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Ann Thorac Surg 2001;71:425-433
© 2001 The Society of Thoracic Surgeons

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Original article: general thoracic

Investigating extrathoracic metastatic disease in patients with apparently operable lung cancer^*

^a Dalhousie University, Halifax, Nova Scotia, Canada
^b Laval University, Quebec City, Quebec, Canada
^c University of Ottawa, Ottawa, Ontario, Canada
^d University of Toronto, Toronto, Ontario, Canada
^e McMaster University, Hamilton, Ontario, Canada
^f University of Western Ontario, London, Ontario, Canada
^g University of British Columbia, Vancouver, British Columbia, Canada

Accepted for publication June 1, 2000.

Address reprint requests to Dr Guyatt, Department of Clinical Epidemiology and Biostatistics, McMaster University Health Sciences Center, Room 2C12, 1200 Main St W, Hamilton, ON, Canada, L8N 3Z5
e-mail: guyatt{at}mcmaster.ca

	Abstract

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

 
Background. The optimal approach to the investigation of possible distant metastases in patients with apparently operable non–small cell lung cancer who do not have symptoms suggesting metastatic disease is controversial.

Methods. We conducted a randomized, controlled trial in thoracic surgery services at mainly academic tertiary- and secondary-care general hospitals. We recruited 634 patients with apparently operable, suspected or proven non–small cell carcinoma of the lung without findings on history, physical examination, laboratory testing, or imaging suggesting extrathoracic metastases. Patients were randomly allocated to receive either mediastinoscopy and computed tomography of the chest and then, depending on the results, immediate thoracotomy or bone scintigraphy and computed tomographic scanning of the head, liver, and adrenal glands.

Results. The relative risk of thoracotomy without cure (the combination of open and closed thoracotomy, incomplete resection, and thoracotomy with subsequent recurrence) in the full investigation group versus the limited investigation group was 0.80 (95% confidence interval [CI], 0.56 to 1.13; p = 0.20). Forty-three patients in the full investigation group and 61 patients in the limited investigation group underwent a thoracotomy but subsequently had recurrence (relative risk, 0.70; 95% CI, 0.47 to 1.03; p = 0.07). Patients in the full investigation group were more likely to have avoided thoracotomy because of extrathoracic metastatic disease than those in the limited investigation group (22 patients versus 10 patients, respectively; relative risk, 2.19; 95% CI, 1.04 to 4.59; p value = 0.04). The total number of negative invasive tests was six in the full investigation group and one in the limited investigation group (relative risk, 6.1; 95% CI, 0.72 to 51.0; p = 0.10) and the total number of invasive tests, 11 versus six, respectively (relative risk, 1.84; 95% CI, 0.68 to 4.98; p = 0.23). The full investigation strategy cost $823 less per patient (95% CIs 2,482 to -725).

Conclusions. Full investigation for metastatic disease in patients with non–small cell lung cancer without symptoms or signs of metastatic disease may reduce the number of thoracotomies without cure. The higher the threshold for considering symptoms to suggest metastatic disease, the more likely it is that investigation will spare patients futile thoracotomy.

	Introduction

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

 
Despite advances in the management of non–small cell lung cancer, recurrence rates after "curative" surgical procedures remain high [1–3]. Many patients have disseminated disease undetected at the time of thoracotomy, and this is the most likely cause of treatment failure and ultimate death. Because imaging may reveal metastatic disease at the time of presentation in up to 50% of patients with abnormalities in history, physical examination, or simple laboratory tests [4], thus preventing noncurative surgical procedures, such patients require additional investigation.

In patients with a negative history, a negative physical examination, and a negative initial laboratory screening, the incidence of metastatic disease is much lower [5]. For this patient group, recommendations differ. Some authors [6–9] advocate proceeding immediately to thoracotomy. Others suggest a more aggressive approach to rule out clinically occult but detectable metastases. These groups suggest that imaging of the adrenal glands [10], head [11], bones [12], liver [13], or some combination of these [14–16] be included in the investigation before thoracotomy in all patients with lung cancer.

