Trends in the Operative Management and Outcomes of T4 Lung Cancer

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1 Trends in the Operative Management and Outcomes of T4 Lung Cancer Farhood Farjah, MD, MPH, Douglas E. Wood, MD, Thomas K. Varghese, Jr, MD, Rebecca Gaston Symons, MPH, and David R. Flum, MD, MPH Surgical Outcomes Research Center, and Divisions of Cardiothoracic Surgery General Surgery, Department of Surgery, University of Washington, Seattle, Washington Background. This study describes temporal trends and increasing age (hazard ratio [HR], 1.02; 95% confidence variables in the operative management and outcomes of interval [CI], 1.00 to 1.03), comorbidity index of 3 vs 0 patients with T4 lung tumors in the general community. (HR, 1.66; 95% CI 1.24 to 2.21), tumor size 3 cm or more Methods. Surveillance, Epidemiology, and End-Results-Medicare data were used for a cohort study (1992 to95% CI, 1.40 to 1.98), and sublobar resection (HR, 1.55; (HR, 1.55; 95% CI, 1.30 to 1.84), N2/N3 nodes (HR, 1.67; 2002) of patients with stage IIIB lung cancer defined by95% CI, 1.26 to 1.90). Mediastinal lymphadenectomy had T4 tumors. Patient characteristics, tumor size, nodal status, use of staging modalities, extent of resection, multi-0.64 to 0.95). Improvements in overall survival over time a significantly lower hazard of death (HR, 0.78; 95% CI, modality therapy, and provider volume were examined. persisted after adjustment for these factors p ( 0.007). Follow-up death data were available through Conclusions. Temporal changes in the operative management of T4 tumors coincided with improvements in Results. Among 13,077 cases of T4 lung tumors, 1177 patients (9%) underwent resection. Over time, use of long-term survival. Our findings corroborate prior work mediastinoscopy (20%) did not change p ( 0.49); mediastinal lymphadenectomy increased from 10% to 29% select patients with T4 lung cancer. and practice guidelines supporting operative therapy for (p < 0.001) and neoadjuvant therapy from 4% to 8% p ( 0.04). Five-year survival rates increased from 15% to 35% (Ann Thorac Surg 2008;86:368 75) (p < 0.001). A higher hazard of death was associated with 2008 by The Society of Thoracic Surgeons T4 tumors of the lung are defined by malignant effu-resectablsions, multiple nodules within 1 lobe, or invasion ofchanges in management have actually occurred in the T4 tumors. It is unknown whether these traditionally unresectable structures, including the general community. heart, great vessels, trachea, esophagus, or vertebrae. In We used the Surveillance, Epidemiology, and Endthe absence of metastases, these tumors represent advanced-stage disease (IIIB) and are usually palliated with trends in the management and outcomes of patients who Results (SEER-Medicare) database to describe temporal radiation or chemotherapy, or both. Accumulating evidence suggests that some T4 tumors can be resectedand conducted exploratory analyses of potential factors underwent operative management of T4 lung tumors, safely with better long-term outcomes than that typically associated with outcomes and underlying any observed associated with stage IIIB lung cancer [1 9]. trends in outcomes. Safe and efficacious surgical therapy for T4 lung tumors likely represents an evolution in cancer management. For instance, given the limitations of radiographic Material and Methods staging of T status, particularly for tumors close to thea retrospective cohort study was conducted on patients chest wall or mediastinum [10], the number of explorations and resections might have increased over time. defined by a T4 tumor and diagnosed between 1992 and with stage IIIB non-small cell lung cancer (NSCLC) Because nodal involvement has been shown to be a2002. An overview of the SEER-Medicare database has strong predictor of poor prognosis among operated patients with T4 tumors [1 3, 5], more extensive preoperaington Institutional Review Board approved this study. been described previously [12]. The University of Washtive and intraoperative staging of the mediastinum might The following