Despite advances in radiation therapy, chemotherapy, Tumor Recurrence After Complete Resection for Non-Small Cell Lung Cancer

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1 Tumor Recurrence After Complete Resection for Non-Small Cell Lung Cancer Matthew D. Taylor, MD, Alykhan S. Nagji, MD, Castigliano M. Bhamidipati, DO, MS, Nicholas Theodosakis, BS, Benjamin D. Kozower, MD, Christine L. Lau, MD, and David R. Jones, MD Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Charlottesville, Virginia Background. Long-term survival after R0 resection for non-small cell lung cancer (NSCLC) is less than 50%. The majority of mortality after resection is related to tumor recurrence. The purpose of this study was to identify independent perioperative and pathologic variables that are associated with NSCLC recurrence after complete surgical resection. Methods. A retrospective examination was performed of a prospectively maintained database of patients who underwent resection for NSCLC from July 1999 to August 2008 at a single institution. Clinicopathologic variables were evaluated for their influence on time to recurrence. Cox s proportional regression hazard model examined the association of recurrence in NSCLC. Results. A total of 1,143 patients met inclusion criteria and had complete follow-up information. Of these patients, 378 (33.1%) had recurrence of the primary cancer. Median follow-up was 24 months (range, months). Preoperative tumor maximum standardized uptake value (SUV max ) greater than 5 was associated with increased risk of recurrence (hazard ratio [HR], 1.81; p 0.01). Preoperative radiation was independently associated with recurrence (HR, 1.98; p 0.05) as well as the presence of pathologic stage II and stage III disease (stage II: HR, 2.53; p 0.05; stage III: HR, 6.49; p 0.006). Subgroup analysis found that sublobar resection was also associated with locoregional recurrence after resection (HR, 4.17; p 0.02) and lymphovascular invasion of distant recurrence (HR, 4.21; p 0.002). Conclusions. In the largest series reported to date on postresectional recurrence of NSCLC, SUV max greater than 5, increasing pathologic stage, and the administration of preoperative radiation were independently associated with NSCLC recurrence after resection. Sublobar resection was independently associated with locoregional recurrence, and lymphovascular invasion was associated with distant recurrence. (Ann Thorac Surg 2012;93: ) 2012 by The Society of Thoracic Surgeons Accepted for publication March 12, Presented at the Fifty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9 12, Address correspondence to Dr Jones, Thoracic and Cardiovascular Surgery, University of Virginia, Department of Surgery, Box , Charlottesville, VA ; djones@virginia.edu. Despite advances in radiation therapy, chemotherapy, and newly developed molecular targeting therapies, long-term survival after resection for non-small cell lung cancer (NSCLC) remains less than 50%. The majority of mortality in postresectional treatment of NSCLC is related to the development of recurrence. A number of studies have investigated clinical, pathologic, and genetic factors that are associated with decreased survival after resection for NSCLC [1 3]. Kameyama and colleagues [1] investigated the new TNM staging system on survival after NSCLC resection in 1,532 patients. Using the new staging system, 5-year survival rates were stage IA, 84.8%; stage IB, 75.2%; stage IIA, 62.4%; stage IIB, 52.1%; stage IIIA, 32.4%; stage IIIB, 15.2%; and stage IV, 30.6%. Kozower and colleagues [2] investigated clinical factors predicting mortality using the Society of Thoracic Surgeons (STS) database consisting of 18,800 lung resections at 111 centers. Independent predictors of mortality included patients undergoing pneumonectomy and bilobectomy, higher American Society of Anesthesiology rating, poor performance status, renal dysfunction, induction chemoradiation therapy, steroid administration, increasing age, urgent procedures, male sex, lower forced expiratory volume in 1 second, and increased body mass index. Lin and colleagues [3] reviewed previous studies linking molecular markers of NSCLC associated with a poor prognosis. These included KRAS, EGFR, and P53 mutations as well as overexpression of cyclin E and VEGF-A. Loss of protein expression of E-cadherin, p16, and -catenin