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Epidemiology of Bronchioloalveolar Carcinoma: Improvement in Survival After Release of the 1999 WHO Classification of Lung Tumors

From the Chao Family Comprehensive Cancer Center, Division of Hematology/Oncology, Genetic Epidemiology Research Institute, and Division of Epidemiology, Department of Medicine, School of Medicine, University of California Irvine, Irvine, CA

Address reprint requests to Jason A. Zell, DO, MPH, Division of Hematology/Oncology, University of California Irvine Medical Center, 101 The City Dr S, Orange, CA 92868; e-mail: jzell{at}uci.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Classification changes for bronchioloalveolar carcinoma (BAC) by the WHO in May 1999 narrowed its definition. This study was undertaken in an attempt to characterize the impact of these changes on the epidemiology of BAC.

PATIENTS AND METHODS: This retrospective study involves data analysis from the population-based Cancer Surveillance Programs of three Southern California counties from 1995 to 2003. BAC cases diagnosed after May 1999 are compared with BAC cases before that time by clinicopathologic variables including survival.

RESULTS: Incident cases (11,969) of non–small-cell lung cancer (NSCLC) were analyzed, including 626 cases of BAC (5.2%). Median overall survival (OS) for BAC patients diagnosed after May 1999 (> 53 months) was significantly improved over median OS for BAC patients before May 1999 (32 months; P = .012). This survival benefit remained after adjustment for sex, smoking status, and stage at presentation (hazard ratio for time of diagnosis before May 1999 compared with a diagnosis after May 1999 = 1.43; P = .015). Median OS for non-BAC NSCLC patients diagnosed before May 1999 (9 months) did not differ from the median OS of such patients afterwards (10 months; P = .09).

CONCLUSION: This epidemiologic study is the first to demonstrate a survival advantage for BAC patients diagnosed after May 1999 compared with BAC patients diagnosed before this time—a finding that persists after adjustment for sex, smoking status, and stage at presentation. We believe that this observed survival benefit likely reflects changes in the revised 1999 WHO classification.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Bronchioloalveolar carcinoma (BAC) is a subset of pulmonary adenocarcinoma with characteristic clinical (eg, bronchorrhea, intrapulmonary shunting),^1-4 radiographic,^5,6 epidemiologic,^1,2,4 and histopathologic features.^7,8 In a recent study analyzing data from the Surveillance, Epidemiology, and End Results (SEER) database, the incidence of BAC is reported to be 3% to 4% of all non–small-cell lung cancer (NSCLC).⁴ While the incidence of adenocarcinoma has risen significantly from 1979 to 1998, the incidence of BAC has risen only slightly.⁴ Women comprised slightly more than half of all BAC cases compared with only approximately 38% of all NSCLC cases, and the 1-year survivorship of BAC (64.9%) was significantly better than NSCLC (37.5%).⁴ However, determining the epidemiology of BAC has been problematic, and estimates of the incidence of this disease have varied widely, in part, because of different interpretations of the definition of BAC. For example, in contrast to the SEER analysis above, another recent study conducted primarily on limited stage tumors reports a rising incidence of BAC, accounting for 24.1% of all adenocarcinomas.⁹ New definitions of BAC by the WHO have contributed to the changing epidemiology of this disease.

Previous reports on the epidemiology of BAC^1,2 were performed using data before 1999, when the widely accepted definition of BAC from the revised and updated WHO Histological Classification of Tumors was released on May 28, 1999.⁸ Because it had been shown that patients with solitary, noninvasive BAC tumors measuring less than 2.0 cm could be cured,¹⁰ WHO restricted the definition of BAC to noninvasive tumors.⁸ By this definition BAC is an adenocarcinoma with a pure bronchioloalveolar growth pattern, without evidence of stromal, vascular, or pleural invasion,⁸ although BAC may still exhibit multifocal involvement via diffuse alveolar spread, and metastatic disease. This definition is much more restrictive than the one previously used by many pathologists and the WHO. For example, in the past, adenocarcinoma with an extensive BAC component would have been classified as BAC.