sequential exclusions were made among have occurred over time. Early success with the use of221,208 lung cancer cases identified through SEERinduction chemoradiation therapy for invasive superior sulcus tumors [11] might have extended to all potentially Accepted for publication April 28, Address correspondence to Dr Flum, Department of Surgery, University of Washington, 1959 NE Pacific, Box , Seattle, WA ; daveflum@u.washington.edu. Medicare: patients diagnosed at the time of autopsy/ death (n 5109), younger than then 66 years of age (n 33,509), without NSCLC histology (n 66,821), without stage IIIB cancer defined by a T4 tumor (n 96,029), with a diagnosis of another malignancy between 3 months before and 6 months after lung cancer diagnosis (n 498), and with partial fee-for-service or concurrent health 2008 by The Society of Thoracic Surgeons /08/$34.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg FARJAH ET AL 2008;86: MANAGEMENT AND OUTCOMES OF T4 LUNG CANCER Table 1. Characteristics for 1177 Patients With T4 Lung Tumors Who Underwent Resection Variable Value Age, mean SD years 74 5 Age grouping, % Male sex, % 58 Race, % White 90 Black 6 Other 4 Missing 1 Comorbidity Index, % Histology, % Adenocarcinoma 50 Squamous 40 Large cell/nos 10 Size 3 cm, % 61 Missing 12 Nodal status, % N0 47 N1 21 N2/N3 22 Missing 10 Mediastinoscopy, % 20 Positron emission tomography, % a 28 Neoadjuvant therapy, % None 90 Radiotherapy 4 Chemotherapy 3 Chemoradiotherapy 3 Extent of Resection (%) Sublobar 26 Lobar 53 Pneumonectomy 20 NOS 2 Mediastinal lymphadenectomy, % b 19 Adjuvant therapy, % c None 53 Radiotherapy 25 Chemotherapy 9 Chemoradiotherapy 12 High-volume surgeon, % 76 Missing 2 High-volume hospital, % 75 Missing 2 a Denominator based on 1998 to 2002 data. b Denominator based on 1994 to 2002 data. c Denominator based on those who survived for at least 30 days after resection. NOS Not otherwise specified; SD standard deviation. maintenance organization enrollment, or both, between 1 year before and 6 months after lung cancer diagnosis (n 6325). The Klabunde-modified Charlson Comorbidity Index (CCI) was calculated using claims within the Physician/ Carrier and Outpatient files in the year before diagnosis [13]. Information about tumor size, location, histology, and nodal status was available through SEER and based on available information within 4 months of diagnosis. The use of staging and therapeutic modalities was defined using claims within the Physician/Carrier and Outpatient files coded by the Healthcare Common Procedure Coding System, International Classification of Diseases, or Revenue Center Codes (Appendix), or both. Billing codes for positron emission tomography (PET) were only available for the period 1998 to 2002, and the code for mediastinal lymphadenectomy was only available between 1994 and Volume measurements were based on average yearly provider volume among SEER- Medicare patients. Providers within the highest quartile of caseload were categorized as a high-volume provider. Outcomes were death within 30 days of operation, time to death from any cause, and time to death from lung cancer. Follow-up was available through 2005 for all cause death data (from Medicare), and through 2004 for cause-specific death data (from SEER). Statistical analyses were conducted using Stata Special Edition 9.2 software (StataCorp, College Station, TX). Unadjusted overall survival estimates were obtained using the Kaplan-Meier method. Estimates of the cumulative incidence of lung cancer death were used to calculate unadjusted lung cancer cause-specific survival rates to account for the competing risk of death from other causes [14]. Logistic regression was used for trend and exploratory analyses of binary end points (healthcare utilization and 30-day death). Cox proportional-hazards models were used for trend and exploratory analyses of time to death from any cause or lung cancer. Survival time was defined as the interval between date of diagnosis and date of death or censoring. Exploratory multivariate analyses were conducted on a case-complete