Clinicians disagree about the desirable extent of imaging investigations in patients with non–small cell lung cancer and a negative screening evaluation because the frequency with which imaging will detect otherwise occult metastatic disease (and thus prevent an unnecessary thoracotomy) is probably lower than 10%, but just how much lower is not certain. Clinicians also disagree about how low the yield must be to justify proceeding directly to thoracotomy. This threshold will depend on the number of false-positive imaging procedures, the value attached to these false-positive scans and their consequences, the value attached to avoiding a thoracotomy without cure, and the costs of the alternative investigational strategies [2].

To help resolve this controversy, we conducted a randomized trial of patients with non–small cell lung cancer in whom initial systematic history, physical examination, laboratory tests, and examination for mediastinal disease failed to suggest metastatic disease. Patients went straight to thoracotomy or underwent additional imaging procedures (computed tomography [CT] of the head and abdomen and bone scan).

The intent of an aggressive investigational strategy in patients with presumed operable non–small cell lung cancer is to detect those with occult metastatic disease at the time of presentation and spare such patients an unnecessary thoracotomy. If the full investigation approach succeeded in this goal, one would expect a greater number of thoracotomies without cure in a comparable group of patients receiving only limited investigation. These thoracotomies without cure would include exploratory thoracotomies, incomplete resections, and apparently successful thoracotomies with subsequent recurrence. This reasoning led us to focus on thoracotomies without cure—most commonly resection with subsequent recurrence—as the primary outcome of interest in our trial.

	Material and methods

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

 
Eligibility
We considered all patients with apparently operable non–small cell lung cancer referred to participating surgeons in one of 11 clinical centers in seven cities. We excluded patients with findings on history, physical examination, laboratory testing, or imaging that suggested extrathoracic metastases. These findings included symptoms or signs suggesting central nervous system involvement (including new or unusual headaches in the prior 6 months, weakness or sensory changes, dizziness or unsteadiness of gait, and neurological findings on physical examination), symptoms or signs suggesting bony involvement distant from the site of the primary lesion (including persistent pain or tenderness localized over a bony surface distant from the site of the primary lesion), serum alkaline phosphatase value greater than 1.5 times the laboratory’s upper limit of normal, and other findings on history or physical examination, chest radiograph, or CT of the chest suggesting unresectable disease.

We excluded four other categories of patients: those medically unfit for operation; patients who, at the time of initial consultation, had already undergone one of the tests under investigation (bone scan, CT of head, or CT of abdomen); patients with previously treated carcinoma other than nonmelanotic skin cancer or in situ carcinoma of the cervix; and those who were unwilling or unable to give informed consent.

To standardize their approach to the threshold of history and physical examination findings that would exclude patients from the study, participating surgeons met before the start of the study. They agreed to take a conservative approach and to exclude patients with any more than minimal symptoms or signs that might suggest extrapulmonary metastatic disease [17].

Randomization
We stratified patients by center and by whether they had lost 10% of their body weight in the last 6 months. We randomized patients within each stratum in blocks of 4 according to a computer-generated random number table to limited or full investigation. Clinical centers with eligible patients contacted the methods center, which confirmed eligibility and informed the caller of the arm to which the patient was allocated, thus ensuring concealment of randomization.

Interventions
Patients allocated to the limited investigation group underwent CT of the chest and mediastinoscopy. In the absence of major mediastinal disease on CT, mediastinoscopy, or both, they underwent thoracotomy.

Patients allocated to the full investigation group underwent bone scintigraphy and CT of the chest, liver, adrenal glands, and head in most patients after a mediastinoscopy. We developed uniform standards for the conduct and interpretation of the imaging procedures. Computed tomographic scan of the liver included infusion of 100 mL of iodinated contrast medium (300 mL of iodine per milliliter of contrast medium) at an injection rate of 1 mL/s with a 20-second scan delay. A minimum of 1-cm collimated contiguous slices was obtained. The CT scan of the head with contrast medium with 5-mm collimation was done contiguously. Hepatic lesions were further assessed by ultrasound, and percutaneous biopsy of those that were still suggestive of malignancy was done to obtain a definitive histological diagnosis. We required histological confirmation for all adrenal lesions greater than 1.5 cm in diameter and a repeat CT scan and a characteristic clinical course for diagnosis of brain metastases. For positive bone scans, additional investigations included plain radiography, CT, and, in select patients, needle aspiration biopsy to obtain a histological diagnosis of suspected metastases.