In the present study, our primary aim is to determine if survival for BAC patients has been affected since the revised 1999 WHO classification system was released, using a large epidemiologic, continuously updated database of cancer distribution in three Southern California counties.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
This was a retrospective study involving analysis of data from the Cancer Surveillance Programs of Orange County, Imperial County, and San Diego County, California (CSPOC/SANDIOCC databases, covering an area with an estimated population of 6.2 million). The CSPOC/SANDIOCC was developed in collaboration with the California Cancer Registry to serve as a model for regional, population-based cancer registries and to contribute to statewide cancer incidence reporting, as described previously.¹¹

Demographic and Clinical Data
Recorded data included demographic information (ie, age, sex, ethnicity, and smoking status), pathology, stage of disease, and survival status. Data were abstracted from medical and laboratory records by trained tumor registrars according to Cancer Reporting in California: Vol. 1, Abstracting and Coding Procedures for Hospital.¹² All new cases of BAC and non-BAC NSCLC cases reported during the period 1995 to 2003 were included in this study.

Tumor site and histology were coded according to criteria specified by the WHO in International Classification of Diseases for Oncology (ICD-O).¹³ Primary site code was searched using the SEER site code for lung and bronchus.¹⁴ Histology codes included adenocarcinoma (8140 to 8239, 8260 to 8550), squamous cell carcinoma (8050 to 8052, 8070 to 8076) large cell carcinoma (8012, 8013, 8022, 8030, 8031), and BAC (8250 to 8254). Staging was grouped into three broad categories that could be classified from clinical and pathologic records. The stages are defined according to SEER summary staging as localized disease, regional disease, and metastatic disease (localized or regional disease with distant metastases). TNM staging and extent of disease were analyzed for available data. For BAC, the method of diagnosis was established by analyzing the hierarchical diagnostic confirmation variable as compared with the surgical treatment method. This was done in an attempt to correctly identify the operative procedure performed, and to detect any diagnoses based purely on cytologic examination of surgically resected specimens. Smoking information was obtained by abstracting the text fields from the database. Patients with any documented history of smoking were classified as ever-smokers. Patients with documentation of no smoking history were classified as never-smokers. Cases lacking documented information on smoking history were excluded from the relevant analyses.

Cases of BAC were compared with all cases of the other major NSCLC subtypes (ie, adenocarcinoma, large cell carcinoma, squamous cell carcinoma) to detect differences in age, sex, smoking status, ethnicity, stage at presentation, and survival. Additionally, all cases of BAC diagnosed from January 1995 to May 1999 were compared with those cases of BAC diagnosed from June 1999 to December 2003, to detect differences in age, sex, smoking status, ethnicity, stage at presentation, and survival. Subset univariate survival analysis was performed on advanced-stage BAC cases, including T4M0 cases, stage IV as a result of intrapulmonary spread, and stage IV as a result of distant metastasis. Lung cancer-specific survival (ie, the proportion of patients not suffering death from lung cancer) was compared for cases of BAC before and after May 1999.

Follow-Up
Cause of death was recorded according to the International Classification of Diseases criteria in effect at the time of death.¹⁴ Hospital registrars contacted patients annually, and CSPOC/SANDIOCC staff annually reviewed state death certificates to identify deceased registry patients. The last date of follow-up was either the date of death or the last date the patient was contacted.

Statistical Analysis
Comparisons of demographic, clinical, and pathologic variables between patients with various categories (eg, patients with BAC or non-BAC NSCLCs) were performed using Pearson ² statistic or Fisher's exact test for nominal variables and Student's t test for continuous variables. Additionally, Pearson ² statistic for nominal variables and Student's t test for continuous variables were used for comparisons of clinical and demographic features of BAC before and after May 1999. Cause of death, and lung cancer-specific survival analyses were adjusted so that each group (ie, before May 1999 and after May 1999) would have equal duration of follow-up, on the basis of the follow-up duration in the latter period. Univariate survival rate analyses were estimated using the Kaplan-Meier method, with comparisons made between groups by the log-rank test. Cox proportional hazards modeling, using time since diagnosis, were performed. Each variable in the model was coded using dummy variables. All statistical analyses were conducted using SAS 9.1 statistical software (SAS Inc, Cary, NC). Statistical significance was assumed for a two-tailed P value less than .05.

