The Role of Adjuvant Radiation Therapy for Resected Stage III Thymoma: A Population-Based Study

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1 GENERAL THORACIC The Role of Adjuvant Radiation Therapy for Resected Stage III Thymoma: A Population-Based Study Benny Weksler, MD, Manisha Shende, MD, Katie S. Nason, MD, MPH, Angela Gallagher, CRNP, Peter F. Ferson, MD, and Arjun Pennathur, MD Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Background. Because of the rarity of the disease and long survival of most patients, the role of adjuvant radiation therapy in patients with surgically resected stage III thymoma is unclear, and few prospective studies are available. The objective was to evaluate the impact of postoperative radiation therapy after resection of stage III thymoma. Methods. The Surveillance, Epidemiology, and End Results (SEER) database was queried for all patients with stage III thymoma who underwent surgical therapy and survived more than 30 days after diagnosis. Survival was estimated with the Kaplan-Meier method. The hazard ratio for death was determined using a Cox proportional hazard model. Results. There were 476 patients with stage III thymoma identified who underwent surgical therapy, did not receive preoperative radiotherapy, and had complete SEER records with regard to radiation treatment. Postoperative radiation therapy was given to 322 patients (67.6%). Patients who received postoperative radiation therapy were younger and had a higher rate of debulking surgery than patients who did not. Patients receiving postoperative radiation had a median overall survival of 127 months (95% confidence interval, to 153.1) compared with 105 months (95% confidence interval, 76.9 to 133.1) in patients treated with surgery alone (p 0.038). However, in multivariate analysis, postoperative radiation was not a significant factor affecting overall survival. Disease-specific survival was significantly improved in the adjuvant radiation group, and in multivariate analysis, improved outcomes were associated with postoperative radiation (p 0.049). Conclusions. In this large population-based study, most patients with stage III thymoma were treated with adjuvant radiation. Postoperative radiation was associated with improved disease-specific survival, but not improved overall survival. (Ann Thorac Surg 2012;93: ) 2012 by The Society of Thoracic Surgeons Thymomas are the most common thymic tumors and originate from the thymic epithelial cell. Thymomas are rare, with an incidence in the United States of 0.13 per 100,000 person-years. There is no difference in incidence between men and women, and thymoma incidence peaks during the seventh decade of life [1]. The Masaoka classification is the most common staging system used for thymoma [2] and is based on the extension of the tumor. Masaoka stage I is defined as a completely encapsulated tumor; stage II as microscopic invasion of the capsule, mediastinal fat, or mediastinal pleura; stage III as a tumor invading surrounding structures (pericardium, great vessels, visceral pleura); stage IVa as serosal dissemination; and stage IVb as systemic dissemination [2]. Thymomas are characterized by an indolent course and low incidence of local and systemic recurrence, Accepted for publication March 1, Presented at the Fifty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9 12, Address correspondence to Dr Weksler, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, 200 Lothrop St, PUH C-800, Pittsburgh, PA 15213; wekslerb@upmc.edu. which, coupled with the rarity of the tumor, makes prospective trials of thymoma treatments challenging. Most of our knowledge on thymomas comes from retrospective, single-institution studies. Based on available evidence, surgery has been the mainstay in the treatment of thymomas. Radiation therapy has been commonly used for patients with unresectable tumors and as adjuvant therapy to surgery. The impact of postoperative radiation therapy in patients with thymoma is unclear. Some investigators recommend postoperative radiation therapy on all patients [3], whereas others question the need for it [4, 5]. Under ideal circumstances, a randomized trial would address whether radiation therapy is warranted in patients with Masaoka stage III thymoma. Because of the difficulties in executing a randomized trial in patients with thymoma, we believe that the next best available option is gathering data from multiple centers. The Surveillance, Epidemiology, and End Results (SEER) database