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Ann Thorac Surg 2003;75:356-363
© 2003 The Society of Thoracic Surgeons
a Department of Thoracic and Cardiovascular Surgery, Uppsala University Hospital, Uppsala, Sweden
b Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden
c Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
Accepted for publication August 24, 2002.
* Address reprint requests to Dr Myrdal, Uppsala University Hospital, Department of Thoracic and Cardiovascular Surgery, SE-751 85 Uppsala, Sweden.
e-mail: gunnar.myrdal{at}thorax.uas.lul.se
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Abstract |
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METHODS: We identified 395 patients with non-small cell lung cancer who had undergone potentially radical operation during 1987 to 1999 at one thoracic surgery institution in central Sweden. Factors independently related to survival were identified in a multivariate analysis. Survival was analyzed in low-, medium-, and high-risk groups based on a risk score calculated from relative hazards for identified risk factors.
RESULTS: Overall 5-year survival among the 395 patients was 51%. The strongest factor predicting prognosis was positive lymph nodes at operation. Higher age, earlier period for operation, impaired lung function, current smoking, and major operative complication were all related to poorer prognosis. Patients with tumor stage Ia had a 5-year survival of 69%, compared to 73% in patients in the low-risk group.
CONCLUSIONS: Tumor stage is the best prognostic indicator after radical operation. Inclusion of other tumor- and patient-related variables did not add prognostic information of clinical relevance beyond that provided by tumor stage alone.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Approximately 80% of new lung cancer cases are of the non-small cell type [2], with an estimated 5-year overall survival rate of 10% to 18% [3, 4]. At present, surgical resection remains the only therapeutic modality with a curative potential in patients with early stage non-small cell lung cancer (according to the current TNM classification [5]).
To ensure that patients with lung cancer receive treatment appropriate for their level of disease, it is necessary to achieve accurate staging by obtaining detailed information about the tumor size, tumor extension, location, and lymph node involvement. Furthermore, little is known about the influences of clinical factors with respect to long-term survival, either separately or in combination with the staging variables.
The aim of the present study was to examine the survival in 395 patients with non-small cell lung cancer potentially cured by operation and to evaluate the impact of different clinical and stage-related factors on the prognosis.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Of the 616 patients, 221 patients were excluded from further analyses: 18 died during the first 30 days after operation, 70 patients underwent explorative thoracotomy as the extension of the tumor did not permit resection (of these 70 patients, 44 had a tumor invading mediastinal organs, 19 invading the thoracic wall or a rib, and in 7 patients both); 97 underwent an incomplete resection, defined as either the presence of positive margins at the pathologic examination or residual tumor as judged by the surgeon (of these 97 patients, 68 showed positive margins at pathologic examination and 29 had residual diseases as assessed by the surgeon—in 16, invasion of the chest wall or diaphragm and in 13, invasion of a mediastinal organ); 30 had a tumor of the carcinoid type; and 3 patients had a lymphoma in the mediastinum with lung involvement. Three patients living outside Sweden were lost to follow-up.
The remaining 395 patients (Table 1) had a completely removed tumor as assessed by the surgeon and showed negative tissue margins at pathologic examination and were considered to be potentially cured by operation. These 395 patients formed the study population. Of these, 255 were men (mean age, 65.8 years; range, 38 to 82 years) and 140 were women (mean age, 63.6 years; range, 27 to 82 years).
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FEV160%) [6], and lung perfusion scans. Clinical characteristics included in the analyses were concomitant diseases (diabetes mellitus, chronic obstructive lung disease, ischemic heart disease, or hypertension, all requiring medication) and major complications (postoperative bleeding leading to reoperation, respiratory failure, bronchopleural fistulas, myocardial infarction, major stroke, renal failure, and cardiac failure). Former smokers were defined as patients who had stopped smoking at least 2 months before operation (Table 1). At all operations the standard open posterolateral approach was used. Mediastinal lymph node samples were taken as routine and node stations were classified in anatomic lymph node chains [7]. Since April 1995, 11 patients had been included in a Scandinavian study on adjuvant therapy. No patients received neoadjuvant treatment.
Data collection and follow-up
Patients potentially eligible for inclusion were identified using an in-hospital database. An individually unique 10-digit national registration number, allocated to all Swedish residents at the time of birth or permanent resident, allowed complete follow-up with respect to survival by computerized linkage to the Swedish Cause of Death Register. These subjects could be assigned a date of death or identified as being alive on 31 December 1999. The mean length of follow-up was 46 months (range, 4 to 156 months). Detailed information on each patient was retrieved from medical records.
The study was approved by the Ethics Committee at the Uppsala University Hospital.
Statistical methods
The observed survival rate for all causes of death was calculated by the actuarial (lifetable) method [8]. The log rank test was used to test for equality of the survival curves in different groups.
