Lung Cancer Screening
【关键词】 Cancer,
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
A 60-year-old woman who quit smoking 20 years earlier comes for a routine visit. She previously smoked one pack of cigarettes a day for 10 years. Her medical history is otherwise unremarkable. She feels well and exercises regularly. Her husband smoked one pack of cigarettes per day for at least 30 years but stopped smoking a decade ago. She asks whether she and her husband should undergo computed tomographic (CT) scanning to screen for lung cancer. What do you advise?
The Clinical Problem
With a projection of more than 160,000 deaths from lung cancer this year, the disease now accounts for 30 percent of deaths from cancer in the United States.1 Since metastatic spread to regional or distant sites is evident in at least three quarters of patients with lung cancer at the time of diagnosis, the five-year survival rate for lung cancer is only about 15 percent. For stage 1 lung cancer, the five-year survival rate exceeds 60 percent. Among women, there has been a 600 percent increase in the incidence of lung cancer during the past 80 years, and rates of death among women with lung cancer in the United States are the highest of any in the world.2 About 50 percent of adults in the United States have smoked; half of them have quit. After smoking cessation, the risk of coronary artery disease drops promptly, whereas the risk of lung cancer does not.3 The net result is that lung cancer has recently superseded coronary artery disease as the leading cause of death among current and former smokers.4,5,6,7,8
The results of randomized trials that were reported 20 years ago showed no significant reduction in deaths from lung cancer with the use of screening that included a combination of chest radiography and cytologic analysis of sputum. Although methodologic limitations in the studies (such as the frequent use of chest radiography in the control group and low compliance with the prescribed frequency of radiography in the experimental group) may have contributed to the negative results,9,10 these findings discouraged routine screening for lung cancer with plain films. More recently, the possibility of early detection of lung cancer with high-resolution CT has renewed interest in lung cancer screening (Figure 1).11,12,13,14 However, as detailed below, decisions regarding the use of this technology must involve a consideration of potential benefits and risks along with the health care costs.15,16,17
Figure 1. Non Small-Cell Lung Cancer Detected by Screening.
In Panel A, a CT scan of the chest shows a 5-mm nonsolid nodule abutting the pleura in the right middle lobe (arrowhead). In Panel B, histopathological analysis of tissue obtained from thoracic resection reveals a subpleural adenocarcinoma of a mixed subtype. The tumor nodule shows infiltrative changes along the left border, with the invasive acinar growth pattern of this carcinoma shown on the nodule (inset) (hematoxylin and eosin). Images are courtesy of the Early Lung Cancer Action Project.
Strategies and Evidence
A number of pilot studies of CT screening have recently been reported. These studies have generally involved groups that are at increased risk for lung cancer, including current and former smokers. Analysis of these results is complicated by a lack of standardized criteria for eligibility and clinical management. Overall, 55 to 85 percent of cancers that are detected in baseline scans and 60 to 100 percent of cancers that are detected in annual follow-up scans are stage 1 (Table 1). In contrast, only 16 percent of cancers that are diagnosed in the course of routine clinical care in the United States are stage 1.1,11,18,19,20,21 Since stage 1 lung cancer is the most curable form of this disease, a high frequency of detection of stage 1 tumors is considered a necessary (though not sufficient) indication of a favorable screening outcome.
Table 1. A Comparison of Lung Cancers Detected during Screening at Baseline and at Annual Follow-up.
Although outcome data are lacking in most of these reports, an observational study from Japan reported a reduction in mortality for patients with lung cancers detected by CT screening.22 Of the lung cancers that were detected by CT scanning of 15,342 subjects, 78 percent were stage 1, with a mean diameter of 1.5 cm, and only 14 percent were either stage 3 or stage 4. The favorability of this staging distribution was greater than that of cancers detected in earlier screening studies with the use of chest radiography. Correspondingly, the overall five-year survival rate improved, from 49 percent for cases detected by chest radiography to 84 percent for those detected by CT.22 Additional data suggesting a lower rate of death among subjects who underwent CT scanning derive from the International Early Lung Cancer Action Project, a multinational, nonrandomized study that involved an initial screening of more than 26,577 subjects and follow-up screening of 19,555 subjects at more than 30 sites.23,24 Of 350 lung cancers that were detected, 82 percent were stage 1. With follow-up as long as 100 months (median time, approximately 40 months), the survival rate for subjects with lung cancer was more than 95 percent.