has also been shown to be a poor prognostic indicator in NSCLC [3]. In contrast, few studies have investigated the relationship of clinicopathologic variables and NSCLC recurrence. By focusing on elucidating what factors affect the time to lung cancer recurrence, we might be able to uncover recurrences earlier and initiate therapy more quickly. The objective of this study was to investigate clinicopathologic factors and their relationship with recurrence in patients who underwent R0 resection for NSCLC by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 1814 TAYLOR ET AL Ann Thorac Surg RECURRENCE AFTER NSCLC RESECTION 2012;93: Patients and Methods Patient Selection A retrospective analysis was performed of a prospectively maintained general thoracic surgery database at the University of Virginia (UVA-GTSD) from July 1999 through August The UVA-GTSD is maintained by the Division of Thoracic and Cardiovascular Surgery and includes all data fields contained within the STS General Thoracic Surgery Database in addition to other important clinicopathologic variables. All standardized variables analyzed represent STS definitions. Cases in which random pieces of data were missing were not excluded from analysis; however variables with large amounts of missing data ( 10%) underwent deletion on a case by case basis. The Human Investigations Committee at UVA approved this study. We abstracted data from the medical records of 1,143 consecutive patients who underwent an R0 surgical resection for NSCLC. All patients underwent surgical intervention for cure. Patients were excluded if they had carcinoid histologic type, second lung primary lesions, or died within 30 days of operation. The selected cases were staged according to the 7th edition of the American Joint Committee on Cancer/International Union against Cancer guidelines adopted in All patient follow-up data were complete as of September 30, Cross-linking medical records between the UVA-GTSD and the UVA Clinical Cancer Registry ascertained recurrence after resection. The UVA Clinical Cancer Registry is a prospectively maintained database of patients with cancer receiving treatment through the UVA Cancer Center. Postoperatively, patients were initially seen at 2 to 3 weeks after resection by the thoracic surgeon and then again every 3 to 6 months; for 5 years they underwent contrastenhanced chest computed tomography (CT) at these appointments. Subsequent to these visits, either a roentgenogram or computed tomographic scan of the chest was reviewed annually. Positron emission tomography (PET) with CT or magnetic resonance imaging was used as clinically warranted. All visits were completed in concert with the referring oncologist. Recurrence was documented either radiographically or histologically in all cases. In this study, locoregional recurrences were defined as recurrence in an ipsilateral lobe of the lung in patients undergoing sublobar resection or recurrence in ipsilateral mediastinal or hilar lymph nodes, or both. In patients who underwent lobectomy or pneumonectomy, locoregional recurrences were defined as involvement of the ipsilateral mediastinal or hilar lymph node, or both. Distal recurrences were defined as recurrence not located in the ipsilateral thorax. Recurrences in patients who had simultaneous locoregional and distant recurrences were defined as distant recurrences for the purpose of the study. Induction chemotherapy and radiation therapy were reserved for patients with superior sulcus tumors and large tumors invading the chest wall. An independent investigator (ASN or NT) abstracted data from clinical records and cross-checked variable information to ensure internal validity and consistency. There were 617 deaths during the time of the study. There were 332 deaths unrelated to cancer recurrence and 268 deaths related to cancer recurrence. In the patients in whom recurrences developed, there were 17 deaths from unrelated causes. At the end of the time interval investigated, 110 patients were alive with NSCLC recurrence. Statistical Analysis A study population of 1,143 patients who underwent R0 resection for NSCLC was selected for analysis. The primary interest was to examine the association between clinicopathologic variables and the incidence of recurrence after R0 resection for NSCLC. The statistical significance of differences in proportions