Ethical Considerations
This research study involved analysis of existing data from the aforementioned Cancer Surveillance Programs with no subject intervention. Information was recorded without identifiers linked to subjects. Therefore, this study was approved by the University of California, Irvine institutional review board under the category exempt status (IRB No. 2004-3971).

	RESULTS

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Demographics
Data on 11,969 incident cases of NSCLC were analyzed. The mean age for the entire group was 68.3 years ± 0.1 SE (Table 1). The majority of patients were white (80.4%), followed by Hispanics (8.3%), Asians (7.8%), African Americans (3.2%), and Others (including Native Americans, 0.3%); 54.1% were male. The vast majority of patients had a history of smoking tobacco, and only 9.7% were never-smokers (Table 1). More than half of the patients in this study (51.9%) had metastatic disease at presentation (Table 1). Adenocarcinoma (n = 6,720) was the predominant NSCLC histologic subtype (56.2%), followed by squamous cell carcinoma (29.6%), large cell carcinoma (9.0%), and BAC (5.2%; Table 1).

Survival Analyses
Survival analyses for each of the NSCLC histologic subtypes are presented in Figure 1. Significant differences in overall survival (OS) were detected. BAC had a median OS of 42 months (95% CI, 32 to 51). The median OS for squamous cell carcinoma was 10 months (95% CI, 10 to 11). The median OS for adenocarcinoma was 9 months (95% CI, 9 to 10); and large cell carcinoma exhibited the poorest median OS at 6 months (95% CI, 5 to 6; P < .0001). Because of the observed similar survival trends for the non-BAC NSCLC subtypes, these data were combined to compare survival of this group with the observed survival in BAC patients. Patients with BAC were found to have a significantly prolonged median OS (42 months; 95% CI, 32 to 51) compared with the median OS of non-BAC NSCLC patients (9 months; 95% CI, 9 to 10; P < .0001). One-year (69.6% v 42.4%), 2-year (58.1% v 27.3%), and 5-year (41.4% v 14.5%) survival rates were improved for BAC compared with non-BAC NSCLC cases.

View larger version (21K): [in this window] [in a new window]   Fig 1. Univariate survival analysis for each NSCLC subtype, estimated using the Kaplan-Meier method. SqCC, squamous cell carcinoma; OS, overall survival; BAC, bronchioloalveolar carcinoma; NSCLC, non–small-cell lung cancer.

On multivariate analyses for the overall group (n = 11,969), factors associated with improved survival included localized stage at presentation (hazard ratio [HR] for metastatic disease = 4.48; 95% CI, 4.18 to 4.79; P < .0001; HR for regional spread = 1.65; 95% CI, 1.53 to 1.78; P < .0001), BAC subtype (HR for non-BAC NSCLC subtypes = 1.71; 95% CI, 1.50 to 1.94; P < .0001), female sex (HR for male sex = 1.15; 95% CI, 1.09 to 1.20; P < .0001), and never-smoker status (HR for never-smoker status = 1.09; 95% CI, 1.00 to 1.18; P = .045; Table 3).

View larger version (17K): [in this window] [in a new window]   Fig 2. Univariate survival analysis for advanced stage BAC patients, estimated using the Kaplan-Meier method. (A) T4M0 stage IIIb BAC caused by separate tumors in the same lobe (n = 12). (B) Stage IV BAC as a result of intrapulmonary spread (n = 67). (C) Stage IV BAC as a result of distant metastasis (n = 59). NR, value not reached; OS, overall survival; BAC, bronchioloalveolar carcinoma.

View larger version (19K): [in this window] [in a new window]   Fig 3. Univariate survival analysis for non-BAC NSCLC and BAC, before and after May 1999 (ie, the release date for the 1999 WHO classification of lung tumors), estimated using the Kaplan-Meier method. NR, value not reached; BAC, bronchioloalveolar carcinoma; OS, overall survival; NSCLC; non–small-cell lung cancer.