Measurement of outcome
The participating surgeons reviewed patients at 6 weeks, 3 months, and then at 3-month intervals for the first year after thoracotomy. At 1 year, we offered all patients, with the exception of those in whom a definitive diagnosis of recurrent disease had already been made, chest radiography, CT of the chest, abdomen, and head, and bone scanning. Patients with positive or equivocal results underwent further investigation as appropriate. When patients declined imaging procedures at 1 year, we followed them for an additional year (a total of 2 years of follow-up).

A central adjudication committee, blind to allocation, reviewed every patient’s records, which included information collected for the study and recorded on study data collection forms as well as copies of documents from the patient’s chart. The committee comprised 2 clinical epidemiologists and 4 thoracic surgeons. The epidemiologists and 2 of the 4 surgeons (a total of 4 adjudicators) independently reviewed each patient’s chart.

The adjudication committee determined if patients had benign or malignant disease. For those who underwent thoracotomy, the committee classified patients as being disease free or as having had recurrence. They classified recurrence as intrathoracic or extrathoracic, and specified the first site of recurrence. The committee members made their initial judgments independently and resolved disagreement by consensus.

Research staff classified patients who did not have thoracotomy according to the reason. In the case of patients for whom the reason was discovery of extrathoracic metastatic disease before operation, the 2 principal investigators independently reviewed the decisions. The 2 reviewers agreed in all but one case which they resolved by consensus.

Before beginning data analysis, we specified a hierarchy of outcomes, from those most important and likely to be affected by the intervention to those least likely to be affected. We reasoned that occult metastases detected by full investigation but missed in the limited investigation were most likely to first appear as extrathoracic metastases. Thus, thoracotomy with subsequent appearance of extrathoracic metastases before any other metastases was the outcome at the top of our hierarchy. We then added thoracotomy with subsequent simultaneous appearance of distant and local metastases. Because both groups had radiologically detectable intrathoracic disease ruled out by thoracic CT, we anticipated that differences in intrathoracic metastases would be less likely. Thus, thoracotomy with any subsequent appearance of metastases was lowest in our hierarchy.

We defined thoracotomy without cure as the combination of an exploratory thoracotomy, unresectable disease at thoracotomy, and thoracotomy with subsequent recurrence. We specified in advance that additional outcomes of interest included the number of patients with benign disease undergoing thoracotomy, and the combined outcome of thoracotomy without cure and thoracotomy in patients with benign disease. We also analyzed deaths and the number of mediastinoscopies separately.

Some patients with apparently resectable lung cancer prove to have benign disease. Occasionally, this is discovered at the time of thoracotomy. One might expect that during the process of investigation for distant metastases, findings that suggest benign disease could emerge, and these findings might obviate the need of a thoracotomy. Thus, the more extensive investigation strategy might also save patients with benign disease an unnecessary thoracotomy. In a previous randomized trial [18], our data suggested that CT scanning of the chest, in contrast to no CT and mediastinoscopy for all patients, reduced the number of thoracotomies in patients with benign disease. We therefore included the number of thoracotomies in patients with benign disease as another important outcome in the current study. Further, we added thoracotomies without cure to thoracotomies in patients with benign disease to create a combined end point we called "unnecessary thoracotomy."

Economic analysis
Using a similar model to one we used previously [18], we determined the costs per patient by prospective collection of data on the type and quantity of services used by each patient. These resource items were then multiplied by the unit price of each service and summed across all services. We documented duration of stay in hospital, time in thoracic surgical wards, intensive care units, and step-down units and documented all major procedures. We adopted a restricted viewpoint, that of the Ontario Ministry of Health, for economic analysis of hospital and imaging costs. The data for the economic analysis came from the period after randomization through initial investigation and treatment, including thoracotomy. We determined the unit price of each service using a model of full allocation of costs conducted for one of the participating hospitals in Ontario. These costs are in 1998 Canadian dollars, and we provide here an indication of the magnitude of Canadian costs by showing our cost estimates for the following: a day on a surgical ward, $595; a day in the intensive care unit with mechanical ventilation, $2,230.50; professional fee for a CT scan of the head, $51.00; total cost of CT of the head, $170.85; professional fee for a lobectomy (including surgeon, surgical assistant, and anesthetist), $1,444.08; and total cost of a lobectomy, $2,569.08.