Recently, in a report of a pilot study associated with a large, randomized trial conducted by the National Cancer Institute, the rate of detection of cancer in stage 1 was 40 percent for baseline screening (16 of 40 cancers detected) and only 25 percent for annual follow-up scanning (2 of 8 cancers detected).25 Factors that potentially contributed to the disparity between these rates and those reported in other series include the small numbers of subjects, the composition of the cohort, and variations among centers in test performance.
Limitations of the Available Studies
Although these findings appear promising, definitive evidence that CT screening reduces mortality associated with lung cancer is lacking. Because available data are from observational studies, possible biases must be considered that might explain or contribute to the apparent improvement in survival among patients who underwent CT screening, as compared with historically poor survival among patients in whom lung cancer was diagnosed on the basis of symptoms.10,26 Lead-time bias refers to the apparent increase in survival attributable to the longer interval after a diagnosis made on the basis of a screening test as compared with one made after the onset of symptoms. Length bias refers to the possibility that relatively slow-growing cancers that are less likely to cause symptoms may be preferentially detected by screening. In the latter case, the apparently longer survival with screening may represent the indolent nature of the tumors that were detected rather than a benefit of screening itself. These biases may be particularly problematic when consideration is given to the end points of early screening, such as five-year rates of survival.27
A related concern is the possibility of overdiagnosis.16 Overdiagnosis is said to occur if small tumors preferentially detected by screening would otherwise remain clinically covert until death from other causes. In such cases, screening results that are apparently favorable with regard to stage distribution or five-year rates of survival may not translate into significant reductions in mortality from lung cancer. Although overdiagnosis is possible, available data suggest it is unlikely.10 Recent reports indicate that small lung cancers that are detected by screening express molecular and biochemical profiles that are indistinguishable from those of lung cancers that are detected after symptoms develop.28,29
Generally, as with breast cancer screening,30 randomized trials have been considered the gold standard for demonstrating that a screening test reduces mortality. However, the rapid advances in CT imaging have greatly complicated rigorous assessment of CT screening, since several generations of important technical improvements are occurring within the time frame required for conducting a single, large, randomized trial.
Risks of Screening
Possible benefits of screening must be weighed against potential harm. Lung cancers appear on spiral CT scans as noncalcified nodules, but only a small fraction of noncalcified nodules that are detected by screening are lung cancers. Screening may subject persons who do not have lung cancer to risks that include anxiety associated with abnormal findings, procedural complications, and substantial costs. Diagnostic procedures that are indicated by CT results may entail invasive surgery,16 and resultant morbidity and mortality might undermine potential benefits associated with diagnosing cancers at an earlier stage.
The fraction of detected noncalcified nodules that prompt an invasive diagnostic workup ranges from 3 to 12 percent (Table 1). In one series, 20 percent of the nodule specimens obtained by thoracotomy turned out to be benign.20,31 Although the surgical management of cases on the basis of positive findings on screening has not resulted in major complications according to reports from several experienced centers, mortality associated with anatomic lobectomy and mediastinal staging may be as high as 3 percent.32 Since patients with abnormal screening results are likely to have smoked, the potential surgical risk is a critical consideration in counseling.21,22,33,34
Features of nodules may help to discriminate between benign and malignant processes, but suggested criteria such as a spiculated distribution of calcium are not sufficiently informative.23 A strategy that was proposed by the Early Lung Cancer Action Project was to determine the rate of growth of nodules.24 For noncalcified nodules that were less than 1 cm in diameter, high-resolution CT scanning was repeated at three months and evaluated visually by the radiologist. In this analysis, the radiologist was looking for either a change in volume (of the entire nodule or of the solid component of a partially solid nodule) or the development of a solid component in a previously nonsolid nodule. With the use of these criteria, the recall rate was 12 percent after screening at baseline24 and fell to 6 percent at follow-up scanning after one year. Among persons who were referred for needle biopsy on the basis of nodule growth, the rate of diagnosis of cancer was 90 percent.