may qualify as such, considering its wide geographic presence and data collection from several states. Our objective was to investigate the role of postoperative radiation in patients who underwent surgery for stage III thymoma using the SEER registry by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg WEKSLER ET AL 2012;93: ADJUVANT RADIATION FOR THYMOMA Material and Methods The University of Pittsburgh Institutional Review Board approved this study, and informed consent was waived. The SEER database is sponsored by the National Cancer Institute and has been used to track cancer incidence and patient survival since The SEER database currently covers approximately 28% of the US population and captures 98% of all cancer cases within the surveyed geographic areas. We used the SEER 17 Registry including the Hurricane Katrina Impacted Louisiana Cases for this analysis (SEER Program [ gov] SEER*Stat Database: Incidence - SEER 17 Regs Research Data Hurricane Katrina Impacted Louisiana Cases, Nov 2009 Sub [ varying], National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2010, based on the November 2009 submission). SEER*Stat software ( version 7.05 was used to query this SEER database for all cases of thymoma using ICD-O-3 codes 8580 (thymoma, malignant NOS), 8581 (thymoma, malignant type A), 8582 (thymoma, malignant type AB), 8583 (thymoma, malignant type B1), 8584 (thymoma, malignant type B2), and 8585 (thymoma, malignant type B3). Codes for thymic carcinoma (8586, 8588, and 8589) were excluded. Patients were included in the analysis if there was documentation of Masaoka stage III classification [2] and the data on surgery and radiation therapy were complete. Although Masaoka classification is not clearly stated in the SEER registry, the database contains data fields (EOD and CS extension 2004, SEER Program Coding and Staging Manual, 2010) that specifically describe tumors invading into adjacent organs or structures in the mediastinum. Patients with thymomas invading into adjacent mediastinal organs or structures were identified as Masaoka stage III. Statistical analysis was performed with SPSS statistical software package version 19.0 (SPSS Inc, Chicago, IL). Continuous data variables were analyzed using Student s t test. Nominal data were analyzed using crosstabs and Pearson s 2 test. Kaplan-Meier survival curves were constructed and compared using the log-rank test. Cox hazard models were created for overall survival and disease-specific survival. Disease-specific survival was defined according to the National Cancer Institute as [t]he percentage of people in a study or treatment group who have not died from a specific disease in a defined period of time. ( cdrid 44311). Nominal variables were included in the Cox model only if significance was reached by the logrank test. Continuous variables were included in the Cox model. The proportionality of hazards was evaluated using the Cox regression analysis with time-dependent covariables. The assumption of proportionality of hazards was tested and was not broken in any of the Cox regression models. Significance was set at a probability value less than Results 1823 We identified 662 patients with stage III thymoma in the SEER database. The majority (n 516) underwent surgical resection. Data on radiation therapy was available for 513 patients. We elected to include only patients with stage III thymoma who underwent surgery and whose SEER records contained complete data on staging, radiation therapy, and surgery (n 499). Of the patients who underwent surgical resection, 18 (3.5%) were treated with preoperative radiation therapy, 322 (64.5%) were treated with postoperative radiation therapy, 5 (1%) were treated with preoperative and postoperative radiation therapy, and 154 (31%) did not receive radiation therapy. Patients treated with preoperative radiation therapy and those treated with preoperative and postoperative radiation therapy were excluded from further analysis. The final cohort included 476 patients. The majority of patients (257, 54%) were classified as thymoma NOS. There were 20 patients (4.2%) with World Health Organization (WHO) type A thymoma, 41 patients (8.6%) classified as WHO type AB, 47 patients (9.9%) with WHO type B1 thymoma, 31 patients (6.5%) with WHO type B2 thymoma, and 80 patients (16.8%) with WHO type B3 thymoma. The final cohort included 322 patients who received postoperative radiation therapy and 154 patients who did not receive any radiation therapy. Patients who