basis and adjusted for clustering at the hospital level. Two-sided p 0.05 was considered statistically significant. Results 369 A total of 13,077 patients with T4 lung tumors were identified. Their mean age standard deviation was 76 6 years, 58% were men, 84% were white, and 47% had comorbidity index of 1 or higher. Of these, 14% underwent exploration or resection, or both. This proportion did not change over time (p 0.60). Only 9% of patients underwent resection (Table 1). Of these patients, 20% underwent mediastinoscopy, and that proportion did not change over time (p 0.49). Use of PET increased from 5% in 1998 to 49% in 2002 (p 0.001). Mediastinal lymphadenectomy was done in 19%, and that proportion increased from 10% in 1994 to 28% in 2002 (p 0.001). Most resected patients did not receive neoadjuvant therapy, although the use of neoadjuvant GENERAL THORACIC

3 370 FARJAH ET AL Ann Thorac Surg MANAGEMENT AND OUTCOMES OF T4 LUNG CANCER 2008;86: Fig 1. Temporal trends in outcomes are presented for (A) 30-day death, (B) 5-year overall survival rates, and (C) 5-year cause-specific survival rates. The error bars show the 95% confidence interval. therapy increased from 4% in 1992 to 8% in 2002 (p 0.04). Of the patients who survived their operation for 30 days, 47% received adjuvant therapy (25% radiation only, 9% chemotherapy only, and 12% chemoradiation therapy). The use of adjuvant therapy decreased from 55% in 1992 to 40% in 2002 (p 0.001). Trends in health care utilization were not affected by adjustment for age, sex, race, comorbidity index, SEER registry, or clustering. Among resected patients with T4 tumors, 10% (95% confidence interval [CI], 8% to 12%) died within 30 days of operation. Thirty-day case-fatality rates did not change significantly over time (p 0.28). Five-year overall and lung cancer cause-specific survival rates were 20% (95% CI, 17% to 22%) and 38% (95% CI, 26% to 41%), respectively. The unadjusted 5-year survival of patients with N2 or N3 disease (8%, 95% CI, 5% to 12%) was significantly lower than that of patients with N0 disease (28%, 95% CI, 24% to 32%). Five-year overall and cause-specific survival rates increased between 1992 and 2002 from 15% to 35% (p 0.001) and 33% to 50% (p 0.001), respectively (Fig 1). Exploratory multivariate analyses were conducted to identify factors associated with outcomes and variables that might explain trends in outcomes over time. Factors associated with a higher odds of 30-day case fatality (Table 2) included increasing age, CCI higher than 0, tumor size 3 cm or larger, or pneumonectomy. Variables associated with a higher hazard of death from any cause included increasing age, CCI of 3 vs 0, size 3 cm or larger, N1 vs N0, N2/N3 vs N0, and sublobar resection (Table 3). Neoadjuvant therapy was not associated with short- or long-term outcomes. In models restricted to the years 1994 to 2002, mediastinal lymphadenectomy was not associated with early death (odds ratio [OR], 0.64; 95% CI 0.30 to 1.37) but was associated with a 22% and 29% lower risk of death due to any cause (HR, 0.78; 95% CI, 0.64 to 0.95) or lung cancer (HR, 0.71; 95% CI, 0.55 to 0.90), respectively. In models restricted to patients who survived their operation for at least 30 days, adjuvant therapy was associated with 60% and 43% higher risk of death due to any cause (HR, 1.40; 95% CI, 1.15 to 1.70) or lung cancer (HR, 1.57; 95% CI, 1.25 to 1.96), respectively. Trend analyses adjusting for factors associated with early death demonstrated a decreasing odds of 30-day death over time (p 0.02). Similarly, after adjustment for variables associated with time to death, the hazard of death due to any cause decreased over time (p 0.007), although a decreasing hazard of death due to lung cancer