Another proposed strategy is to use positron-emission tomography (PET) for further evaluation of suspicious nodules. In a recent screening study involving 1035 high-risk persons (i.e., those with a history of more than 20 pack-years of smoking),21 PET imaging was performed in 42 persons with suspicious nodules. Of the 20 PET scans that were classified as positive, 18 were confirmed to be diagnostic of lung cancer.21 An alternative diagnostic approach is the use of transthoracic needle biopsy in all patients with positive results on CT screening, with only cases of documented lung cancer referred for surgery.35 Further research is needed to compare the relative benefits and risks of transthoracic needle biopsy and PET scanning; costs and availability may be limiting factors.
Randomized Clinical Trials
The National Cancer Institute initiated the National Lung Cancer Screening Trial in 2002 to evaluate whether CT screening leads to a significant improvement in mortality associated with lung cancer; full accrual was completed in February 2004. The trial includes 50,000 subjects who were randomly assigned to undergo CT screening with multidetector-row scanners (mostly four rows) or chest radiography annually for three years, with planned follow-up for mortality through 2009. A European randomized trial comparing CT screening (with the use of 16-row scanners and computer-assisted detection tools) with standard care among almost 20,000 persons with a history of heavy smoking should be completed around 2010. Elements of data acquisition in these trials are being standardized to facilitate pooled analysis of the final results.36
Areas of Uncertainty
Benefits of Screening
In the absence of data from definitive trials, it is uncertain whether CT screening reduces mortality from lung cancer. If screening proves to be effective overall, more data will be needed to identify the patients who are most likely to benefit from it.37 The optimal approach to the management of nodules that are detected by screening remains unclear; various strategies are being evaluated in parallel with screening trials.38,39
Rates of smoking cessation may be higher after CT screening for lung cancer than they are with counseling alone. In the year after CT screening, 14 percent of the smokers in the Mayo Clinic cohort had quit smoking, as compared with an expected rate of 5 to 7 percent in the general population.40 In another cohort, a rate of smoking cessation of 23 percent was reported six months after CT screening.41 These success rates rival those reported after pharmacologic interventions. However, they require confirmation in further studies.
Effect of Advancing Technology
The rapid technological advances in scanning methods raise questions about how best to evaluate the value of these tools.42,43 Ten years ago, it took a typical single-detector CT scanner several minutes to provide views (slices) that were 10 mm thick along the entire length of the thorax, and consequently, the respiratory motion of chest structures seriously compromised the image resolution. After several generations of refinement of multidetector CT scanners, 64-row scanners can create an image of the entire thorax with a slice thickness of 0.625 mm in less than three seconds. These thinner slices may allow for a better characterization of nodules, as well as increase the ability to detect cancers arising in the central airways (such as the small-cell lung cancer shown in Figure 2).24,44 Even higher-resolution imaging platforms, now being used in preclinical drug development,45 are expected to be applied to screening (see Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). Since interpretation of the large quantity of images that are generated requires new processing software, the National Cancer Institute has developed the Lung Imaging Database Consortium to accelerate the development of such software.46
Figure 2. Small-Cell Lung Cancer Detected by Screening.
In Panel A, a prone position CT scan of the chest shows a peripheral 1.1-cm solid nodule in the posterior segment of the right upper lobe (arrowhead). In Panel B, cytopathological features of cells obtained by fine-needle aspiration biopsy are consistent with small-cell carcinoma (hematoxylin and eosin). Images are courtesy of the Early Lung Cancer Action Project.