received postoperative radiation therapy were significantly younger than patients who were treated with surgery alone. There were no differences between the groups with regards to sex, race, incidence of WHO type B3 thymoma, histologic grade IV, or tumor size (Table 1). The patients had undergone a variety of surgical procedures. The majority (165, 34.7%) had radical excision; others had simple partial excision of the thymus (115, 24.2%) or complete excision of the thymus (103, 21.6%). Debulking was performed in 26 patients (5.5%). The procedure in the remaining 67 patients was not specified. Patients who received postoperative radiation therapy had a higher incidence of debulking surgery than patients who were treated with surgery alone (Table 1). Median survival for the whole cohort was 112 months (95% confidence interval, 94.0 to 129.9) and cumulative 10-year survival was 49%. Median follow-up was 51 months. Patients who received postoperative radiation therapy had a median survival of 127 months (95% confidence interval, to 153.1) compared with105 months (95% confidence interval, 76.9 to 133.1) in patients treated with surgery alone (p 0.038; Fig 1). Sex, race, histologic grade, and WHO type B3 histology did not affect overall survival (Table 2). In multivariate analysis using a Cox hazard model, postoperative radiation therapy and tumor size did not affect overall survival (Table 3). Age at diagnosis was the only variable affecting overall survival of patients with stage III thymoma in the multivariate analysis (hazard ratio, 1.034; 95% confidence interval, to 1.048; p 0.001), indicating that the increase in overall survival in the group that received postoperative radiotherapy (Fig 1) was likely related to the fact that the patients who received GENERAL THORACIC

3 GENERAL THORACIC 1824 WEKSLER ET AL Ann Thorac Surg ADJUVANT RADIATION FOR THYMOMA 2012;93: Table 1. Patient Characteristics Characteristic Full Cohort (n 499) Surgery Alone (n 154) Surgery With Postoperative RT (n 322) p Value Male sex (%) 279 (55.9%) 92/154 (59.7%) 168/322 (52.1%) Caucasian race (%) a 355 (71.3%) 115/154 (74.7%) 220/321 (68.1%) Age (y) WHO type B3 thymoma (%) b 85 (36.8%) 24/74 (32.4.7%) 56/145 (38.6%) Grade IV histology (%) c 6 (8.1%) 2/19 (11.1%) 4/53 (7.5%) Tumor size (mm) Debulking surgery only (%) d 30 (6.1%) 4/149 (2.8%) 22/318 (6.9%) Preoperative RT (%) 18 (3.6%) Postoperative RT (%) 322 (64.5%) Preoperative and postoperative RT (%) 5 (1%) a Data available for 498 patients. b Data available for 231 patients. c Data available for 74 patients. d Data available for 490 patients. RT radiation therapy; WHO World Health Organization. postoperative radiation therapy were significantly younger than the patients who were treated with surgery alone. We also analyzed factors affecting disease-specific survival. In univariate analysis, race and postoperative radiation therapy were significant factors affecting diseasespecific survival (Table 4). In multivariate analysis, Caucasian race and postoperative radiation therapy remained important variables affecting disease-specific survival (Table 5). Patients treated with postoperative radiation therapy experienced an improved diseasespecific survival when compared with those who were not treated with postoperative radiation (Fig 2). Comment In this large population-based study, postoperative radiation therapy was found to be an important factor associated with improved disease-specific survival in patients operated on for Masaoka stage III thymoma. In multivariate analysis, postoperative adjuvant radiation was not significantly associated with improved overall survival. Patients receiving radiation therapy were younger and had a higher rate of debulking surgery. This may indicate a provider bias in recommending radiation therapy to younger patients and not to older patients in the SEER database cohort. It is also possible that the older patients in the cohort were more likely to refuse radiation or had comorbidities that prevented the administration of radiation therapy. Unfortunately, the data in the SEER database do not include the variables needed to clarify this point. The role of complete resection also could not be determined from the SEER data. In this cohort, 30 patients had debulking surgery only. Debulking was not a factor affecting long-term survival Fig 1. Kaplan-Meir overall survival curve of the full cohort, patients treated with surgery alone, and those treated with surgery followed by radiation therapy (RT).