for categorical variables was evaluated by Pearson s 2 test or Fisher s exact test where appropriate (p 0.05). The statistical significance of differences in mean values for continuous variables was assessed using single-factor analysis of variance (p 0.05). Multiple testing bias was reduced with adjustments using the false discovery rate. Kaplan- Meier plots were developed to represent the unadjusted relationship between the probability of recurrence and months of follow-up after R0 resection for NSCLC. The log-rank test examined this association with the probability of recurrence. Based on the continuous variables, the maximum standardized uptake value (SUV max ) was categorized into less than or equal to 2.5, greater than 2.5, and less than or equal to 5.0 and greater than 5.0, and tumor size was dichotomized into less than 3 cm or greater than or equal to 3 cm. We developed these intervals based on our data to provide clinically relevant strata while probing to identify the subset of SUV max and tumor size with the greatest predictive potential. Because SUV max less than 2.5 in lung tumors is less indicative of malignancy, we used this value to represent the referent category [4]. Categorization of continuous data assumes that the relationship between the predictor and the response is flat within intervals, which is less reasonable than the standard linearity assumption. The need for dummy variables and multiple intervals leads to less power and imprecision. Nevertheless, since categorization is more clinically useful, we examined these associations as described. Separate Cox s proportional regression hazard models estimated the recurrence function after resection. Pathologic covariates were selected if their association with recurrence was significant (p 0.05) in unadjusted models. The covariates in the models included age, sex, use of preoperative radiation, use of preoperative chemotherapy, preoperative Eastern Cooperative Oncology Group status, history of tobacco use, pack years of smoking before operation, presence of diabetes mellitus, steroid use, weight loss over the 3 months preceding surgery, SUV max, pathologic tumor stage, tumor size, nodal stage, tumor type, primary procedure, lymphovascular invasion, preprocedural albumin level, and arterial, lymphatic, or pleural invasion. The relationship between these clinicopathologic influences and the number of months after R0 resection were assessed by calculating

3 Ann Thorac Surg TAYLOR ET AL 2012;93: RECURRENCE AFTER NSCLC RESECTION relative HRs as a function of recurrence after adjustment. Data were analyzed using SAS software, version 9.1 (SAS Institute, Cary, NC) and SPSS 20 (SPSS, Inc, Chicago, IL). Results Table 1. Patient Demographics Variable No. % Sex (M-F) 601:542 52:48 Race White 1, African American Other Type of procedure Lobectomy Pneumonectomy Segmentectomy Wedge resection Stage IA Stage IB Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IV Histologic type Adenocarcinoma Squamous cell Other NSCLC NSCLC non-small cell lung cancer. Table 2. Anatomic Location of NSCLC Recurrences Location No. % Ipsilateral lung Lymph node/mediastinum Brain Contralateral lung Bone Liver Chest wall Pleura Adrenal gland Kidney Multiple sites NSCLC non-small cell lung cancer. The demographic characteristics of the population are shown in Table 1. Induction chemotherapy alone was performed in 35 patients and induction chemoradiation therapy was performed in 64 patients. Patients excluded from the study included 10 patients who died within 30 days of operation (0.8%), 50 patients with lung carcinoid (4%), and 61 patients with second primary lung tumors (5%). There was pathologic confirmation of radiologic evidence of NSCLC recurrence in 325 of 378 NSCLC recurrences (86%). Median follow-up was 24 months (range, months). We evaluated 23 clinicopathologic variables in this study. Table 2 demonstrates the location of recurrences for patients included in this study. Patients in whom there were multiple locations of recurrence were most common. Multiple locations of recurrence were followed by ipsilateral lung involvement and brain metastasis in terms of frequency. We found a total of 378 recurrences in this study, representing 33% of the patient population. Locoregional recurrence was documented in 94 patients, representing 8% of the population. There were 284 