4 Ann Thorac Surg FARJAH ET AL 2008;86: MANAGEMENT AND OUTCOMES OF T4 LUNG CANCER Table 2. Multivariate Analysis of Factors Associated With 30-Day Death Variable was not significant (p 0.07). The influence of PET on trends in outcomes over time could not be examined because there were no significant changes in outcomes during the period 1998 to 2002 when claims for PET were available. Comment OR (95% CI) Age 1.07 ( ) Male Sex 1.47 ( ) Race White 1.00 Black 2.08 ( ) Other 0.38 ( ) Comorbidity Index ( ) ( ) ( ) Size 3 cm 2.73 ( ) Histology Adenocarcinoma 1.00 Squamous 1.65 ( ) Large cell/nos 2.29 ( ) Nodal status N N ( ) N2/N ( ) Mediastinoscopy 0.86 ( ) Neoadjuvant therapy 0.95 ( ) Extent of resection Lobar 1.00 Pneumonectomy 2.30 ( ) Sublobar 0.76 ( ) NOS 3.67 ( ) High-volume surgeon 0.84 ( ) High-volume hospital 0.69 ( ) CI confidence interval; NOS not otherwise specified; OR odds ratio. T4 tumors of the lung have long been considered unresectable and associated with a poor prognosis. Increasingly, however, it has been recognized that the biologic behavior of stage IIIB lung cancer is heterogeneous and largely defined by the degree of lymph node involvement a surrogate for distant metastases. T4 N0-1 tumors have historically been designated as stage IIIB because of perceptions of unresectability, but the biology of a tumor that has the misfortune of poor location (T4) is likely very different than a tumor that has developed contralateral lymph node metastases (N3). Because T4 N0 tumors are not likely to be similar to T1-T4 N3 tumors with regards to their propensity to metastasize, select patients have improved opportunity for cure with surgical resection. Findings from this study show patients with T4 tumors who underwent operative management had better 5-year overall survival rates (20%) than the aggregate survival estimate for stage IIIB lung cancer (3% to 7%) [15]. Certain aspects of staging and management have changed over time, including increased use of PET, mediastinal lymphadenectomy, and neoadjuvant therapy, and decreased use of adjuvant therapy. Coincident with these changes, unadjusted 5-year overall and lung cancer specific survival rates have increased significantly over time, although 30-day case-fatality rates have not. Factors associated with adverse outcomes include increasing age and number of comorbid conditions, tumor size larger than 3 cm, lymph node involvement, sublobar resection, and adjuvant therapy. Adjustment for changes in these and other factors over time suggests that the risks of early and late death have decreased over time. The results of this nationally representative study corroborate previous reports [1 9] and current practice guidelines [16, 17] recommending operative management for select patients with T4 tumors. Table 3. Multivariate Analysis of Factors Associated With Time to Death Death Due to Any Cause HR (95% CI) 371 Lung Cancer Death HR (95% CI) Age 1.02 ( ) 1.00 ( ) Male sex 1.07 ( ) 0.99 ( ) Race White Black 1.31 ( ) 1.33 ( ) Other 0.98 ( ) 0.87 ( ) Comorbidity index ( ) 1.25 ( ) ( ) 1.07 ( ) ( ) 1.58 ( ) Size 3 cm 1.55 ( ) 1.76 ( ) Histology Adenocarcinoma Squamous 0.98 ( ) 0.97 ( ) Large cell/nos 1.25 ( ) 1.30 ( ) Nodal status N N ( ) 1.61 ( ) N2/N ( ) 1.99 ( ) Mediastinoscopy 0.98 ( ) 1.03 ( ) Neoadjuvant therapy 0.83 ( ) 0.78 ( ) Extent of resection Lobar Pneumonectomy 1.19 ( ) 1.15 ( ) Sublobar 1.55 ( ) 1.56 ( ) NOS 1.98 ( ) 2.32 ( ) High-volume hospital 0.83 ( ) 0.84 ( ) CI confidence interval; HR hazard ratio; NOS not otherwise specified. GENERAL THORACIC

5 372 FARJAH ET AL Ann Thorac Surg MANAGEMENT AND OUTCOMES OF T4 LUNG CANCER 2008;86: Accurate staging of tumor extent is an important component of lung cancer management. Computed tomography (CT) of the chest has limited value in characterizing tumor invasion. Whereas clinical staging tends to underestimate tumor stage, radiographic staging with CT tends to overstage T status in more than 50% of patients [10]. More accurate staging can be achieved by thoracic exploration, leading to appropriate surgical therapy for patients with T1-T3 tumors and a more informed decision about the resectability of true T4 tumors. Surprisingly, we did not observe an increase in the proportion of explorations or resections, or both, over time among patients with T4 tumors. Although imaging resolution has likely improved with time, the ability of CT imaging to define