Univariate and multivariate analyses performed to identify factors related to death (by any cause) were based on the standard Cox proportional hazard model [8]. The relative hazard (RH = exp(ß1)) was used as a measure of the risk of death in different categories, where ß1 is the basic measure in the Cox model.
Continuous variables were tested in their original continuous form, a logarithmic form, and with a set of dummy variables representing ranges, defined by commonly used or standard cutoff points. The RH ratios and their 95% confidence intervals are in general given for the variable in both the optimal continuous form and the dichotomized form, as this way of presenting the results was considered most informative. In the multivariate analyses the variables were used first in their continuous form, the original (year of operation) or logarithmic (age, percent predicted FEV1, and tumor size) form and then in their optimal dichotomized form with the best discriminatory power.
To analyze categorized variables a set of dummy variables was used.
Variables significantly related to mortality in the univariate analysis were considered in the multivariate analysis (p 0.05). Variables entered into the analysis are shown in Table 1. On the basis of the results of the multivariate analysis of the influence of different variables on survival (Table 2),
a risk score was computed for each patient. Risk Score = exp(1.14 x {year since 1987} + 0.13 x {tumor stage Ib} + 0.68 x {tumor stage II} + 0.76 x {tumor stage III} - 0.05 x {ln(age)} - 0.57 x {ln(percent predicted FEV)} + 2.56 x {tumor growth in pleura parietal} + 0.55 x {major complication} + 0.26 x {active smoker}).
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Because the basic models used assume that the RH are constant over time, separate models were estimated for follow-up at less than 36 months and 
36 months after operation. In an additional step, stratified standard Cox models were used for analysis of the interaction between risk factors. Finally, interaction was tested for by introduction of an interaction variable. Spearman rank correlation was used to test for correlation between tumor size and lymph node involvement.
To test for trends in the distribution of risk factors over time the Cochran-Armitage trend test was used.
All statistical calculations were performed with the SAS 6.12 statistical procedure (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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In the multivariate analysis, stage was chosen and used in the full model including both tumor- and patient-related variables (Table 2). There was a correlation (Spearman’s coefficient = 0.17, p < 0.001) between tumor size and lymph node involvement; N1–N2 disease being present in 22% of the patients with T1 (tumor less than 3 cm in diameter) an in 39% of those with T2. Furthermore, 3% of patients with T1 tumors had N2 disease and 9% if T2.
In the full model in which all variables were considered (Table 2), age more than 60 years, earlier time period of operation, impaired lung function, current smoking (Fig 3), and major complication in connection with operation, together with advanced stage, were all significantly related to poorer long-term survival. Also patients who underwent pneumonectomy had decreased survival compared with lobectomy in the univariate analysis (RH = 1.5, 95% confidence interval [CI] = 1.2 to 1.8). However, after adjustment for other risk factors in the multivariate analysis, pneumonectomy gave no further prognostic information. During the study period the proportion of patients undergoing pneumonectomy decreased significantly (from 38% in 1987 to 1989 to 16% in 1996 to 1999; p = 0.001).
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A risk score for mortality was calculated for each patient, using the final multivariate model. When patients were categorized according to that risk score, the low-risk group had a 5-year survival rate of 73%, compared to 26% in the high-risk group (Fig 4). Patients’ characteristics in each risk group are presented in Table 3.
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During the study period the proportions of patients with impaired lung function and current smokers decreased significantly (p values for trend = 0.006 and 0.003, respectively), The proportion of patients who had never smoked was unchanged.
Risk factors for different time periods after operation
The effects of the risk factors were virtually the same (year of operation not included) for deaths occurring within or more than 3 years after operation. An exception was major complications in connection with the primary surgical procedure, which increased the risk only for deaths occurring within 36 months after operation, with RH = 2.0 (95% CI = 1.5 to 2.5) compared to RH = 1.1 (95% CI = 0.2 to 2.0) for death after 36 months from operation. A majority of the patients with tumors in an advanced stage died within 36 months, and after that time too few were at risk to allow valid analyses.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Approximately 30% of the patients who were considered to have early stage disease (Ia) died within 5 years after operation. This is likely to reflect the presence of undetected lymph node metastases and verify the notion that large proportions of patients with lung cancer are understaged with current techniques. The finding that as many as 22% of the small tumors (T1) had spread to lymph nodes (N1 or N2) corroborates results from an earlier study [10]. This finding emphasizes the importance of careful lymph node examination, with systematic sampling, also in patients with small tumors, to obtain appropriate staging information [11, 12].
Regardless of the tumor size, lymph node involvement, regional or mediastinal, increased the risk of death by approximately 100%. In comparison, an increased tumor size increased the risk moderately. Earlier studies have also shown that lymph node involvement is strongly associated with decreased survival in patients with small tumors [5].