distant recurrences, representing 25% of the population studied. Table 3 illustrates the unadjusted association of clinicopathologic variables with recurrence. Sublobar resection, preoperative radiation therapy, SUV max, lymphovascular invasion, presence of node-positive disease, tumor size, pathologic stage, and arterial invasion were all associated with increased NSCLC recurrence and decreased time to recurrence. Table 3. Correlation of Clinicopathologic Variables With Recurrence After R0 Resection Variable No. No. of NSCLC Recurrences (%) Log-Rank p Value Type of resection Lobectomy/ (31.7) pneumonectomy Segmentectomy/Wedge (39.1) Resection Stage I (29.1) Stage II (37.6) Stage III (46.9) Tumor size (cm) 3 cm (31.1) cm (35.8) Nodal status N (29.9) N1/N (41.9) Lymphovascular invasion Present (41.0) Absent (30.9) Arterial invasion 0.05 Present (44.6) Absent 1, (32.2) SUV max (36.3) (38.0) (40.8) Preoperative radiation therapy Yes 64 28/ No 1, /1,079 SUV max maximum standard- NSCLC non-small cell lung cancer; ized uptake value. 1815

4 1816 TAYLOR ET AL Ann Thorac Surg RECURRENCE AFTER NSCLC RESECTION 2012;93: Table 4. Multivariate Analysis of Risk Factors for All NSCLC Recurrences Variable Hazard Ratio 95% CI p Value Preoperative radiation SUV max Reference Reference Reference Stage I Reference Reference Reference Stage II Stage III CI confidence interval; NSCLC non-small cell lung cancer; SUV max maximum standardized uptake value. In our adjusted analysis, we found that SUV max greater than 5 was independently associated with decreased time to recurrence (Table 4). Also, pathologic stage II and stage III were independently associated with recurrence and shortened time to recurrence. Finally, preoperative radiation was found to be independently associated with recurrence after NSCLC resection. Figs 1 to 3 illustrate the Kaplan-Meier plots for the unadjusted relationship between the probability of recurrence and months of follow-up after R0 resection for NSCLC. Fig 1 demonstrates an increased percentage of recurrence in patients with pathologic stage II and stage III compared with patients with stage I disease. Figure 2 shows increasing recurrence rates based on increasing preoperative tumor SUV max. Figure 3 demonstrates a significant increase in recurrence rates associated with preoperative radiation therapy. Table 5 lists the independent associations of locoregional recurrences in patients undergoing NSCLC resection. Stage III disease was independently associated with locoregional recurrence. Subgroup analysis also found that sublobar resection was independently associated with locoregional recurrence. Preoperative tumor SUV max greater than 5 and radiation therapy were not associated with locoregional recurrence. Figure 4 illustrates the Kaplan-Meier plot for the unadjusted relationship of locoregional recurrence to the type of surgical procedure (sublobar versus lobectomy/pneumonectomy). There was an increased rate of locoregional recurrence in patients undergoing sublobar resection. Table 6 shows the multivariate analysis of factors associated with distant recurrence in patients undergoing NSCLC resection. In patients with distant recurrences after resection, SUV max greater than 5 and stage III disease were independently associated with distant recurrences. Preoperative radiation therapy in this subgroup analysis was not found to be independently associated with distant recurrence. Interestingly, lymphovascular invasion was found to be independently associated with distant recurrence in this population. Figure 5 illustrates the Kaplan-Meier plot for the unadjusted relationship of distant recurrence based on the presence of lymphovascular invasion. The presence of lymphovascular invasion was associated with an increased rate of distant recurrences. Comment This study investigated the significance of clinicopathologic variables on the time to NSCLC recurrence after R0 resection. SUV max, pathologic stage, and preoperative radiation were independently associated with recurrence in all patients in the study. Fluorodeoxyglucose/PET has become an important method used by clinicians for the staging of NSCLC. Fig 1. Kaplan-Meier plot for the unadjusted relationship between pathologic stage and recurrence after R0 resection for NSCLC. (5 YRR 5-year recurrence rate; NSCLC non-small cell lung cancer; Path pathologic.)