Statistical analysis
We used Mantel-Haenszel ² analysis allowing for stratification by center and weight loss to compare the proportions of outcomes in the two groups, and calculated relative risks and the associated confidence intervals (CIs). Our primary analysis was adjusted only for the stratification variables; secondary analysis adjusted for a wide variety of baseline characteristics. Because the adjusted analysis yielded essentially the same results as the primary analysis, we report only the latter.

For costs, the skewed distribution dictated use of nonparametric methods. We used a bootstrapping approach to calculate the 95% CIs for the difference between mean hospital costs, patient costs, and total costs in the two groups [19].

The principal investigators and the data analyst were blind to patient groups (that is, they viewed results of the primary outcomes only as group A and group B) until the primary analyses were complete. A group of thoracic surgeon study investigators reviewed the blinded results and commented on additional analyses required, and interpretation of the results, before the analysis was unblinded.

	Results

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

 
Recruitment and patient characteristics
We randomized the first patient in January 1992 and the final patient in September 1995 and saw the last patient in follow-up in August 1997. We reviewed 2,222 patients of whom 1,588 were ineligible (Table 1). Because patients often had more than one reason for being ineligible, the number in Table 1 is greater than the number of ineligible patients. Examples of "other" reasons for ineligibility include cognitive impairment, pregnancy, and bilateral lung lesions. We randomized the remaining 634 patients, 318 to full investigation and 316 to limited investigation. The two groups were similar on all key characteristics (Table 2).

Investigations undertaken
Full investigation group
Of the 318 patients randomized to full investigation, 315 underwent a CT scan of the chest, 306 underwent CT of the head, 308 had CT of the abdomen, and 302 underwent bone scanning. Of the 7 patients who did not have any of the tests that were part of the full investigation strategy done, administrative error was responsible in 1 patient; the lesion disappeared from the chest radiograph before tests were done in 3; mediastinoscopy showed unresectable disease, and chemotherapy was initiated without further investigation in 1; and 2 patients refused the tests. Fourteen patients received one or more tests, but testing was not complete; in 3 the attending physician concluded the patient had benign disease before scanning was complete; administrative error was responsible in 4; 4 patients refused; metastatic disease on a prior test made further investigation redundant in 1; renal failure contraindicated use of contrast medium in 1; and 1 patient died before the investigation was complete. Table 3 presents the final pathological staging.

Comparisons of primary and secondary outcomes of full and limited investigation strategies
Table 4 presents the key outcomes of the study. In this table and in the text, we present all relative risks in the full investigation group versus the limited investigation group. Thus, relative risks greater than 1 suggest an increased risk in the full investigation group, and relative risks less than 1 suggest a decreased risk in the full investigation group.

Forty-three patients in the full investigation group and 61 patients in the limited investigation group underwent a thoracotomy but subsequently had recurrence (relative risk, 0.70; 95% CI, 0.47 to 1.03; p = 0.07). Table 5 lists the sites of recurrence in these patients. The largest difference between the two groups in recurrences is not found where one might expect it, that is, in recurrences that first appeared in extrathoracic sites. Rather, the major differences between groups are in recurrences that were both intrathoracic and extrathoracic at the time of presentation and those that were only intrathoracic.

Comparison of costs
Table 7 summarizes the comparison of costs. Costs of the imaging investigations are divided between professional costs and hospital costs. Because of additional costs associated with the imaging investigations, the average professional fees for the full investigation group were approximately $200 greater than for the limited investigation group, and this difference was significant. However, differences in total costs were influenced more by the additional surgical procedures, particularly thoracotomies, in the limited investigation group. Thus, mean overall costs were approximately $800 greater in the limited investigation group, though the difference between groups may have been from chance.

	Comment

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

For those patients who did not have a thoracotomy, we examined the reasons (see Table 6). We found that a greater number of patients undergoing full investigation (22 patients) than undergoing limited investigation (10 patients) avoided a thoracotomy on the basis of extrathoracic metastatic disease (p = 0.04). This suggests the possibility that the extensive workup prevented 12 futile thoracotomies that would otherwise have been undertaken.