Management of Small Cancers Detected by Screening
In the Milan cohort,21 all patients with lung nodules that were less than 5 mm in diameter underwent annual repeated CT. Only the nodules that were clearly growing, as shown by annual scanning, were diagnostically evaluated. With the use of this conservative approach, all detected cancers were still found to be stage 1, and there were no cancers detected on the basis of symptoms in the interval between the annual screenings.21 Data are needed to guide the optimal management of small lung cancers that are detected by CT, since the management of these tumors will probably differ from that of larger cancers detected by radiography.23,47,48,49,50
Costs and Cost-Effectiveness
An important concern about widespread CT screening relates to cost. For current smokers, one study projected that the cost of additional health care associated with lung cancer would be $116,300 per quality-adjusted life-year gained; this study used a computer-simulated modeling analysis that was based on assumptions derived from early reports of screening.15 A recently published analysis used actual cost data from a screening study that relied heavily on noninvasive techniques (such as the evaluation of nodule growth by repeated CT scanning at three months) to guide the workup51; this approach was associated with a cost of only $2,500 per person-year of life saved. The great disparity between these estimates underscores the need for further research in this area.
Guidelines from Professional Societies
In a recently updated statement, the American Cancer Society continues to recommend that CT screening not be performed in asymptomatic at-risk persons.52 Recognizing that many persons with a history of heavy smoking are choosing on their own to be screened (despite the fact that such screening is not routinely covered by insurance), the American Cancer Society recommends that such persons first discuss screening with their physicians and that such testing be done only in experienced centers that are linked to multidisciplinary specialty groups for diagnosis and follow-up.52
The U.S. Preventive Services Task Force also has updated its recommendations on the basis of a review of the published literature as of January 2003 (www.ahrq.gov/clinic/uspstf/uspslung.htm). In contrast to its earlier recommendation against screening, the task force now makes no recommendation (either for or against) the use of CT in persons who have no symptoms of lung cancer. If screening is being considered, physicians are advised to discuss with the patient the pros and cons, with an emphasis on the lack of studies showing that screening helps people live longer and on reports that false positive test results are common and can lead to unnecessary worry, testing, and surgery.10
Summary and Recommendations
Although CT screening for the detection of lung cancer has appeared to increase markedly the percentage of cases of lung cancer that are diagnosed in stage 1 among persons with a history of heavy smoking, the results of randomized trials are not yet available to assess whether such screening reduces mortality. Furthermore, the promising results reported from experienced centers may not be readily achieved in other settings. Consequently, many persons who seek screening for lung cancer ― such as the woman described in the vignette, who does not have the equivalent of a 20-pack-year history of smoking and is therefore at low risk for lung cancer ― may have a greater chance of iatrogenic harm than benefit from such screening. At this point, we would not recommend CT screening to such a patient. However, the husband described in the vignette has a smoking history that would be associated with a higher risk. In response to the patient's question, it would be reasonable to discuss the possibility of detection of lung cancer in an early, more curable stage but also the risks, including the possibility of unnecessary invasive procedures. Table 2 summarizes issues to consider in such a discussion. Any patient who is a current smoker should be advised to stop smoking; the evidence in support of this recommendation is far greater than the evidence for CT screening. Patients who are interested in CT screening should be encouraged to participate in screening-management trials designed to help define the best practice.
Table 2. Points about Screening for Lung Cancer to Share with Patients.
The views expressed in this article do not necessarily represent the views of the National Cancer Institute, the National Institutes of Health, or the Department of Health and Human Services.
We are indebted to Sheila Ross and to Drs. Robert Smith, Alfredo Martinez, and David Yankelevitz for helpful discussions.
Source Information
From the Intervention Section, Cell and Cancer Biology Branch, Lung Cancer and Aerodigestive Chemoprevention Faculty, Center for Cancer Research, National Cancer Institute, Bethesda, Md. (J.L.M.); and the Cancer Imaging Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Md. (D.C.S.).
Address reprint requests to Dr. Mulshine at the National Institutes of Health Clinical Center, Rm. 12N226, Cell and Cancer Biology Branch, Bethesda, MD 20892, or at mulshinj@mail.nih.gov.
References
Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8-29.
Patel JD, Bach PB, Kris MG. Lung cancer in US women: a contemporary epidemic. JAMA 2004;291:1763-1768.