5 Ann Thorac Surg TAYLOR ET AL 2012;93: RECURRENCE AFTER NSCLC RESECTION 1817 Fig 2. Kaplan-Meier plot for the unadjusted relationship between tumor SUV max and recurrence after R0 resection for NSCLC. (5 YRR 5-year recurrence rate; NSCLC non-small cell lung cancer; SUV max maximum standardized uptake.) Previous work has demonstrated that fluorodeoxyglucose/pet SUV max in primary NSCLC tumors correlates with both tumor and nodal status [5]. Furthermore, several studies have demonstrated the predictive power of SUV max on patient survival [6, 7]. SUV max has been associated with increased risk of recurrence in NSCLC. Koo and colleagues [8] investigated factors associated with recurrence in 310 patients with stage I and stage II disease. There were a total of 106 recurrences in the study population. SUV max of greater than or equal to 4.5 was found to be an independent predictor of recurrence after resection, with an odds ratio of Additionally, Shiono and associates [9] demonstrated that SUV max of greater than or equal to 4.7 was found to be an independent predictor of recurrence in stage I NSCLC. These 2 studies did not stratify patients based on the location of recurrence to determine whether SUV max was more predictive in locoregional than in distant recurrences. In our study, subgroup analysis revealed that SUV max greater than 5 was associated with distant recurrences, whereas the predictive nature of SUV max greater than 5 did not reach statistical significance in the patients with locoregional recurrences. was found to be independently associated with time to recurrence in this study. Subgroup Fig 3. Kaplan-Meier plot for the unadjusted relationship between preoperative radiation and recurrence after R0 resection for NSCLC. (5 YRR 5-year recurrence rate; NSCLC non-small cell lung cancer.)

6 1818 TAYLOR ET AL Ann Thorac Surg RECURRENCE AFTER NSCLC RESECTION 2012;93: Table 5. Multivariate Analysis of Risk Factors for Locoregional NSCLC Recurrences Variable Hazard Ratio 95% CI p Value Sublobar resection SUV max Reference Reference Reference Stage I Reference Reference Reference Stage II Stage III CI confidence interval; NSCLC non-small cell lung cancer; SUV max maximum standardized uptake value. Table 6. Multivariate Analysis of Risk Factors for Distant NSCLC Recurrences Variable Hazard Ratio 95% CI p Value Lymphovascular invasion SUV max Reference Reference Reference Stage I Reference Reference Reference Stage II Stage III CI confidence interval; NSCLC non-small cell lung cancer; SUV max maximum standardized uptake value. analysis in our study based on the location of recurrence found that stage III disease was independently associated with both locoregional and distant recurrences. Previous studies have associated NSCLC recurrence with pathologic stage. Kelsey and colleagues [10] investigated the risk of recurrence after surgical resection for stage I and stage II NSCLC. The overall risk of recurrence was 36% compared with an overall recurrence rate of 33% in this study. greater than IA was independently associated with a higher risk of recurrence, with an HR of Varlotto and coworkers [11] investigated factors associated with recurrence in 373 patients with stage I through stage IIIA NSCLC who underwent resection. In this study of 373 patients, advanced TNM staging was associated with an increased risk of distant NSCLC recurrence. Although these 2 studies establish the importance of pathologic stage to the risk of recurrence, they use the 6th edition of the International Association for the Study of Lung Cancer and not the most recent 7th edition. Pepek and colleagues [12] described the ability of the TNM 7 staging system to detect locoregional recurrence in comparison to the 6th edition. Converting from the 6th edition to the 7th edition resulted in a 21% stage migration 13% upstaged and 8% downstaged. We also found that preoperative radiation was associated with increased risk of recurrence. When performing subgroup analysis on the location of recurrence, preoperative radiation was not associated with locoregional or distant recurrence. We believe that this finding likely represents the underlying aggressive tumor characteristics for which patients received preoperative radiation. Sublobar resection was found to be an independent predictor of locoregional recurrence in our study. Tumor size was not associated with an increased risk of recurrence in the sublobar resection group (2.3 cm in the group with recurrence, 2.2 cm in the group without recurrence; p 0.3). In contrast, Bando and colleagues Fig 4. Kaplan-Meier plot for the unadjusted relationship between type of procedure and locoregional recurrence after R0 resection for NSCLC. (5 YRR 5-year recurrence rate; NSCLC non-small cell lung cancer.)