4 Ann Thorac Surg WEKSLER ET AL 2012;93: ADJUVANT RADIATION FOR THYMOMA Table 2. Univariate Analysis of Factors Affecting Overall Survival Risk Factor p Value Tumor size Surgery (debulking versus resection) Histologic grade (1 versus 4) Race (non-caucasian versus Caucasian) WHO grade B3 histology Sex (male versus female) Postoperative RT Age RT radiation therapy; WHO World Health Organization. Table 4. Univariate Analysis of Factors Affecting Disease- Specific Survival Risk Factor p Value Race (non-caucasian versus Caucasian) Histologic grade (1 versus 4) WHO grade B3 histology Debulking Surgery (debulking versus resection) Tumor size Sex (male versus female) Age Postoperative RT RT radiation therapy; WHO World Health Organization GENERAL THORACIC or disease-specific survival, and the majority of patients who had debulking also had radiation therapy. This is contrary to most reports, in which complete resection was an important factor affecting survival [6, 7]. Our findings are likely attributable to a small number of patients who underwent debulking (a small sample size resulting in a lack of statistical power to detect differences). Also, many patients underwent a partial or simple excision of the thymus, a procedure that is not recommended in patients with thymoma. Most surgeons consider a complete excision of the thymus en bloc with the tumor to be the standard of care. We did not find differences in survival in patients undergoing different surgical procedures. The role of postoperative adjuvant radiation therapy patients who undergo surgical resection of thymoma is still somewhat controversial. Although some physicians recommend postoperative radiation therapy on all patients with resected thymoma [3], the majority prefers to stratify the need for postoperative radiation based on the stage of the disease and the completeness of resection [8]. To make the issue more confusing, there are very few prospective trials [9 11], and several reports include thymomas and thymic carcinomas together, generating data of unclear significance considering the different natural histories of thymoma and thymic carcinoma [9, 12 14]. It is clear that patients who undergo incomplete resection and are left with positive microscopic margins, or who have debulking only, should get radiation therapy. In one trial using radiation therapy in unresectable patients with thymoma, disease-free survival was 82% and overall survival was 72% at 5 years [10]. Reported survival in uncontrolled series is less impressive and Table 3. Cox Hazard Model of Factors Affecting Overall Survival Risk Factor p Value HR (95% CI) Tumor size ( ) Age ( ) Postoperative RT ( ) CI confidence interval; HR hazard ratio; RT radiation therapy. ranges from 45% to 50% [15], but still, radiation does have a significant effect on thymomas. Approximately 30% of patients with stage III thymoma will suffer a recurrence [16]. Most common sites are the pleura (54%) and the tumor bed (23%) [17]. This pattern of failure encourages the use of postoperative radiation therapy in an attempt to control the tumor bed. Although widely recommended, there is little evidence that postoperative radiation therapy decreases recurrence or improves survival in patients with stage III thymomas. Curran and colleagues [13] reported 117 patients with thymoma. There were 26 patients completely resected with stage II and III thymoma, and 5 received postoperative radiation therapy. Of the 21 patients not receiving radiation, 8 (38.1%) experienced a recurrence in the mediastinum. There were no mediastinal recurrences in the 5 patients who received adjuvant radiation. Twentyeight patients with stage III disease had incomplete resection or debulking, and 20 underwent postoperative radiation therapy. Mediastinal recurrence was decreased in patients who received postoperative radiation. Mangi and associates [18] reported on 45 patients with stage III thymoma, with 38 patients receiving postoperative radiation. Recurrence rate was similar (29% for surgery alone versus 32% for surgery followed by radiation). Kondo and Monden [7] could not demonstrate an advantage of postoperative radiation therapy in 78 patients with stage III thymomas when compared with 31 patients treated with surgery alone. Their reported recurrence rate was 26% for patients undergoing surgery alone and 23% for patients undergoing surgery followed by radiation ther- Table 5. Cox Hazard Model of Variables Affecting Cancer- Specific Survival Risk Factor p Value HR (95% CI) Tumor size ( ) Age ( ) Postoperative RT ( ) Race (non-caucasians versus Caucasians) ( ) CI confidence interval; HR hazard ratio; RT radiation therapy.