tumor invasion into adjacent structures has likely not. Because the consequences of overstaging are more ominous than understaging given the potential for recommending palliative rather than curative therapy patients with a limited extent of T4 disease by radiographic staging should be considered for surgical exploration to maximize the chance of cure. Although not recommended in recent practice guidelines [16, 17], thoracic exploration might be a necessary and appropriate component of staging for select patients with potentially resectable, clinically staged T4 N0-1 lung cancer. The strong association between nodal status and survival described in this and other studies [1 3, 5] is the basis for recent practice guidelines recommending (1) routine PET and mediastinoscopy for all potentially resectable patients with T4 tumors and (2) resection only for those with N0-1 nodal status [16, 17]. One reason for the high proportion (22%) of N2/N3 disease among operated on patients in our cohort may have been inadequate mediastinal staging. Rapid adoption of PET resulted in 49% of patients having been staged with this modality in 2002, but the use of mediastinoscopy did not increase over the time. In 2002, only 10% of resected patients underwent both PET and mediastinoscopy. Long-term outcomes associated with surgical therapy for T4 lung cancer will likely improve further if surgeons more accurately select only patients with N0-1 disease. Despite a significant rise in use of neoadjuvant therapy over time, we found no association between neoadjuvant therapy and survival. These findings are in contrast with recent results from a multicenter, prospective trial of superior sulcus tumors demonstrating improved survival rates associated with the use of induction chemoradiation therapy compared with historical data [18]. One explanation is that neoadjuvant therapy may not improve the ability to achieve complete resection in patients with T4 disease and that preoperative therapy is not beneficial so long as complete resection is accomplished. Alternatively, patients in the general community who would be expected to benefit from neoadjuvant therapy for instance those with systemic disease evidenced by mediastinal nodal involvement might not have been offered surgical therapy. Another possible explanation relates to the type of induction therapy used. In the Southwest Oncology Group (SWOG) trial, patients with superior sulcus tumors received only chemoradiation therapy, whereas patients in our cohort received radiation, chemotherapy, and chemoradiation therapy. Survival rates are known to vary by type of induction therapy [19]. Finally, our cohort likely consisted of a heterogeneous group of T4 tumors, whereas the SWOG trial consisted only of patients with superior sulcus tumors, including T3 and T4 tumors. This difference in patient composition is unlikely to explain the apparent lack of benefit of neoadjuvant therapy, because excellent outcomes have been reported among heterogeneous groups of T4 patients [4, 6] and groups defined by mediastinal invasion [2], airway involvement [5], superior vena cava invasion [8], and multi-focal lobar involvement [7, 9]. Importantly, we found no association between neoadjuvant therapy and an increased risk of early death after resection. The use of adjuvant therapy decreased over time and was associated with a significantly increased risk of death. Adjuvant radiation therapy is used for local control of incompletely resected tumors and adjacent lymph nodes, whereas adjuvant chemotherapy is used to treat suspected occult systemic disease. The declining use of adjuvant therapy over the study period may be the result of better preoperative patient selection. Meta-analyses of trials of adjuvant therapy for early-stage lung cancer revealed survival benefits associated with adjuvant chemotherapy [20] and survival decrements associated with radiation therapy [21]. In our study, adjuvant radiation therapy (HR, 1.38; 95% CI, 1.11 to 1.72) and chemotherapy (HR, 1.46; 95% CI, 1.06 to 2.01) were both associated with a higher risk