Table 5 supports these findings in that the number of patients with recurrence was 61 in the limited investigation group and 43 in the full investigation group (relative risk, 0.70; 95% CI, 0.47 to 1.03; p = 0.07). On the other hand, the distribution of sites of recurrence raises some questions about this difference. Consider the case of patients in whom full investigation at the time of diagnosis reveals distant metastases, but who are otherwise eligible for surgical intervention. Such patients, if studies are not done, proceed to thoracotomy. One would expect that at some subsequent time, these patients will be seen with symptoms and signs of the distant metastases that were present and potentially detectable at the time of thoracotomy. Possibly they will have simultaneous distant and local metastases. Least likely is a presentation with local metastases only.

Table 5 shows that the number of patients who underwent thoracotomy and who subsequently were seen with extrathoracic metastases first was virtually identical in the full investigation and limited investigation groups. The differences in the category "thoracotomy without cure" resulted from larger numbers of patients in the limited investigation group who were seen with "distant and local disease simultaneously" or who were seen with "intrathoracic disease" only. These results resulted from a reduction in thoracotomy without cure as a result of discovery of metastatic disease at the time of initial investigation in the full investigation group, but they are also consistent with chance differences in thoracotomy without cure in the two groups.

Therefore, although the data provide only limited support for patient benefit from full investigation, there appears little evidence of harm. We did find an increase in the number of fruitless invasive investigations searching for liver, adrenal gland, and bone metastases, but the difference between the full investigation (six negative biopsy results) and limited investigation (one negative biopsy result) groups was small.

Table 7 shows a significant cost difference of more than $200 in professional fees between the two groups. Professional costs associated with the imaging procedures, greater in the full investigation group, are responsible for the difference. However, hospital costs were more than $1,000 higher in the limited investigation group, a difference that, assuming no true difference between groups, is consistent with a chance effect. This difference is responsible for the trend toward greater overall costs in the limited investigation group and is from the greater number of thoracotomies in that group. If this difference is a chance phenomenon (that is, in the long run hospital costs would be the same in the two strategies), true costs would be ultimately greater in the full investigation group because of additional procedures, though the difference would be small.

How widely can these costs be generalized? Most health care costs in the United States are higher than in Canada, and this general difference would tend to inflate the cost difference between treatment groups in the former country. However, this assumes that the ratio of professional fees to hospital costs (that is, relative prices) are similar in the United States and Canada, an assumption that may not be true.

Some patients proved to have benign disease. The reason is that, for some patients, surgeons make the decision about the extent of imaging investigations before they have a definitive diagnosis. For instance, in a heavy smoker with a newly discovered nodule, the surgeon will decide on the investigational approach before conducting the invasive tests required for a histological diagnosis. We designed our study to reflect real-world practice. In the real world, the choice of diagnostic approach will influence the outcome of some patients who ultimately prove to have benign disease, and it is therefore appropriate to include the clinical and economic outcomes of these patients in the analysis.

Aspects of the design and implementation of this study make it likely that we obtained an unbiased assessment of the impact of imaging the abdomen, brain, and bone versus proceeding, after mediastinoscopy and CT of the chest, straight to thoracotomy. These include the concealed randomization, intention-to-treat analysis, blinding of the adjudication of outcome, and the 100% follow-up of randomized patients.

Critical to the interpretation of our data is the issue of what constitutes an asymptomatic patient. Investigators have repeatedly demonstrated that symptomatic patients have a far higher risk of metastatic disease in the brain, bone, and liver than do asymptomatic patients, but they have left the definition of what constitutes a symptomatic patient unspecified or poorly defined. Clinicians have considerable room for interpretation in this regard. For instance, does a patient with mild, chronic, unchanged headaches have symptoms suggestive of brain metastases warranting a CT head scan?

In the current study, we went to considerable effort to standardize the interpretation of what constitutes symptoms suggesting metastatic disease [17]. We were generally successful, and participating surgeons used conservative criteria, excluding most patients with even mild symptoms [17]. However, even among the study participants, there was some heterogeneity. Further, the patients with mild symptoms enrolled in the trial were more likely to have occult metastatic disease than participants who had no symptoms at all [17]. These findings strongly suggest that our results are applicable only when surgeons use conservative criteria for what they regard to be symptoms suggestive of metastatic disease, and our results are not generalizable to surgeons using a higher threshold of what they regard to be symptoms mandating further imaging investigations.

