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(Chest. 2003;124:1828-1833.)
© 2003 American College of Chest Physicians

Tumor Size Predicts Survival Within Stage IA Non-Small Cell Lung Cancer*

Jeffrey L. Port, MD; Michael S. Kent, MD; Robert J. Korst, MD, FCCP; Daniel Libby, MD, FCCP; Mark Pasmantier, MD and Nasser K. Altorki, MD

* From the Department of Cardiothoracic Surgery, Weill-Cornell Medical Center, New York, NY.

Correspondence to: Nasser K. Altorki, MD, FCCP, Department of Cardiothoracic Surgery, Suite M404, Weill Medical College of Cornell University, 525 East 68th St, New York, NY 10021; e-mail: nkaltork{at}med.cornell.edu


   Abstract
TOP
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Study objectives: The basic premise of CT screening is that size is an important determinant of survival in lung cancer. We sought to examine this hypothesis within stage IA non-small cell lung cancer (NSCLC).

Methods: A retrospective analysis of all patients with pathologically confirmed stage IA NSCLC resected from 1991 to 2001 was conducted. All but seven patients underwent anatomic lung resection and mediastinal lymph node dissection. Kaplan-Meier survival analysis was performed to estimate the 5-year overall and disease-specific survival probability stratified by tumor size. The influence of age, gender, histology, and tumor size on survival was also analyzed using a Cox proportional hazards regression model.

Results: There were 244 patients (mean age, 66.7 years; 45.1% were men). Lobectomy was performed in 229 patients, segmentectomy in 8 patients, and wedge resection in 7 patients. Operative mortality was 0.4%. Histologic breakdown was as follows: adenocarcinoma (59.4%), squamous (18.9%), bronchoalveolar (15.2%), large cell (4.5%), and poorly differentiated (2.0%). The median follow-up time for all patients was 2.6 years. The 5-year survival probability for all patients was 71.1% (95% confidence interval [CI], 63.6 to 78.6%). For 161 patients with tumor sizes <= 2.0 cm, the 5-year survival probability was 77.2% (95% CI, 68.6 to 85.8%) in comparison with 60.3% (95% CI, 46.7 to 73.8%) in 83 patients with tumor size > 2.0 cm (p = 0.03 by log-rank test). The overall 5-year disease-specific survival was 74.9% (95% CI, 67.6 to 82.2%). Disease-specific survival was 81.4% (95% CI, 73.3 to 89.4%) for patients with tumors <= 2.0 cm and 63.4% (95% CI, 49.6 to 77.1%) for patients with tumors > 2.0 cm.

Conclusions: These data suggest that size within stage IA is an important predictor of survival and that further substaging should be considered.

Key Words: lung cancer • stage IA • survival • tumor size


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Bronchogenic carcinoma is the leading cause of cancer deaths among men and women in the United States. In the United States, approximately 170,000 new cases of lung cancer will be diagnosed each year and 160,000 patients will die of their disease.1 In North America, < 15% of patients will present with stage I disease, where surgical resection results in a 5-year survival of 60 to 80%. The improved survival in patients with stage I has rekindled interest in lung cancer screening in order to detect smaller and potentially more curable lesions. The premise of screening relies on the notion that size is an important determinant of stage distribution and ultimately of improved survival if the expected shift to stage I is realized. The relationship between size and survival is recognized by the current staging system, with a distinct difference in survival between tumors < 3 cm and those > 3 cm in size. However, little information is available to determine whether size remains an important determinant of survival when only tumors < 3 cm are considered. In this study, we evaluated the relationship between tumor size and survival in patients with completely resected stage IA non-small cell lung cancer (NSCLC).


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
We conducted a retrospective chart review of all patients with NSCLC surgically treated at our institution between January 1990 and December 2001. All patients with completely resected pathologic stage IA NSCLC were identified. Hospital and office records were examined for demographic and pathologic data including age, gender, histology, and tumor size. Tumor size was categorized around the value of 2 cm.