The present study, in which mediastinoscopy was performed in patients with positive computed tomographic findings, included a small number of patients with N2 disease (n = 30). The survival in these patients was poor, but not inferior to that in patients with N1. This finding probably reflects understaging of patients from N2 to N1, which would decrease the observed survival in the N1 group. No doubt more frequent use of mediastinoscopy could have improved the preoperative identification of patients with N2 disease. The accuracy of the staging is of great importance for correct prediction of the prognosis in patients with lymph node involvement [13]. Mediastinoscopy also has the potential to reduce the rate of explorations of unresectable tumors. This rate was quite high in the present study (11%). When mediastinoscopy has been performed routinely in all candidates for radical operation, excluding only small peripheral lesions without enlargement of the mediastinal lymph nodes on computed tomographic scan [14, 15], the incidence of unresectable tumors has been reported to be 4% to 5%. Positron emission tomographic scans have shown high sensitivity but lower specificity for detection of local and distant metastases [16, 17]. Positron emission tomographic investigations, combined with mediastinoscopy in positive cases, could optimize the preoperative staging further.
Operation in older patients has been a subject of concern because of the morbidity and mortality [18]. We found poorer survival among older patients, both before and after adjustment for other risk factors. The use of all causes of mortality may have overestimated the risk of death in older patients, and could have contributed to this finding. Smoking is an established risk factor for early death [6]. In the present study, current smokers had poorer survival than former smokers. We have previously reported an increased early mortality among patients who sustained major complications after lung cancer operation [6]. The present findings indicate that patients with major complications are at increased risk for death up to 3 years after operation. Furthermore, patients with reduced lung function were at increased risk. Thus, optimal medication to prevent complications, cessation of smoking, and physiotherapy may improve the outcome in all patients undergoing lung cancer operation.
Of all potential tumor-related prognostic factors only histologic cell type and stage-related variables were considered in this study. Vascular invasion, for example, which is proposed to be the first step toward hematogenous tumor cell dissemination, provides additional prognostic information and may be a rationale for adjuvant treatment [19].
To assess the potential value of additional prognostic information obtained from a combination of tumor-related factors and clinical variables, compared to tumor stage alone, a risk score was calculated and the patients were categorized accordingly. As many as 27% of the patients in the low-risk group and considered potentially cured by surgery alone died within 5 years after the operation. The corresponding mortality among patients in the high-risk group was 74%. It appears that our expanded predictive model does not add significantly to the information obtained from the staging system alone. The predicted outcome based on the risk score was comparable to that based on tumor stage. Patients with tumor stage Ia had a 5-year mortality of 31%, which is comparable to that in the low-risk group.
The overall aim of attempts at prognostic prediction is to identify patients potentially suitable for adjuvant therapy. At present there is no evidence that such therapy is beneficial in patients potentially cured by operation. To improve the prognosis in these patients with NCSLC it is necessary to identify the optimal adjuvant therapy. There are a number of ongoing clinical trials aimed at developing multimodality treatment strategies [20] that might improve survival further in limited disease.
In conclusion, this study points at an improvement in prognosis over time, especially among patients with limited disease (stage Ia). Furthermore, this study confirms that the tumor stage is the most important prognostic factor. Patient-related characteristics did not add information of clinical relevance over and above that provided by tumor stage alone. This finding further underlines the importance of accurate staging, both preoperatively and perioperatively. If the current adjuvant therapy alternatives prove to be effective, the staging effort will be valuable in selecting patients for appropriate treatment.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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hle E. Trends in lung cancer incidence in Sweden with special reference to period and birth cohorts. Cancer Causes and Control 2001;12:539-549.[Medline]
hle E. Outcome after lung cancer surgery. Factors predicting early mortality and major complications. Eur J Cardio-thorac Surg 2001;20:694-699.This article has been cited by other articles:
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  P. S. Nia and P. Van Schil Has smoking status only a prognostic value in patients with stage I pulmonary adenocarcinomas? Ann. Thorac. Surg., January 1, 2007; 83(1): 358 - 358. [Full Text] [PDF]
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D. E. Paull, G. M. Updyke, M. A. Baumann, H. W. Chin, A. G. Little, and S. A. Adebonojo Alcohol Abuse Predicts Progression of Disease and Death in Patients with Lung Cancer Ann. Thorac. Surg., September 1, 2005; 80(3): 1033 - 1039. [Abstract] [Full Text] [PDF]
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 H. Kato, Y. Ichinose, M. Ohta, E. Hata, N. Tsubota, H. Tada, Y. Watanabe, H. Wada, M. Tsuboi, N. Hamajima, et al. A Randomized Trial of Adjuvant Chemotherapy with Uracil-Tegafur for Adenocarcinoma of the Lung N. Engl. J. Med., April 22, 2004; 350(17): 1713 - 1721. [Abstract] [Full Text] [PDF]
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