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Correlation of Tumor Size and Survival in Patients With Stage IA Non-small Cell Lung Cancer^*

^* From the Departments of Radiology (Drs. Patz, Rossi, and Goodman) and Thoracic Surgery (Dr. Harpole), and Division of Biometry, Community and Family Medicine (Dr. Herndon), Duke University Medical Center, Durham, NC.

Correspondence to: Edward F. Patz, Jr., MD, Department of Radiology, Box 3808, Duke University Medical Center, Durham, NC 27710; e-mail: patz0002{at}mc.duke.edu

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Objective: The purpose of this study was to determine the relationship between tumor size and survival in patients with stage IA non-small cell lung cancer (non-small cell lung cancer; ie, lesions < 3 cm).

Method: Five hundred ten patients with pathologic stage IA (T1N0M0) non-small cell lung cancer were identified from our tumor registry over an 18-year period (from 1981 to 1999). There were 285 men and 225 women, with a mean age of 63 years (range, 31 to 90 years). The Cox proportional model was used to examine the effect on survival. Tumor size was incorporated into the model as a linear effect and as categorical variables. The Kaplan-Meier product limit estimator was used to graphically display the relationship between the tumor size and survival.

Results: The Cox proportional hazards model did not show a statistically significant relationship between tumor size and survival (p = 0.701) as a linear effect. Tumor size was then categorized into quartiles, and again there was no statistically significant difference in survival between groups (p = 0.597). Tumor size was also categorized into deciles, and there was no statistical relationship between tumor size and survival (p = 0.674).

Conclusions: This study confirms stratifying patients with stage IA non-small cell lung cancer in the same TNM classification, given no apparent difference in survival. Unfortunately, these data caution that improved small nodule detection with screening CT may not significantly improve lung cancer mortality. The appropriate prospective randomized trial appears warranted.

Key Words: lung cancer • lung cancer screening • pulmonary nodules

	Introduction

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Lung cancer remains a major health problem in the United States, with an estimated overall 5-year survival rate of 13%.¹ Attempts to improve outcomes with screening trials using sputum cytology and chest radiography failed to clearly demonstrate a decline in disease-specific mortality.^{2 3 4 5 6} Recently, new screening trials with thoracic CT have been proposed, suggesting that the ability of CT to detect smaller lesions will result in identifying earlierstage disease, and thus lead to improvements in survival rates and lung cancer mortality.^{7 8 9}

While several studies have demonstrated that patients with T1 lesions and stage IA disease do better than patients with T2 lesions and stage IB disease, there is minimal information correlating tumor size with survival among patients with lesions T1, stage IA disease (ie, lesions < 3 cm).^{10 11 12} This study examines the relationship between tumor size and survival in patients with stage IA disease, in order to determine if these individuals with smaller lesions truly have improved outcomes.

	Materials and Methods

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Patients
The Thoracic Oncology and Comprehensive Cancer Center tumor registries at our institution retrospectively identified 510 consecutive patients, 285 men and 225 women, with a mean age of 63 years (range, 31 to 90 years) with surgically resected, pathologic stage IA (T1N0M0) non-small cell lung cancer. The surgical and pathologic reports were reviewed to ensure that appropriate size, histology, and stage were recorded.

One hundred ninety-five patients (38%) had squamous cell carcinoma, 235 patients (46%) had adenocarcinoma, 45 patients (9%) had bronchioalveolar cell carcinoma, and 35 patients (7%) had large cell carcinoma.

The most recent survival data were obtained through the tumor registries and medical records.

Statistical Considerations
The Cox proportional hazard model was used to examine the effects of tumor size on survival, where survival was defined as the time between the date of resection and death regardless of cause. Patients remaining alive had their survival time censored at last follow-up. Tumor size was incorporated into the model as a linear effect and categorical variables. The initial categories were created by stratifying lesions into quartiles according to size. To further investigate the potential nonlinear relationship between tumor size and survival, size was categorized into deciles. No other covariables were analyzed.

The Kaplan-Meier product limit estimator was used to graphically display the relationship between tumor size and survival based on lung cancer death.

	Results

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Linear Effects of Tumor Size
Tumor size was incorporated into the Cox proportional hazards model as a linear effect on survival, and was not found to be statistically significant (regression coefficient, 1.08; standard error of estimate, 0.196; likelihood ratio test p value, 0.701). The distribution of tumor size is shown in Figure 1 .

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Distribution of tumor size.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Survival stratified by tumor size quartiles. Q = quartile.