5 GENERAL THORACIC 1826 WEKSLER ET AL Ann Thorac Surg ADJUVANT RADIATION FOR THYMOMA 2012;93: Fig 2. Kaplan-Meir disease-specific survival of patients treated with surgery alone and those treated with surgery followed by radiation therapy (RT). apy. Utsumi and coworkers [4] also did not show an advantage for stage III patients receiving postoperative radiation therapy. Finally, a meta-analysis by Korst and colleagues [19] analyzed the effect of postoperative radiation therapy in patients with invasive thymomas. There were 69 stage III patients who did not receive postoperative radiation and 53 patients who received postoperative radiation therapy. There was no difference in tumor recurrence between patients who received postoperative radiation and those who did not. The role of postoperative radiation therapy in stage I thymoma is not controversial. Patients with stage I disease have a local recurrence rate between 0% and 4% [6, 7, 20], and radiation therapy is unlikely to improve on those results. Indications for postoperative radiation therapy in completely resected stage II thymoma are debated, although most studies have shown no decrease in recurrence rates with postoperative radiotherapy [4, 7, 18, 21 23]. Few studies have addressed the role of preoperative therapy in patients with thymoma. Currently, a prospective phase II study (NCT ) is recruiting high-risk thymoma patients to receive preoperative chemotherapy (cisplatin and etoposide) and radiation therapy. Although an important study, it is not randomized, and the rate of resectability and overall survival will have to be compared with historic controls. In our practice, we recommend preoperative therapy for patients with bulky disease that appears to be invading adjacent structures. We do not routinely pretreat patients who appear to have resectable disease that is not invading adjacent structures. We identified two previous reports on thymoma and radiation therapy using the SEER database. Forquer and associates [24] analyzed thymoma and thymic carcinoma patients from the SEER database using SEER historic stage and searched for patients with localized and regional disease. There were 900 patients in the analysis: 274 patients with localized disease and 626 with regional disease. In patients with regional disease, postoperative radiation therapy approached significance (p 0.08) in improving survival. This study included patients with thymic carcinoma and used the very generic SEER historic staging, in which regional disease is not defined and could include patients with stage IVa thymoma. Fernandes and coworkers [12] reported on 1,334 patients with thymoma from the SEER database excluding patients with thymic carcinomas, similar to our methodology. Stage of disease was determined by tumor invasion and classified according to Masaoka stage. The addition of postoperative radiation therapy significantly improved overall survival in univariate analysis, similar to our findings, but did not reach statistical significance in multivariate analysis. Our study differs from these two reports by excluding thymic carcinoma patients, including all thymoma diagnosis (codes 8580 through 8585), analyzing only patients with stage III thymoma, and including an analysis of disease-specific survival. Interestingly, Caucasian race was also associated with better disease-specific survival in our study. There was no significant difference in the rate of radiation therapy received by Caucasians and non-caucasian patients, but non-caucasian patients were more likely to have debulking surgery only (3.7% of Caucasians underwent debulking versus 10.1% of non-caucasians; p 0.008; data not shown). We did not find that size of the tumor or WHO histology were important determinants of survival. This is in disagreement with Wright and associates [14] who reported that tumors larger than 8 cm and WHO histologic staging were important determinants of survival. It is possible that the inclusion of patients with stage C disease (thymic carcinoma) in the report by Wright and colleagues affected those variables.

6 Ann Thorac Surg WEKSLER ET AL 2012;93: ADJUVANT RADIATION FOR THYMOMA This is a retrospective database study, and it is limited by its design. The SEER database is constrained by the number of reported variables and is lacking several important data points, such as whether patients received chemotherapeutic agents, the dose of radiation therapy, and the patients comorbidities. The lack of information on chemotherapy is problematic when studying diseases such as advanced-stage thymoma that may respond to systemic therapy. In addition, management strategies are affected by provider selection bias. The SEER database may have additional limitations, such as inaccuracies in reporting and nonuniform criteria for pathologic diagnosis of the disease. The use of nonuniform pathologic classification may be particularly important when using the SEER database to study thymoma in light of the variability in classifying thymoma according to the WHO classification among different pathologists based on the number of sections studied [25]. The