Univariate associations between tumor size category and other prognostic factors were explored by the {chi}2 test (gender, histology) and the t test (age). Kaplan-Meier survival analysis was performed to compare the 5-year overall and disease-specific survival probability by tumor size category (log-rank test). The independent effect of several factors including age, gender, histology, and tumor size on survival was also analyzed using a Cox proportional hazards regression model. Tumor size was explored in this model as both a categorical (<= 2 cm vs > 2 cm) and continuous variable.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics are presented in Table 1 . Two hundred forty-four patients were studied. Twenty-two patients had their tumor detected as part of an ongoing CT screening program. All patients underwent a complete mediastinal lymph node dissection at the time of thoracotomy. Median follow-up for all patients was 31 months. Tumor size distribution is illustrated in Figure 1 . The overall 5-year survival was 71.1% (95% confidence interval [CI], 63.6 to 78.6%) [Fig 2 ]. Forty-nine patients had either a local or distant recurrence, and all of these patients died from recurrent disease. Ten additional patients died from causes unrelated to lung cancer. Survival for patients with tumors <= 2.0 cm was 77.2% (95% CI, 68.6 to 85.8%), and survival for patients with tumors > 2.0 cm was 60.3% (95% CI, 46.7 to 73.8%) [Fig 3 ]. This difference in survival was statistically significant (p = 0.03, by log-rank test). In the multivariate Cox regression model, patients with tumor size > 2 cm vs <= 2 cm demonstrated a hazard ratio of 1.47 (Table 2 ). Although the hazard ratio for tumor size > 2 cm was not statistically significant (p = 0.15) after controlling for covariates, the 95% CI for the hazard ratio was consistent with evidence for an increased risk of death (95% CI, 0.87 to 2.48). Tumor size modeled as a continuous variable in the multivariate Cox regression model demonstrated a similar relationship with risk of death (hazard ratio, 1.42; 95% CI, 0.94 to 2.15; p = 0.09).


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  		Table 1.. Patient Characteristics

 


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  		Figure 1.. Distribution of tumor size.

 


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  		Figure 2.. Overall survival of 244 patients with stage IA NSCLC.

 


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  		Figure 3.. Overall survival of patients with tumors <= 2 cm or > 2 cm.

 

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  		Table 2.. Cox Proportional Hazards Model for Independent Predictors of Death

 
Disease-Specific Survival
The overall 5-year disease-specific survival was 74.9% (95% CI, 67.6 to 82.2%) [Fig 4 ]. Disease-specific survival was 81.4% (95% CI, 73.3 to 89.4%) for patients with tumors <= 2.0 cm and 63.4% (95% CI, 49.6 to 77.1%) for patients with tumors > 2.0 cm (Fig 5 ). This difference in disease-specific survival was statistically significant (p = 0.02, by log-rank test). In the multivariate Cox regression model, patients with tumor size > 2 cm vs <= 2 cm demonstrated a hazard ratio of 1.69 for cancer-related mortality (Table 3 ). Although the hazard ratio for tumor size > 2 cm only approached statistical significance (p = 0.08) after controlling for covariates, the 95% CI for the hazard ratio was consistent with evidence for an increased risk of cancer-related mortality (95% CI, 0.95 to 3.01). Tumor size modeled as a continuous variable in the multivariate Cox regression model demonstrated a similar relationship with risk of cancer-related mortality (hazard ratio, 1.87; 95% CI, 1.18 to 2.96; p = 0.008).



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  		Figure 4.. Disease-specific survival of all patients.

 


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  		Figure 5.. Disease-specific survival of patients with tumors <= 2 cm or > 2 cm.

 

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  		Table 3.. Cox Proportional Hazards Model for Independent Predictors of Disease-Specific Death

 

   Discussion
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The current lung cancer staging system clearly recognizes a difference in survival between tumors < 3 cm and those > 3 cm. This distinction is well supported by several retrospective studies2 3 4 5 6 that have shown a survival advantage for stage I patients with T1 tumors vs T2 tumors. However, there is conflicting evidence to support the impact of size as a determinant of outcome when only tumors < 3 cm in size are considered. This issue has important implications for lung cancer screening as well as for future refinements of the lung cancer staging system. If the expected survival of a subcentimeter tumor is no different than that of a 3-cm tumor, the ability of CT scans (as opposed to plain chest radiographs) to detect these small lesions may not translate into a meaningful survival benefit.

The study by Patz et al7 is the largest study to date that has examined the relationship between size and outcome in pathologic stage IA patients. The authors analyzed the survival of 510 patients with pathologic stage IA lung cancer. All patients were treated at a single institution over an 18-year period. Surprisingly, no correlation was found between tumor size and survival, regardless of whether size was considered as a discrete or continuous variable. Several confounding variables may explain this unexpected result.8 First, the overall survival of 80% in this series was unusually high. Given the low number of deaths in the cohort of patients analyzed, the study may have been underpowered to detect the influence of size on survival. In addition, overall survival rather than disease-specific survival was reported. This may have further reduced the power of the study to observe a correlation between size and survival, given that up to one half of the deaths in stage IA lung cancer are from causes unrelated to lung cancer.9

In contrast, our results suggest an improvement in survival for patients with tumors <= 2 cm within stage IA. By Kaplan-Meier analysis, tumor size was a significant predictor of both overall (p = 0.03) and disease-specific (p = 0.02) mortality. However, tumor size approached but did not attain statistical significance by multivariate analysis. This is likely due to the diminished power that resulted from including four independent variables in a model with only 59 events in total. Two observations support this hypothesis. First, the power of the study increases when size is analyzed as a continuous rather than a discrete variable. When size was evaluated in this fashion, the p value decreased to 0.09 (from 0.015) and the CI shifted farther to the right (95% CI, 0.94 to 2.15). Also, power is increased by examining disease-specific rather than overall mortality. When this was done, tumor size was a highly significant predictor of survival (p = 0.008).