Cause of Death and Lung Cancer–Specific Survival for BAC Before and After May 1999
Cause of death data were available for 87.9% of deaths, for a total of 7,738 records available for analysis. Overall, 85.8% of patient deaths were caused by lung cancer itself, with 14.2% of deaths related to death from other causes. In the BAC group, 206 deaths caused by lung cancer were reported (80.5%) compared with 6,435 deaths caused by lung cancer (86.0%) for the non-BAC NSCLC group, representing a statistically significant difference (P = .013). All data for BAC patients were censored at 53 months (ie, the length of follow-up in the period June 1999 to December 2003) to allow for equal follow-up duration in both time periods, and cause of death analysis was performed. During the period January 1995 to May 1999, 140 deaths caused by lung cancer (82.8% of 169 total deaths) were reported, which was similar to the proportion of deaths caused by lung cancer in the period June 1999 to December 2003 (77.1%; n = 70 total deaths; P = .31). From January 1995 to May 1999, 37 deaths caused by lung cancer (30.8%) occurred in BAC patients with localized disease at time of presentation, with 34 deaths caused by lung cancer occurring in BAC patients having regional spread (28.3%), and 49 deaths caused by lung cancer occurring in BAC patients with metastatic disease (40.8%). During the period June 1999 to December 2003, only five deaths caused by lung cancer (10.9%) were attributed to BAC patients with localized disease at the time of presentation (six deaths as a result of other causes were noted in this group), only eight deaths caused by lung cancer in the BAC group having regional spread (17.4%), and 33 deaths caused by lung cancer (71.7%) in the BAC group with metastatic disease. These differences in the proportion of deaths caused by lung cancer by stage at presentation during the period January 1995 to May 1999 versus June 1999 to December 2003 were statistically significant (P = .001).

As stated above, nearly half of all BAC patients before and after May 1999 had localized stage at presentation, yet, significant differences in survival and cause of death were noted for localized stage BAC. In an attempt to elucidate the overall effects of these differences, lung cancer-specific survival analyses were conducted after censoring all data beyond 53 months, to allow for equal follow-up duration before and after May 1999. Lung cancer–specific survival analysis revealed a significant improvement in survival for BAC patients diagnosed during the period June 1999 to December 2003 (median OS not reached) versus those diagnosed from January 1995 to May 1999 (median OS = 47 months; 95% CI, 30 to 64; P < .0001; Fig 4). Accordingly, 1-year and 2-year lung cancer-specific survival rates were improved in those patients diagnosed from June 1999 to December 2003 compared with those patients diagnosed from January 1995 to May 1999 (Fig 4).

View larger version (20K): [in this window] [in a new window]   Fig 4. Lung cancer-specific univariate survival analysis for BAC, before and after May 1999 (ie, the release date for the 1999 WHO classification of lung tumors), estimated using the Kaplan-Meier method. NR, value not reached; OS, overall survival; BAC, bronchioloalveolar carcinoma.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

This epidemiologic study is the first to demonstrate a survival advantage for patients with BAC who were diagnosed after May 1999 compared with BAC patients diagnosed before May 1999 (ie, the release date for the revised 1999 WHO classification of lung tumors). Even after adjustment for stage at presentation, sex, and smoking status, this observed survival advantage persists, demonstrating that other factors must contribute to this observed survival improvement.