of death. The most likely reason for these discrepant findings is confounding. Because we could not measure (and therefore adjust) for the indications for adjuvant therapy, it is likely that the apparently higher risk of death associated with adjuvant therapy is actually a consequence of the indications for therapy rather than therapy itself. Other potential explanations are that adjuvant therapy was not used for the appropriate indications, alkylating rather than platinum-based agents were used during the period of study [20], the results of the meta-analyses are not generalizable to patients with T4 tumors, or adjuvant therapy is truly detrimental. The risk of adverse outcomes after operative management was associated with nonmodifiable factors. Increasing age, comorbid conditions, and tumor size were associated with higher risks of early- and long-term death in our cohort, but 5-year overall survival rates for operated patients older than 80 years (15%, 95% CI, 10% to 22%), with a comorbidity index of 3 (14%, 95% CI, 7% to 22%), or with a tumor 3 cm or larger (16%, 95% CI, 14% to 29%) were still higher than aggregate survival estimates for stage IIIB cancer (3% to 7%). An observational study such as this one cannot prove that operative management led to better survival rates in these subgroups, although it remains a plausible explanation given the findings. Factors associated with adverse outcomes should be discussed with patients as a standard part of informed consent, but risk factors should not obviate

6 Ann Thorac Surg FARJAH ET AL 2008;86: MANAGEMENT AND OUTCOMES OF T4 LUNG CANCER thoracic surgical consultation or resection in appropriately selected patients. Subsequent studies should attempt to identify modifiable risk factors for adverse outcomes associated with operative management of T4 tumors. This investigation has several limitations. Our findings may be generalizable to elderly Medicare beneficiaries only, but only if management and outcomes are different for patients 65 and younger or those with alternative health plans. We were not able to adjust for important factors associated with outcome such as lung function, performance status, residual tumor, lymphovascular invasion, bulky vs microscopic nodal involvement, degree of invasion, involved viscera, or operative details potentially leading to spurious associations in our exploratory analyses. We included surgeon and hospital volume in exploratory models to adjustment for the potentially confounding effects of previously described volume-outcome relationships [22 24], but in our models we did not observe these associations. A likely explanation is the method of calculating volume using the SEER-Medicare population, which tends to bias the volume-outcome relationship towards the null [25] and may have resulted in inadequate adjustment. Results pertaining to cause-specific survival should be interpreted with caution, because SEER records the cause of death based on death certificate information, and the validity of this approach is controversial [26]. Patients with missing covariate data had significantly higher 30-day case-fatality rates (16% vs 8%, p 0.001) and lower 5-year overall survival rates (11% vs 23%, p 0.001), possibly biasing exploratory multivariate analyses. The main findings of our study health care utilization and outcome estimates and trend analyses would not have been biased because these calculations did not exclude patients with missing covariate data from the analysis. This study has several implications. Patients with limited T4 N0-1 disease may be amenable to complete surgical resection with a substantially better chance of survival than patients with other manifestations of disease also classified as stage IIIB. The former should receive consultation with an experienced thoracic surgical oncologist, as recommended by current guidelines [16, 17]. When counseling patients selected to undergo resection on the risks and benefits of surgical therapy, surgeons can supplement information about their individual or institutional experience with