7 Ann Thorac Surg TAYLOR ET AL 2012;93: RECURRENCE AFTER NSCLC RESECTION 1819 Fig 5. Kaplan-Meier plot for the unadjusted relationship between lymphovascular invasion and distant recurrence after R0 resection for NSCLC. (5 YRR 5-year recurrence rate; NSCLC non-small cell lung cancer.) [13] reported higher rates of recurrence associated with sublobar resection in patients with tumor size greater than 2 cm. In this study, patients with tumor size less than 2 cm had locoregional recurrence rates of 1.9% compared with 33% in patients with tumors greater than 2 cm. The differing conclusion in this study may be related to our larger sample size and the fact that 50% of our patients underwent wedge resection in contrast to this previously published study in which all patients underwent segmentectomy. Our study supports the previous work by Kelsey and colleagues [10] evaluating the predictors of locoregional recurrence in 975 patients with stage I and stage II NSCLC. Ginsberg and colleagues [14] found a 3-fold increase in locoregional recurrences in patients with T1N0 disease undergoing segmentectomy or wedge resection. The role of sublobar resection for T1aN0M0 NSCLC is currently being investigated in the CALGB trial. Lymphovascular invasion was found to be an independent predictor of distant recurrence in this study. Shiono and colleagues [9] found lymphovascular invasion to be an independent predictor of overall recurrence in patients with stage I NSCLC. This study did not evaluate the relationship of the location of recurrence and the association of tumor lymphovascular invasion. Kelsey and colleagues [10] also found that lymphovascular invasion was associated with locoregional failure. This study evaluated only patients with stage I and stage II NSCLC, unlike our patient population, and did not perform subgroup analysis of patients with distant recurrence. Limitations to this study include the retrospective nature of our analyses and therefore the potential for selection bias. The second limitation is that the protocol for interval follow-up was between 3 and 6 months. It is possible that the time to recurrence may be inaccurate because we did not evaluate patients sooner. However the data represented in this study uniformly uses this surveillance strategy and one would expect the potential error in time to recurrence to be spread throughout the entire population studied. A third limitation of this study is that PET/CT imaging was performed on multiple scanners, which could potentially influence the interpretation of SU- V max. However given that our institution is a tertiary care center with a referral base of several states, it would be difficult to obtain specifications of PET/CT scanners used on all patients in this study. We attempted to address this by having our nuclear radiologists interpret the images at our institution. Another limitation of the study is that only 539 of the 1,143 patients had PET/CT performed, subjecting our results to the potential for selection bias. Many of the patients did not have PET/CT performed because their NSCLC was diagnosed before PET/CT became the standard of care or their insurance would not cover the cost of the imaging modality. Despite this shortcoming, to our knowledge our study is the largest series published investigating the role of SUV max to NSCLC recurrence. Additionally, 30% of our patients who underwent wedge resection had inadequate sampling of all nodal stations, potentially leading to understaging of patients who underwent sublobar resection. Future directions will involve multiple studies. First, we will investigate tumors from patients in whom recurrence developed in this study and perform gene array analysis to ascertain possible gene targets for preventing recurrence. By understanding the molecular pathways of recurrence, we might be able to halt or slow the development of recurrent disease. Second, current recommendations for postoperative adjuvant therapy include only the presence of nodal disease. This study suggests further investigation in patients with stage I disease, SUV max greater than 5, and tumor lymphovascular invasion. Based on our results, these 2 variables were independent predic-

8 1820 TAYLOR ET AL Ann Thorac Surg RECURRENCE AFTER NSCLC RESECTION 2012;93: tors of distant recurrence, and the use of adjuvant chemotherapy may be warranted to help prevent recurrences. To better address this issue, a multicenter trial is necessary. In conclusion, in this single-institution study investigating clinicopathologic variables and the correlation to recurrence after R0 resection for NSCLC, preoperative radiation therapy, tumor SUV max greater than 5, and pathologic stage II and stage III were independently associated with recurrence and time to NSCLC recurrence. Sublobar resection was an independent predictor of locoregional recurrence, and lymphovascular invasion was an independent predictor of distant recurrence after NSCLC resection. References 1. Kameyama K, Takahashi M, Ohata K, et al. Evaluation of the new TNM staging system proposed by the International Association for the Study of Lung Cancer at a single institution. J Thorac Cardiovasc Surg 2009;137: Kozower BD, Sheng S, O Brien SM, et al. STS database risk models: predictors of