	Discussion

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Despite continued advances in diagnostic techniques, treatment protocols, and tumor biology, the survival rate for lung cancer has shown only minimal improvements over the past several decades. Most patients still present with advanced disease, at which time therapeutic options are less than optimal.¹

One strategy directed at improving outcome is screening and early detection. It has been suggested that if lesions are discovered when small, patients will have an earlier stage of disease, and this should result in improved lung cancer mortality. This theory was tested initially in several large lung cancer screening trials and a case-control study using sputum cytology and conventional chest radiography.^{2 3 4 5} These studies found that if lung cancer was indeed detected at an earlier stage, that more cancers were resectable, and that 5-year survival rates were better in the screening group as compared to the control population. Unfortunately, the final analysis showed that disease-specific mortality rates from lung cancer were not statistically different between the two groups. In addition, several sobering findings became apparent. Approximately 50% of patients who developed lung cancer were "interval" cases (patients with normal conditions at initial screening who developed symptoms before the next follow-up), and some patients presenting with small primary lesions had already developed disseminated disease. Thus, the use of chest radiography or sputum cytology to screen for lung cancer was not recommended.

Recently, the results of these studies have been questioned and criticized. Concerns about the study design, the statistical analysis, and the technology of these previous screening trials have prompted a renewed interest in reexamining this issue.^{13 14 15 16 17 18}

New screening trials have been initiated using more advanced imaging modalities, particularly low-dose spiral CT. Prevalence data from these trials have shown that CT can detect smaller nodules than conventional chest radiographs, and that up to 2.7% of patients had lung cancer.^{7 8} Nevertheless, it remains unclear if detection of small cancers by CT will result in an earlier-stage disease and then translate into a statistically significant improvement in lung cancer mortality.

While differences in survival between patients with T1 (< 3 cm) and T2 (> 3 cm) lesions have been determined in previous studies (5- and 10-year survival for T1N0 disease was 82% and 74%, respectively; 5- and 10-year survival for T2N0 disease was 68% and 60%, respectively; p < 0.0004),^{10 12} a similar relationship for different-sized lesions < 3 cm has not been established. The implication of such a relationship would be that patients with a 5-mm nodule (approximately 10⁸ tumor cells) would have a better prognosis than patients with a 10-mm nodule (approximately 10⁹ tumor cells) or a 3-cm nodule (approximately 2 x 10¹⁰ tumor cells). Yet, there are no clinical or experimental data to support that there is a threshold that represents an essential prognostic determinate. In fact, there is some evidence,¹² including the results of the current study, that suggests that detection of small nodules does not impact on patient survival. Thus, given that the previous screening trial with chest radiographs did not show improvements in disease-specific mortality, it remains to be seen that detecting even smaller nodules with CT will alter the natural history of lung cancer.

Clinical studies have shown that metastases can be seen in tumors of any size. The preliminary CT screening trials themselves determined that up to 30% of small primary cancers metastasized to regional lymph nodes or distant sites on initial examination.^{7 8 9} In addition, tumor cells can be found in the peripheral blood and bone marrow of patients with all stages of disease.^{19 20 21 22} More recent experimental studies supporting these data suggested that tumors co-opt normal vessels, and metastatic disease occurs even when lesions are < 1 mm.²³ In fact, by the time a lesion has grown to 5 mm (close to the limits of nodule detection by CT), the cancer is late in the biology of the disease (host death typically occurs at 10¹² tumor cells). The exact time at which metastases or genetic changes result in an aggressive, malignant phenotype is not well established.^{24 25 26} All of these findings suggest that small nodule detection by imaging techniques does not necessarily correspond to the biological behavior of lung cancer.

While this study did not analyze a number of variables including cell type and patient age, the data do not demonstrate a statistically significant relationship between small-size lesions and survival. These data confirm prior studies, and support stratifying primary lung tumors < 3 cm in the same category for prognostic and therapeutic purposes.

Detecting small lesions and screening for lung cancer are complex and controversial issues, and imaging alone may not be the solution to improve lung cancer mortality. As more is understood about the biology of lung cancer, it seems that an integration of imaging findings, molecular characteristics of the tumor, and host response to the malignancy will be necessary to have an impact on this disease. Although we remain optimistic about improving outcomes in lung cancer, we caution against the routine widespread use of early detection methods until true statistical mortality advantages are demonstrated in the appropriate prospective randomized trials.

Received for publication September 3, 1999. Accepted for publication December 29, 1999.

	References

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