outcomes based on data from this nationally representative experience. The preliminary data generated from our exploratory analyses might be used to plan multicenter, prospective investigations of staging and multimodality therapy that could help to define the evaluation and selection of patients to be considered for advanced surgical treatment with curative intent. Improved application of staging modalities (PET and mediastinoscopy) is especially important in the evaluation of locally advanced lung cancer and is critical for selecting patients that may most benefit from an operation. This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. We acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development and Information, Centers for Medicare and Medicaid Services; Information Management Services Inc; and the SEER Program tumor registries in the creation of the SEER-Medicare database. Farhood Farjah was supported by a Cancer Epidemiology and Biostatistics Training Grant (T32 CA ) and National Research Service Award (F32 CA ) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. References Bernard A, Bouchot O, Hagry O, Favre JP. Risk analysis and long-term survival in patients undergoing resection of T4 lung cancer. Eur J Cardiothorac Surg 2001;20: Doddoli C, Rollet G, Thomas P, et al. Is lung cancer surgery justified in patients with direct mediastinal invasion? Eur J Cardiothorac Surg 2001;20: Fukuse T, Wada H, Hitomi S. Extended operation for nonsmall cell lung cancer invading great vessels and left atrium. Eur J Cardiothorac Surg 1997;11: Macchiarini P, Dulmet E, De Montpreville V, et al. 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7 374 FARJAH ET AL Ann Thorac Surg MANAGEMENT AND OUTCOMES OF T4 LUNG CANCER 2008;86: Shen KR, Meyers BF, Larner JM, Jones DR. Special treatment issues in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132(3 suppl):290s 305S. 18. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007;25: Wright CD, Menard MT, Wain JC, et al. Induction chemoradiation compared with induction radiation for lung cancer involving the superior sulcus. Ann Thorac Surg 2002;73: Alam N, Darling G, Shepherd FA, Mackay JA, Evans WK. Postoperative chemotherapy in nonsmall cell lung cancer: a systematic review. Ann Thorac Surg 2006;81: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2005:CD Bach PB, Cramer LD, Schrag D, Downey RJ, Gelfand SE, Begg CB. The influence of hospital volume on survival after resection for lung cancer. N Engl J Med 2001;345: Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002;346: Birkmeyer JD, Stukel TA, Siewers AE, Goodney PP, Wennberg DE, Lucas FL. Surgeon volume and operative mortality in the United States. N Engl J Med 2003;349: Hollenbeck BK, Hong J, Zaojun Y, Birkmeyer JD. Misclassification of hospital volume with surveillance, epidemiology, and end results Medicare data. Surg Innov 2007;14: Bach PB, Guadagnoli E, Schrag D, Schussler N, Warren JL. Patient demographic and socioeconomic characteristics in the SEER-Medicare database applications and limitations. Med Care 2002;40(8 suppl):iv Appendix Billing Codes Used to Define Staging and Therapy Resection HCPCS Exploration HCPCS Chemotherapy HCPCS C9017 J0182 J8510 J8530 J8560 J8610 J899 J9000 J9001 J9010 J9045 J9060 J9062 J9070 J9080 J9090 J9091 J9092 J9093 J9094 J9095 J9096 J9097 J9170 J9180 J9181 J9182 J9190 J9201 J9206 J9208 J9230 J9250 J9260 J9265 J9280 J9290 J9291 J9350 J9360 J9370 J9375 J9380 J9390 J9999 Q0083 Q0084 Q0085 Q0125 Q0127 Q0128 Q0129 S0178 S0182 S9329 S9330 S9331 ICD-9 V58.1 V66.2 V RCC Radiation therapy HCPCS C1716 C1717 C1718 C1719 C1720 C1790 C1791 C1792 C1793 C1794 C1795 C1796 C1797 C1798 C1799 C1800 C1801 C1802 C1803 C1804 C1805 C1806 C2616 G0126 G0173 ICD-9 V58.0 V66.1 V Billing Codes Used to Define Staging and Therapy PET HCPCS G0125 G0126 G0210 G0211 G212 G Mediastinoscopy/otomy HCPCS Mediastinal lymphadenectomy HCPCS HCPCS Healthcare Common Procedure Coding System; ICD-9 International Classification of Diseases, 9th Clinical Modification; PET positron emission tomography; RCC Revenue Center Code.