In summary, our methodologically rigorous randomized trial provides some support for extensive investigation for extrathoracic metastases in patients without suggestive symptoms or signs. Our findings apply directly to situations where clinicians use conservative criteria for deciding on the presence of new symptoms that raise the suspicion of brain, bone, or abdominal metastases. If clinicians use less conservative criteria, the case for extensive investigation becomes even stronger.

	Acknowledgments

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

 
We thank Gordon Blackhouse, MBA, for his help with the bootstrapping approach we used for the economic analysis.

Dr Deborah J. Cook is a Career Scientist of the Ontario Ministry of Health. Dr Bernie O’Brien is supported by a career award in health sciences from the Medical Research Council and Prescription Drug Manufacturer’s Association of Canada.

This study was supported by the Ontario Ministry of Health and the National Cancer Institute of Canada.

We acknowledge the following for their important contribution to the conduct of the study: Chenta Bhatt, HRT, Robert Campbell, MD, Christine Clark, Debbie DesLauriers, RN, Jane Flett, RN, Melvyn Goldberg, MD, Geralynn Hirsch, RN, Frances Y. L. Hui, BSc, Joel Kirsh, MD, Daniel Rappaport, MD, Harold J. Sachs, MD, Kathy Yip, MD, and Natalie Zankowicz, BScN.

	Footnotes

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

 
^* The authors, including their roles in the project, are listed in the Appendix.

	Appendix. Members of the Canadian Lung Oncology Group who participated in this study and their roles

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

 
Protocol Development: Gordon H. Guyatt, MD (Chair of Protocol Development and Co-principal Investigator), Drew C. G. Bethune, MD, Jean Deslauriers, MD, Richard I. Inculet, MD, Michael S. Lefcoe, MD, Timothy L. Winton, MD, Farid M. Shamji, MD, Thomas R. J. Todd, MD, and Stephen D. Walter, PhD

Study Coordination: Deborah J. Cook, MD (Chair and Co-principal Investigator), Gordon H. Guyatt, MD, Lisa A. Buckingham, BA, J. Suzanne Duchesne, Humaira Khan, BA, and Susan M. Troyan, BA

Radiology Coordination: Michael S. Lefcoe, MD

Recruitment and Follow-up:

Halifax: Drew C. G. Bethune, MD (Center Coordinator), Claude Bugden, MD, and Myrna Yazer, RN, BN

Quebec City: Jean Deslauriers, MD (Center Coordinator), Pierre Bedard, BScN, Guy Carrier, MD, Sylvie Ferland, MD, and Brigitte Fournier, BScN

Hamilton: John D. Miller, MD (Center Coordinator), W. Fred Bennett, MD, Ellen McDonald, RN, and Raymond P. Torbiak, MD

Ottawa: Farid M. Shamji, MD (Center Coordinator), Gary Marryatt, Fred R. Matzinger, MD, and Kenneth R. Reid, MD

Toronto: Timothy L. Winton, MD (Center Coordinator), Gail E. Darling, MD, Aaron Hendler, MD, Stephen Herman, MD, Michael R. Johnston, MD, Donald P. Jones, MD, Margaret Keresteci, BA, Shafique Keshavjee, MD, Martin F. McKneally, MD, F. Griffith Pearson, MD, Robyn Pugash, MD, Robert Bruce, MD, Susan M. Rosgen, RN, CCRA, Marvin Steinhardt, MD, and Thomas R. J. Todd, MD

London: Richard I. Inculet, MD (Center Coordinator), Alan G. Casson, MB, Michael S. Lefcoe, MD, and Richard A. Malthaner, MD

Vancouver: Joanne Clifton, BA (Center Coordinator), Kenneth G. Evans, MD, Richard J. Finley, MD, Guy Fradet, MD, Nestor L. Muller, MD, Bill Nelems, MD, and Catherine Staples, MD

Adjudication: Gordon H. Guyatt, MD (Chair), Deborah J. Cook, MD, Gail E. Darling, MD, Richard I. Inculet, MD, Michael R. Johnston, MD, and Timothy L. Winton, MD

Economic Analysis: Bernie O’Brien, PhD (Chair), Ron Goeree, MA, and Lauren E. Griffith, MSc