After May 1999, there were differences in the extent of disease at diagnosis for BAC patients. While the proportion of localized BAC remained similar in both periods, more patients after May 1999 were diagnosed with metastatic disease at presentation. Interestingly, a survival benefit favoring patients diagnosed after May 1999 was detected for those BAC patients with localized disease but not for those with regional spread or metastatic disease at presentation. To further characterize this observed survival benefit, cause of death analyses and lung cancer-specific survival analyses were conducted. These analyses provide important insights into the changing epidemiology of BAC since the time of the revised 1999 WHO classification. Patients with BAC, who presented with localized or regional disease after May 1999, were less likely to die from lung cancer than similarly staged BAC patients before May 1999. For BAC patients diagnosed before May 1999, 40.8% of deaths caused by lung cancer were in patients with metastatic disease at presentation, and a full 30.8% of the deaths caused by lung cancer were in patients with local disease at the time of presentation. This contrasts with the cause of death reported for BAC patients diagnosed after May 1999, where the majority of deaths caused by lung cancer (71.7%) were in patients with metastatic disease at presentation, and only 10.9% of the deaths caused by lung cancer occurred in patients with local disease at the time of presentation. In fact, BAC patients with localized disease at presentation, who were diagnosed after 1999 (150 total cases), were just as likely to die as a result of lung cancer (five cases) as they were to die as a result of other causes (six cases). The 150 BAC patients diagnosed after May 1999 with localized disease at presentation represents the largest group of patients by stage at diagnosis (48.7%; Table 4). Thus, despite the slightly greater proportion of BAC patients with metastatic disease at presentation detected after May 1999, who will eventually die of lung cancer, the improved overall survival for this large group of local stage at presentation BAC patients contributes greatly to the overall survival benefit of all BAC patients diagnosed after May 1999 (Fig 3). Additionally, these observed differences in the proportion of deaths caused by lung cancer by stage at presentation contribute to the large increase in lung cancer–specific survival (Fig 4) for BAC cases diagnosed after May 1999 when compared with BAC cases diagnosed before May 1999.

We hypothesize that these evolving epidemiologic trends for BAC are caused by the revised 1999 WHO classification itself. The overall survival differences and lung cancer–specific survival differences detected here may be a result of adherence to the 1999 WHO classification system by pathologists, excluding many patients with pleural involvement, or adenocarcinoma subtype from the diagnosis of BAC. The lack of survival benefit for non-BAC NSCLC cases diagnosed after May 1999 compared with those diagnosed before May 1999, as depicted in Figure 3, argues against an overall improvement in lung cancer management during this time period. These observations support claims by others that BAC constitutes a distinct pathologic entity from the non-BAC NSCLCs.^8,15,16 The lung cancer-specific survival analysis and cause of death analysis in this study indicate there may be two distinct clinical subtypes of BAC in the era after May 1999: an aggressive form, presenting as multifocal BAC or BAC with distant metastasis that is quickly fatal, and a more indolent form, presenting as a solitary pulmonary nodule that is slow growing and is associated with superior survival characteristics. Within the subset of patients with advanced stage BAC, we have demonstrated an improvement in survival for BAC patients with intrapulmonary disease compared with those with distant metastasis beyond the thorax (Fig 2). Recently, Travis et al¹⁶ have called attention to the fact that the current staging system for multicentric adenocarcinomas may be problematic. Similar to our reported finding of an excellent (82%) 3-year survival rate noted for BAC patients with T4M0 disease, Battafarano et al¹⁷ reported a 66.5% 3-year survival rate for surgically resected T4N0M0 NSCLC tumors. Additionally, an analysis by Roberts et al¹⁸ of 14 patients with surgically resected multifocal lung BAC (including 10 patients with pathologically confirmed stage IIIb or stage IV disease) revealed a 64% 5-year survival rate. These two studies together suggest that patients with multicentric BAC indeed benefit from surgery. In addition to the above studies, our epidemiologic analysis reveals that patients with stage IV multicentric BAC (as a result of intrapulmonary spread) have a significantly better prognosis than patients with stage IV BAC as a result of distant metastasis, and supports the modification of subsequent classification systems to reflect these differences.

Findings in this study correlate with other studies showing a higher proportion of females, more never-smokers, earlier stage at presentation, and improved stage-adjusted survival for patients with BAC compared with patients with other types of NSCLC.^1-4 Females, never-smokers, and patients with adenocarcinoma or BAC were found by others to have improved responsiveness to the oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib.^15,19-21 Somatic mutations in lung tumors at exons 18 through 21 of EGFR-1 were detected in patients responsive to gefitinib^22,23 and erlotinib.²⁴ These were comprised of a group of lung tumors classified as adenocarcinoma, pure BAC, or adenocarcinoma with BAC features. Analyses in many of these studies included cases of BAC, using previous WHO definitions (ie, adenocarcinoma with BAC features would be labeled as BAC) instead of using strict adherence to the revised 1999 WHO definition.^15,22,25 With the potential impact of the revised 1999 WHO classification on survival in patients with BAC demonstrated in this study, and given the heterogeneity of responses of the various EGFR tyrosine kinase inhibitors in patients with NSCLC, we believe that strict adherence to these revised definitions will help unify results from subsequent studies on BAC and define a subset of lung cancer with similar mutational profiles and distinct clinical presentation.