Other investigators have also suggested the impact of size on survival. Martini et al,10 in a review of 598 patients with stage I tumors, demonstrated that size did impact on survival within stage IA; the survival of patients with lesions < 1 cm was significantly greater than those whose tumors were between 1 cm and 3 cm. Similar results are reported by Padilla et al.5 These authors reported a statistically significant survival advantage for patients with tumors <= 2 cm. Although our findings lend support to the concept of screening, one should exercise some caution in interpreting these results. First, our data are essentially registry data derived from patients not included in a rigorous screening program and therefore not representative of a screened population. Second, although size may be a predictor of survival within stage IA, it is well recognized that small, peripheral tumors may already harbor occult lymph node metastases at the time of diagnosis, and thus represent advanced stage disease despite their small size.1 Indeed, up to 25% of patients with clinical stage IA lung cancer are found to harbor lymph node disease at the time of resection.11

Preliminary data, however, from screening protocols do suggest that smaller lesions are likely to represent earlier stage and potentially more curable disease. Of the 27 cancers detected in the Early Lung Cancer Action Project,12 22 were pathologic stage IA; of the 15 cancers < 1 cm in size, only 2 were found to have lymph node metastases. Furthermore, the propensity of tumors to metastasize is likely to be proportional to their size. Ishida et al13 found the incidence of lymph node spread to be 38% for tumors > 2 cm, 17% for tumors between 1 cm and 2 cm, and nearly zero in lesions < 1 cm.

This study provides preliminary support for the theory that size may correlate to some degree with biology and that small lesions do represent early stage disease. It provides some reassurance that there may be a size threshold below which there is minimal or reduced risk of tumor metastases. Our results would also suggest that there should be further substaging of stage IA lesions with tumors < 2 cm in size contained in a separate substage. This refinement would better clarify which patients might benefit from novel adjuvant or neoadjuvant therapeutic interventions.


   Footnotes
 
Abbreviations: CI = confidence interval; NSCLC = non-small cell lung cancer

Received for publication December 27, 2002. Accepted for publication May 27, 2003.


   References
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Greenlee, R, Murray, T, Bolden, S, et al (2000) Cancer statistics, 2000. CA Cancer J Clin 50,7-33[Abstract]
  2. Suzuki, K, Nagai, K, Yoshida, J, et al Conventional clinicopathologic prognostic factors in surgically resected nonsmall cell lung carcinoma. Cancer 1999;86,1976-1984[CrossRef][ISI][Medline]
  3. Ichinose, Y, Yano, T, Asoh, H, et al Prognostic factors obtained by a pathologic examination in completely resected non-small cell lung cancer: an analysis of each pathologic stage. J Thorac Cardiovasc Surg 1995;110,601-605[Abstract/Free Full Text]
  4. Suzuki, K, Nagai, K, Yoshoda, J, et al Prognostic factors in clinical stage I non-small cell lung cancer. Ann Thorac Surg 1999;67,927-932[Abstract/Free Full Text]
  5. Padilla, J, Penalver, J, Calvo, V, et al Model of mortality risk in stage I non-small cell bronchogenic carcinoma. Arch Bronconeumol 2001;37,287-291[Medline]
  6. Rena, O, Oliaro, A, Cavallo, A, et al Stage I non-small cell lung carcinoma: really an early stage? Eur J Cardiothorac Surg 2002;21,514-519[Abstract/Free Full Text]
  7. Patz, E, Rossi, S, Harpole, D, et al Correlation of tumor size and survival in patients with stage IA non-small cell lung cancer. Chest 2000;117,1568-1571[Abstract/Free Full Text]
  8. Black, W Unexpected observations on tumor size and survival in stage IA non-small cell lung cancer. Chest 2000;117,1532-1534[Free Full Text]
  9. Marcus, P, Bergstrallh, E, Fagerstrom, R, et al Lung cancer mortality in the Mayo Lung Project: the impact of extended follow-up. J Natl Cancer Inst 2003;(in press)
  10. Martini, N, Bains, M, Burt, M, et al Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109,120-129[Abstract/Free Full Text]
  11. Ohta, Y, Oda, M, Wu, J, et al Can tumor size be a guide for limited surgical resection in patients with peripheral non-small cell lung cancer? Assessment from the point of view of nodal micrometastasis. J Thorac Cardiovasc Surg 2001;122,900-906[Abstract/Free Full Text]
  12. Henschke, C, McCauley, D, Yankelevitz, D, et al Early Lung Cancer Action Project: overall design and results from baseline screening. Lancet 1999;354,99-105[CrossRef][ISI][Medline]
  13. Ishida, T, Yano, T, Maeda, K Strategy for lymphadenectomy in lung cancer 3 cm or less in diameter. Ann Thorac Surg 1990;50,708-713[Abstract]



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