mortality and major morbidity for lung cancer resection. Ann Thorac Surg 2010;90:875 81; discussion Lin J, Beer DG. Molecular predictors of prognosis in lung cancer. Ann Surg Oncol 2012;19: Al-Sugair A, Coleman RE. Applications of PET in lung cancer. Semin Nucl Med 1998;28: Vansteenkiste JF, Stroobants SG, Dupont PJ, et al. Prognostic importance of the standardized uptake value on (18)Ffluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: an analysis of 125 cases. Leuven Lung Cancer Group. J Clin Oncol 1999;17: Cerfolio RJ, Bryant AS, Ohja B, Bartolucci AA. The maximum standardized uptake values on positron emission tomography of a non-small cell lung cancer predict stage, recurrence, and survival. J Thorac Cardiovasc Surg 2005;130: Paesmans M, Berghmans T, Dusart M, et al. Primary tumor standardized uptake value measured on fluorodeoxyglucose positron emission tomography is of prognostic value for survival in non-small cell lung cancer: update of a systematic review and meta-analysis by the European Lung Cancer Working Party for the International Association for the Study of Lung Cancer Staging Project. J Thorac Oncol 2010;5: Koo HK, Jin SM, Lee CH, et al. Factors associated with recurrence in patients with curatively resected stage I-II lung cancer. Lung Cancer 2010;73: Shiono S, Abiko M, Sato T. Positron emission tomography/ computed tomography and lymphovascular invasion predict recurrence in stage I lung cancers. J Thorac Oncol 2010;6: Kelsey CR, Marks LB, Hollis D, et al. Local recurrence after surgery for early stage lung cancer: an 11-year experience with 975 patients. Cancer 2009;115: Varlotto JM, Recht A, Flickinger JC, Medford-Davis LN, Dyer AM, Decamp MM. Factors associated with local and distant recurrence and survival in patients with resected nonsmall cell lung cancer. Cancer 2009;115: Pepek JM, Chino JP, Marks LB, et al. How well does the new lung cancer staging system predict for local/regional recurrence after surgery? A comparison of the TNM 6 and 7 systems. J Thorac Oncol 2011;6: Bando T, Yamagihara K, Ohtake Y, et al. A new method of segmental resection for primary lung cancer: intermediate results. Eur J Cardiothorac Surg 2002;21: Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995; 60: DISCUSSION DR CHADRICK DENLINGER (Charleston, SC): Thank you, Dr Taylor, for this excellent presentation. I think you have used an excellent resource and it is important that you are evaluating your own results. In the future, as we develop better chemotherapeutic agents, studies of this nature will take on even greater value. I have several questions with regards to some of your data. As expected, the greatest predictors of recurrence in your study were the tumor stage, the T status, as well as the N status. Another factor which you identified was the SUV determined by PET imaging. There have been other studies looking at the SUV values, and they have shown that it is more predictive among patients with adenocarcinoma relative to squamous cell cancers. Have you considered looking at different histological subtypes, specifically focusing on adenocarcinoma and the relevance of the SUV among this patient cohort? DR TAYLOR: That is a very good question. We did not perform a subgroup analysis based on histology for this study. However, we have published in the past that, as you said, adenocarcinoma does correlate more with the SUV max, and in fact we have shown several molecular markers, including GLUT1 and P53, correlate with adenocarcinoma as compared to squamous, so I definitely think that that may be a study to look at in the future. DR DENLINGER: The second question I have relates to the patients that received induction radiation therapy, which you have shown as a predictor for local recurrence. Did you look only at pathological stage or did you look at the clinical stage of these patients before their induction therapy? My question relates to the fact that these patients were given induction therapy presumptively for some reason. They most likely had larger tumors or another reason why they did not go straight to surgery. This may bias the analysis, and it is likely that there were tumor-related factors rather than the radiation itself which should be associated with a greater recurrence rate. DR TAYLOR: Another great question. We did not look at clinical stage. We looked at pathologic stage only, so while I think it was significant, I do agree with you that patients that do receive preoperative radiation therapy likely have more advanced disease. I have looked at our pathologic stage and looked between patients that had node-positive disease versus those patients that did not have node-positive disease, specifically related to whether they have had preoperative radiation. Patients that had preoperative radiation had a higher percentage of node-positive disease compared to those that did not. DR DENLINGER: My final question relates to the sublobar resections, which had a much higher risk of locoregional recurrence. Did you evaluate tumor size? Traditionally we think of the standard operation for lung cancer being a lobectomy. Now there is a growing question regarding the best management of smaller tumors, so did you correlate tumor size with the risk for recurrence among the sublobar group?