SEER database also suffers limitations because it is compiled from fixed geographic locations, and it may not detect patients who had surgery in one SEER reporting state and had radiation therapy in a non-seer reporting state, or vice versa. How patient mobility affects the data is unknown. Also, defining the disease-specific survival and determining the true cause of death may be difficult. It is possible that some patients who were classified as dying from other causes actually died as a result of their thymoma. Even with all its shortcomings, we believe that the SEER database is a useful tool for clinicians to address difficult questions and gaps in knowledge. Treatment of thymomas is a good example; it is a rare disease, and randomized trials of thymoma treatments have not been done. The SEER database allows a good sample of a large number of patients treated at multiple institutions, allows a long follow-up, and reflects true practice patterns in the United States. Patients with Masaoka stage III thymoma have a 30% recurrence rate at 5 years, with recurrence in the tumor bed in a significant portion of patients [16]. The use of postoperative radiation in completely resected patients is still somewhat controversial and several studies have shown no advantage to postoperative radiation. The rarity of the disease, its relatively indolent course that leads to long-term survival, and a low local failure rate after complete resection are barriers to properly executed prospective trials. The present study demonstrates that adding postoperative radiation to surgery is associated with an improved disease-specific survival. Prospective, multiinstitutional, and long-term studies on the effects of radiation are needed in patients with stage III thymoma. The authors would like to thank Shannon Wyszomierski for her expert editorial review of the manuscript. References 1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010;5(10 Suppl 4):S Masaoka A. Staging system of thymoma. J Thorac Oncol 2010;5(10 Suppl 4):S Zhu G, He S, Fu X, Jiang G, Liu T. Radiotherapy and prognostic factors for thymoma: a retrospective study of 175 patients. Int J Radiat Oncol Biol Phys 2004;60: Utsumi T, Shiono H, Kadota Y, et al. Postoperative radiation therapy after complete resection of thymoma has little impact on survival. Cancer 2009;115: Mangi AA, Wain JC, Donahue DM, Grillo HC, Mathisen DJ, Wright CD. Adjuvant radiation of stage III thymoma: is it necessary? Ann Thorac Surg 2005;79: Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995;60: Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76: Fuller CD, Ramahi EH, Aherne N, Eng TY, Thomas CR Jr. Radiotherapy for thymic neoplasms. J Thorac Oncol 2010; 5(10 Suppl 4):S Loehrer PJ Sr, Jiroutek M, Aisner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 2001;91: Sur RK, Pacella JA, Donde B, Levin CV, Cooper K. Role of radiotherapy in stage III invasive thymomas. S Afr J Surg 1997;35: Zhang H, Lu N, Wang M, Gu X, Zhang D. Postoperative radiotherapy for stage I thymoma: a prospective randomized trial in 29 cases. Chin Med J (Engl) 1999;112: Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol 2010;5: Curran WJ Jr, Kornstein MJ, Brooks JJ, Turrisi AT 3rd. Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 1988;6: Wright CD, Wain JC, Wong DR, et al. Predictors of recurrence in thymic tumors: importance of invasion, World Health Organization histology, and size. J Thorac Cardiovasc Surg 2005;130: Yoshida H, Uematsu M, Itami J, et al. The role of low-dose hemithoracic radiotherapy for thoracic dissemination of thymoma. Radiat Med 1997;15: Ruffini E, Mancuso M, Oliaro A, et al. Recurrence of thymoma: analysis of clinicopathologic features, treatment, and outcome. J Thorac Cardiovasc Surg 1997;113: Myojin M, Choi NC, Wright CD, et al. Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study. Int J Radiat Oncol Biol Phys 2000;46: Mangi AA, Wright CD, Allan JS, et al. Adjuvant radiation therapy for stage II thymoma. Ann Thorac Surg 2002;74: Korst RJ, Kansler AL, Christos PJ, Mandal S. Adjuvant radiotherapy for thymic epithelial tumors: a systematic review and meta-analysis. Ann Thorac Surg 2009;87: Cowen D, Richaud P, Mornex F, et al. Thymoma: results of a multicentric retrospective series of 149 non-metastatic irradiated patients and review of the literature. FNCLCC trialists. Fédération Nationale des Centres de Lutte Contre le Cancer. Radiother Oncol 1995;34: Singhal S, Shrager JB, Rosenthal DI, LiVolsi VA, Kaiser LR. Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg 2003;76: Rena O, Papalia E, Oliaro A, et al. Does adjuvant radiation therapy improve disease-free survival in completely resected Masaoka stage II thymoma? Eur J Cardiothorac Surg 2007;31: Chen YD, Feng QF, Lu HZ, et al. Role of adjuvant radiotherapy for stage II thymoma after complete tumor resection. Int J Radiat Oncol Biol Phys 2010;78: GENERAL THORACIC

7 GENERAL THORACIC 1828 WEKSLER ET AL Ann Thorac Surg ADJUVANT RADIATION FOR THYMOMA 2012;93: Forquer JA, Rong N, Fakiris AJ, Loehrer PJ Sr, Johnstone PA. Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease. