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Ann Thorac Surg 1999;68:309-315
© 1999 The Society of Thoracic Surgeons

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Original Articles

Surgeons’ assessment of symptoms suggesting extrathoracic metastases in patients with lung cancer^*

^a Department of Clinical Epidemiology and Biostatistics, McMaster University Health Sciences Center, Hamilton, Canada
^b Department of Surgery, McMaster University Health Sciences Center, Hamilton, Canada
^c Department of Surgery, University of Toronto, Toronto, Canada
^d Department of Surgery, Dalhousie University, Halifax, Canada
^e Department of Surgery, University of Western Ontario, London, Canada
^f Department of Surgery, University of British Columbia, Vancouver, Canada
^g Department of Thoracic Surgery, Laval University, Quebec City, Canada

Address reprint requests to Dr Guyatt, Department of Clinical Epidemiology and Biostatistics, McMaster University Health Sciences Center, Room 2C12, 1200 Main St West, Hamilton, ON L8N 3Z5, Canada

	Abstract

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Background. In patients with apparently operable non-small cell lung cancer (NSCLC), clinicians often omit investigation for M disease in asymptomatic patients. Previous investigations have not specified in detail what is meant by "symptomatic," and this could differ between surgeons. We have investigated the extent to which surgeons’ criteria differ for presence of symptoms.

Methods. Participating surgeons from seven centers, enrolled patients they judged "asymptomatic" in a randomized trial of investigational strategies for NSCLC. Patients completed a structured questionnaire describing symptoms of the central nervous system (CNS). In 685 patients, we documented CNS symptom recurrence after resectional surgery over 1 year of follow-up.

Results. Two centers enrolled only patients without even the mildest symptoms. Three centers took an intermediate approach, occasionally classifying patients with mild symptoms as "asymptomatic" and thus enrolling them in the trial. Two centers classified an appreciable number of patients with minimal symptoms, and occasionally with more than minimal symptoms, as "asymptomatic." Patients with even mild CNS symptoms were more likely to subsequently present with CNS metastases.

Conclusions. Thoracic surgeons differ in their ideas of what may constitute the symptoms of M disease. Patients with structured questionnaire results that suggest symptoms of CNS disease are more likely to have CNS symptom recurrence after resectional surgery.

	Introduction

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Patients presenting with non-small cell lung cancer (NSCLC) who have extrathoracic metastases will not benefit from resectional surgery. Therefore, clinicians often undertake imaging investigations in patients in whom history or physical examination suggests metastatic disease [1]. When history and physical examination do not suggest metastatic disease, the value of additional imaging is far less certain and, in the absence of mediastinal disease, many clinicians will forego additional imaging and proceed directly to thoracotomy [2–6].

What constitutes a positive history may not be self-evident. For instance, if a patient has had mild weekly headaches for the previous 6 months, does his history suggest brain metastases? If he has chronic back pain that has been worse than usual for the previous 3 months, should the clinician seriously consider bone metastases?

To resolve the controversy regarding the possible benefit of imaging for extrathoracic metastases, we conducted a randomized trial in patients with NSCLC. We enrolled patients in whom initial systematic history, physical examination, laboratory tests, and examination for mediastinal disease failed to suggest metastatic disease. Patients who were not suspected of having metastatic disease were then randomized, proceeding directly to thoracotomy or undergoing additional imaging procedures, namely head computerized tomographic (CT) scan, bone scan, and abdominal CT scan, before considering thoracotomy. We are currently completing follow-up of patients enrolled in this study.

A crucial issue in our trial was which patients should participate. For instance, should we enroll the 2 patients described above who have some, perhaps minimal, suggestion that they might have metastatic disease? Implicit in this question is whether surgeons differ in their criteria, classifying patients as "positive" (suggestion of metastatic disease, further investigation necessary) or "negative" (no suggestion of metastatic disease, proceeding directly to thoracotomy should be considered) after taking a history. Our trial provided an opportunity to examine the consistency with which clinicians make the judgement of whether patients have symptoms of extrathoracic disease mandating additional imaging procedures.

	Patients and methods

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We considered all NSCLC patients referred to participating surgeons in seven clinical centers (Halifax, Quebec City, Ottawa, Toronto, Hamilton, London, Vancouver). We excluded all patients who met any of the following criteria: (1) Findings on history, physical examination, or testing suggesting extra thoracic metastases, including: symptoms or signs suggesting central nervous system (CNS) involvement such as new severe headaches, or motor or sensory changes; symptoms or signs suggesting bone involvement, such as new bone pain; elevated alkaline phosphatase (1.3 times the upper limit of the local laboratory on two occasions); other findings suggesting unresectable disease, including gross mediastinal disease, superior vena cava syndrome, metastases to the contralateral lung, scalene lymph node involvement, malignant pleural effusion, or recurrent laryngeal nerve palsy. (2) Medically unfit for surgery. (3) Patients presenting with one of the tests under investigation (bone scan, CT of head, CT of abdomen) already performed. (4) Unwillingness or inability to give informed consent.

Participating surgeons met before the start of the study to standardize the history and physical examination findings that would exclude patients from the study. To facilitate this discussion, the surgeons considered 4 case scenarios: a patient with mild headaches for 2 weeks, a patient with mild headaches for 3 months, an asymptomatic patient with a liver margin 4 cm below the right costal margin, and a patient with recent exacerbation of chronic, recurrent back pain. Essentially, the participants agreed to take a conservative approach and to exclude patients with more than minimal symptoms or signs suggesting extra pulmonary metastatic disease.

Study surgeons documented new referrals of patients with NSCLC. They decided if patients were eligible, and if not they noted the reason for ineligibility. The present report considers 2 groups of patients. The first are those who met inclusion criteria and were enrolled in the study. The second group are those who were excluded because of histories suggesting metastatic disease to the CNS, or to bone.

Symptom questionnaire
Study nurses participated in a short training session in which they received basic instruction in questionnaire administration. These nurses met, independently of the surgeons, with both included and excluded patients. Included patients and those excluded because of a suspicion of metastatic disease completed a questionnaire inquiring about their symptoms. The questionnaire asked about CNS-associated symptoms, including headache, unusual sensations, dizziness, and pain or tenderness that might be associated with bony metastases. Responses to these questions were assigned to a 5 point scale. For example, the response options for headache were as follows: (1) I never get headaches. (2) I rarely get headaches. (3) I sometimes get headaches but they have not changed in the last 6 months. (4) I sometimes get headaches that are worse (more frequent or severe) the last 6 months. (5) During the last 6 months, I have gotten severe headaches that I never had before.

Similarly, response options for unusual sensations spanned the range from no unusual sensations or numbness, to symptoms some of the time, to frequent and severe unusual sensations or numbness. Response options for balance problems ranged from not feeling dizzy or unsteady at all, to some dizziness, to suffering from severe dizziness or unsteadiness in the last 6 months. Symptoms of bone involvement ranged from no pain or tenderness over any bones, to some pain, to severe pain and tenderness over the bones. As with headache, response options were also based on the symptom being a change from the patient’s usual state.

For liver imaging, we accepted lesions that were both multiple and characteristic of metastases; other lesions required histologic confirmation. For adrenal imaging, histologic confirmation was required for all lesions. For patients with characteristic brain CT, a repeat scan was conducted in 4 weeks time and patients were followed to determine if their clinical course was consistent with metastatic disease to the brain. For bone metastases we relied on a combination of histological confirmation, characteristic scan, and follow-up.

Statistical analysis
For each center we calculated the distribution of responses to each symptom question for both groups of patients, those included and those excluded due to symptoms suggesting metastatic disease. For CNS-associated symptoms, we calculated the distribution of scores in patients excluded because of suspected CNS disease. We also calculated the distribution of the highest scores (those most likely to suggest metastatic disease) in each patient among the 3 items probing CNS symptoms. For symptoms associated with bone metastases we calculated the distribution of scores in patients excluded due to suspected tumor spread to bone. We tested whether the distribution of scores differed between centers, and between included and excluded patients using a chi-square test. We interpreted p values of 0.05 or less as statistically significant.

We also examined the association between the presence of symptoms on the questionnaire and the likelihood of having metastatic disease in the territory suggested by the symptoms in patients enrolled in the study. We classified symptoms as minimal (1 or 2 on a 5 point scale) or more than minimal (3, 4, or 5). We then examined the relation between the magnitude of symptoms and whether patients who underwent resectional surgery ultimately proved to have metastatic disease in the relevant territory. We conducted a Fisher’s exact test for each comparison.

	Results

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Recruitment and patient characteristics
We reviewed 2,232 patients with presumed NSCLC for possible inclusion in this study. We enrolled 685 patients, and all results we report are from the entire group, including both those in the limited investigation arm and in the full investigation arm. Of the 1,547 patients whom we excluded, the reasons for exclusion were suspected CNS disease in 66 patients and suspected bony metastases in 174 patients.

Tables 1 to 3 present the responses in all centers to the 3 CNS-associated questions of headache, abnormal sensations, and abnormal weakness in both enrolled patients and in those excluded due to suspected CNS metastases. Table 4 presents the distribution of the highest score in any of the 3 CNS associated items. Table 5 presents the distribution of responses to the question of bone metastasis symptoms in both patients who were recruited and in those excluded due to suspected bony metastases.

In all analyses the distribution of symptoms was very different in those included versus those excluded (p < 0.00001 in all cases). Distribution of symptoms in those excluded differed little across centers and reached statistical significance in two analyses (Tables 4 and 5).

Table 6 presents the relationship between symptoms and the ultimate occurrence of metastatic disease after resectional surgery. Table 6 demonstrates that for all 3 CNS symptoms there was a trend toward a greater likelihood of recurrence in patients with symptoms. For headaches, this relation was statistically significant.

	Comment

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The approach, whereby symptomatic patients are investigated, whereas asymptomatic patients proceed directly to thoracotomy, seems relatively straightforward until one considers what is meant by "asymptomatic." One can think of a gradient from, for example, a patient with mild tension headaches once a month whose pattern of headaches has not changed; to a similar patient whose headaches have become more frequent during the last month; to a patient whose headaches have changed in character, severity, and frequency and are now more severe when lying flat or when coughing. Consideration of these patients demonstrates that symptoms are a continuum, that symptoms can be so mild as to not warrant investigation, and that clinicians must choose a threshold at which symptom severity is sufficient to warrant investigation.

Previous studies, both distinguishing between symptomatic and asymptomatic patients, and documenting differences in prevalence of metastatic disease, have failed to adequately address this issue. Some studies provide no detail as to how classified patient history suggests possible metastases [3, 7–11]. Others simply list symptoms, such as skeletal pain, bone pain, headache, or nausea, without addressing issues of symptom intensity, or change from the usual pattern of symptoms [4, 5, 12–17]. Some studies provide more detail (for example "bone pain that had continued for more than 1 year without exacerbating was considered to be a negative clinical factor") but do not specify criteria for duration, severity, and change from the usual pattern [18, 19].

This failure to offer clear criteria for determining symptom threshold might not be a problem if there was a clear consensus among surgeons as to when symptoms became worthy of investigation for metastatic disease, and this consensus was reflected in their practice. In our study, we made a special effort to try to achieve this consensus and standardization of practice. Thus, we tried to achieve consistency regarding criteria for including patients in a trial in which there was a 50% chance that patients would go straight to thoracotomy (without imaging investigations to look for extra pulmonary metastatic disease.)

In general, we succeeded in establishing a consensus. Participating surgeons were conservative in their approach, seldom enrolling patients with any appreciable symptoms suggestive of metastatic disease. Nevertheless, there remained considerable heterogeneity across centers. The centers fell into 3 groups: at 2 institutions the surgeons were extremely conservative, enrolling virtually no one with any type of symptom; at 3 institutions the surgeons were still very conservative, but would occasionally enroll patients with minimal symptoms; and 2 institutions in which 5% or more of the patients recruited had symptoms suggesting metastatic disease.

Apparent discrepancies between surgeons’ decisions about enrollment and the results of the symptom questionnaire have many possible explanations. Surgeons may have interviewed patients with a companion who provided additional information. Patients may have had an opportunity to reflect upon their symptoms between the interview with the surgeon and completing the questionnaire, always following the surgeons’ meeting. Surgeons’ interview questions may have been much more detailed than those of the questionnaire. Differences in the extent of symptoms among enrolled patients between centers have fewer explanations. Either surgeons’ criteria, or the administration of the questionnaire by the nurses was different. Given the simplicity of the questionnaire, and the training of the nurses in questionnaire administration, the former explanation seems far more likely.

Heterogeneity of the surgeons’ behavior occurred despite our considerable efforts to achieve a consensus. It is likely that far greater heterogeneity in criteria, for symptoms mandating additional imaging for patients with NSCLC, exists in normal clinical practice.

To the extent that there is a relationship between the magnitude of symptoms and the likelihood of metastatic disease, this heterogeneity is important. With respect to obvious symptoms, there clearly is a relationship. Previous studies examining symptomatic patients, have shown a much higher likelihood of metastatic disease than studies examining asymptomatic patients (despite the lack of clarity in what constitutes significant symptoms) [1].

The relationship between the magnitude of symptoms and the likelihood of metastatic disease might not be seen in a study such as ours if the symptoms presented tended to be less dramatic. Our ability to examine this issue was limited by the small number of patients who developed extrathoracic metastatic disease after resectional surgery. However, for the 3 CNS symptoms we found a trend suggesting that a greater number of symptoms increased the likelihood of metastatic disease in the brain, and for headaches the relationship reached conventional levels of statistical significance.

Our results have a number of implications. First, thoracic surgeons should be aware of the potential for variability in clinical judgement regarding investigation for distant metastases in patients, and give conscious and deliberate consideration to where they place the threshold of the investigation. Second, thoracic surgeons as a group should consider working toward a consensus on when to investigate, and communicate this consensus to their trainees. Third, further investigations in this area should ensure that criteria, for symptoms suggesting metastatic disease, are as explicit as possible, and continue to monitor adherence to these criteria over the course of the studies.

	Acknowledgments

 
We acknowledge the following for their important contribution to the conduct of the study: Pierre Bedard BscN, Chenta Bhatt HRT, Claude Bugden MD, Robert Campbell MD, Debbie Deslauriers RN, Sylvie Ferland MD, Jane Flett RN, Melvyn Goldberg MD, Frances Y.L. Hui BSc, Louis F. Jacques MD, Frederick R.K. Matzinger MD, Martin F. McKneally MD, Bill Nelems MD, F. Griffith Pearson MD, Raymond P. Torbiak MD, Kathy Yip MD, and we offer a special acknowledgment to Deborah Maddock for her work in the organizational aspects of study planning and implementation.

Doctor Cook is a Career Scientist of the Ontario Ministry of Health. Doctor Walter holds a National Health Scientist award from Health Canada. This study was supported by the Ontario Ministry of Health and the National Cancer Institute.

	Footnotes

 
^* The members of the Canadian Lung Oncology Group are listed in Appendix 1.

	Appendix 1. Members of the Canadian Lung Oncology Group who participated in this study, and their roles

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Protocol Development: Drew C.G. Bethune, MD, Jean Deslauriers, MD, Gordon H. Guyatt, MD, (Chair of Protocol Development and Principal Investigator), 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), 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, Robert Campbell, MD, Geralynn Hirsch, RN, and Myrna Yazer, RN

Quebec City: Jean Deslauriers, MD (Center Coordinator), Louis F. Jacques, MD, Guy Carrier, MD, Sylvie Ferland, MD, Pierre Bedard, BScN, Debbie Deslauriers, RN, and Brigitte Fournier, BScN

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

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

Toronto: Timothy L. Winton, MD (Center Coordinator), Gail E. Darling, MD, Melvyn Goldberg, MD, Shafique Keshavjee, MD, Aaron Hendler, MD, Donald P. Jones, MD, Michael R. Johnston, MD, Martin F. McKneally, MD, Thomas R.J. Todd, MD, F. Griffith Pearson, MD, Robin Pugash, MD, Robert Bruce, MD, Marvin Steinhardt, MD, Kathy Yip, MD, Jane Flett, RN, Frances Y.L. Hui, BSc, Margaret Keresteci, BA, and Susan M. Rosgen, RN

London: Richard I. Inculet, MD, (Center Coordinator), Alan G. Casson, MD, Richard A. Malthaner, MD, Michael S. Lefcoe, MD, Chenta Bhatt, HRT, and Natalie Zankowicz, BScN

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

Adjudication: Deborah J. Cook, MD, Gail E. Darling, MD, Gordon H. Guyatt, MD, Richard I. Inculet, MD, Michael R. Johnston, MD, and Susan Troyan, BA

Economic Analysis: Ron Goeree, MA, and Bernie O’Brien, PhD

Statistical Analysis: Lauren E. Griffith, MSc, and Stephen D. Walter

Writing Committee: Michael S. Lefcoe, MD, Michael R. Johnston, MD, and Timothy L. Winton, MD

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited 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 Add to Personal Folders Download to citation manager Author home page(s): Gordon H. Guyatt John D. Miller Michael R. Johnston Timothy L. Winton Alan G. Casson Gail E. Darling Richard J. Finley Jean Deslauriers Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guyatt, G. H. Articles by Deslauriers, J. Search for Related Content PubMed PubMed Citation Articles by Guyatt, G. H. Articles by Deslauriers, J. Related Collections Related Article