In general, our results are consistent with the majority of reports showing at least a modest survival benefit observed for NSCLC patients who were never-smokers.^26-30 One possible explanation for why the effect of smoking on survival in our study is so modest is likely related to the fact that 2,265 cases (ie, 18.9% of our total study population) had no recorded smoking history. Subset analyses of these excluded patients reveal a significant decrease in median survival when compared with either the ever-smokers or never-smokers (data not shown). Review of the text files for these cases indicated that many of these patients died soon after diagnosis, during their initial hospital admission; often, they did not have a primary oncologist, and limited historical data was available for these cases. Because a large proportion of ever-smokers likely exist in this poor-prognostic group, the detrimental effects of smoking on survival in our study may be blunted. However, with available information on smoking status for 81.1% of the population of interest in this study, we believe the analyses incorporating data on smoking status here represent an important aspect of this study. Integrating smoking history into the epidemiology of lung cancer is of utmost importance, and yet, such information can be difficult to obtain in population-based studies. For example, currently, the SEER database does not contain information related to smoking history.

As a population-based study with inherent strengths in the observational analysis of large numbers of BAC cases over different time periods, it is acknowledged that certain limitations exist. With such a large number of BAC patients from a variety of hospitals, it is not possible to perform detailed histologic review for diagnostic confirmation of each case. Because accurate diagnosis of BAC requires histologic examination of the entire lesion, cytology specimens are considered inadequate for diagnosis. However, in this population-based analysis, greater than 92% of the BAC tumor specimens were analyzed using histology specimens, and nearly 70% of cases from the entire group of BAC patients had specimens involving either pneumonectomy, lobectomy, or wedge-resection samples. Thus, adequate tissue samples were available for accurate diagnosis of BAC in the majority of cases in this study.

The impact of the 1999 WHO classification on the epidemiology of BAC has been investigated by others. A retrospective study identified and analyzed all cases of BAC at a single institution between 1990 and 1997.³¹ When these 51 cases were pathologically re-evaluated using the revised 1999 WHO classification, only 47% were reclassified as true or classic BAC. The remaining patients were categorized as adenocarcinoma with BAC features (ie, nonclassic). There were no significant differences comparing sex, smoking history, age at diagnosis, presenting complaint, or stage between classic versus nonclassic BAC.³¹ However, the study was not powered to detect differences in these clinical variables and the investigators did not perform survival analyses.

The present study clearly demonstrates epidemiologic differences between BAC cases diagnosed after the release of the 1999 WHO definition compared with BAC cases diagnosed before that time. Survival analysis, analysis according to sex, smoking status, and stage at presentation allow us to analyze these differences in light of the revised 1999 WHO classification of lung tumors. The vast majority of these patients have not been treated with oral EGFR tyrosine kinase inhibitors since the first oral EGFR tyrosine kinase inhibitor, gefitinib, was not approved by the US Food and Drug Administration until 2003.³² We believe that our data reflect the adherence of community pathologists to the revised 1999 WHO classification of lung tumors, and this study reveals the changing epidemiology of BAC. Our findings support the characterization of BAC as a distinct entity of NSCLC. The recent 2004 WHO classification retained the same pathologic definition of BAC¹⁶ and thus, future studies on BAC, using the revised 1999 WHO criteria, may allow us to further define the epidemiology of BAC and lead to new treatment modalities.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by University of California Irvine Divisions of Hematology/Oncology, and Epidemiology.

Presented in part at the 17th annual conference of the California Association of Regional Cancer Registries, San Francisco, CA, March 21, 2005 and at the 11th World Conference on Lung Cancer, Barcelona, Spain, July 6, 2005.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted June 22, 2005; accepted August 9, 2005.

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