Enstrom JE, Heath CW Jr. Smoking cessation and mortality trends among 118,000 Californians, 1960-1997. Epidemiology 1999;10:500-512.
Tong L, Spitz MR, Fueger JJ, Amos CA. Lung carcinoma in former smokers. Cancer 1996;78:1004-1010.
Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst 2003;95:470-478.
Lenfant C. Shattuck lecture: clinical research to clinical practice -- lost in translation? N Engl J Med 2003;349:868-874.
Annual smoking-attributable mortality, years of potential life lost, and economic cost -- United States, 1995-1999. MMWR Morb Mortal Wkly Rep 2002;51:300-303.
Ambrogi V, Pompeo E, Elia S, Pistolese GR, Mineo TC. The impact of cardiovascular comorbidity on the outcome of surgery for stage I and II non-small-cell lung cancer. Eur J Cardiothorac Surg 2003;23:811-817.
Fontana RS. The Mayo Lung Project: a perspective. Cancer 2000;89:Suppl:2352-2355.
Humphrey LL, Teutsch S, Johnson M. Lung cancer screening with sputum cytologic examination, chest radiography, and computed tomography: an update for the U.S. Preventive Services Task Force. Ann Intern Med 2004;140:740-753.
Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99-105.
Henschke CI, Naidich DP, Yankelevitz DF, et al. Early Lung Cancer Action Project: initial findings on repeat screenings. Cancer 2001;92:153-159.
Kaneko M, Kusumoto M, Kobayashi T, et al. CT screening for lung cancer in Japan. Cancer 2000;89:Suppl:2485-2488.
Mulshine JL. Screening for lung cancer: in pursuit of pre-metastatic disease. Nat Rev Cancer 2003;3:65-73.
Mahadevia PJ, Fleisher LA, Frick KD, Eng J, Goodman SN, Powe NR. Lung cancer screening with helical computed tomography in older adult smokers: a decision and cost-effectiveness analysis. JAMA 2003;289:313-322.
Swensen SJ, Jett JR, Midthun DE, Hartman TE. Computer tomographic screening for lung cancer: home run or foul ball? Mayo Clin Proc 2003;78:1187-1188.
Brenner DJ. Radiation risks potentially associated with low-dose CT screening of adult smokers for lung cancer. Radiology 2004;231:440-445.
Sobue T, Moriyama N, Kaneko M, et al. Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol 2002;20:911-920.
Nawa T, Nakagawa T, Kusano S, Kawasaki Y, Sugawara Y, Nakata H. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest 2002;122:15-20.
Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer screening with CT: Mayo Clinic experience. Radiology 2003;226:756-761.
Pastorino U, Bellomi M, Landoni C, et al. Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet 2003;362:593-597.
Kakinuma R. Low-dose helical CT screening for lung cancer: the Japanese experience and perspective. In: Proceedings of the International Association for the Study of Lung Cancer Workshop, Tokyo, November 7, 2003:18. abstract.
Henschke CI, Yankelevitz DF, Naidich DP, et al. CT screening for lung cancer: suspiciousness of nodules according to size on baseline scans. Radiology 2004;231:164-168.
Henschke CI, Yankelevitz DF, Smith JP, et al. CT screening for lung cancer: assessing a regimen's diagnostic performance. Clin Imaging 2004;28:317-321.
Gohagan JK, Marcus PM, Fagerstrom RM, et al. Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer. Lung Cancer 2005;47:9-15.
Mulshine JL, Tockman MS, Smart CR. Considerations in the development of lung cancer screening tools. J Natl Cancer Inst 1989;81:900-906.
Flehinger BJ, Kimmel M, Melamed MR. The effect of surgical treatment on survival from early lung cancer: implications for screening. Chest 1992;101:1013-1018.
Bianchi F, Hu J, Pelosi G, et al. Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clin Cancer Res 2004;10:6023-6028.
Mulshine JL, Weinstein JN. Is the gene expression pattern of lung cancer detected by screening with spiral computed tomography different from that of symptom-detected lung cancer? Clin Cancer Res 2004;10:5973-5974.