Statistical Analysis: Lauren E. Griffith, MSc, and Stephen D. Walter, PhD, with the participation of Gordon H. Guyatt, MD, and Deborah J. Cook, MD

Writing Committee: Gordon H. Guyatt, MD (Chair), Alan G. Casson, MB, Deborah J. Cook, MD, Jean Deslauriers, MD, Lauren E. Griffith, MSc, Richard I. Inculet, MD, Michael R. Johnston, MD, Michael S. Lefcoe, MD, John D. Miller, MD, Bernie O’Brien, PhD, Thomas R. J. Todd, MD, and Timothy L. Winton, MD

	References

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments Appendix. Members of the... References

 

1. Naruke T., Goya T., Tsuchiya R., Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988;96:440-447.[Abstract]
2. Conill C., Astudillo J., Verger E. Prognostic significance of metastases to mediastinal lymph node levels in resected non–small cell lung carcinoma. Cancer 1993;72:1199-1202.[Medline]
3. Mountain C.F. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
4. Silvestri G.A., Littenberg B., Colice G.L. The clinical evaluation for detecting metastatic lung cancer. A meta-analysis. Am J Respir Crit Care Med 1995;152:225-230.[Abstract]
5. Hillers T.K., Sauve M.D., Guyatt G.H. Analysis of published studies on the detection of extrathoracic metastases in patients presumed to have operable non–small cell lung cancer. Thorax 1994;49:14-19.[Abstract/Free Full Text]
6. Ramsdell J.W., Peters R.M., Taylor A.T., Jr, Alazraki N.P., Tisi G.M. Multiorgan scans for staging lung cancer. Correlation with clinical evaluation. J Thorac Cardiovasc Surg 1977;73:653-659.[Abstract]
7. Hooper R.G., Beechler C.R., Johnson M.C. Radioisotope scanning in the initial staging of bronchogenic carcinoma. Am Rev Respir Dis 1978;118:279-286.[Medline]
8. Donato A.T., Ammerman E.G., Sullesta O. Bone scanning in the evaluation of patients with lung cancer. Ann Thorac Surg 1979;27:300-304.[Abstract]
9. Johnston M.R. Selecting patients with lung cancer for surgical therapy. Semin Oncol 1988;15:246-254.[Medline]
10. Sandler M.A., Pearlberg J.L., Madrazo B.L., Gitschlag K.M., Gross S.C. Computed tomographic evaluation of the adrenal gland in the preoperative assessment of bronchogenic carcinoma. Radiology 1982;145:733-736.[Free Full Text]
11. Butler A.R., Leo J.S., Lin J.P., Boyd A.D., Kricheff I.I. The value of routine cranial computed tomography in neurologically intact patients with primary carcinoma of the lung. Radiology 1979;131:399-401.[Abstract]
12. Matthews M.J., Kanhouwa S., Pickren J., Robinette D. Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer Chemother Rep 1973;4:63-67.
13. Heitzman R.E. The role of computed tomography in the diagnosis and management of lung cancer: an overview. Chest 1986;98:237-241.[Abstract/Free Full Text]
14. Hayes T.P., Davis L.W., Raventos A. Brain and liver scans in the evaluation of lung cancer patients. Cancer 1971;27:362-363.[Medline]
15. Modini C., Passariello R., Iascone C., et al. TMN staging in lung cancer. Role of computed tomography. J Thorac Cardiovasc Surg 1982;84:569-574.[Abstract]
16. Kelly R.J., Cowan R.J., Ferree C.B., Raben M., Maynard D.C. Efficacy of radionuclide scanning in patients with lung cancer. JAMA 1979;242:2855-2857.[Abstract]
17. Guyatt G.H., Cook D.J., Griffith L.E., et al. Surgeons’ assessment of symptoms suggesting extrathoracic metastases in patients with lung cancer. Ann Thorac Surg 1999;68:309-315.[Abstract/Free Full Text]
18. Canadian Lung Oncology Group. Investigation for mediastinal disease in patients with apparently operable lung cancer. Ann Thorac Surg 1995;60:1382-1389.[Abstract/Free Full Text]
19. Briggs A.H., Wonderling D.E., Mooney C.Z. Pulling cost-effectiveness analysis up by its bootstraps: a non-parametric approach to confidence interval estimation. Health Econ 1997;6:327-340.[Medline]

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