9 Ann Thorac Surg TAYLOR ET AL 2012;93: RECURRENCE AFTER NSCLC RESECTION DR TAYLOR: I have looked at that data, and it turns out that there is no difference in tumor size between those patients that recurred and those that didn t. In the patients that did not recur, the average tumor size was 2.2 cm. The tumor size of the patients that had recurrences was 2.3 cm, not statistically significant. DR DENLINGER: Thank you. Once again, I think you have got a great resource that you have utilized for this study. DR RICHARD H. FEINS (Chapel Hill, NC): It seems to me that of all of the variables that you had, one distinguishing factor was that you had only one variable that was a preoperative and that was the SUV. I wonder whether you have given any thought to 1821 looking at neoadjuvant chemotherapy for this group, particularly since you had a higher p value for distant metastases in this group than you did for local recurrence. DR TAYLOR: I think that is a great point and definitely something we could look at in the future. I mentioned the use of the data to potentially use for patients as adjuvant, and I definitely think that there is some utility in investigating patients that have neoadjuvant, saying that based upon our data, SUV max values greater than 5, if you have that, maybe that would put you in the category in which neoadjuvant therapy would be beneficial. Requirements for Maintenance of Certification in 2012 Diplomates of the American Board of Thoracic Surgery (ABTS) who plan to participate in the 2012 Maintenance of Certification (MOC) process as Certified-Active must hold an unrestricted medical license in the locale of their practice and privileges in a hospital accredited by the JCAHO (or other organization recognized by the ABTS). In addition, a valid ABTS certificate is an absolute requirement for entrance into the MOC process. If your certificate has expired, the only pathway for renewal of a certificate is to take and pass the Part I (written) and the Part II (oral) certifying examinations. The CME requirements are 150 Category I credits earned since January 1, At least half of these CME hours need to be in the broad area of thoracic surgery. Category II credits are not allowed. Interested individuals should refer to the Board s website ( for a complete description of acceptable CME credits. Diplomates will be required to take and pass a secured exam after their application has been approved. Taking SESATS in lieu of the secured exam is not an option. The secured exam will be given from September 10 to September 22, 2012, at Pearson Vue Testing Centers, which are located nationwide. Diplomates will have the opportunity to select the day and location of their exam. Diplomates who wish to maintain a Certified-Active status will be required to submit a summary of cases and will be required to participate in an outcomes database. For more details about this requirement, please visit the Board s website. Diplomates may apply for MOC in the year their certificate expires or, if they wish to do so, they may apply up to two years before it expires. However, the new certificate will be dated 10 years from the date of expiration of their original certificate or most recent MOC certificate. In other words, going through the MOC process early does not alter the 10-year validation. Diplomates certified prior to 1976 (the year that time-limited certificates were initiated) are also required to participate in MOC if they wish to maintain valid certificates. The deadline for submitting an application for MOC is May 1, 2012; however, the Board will accept late applications until June 15, A brochure outlining the rules and requirements for MOC in thoracic surgery is available on the Board s website. For additional information, please contact the American Board of Thoracic Surgery, 633 N St. Clair St, Ste 2320, Chicago, IL 60611; telephone (312) ; fax (312) ; info@abts.org by The Society of Thoracic Surgeons Ann Thorac Surg 2012;93: /$36.00 Published by Elsevier Inc