Timins JK. Controversies in mammography. N J Med 2005;102:45-49.
Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience. Radiology 2005;235:259-265.
Warner EE, Mulshine JL. Surgical considerations with lung cancer screening. J Surg Oncol 2003;84:1-6.
Sobue T, Suzuki T, Matsuda M, Kuroishi T, Ikeda S, Naruke T. Survival for clinical stage I lung cancer not surgically treated: comparison between screen-detected and symptom-detected cases. Cancer 1992;69:685-692.
Henschke CI, Wisnivesky JP, Yankelevitz DF, Miettinen OS. Small stage I cancers of the lung: genuineness and curability. Lung Cancer 2003;39:327-330.
Yankelevitz DF, Reeves AP, Kostis WJ, Zhao B, Henschke CI. Small pulmonary nodules: volumetrically determined growth rates based on CT evaluation. Radiology 2000;217:251-256.
Hirsch FR, Bunn PA Jr, Dmitrovsky E, et al. IV International Conference on Prevention and Early Detection of Lung Cancer, Reykjavik, Iceland, August 9-12, 2001. Lung Cancer 2002;37:325-344.
van Klaveren RJ, de Koning HJ, Mulshine J, Hirsch FR. Lung cancer screening by spiral CT: what is the optimal target population for screening trials? Lung Cancer 2002;38:243-252.
Smith RA. Lung cancer screening with spiral CT: how can it work, reviewed. Oncology (Huntingt) 2004;18:578-583.
Warner EE, Mulshine JL. Lung cancer screening with spiral CT: toward a working strategy. Oncology (Huntingt) 2004;18:564-575.
Cox LS, Clark MM, Jett JR, et al. Change in smoking status after spiral chest computed tomography scan screening. Cancer 2003;98:2495-2501.
Ostroff JS, Buckshee N, Mancuso CA, Yankelevitz DF, Henschke CI. Smoking cessation following CT screening for early detection of lung cancer. Prev Med 2001;33:613-621.
Sackett DL, Wennberg JE. Choosing the best research design for each question. BMJ 1997;315:1636-1636.
Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887-1892.
Kostis WJ, Reeves AP, Yankelevitz DF, Henschke CI. Three-dimensional segmentation and growth-rate estimation of small pulmonary nodules in helical CT images. IEEE Trans Med Imaging 2003;22:1259-1274.
Kiessling F, Greschus S, Lichy MP, et al. Volumetric computed tomography (VCT): a new technology for noninvasive, high-resolution monitoring of tumor angiogenesis. Nat Med 2004;10:1133-1138.
Clarke LP, Croft BY, Staab E, Baker H, Sullivan DC. National Cancer Institute initiative: lung image database resource for imaging research. Acad Radiol 2001;8:447-450.
Asamura H, Suzuki K, Watanabe S, Matsuno Y, Maeshima A, Tsuchiya R. A clinicopathological study of resected subcentimeter lung cancers: a favorable prognosis for ground glass opacity lesions. Ann Thorac Surg 2003;76:1016-1022.
Okada M, Yoshikawa K, Hatta T, Tsu-bota N. Is segmentectomy with lymph node assessment an alternative to lobectomy for non-small cell lung cancer of 2 cm or smaller? Ann Thorac Surg 2001;71:956-960.
Sugarbaker DJ, Strauss GM. Extent of surgery and survival in early lung carcinoma: implications for overdiagnosis in stage IA nonsmall cell lung carcinoma. Cancer 2000;89:Suppl:2432-2437.
Tsushima Y, Endo K. Analysis models to assess cost effectiveness of the four strategies for the work-up of solitary pulmonary nodules. Med Sci Monit 2004;10:MT65-MT72.
Wisnivesky JP, Mushlin AI, Sicherman N, Henschke C. The cost-effectiveness of low-dose CT screening for lung cancer: preliminary results of baseline screening. Chest 2003;124:614-621.
Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer, 2004. CA Cancer J Clin 2004;54:41-52.
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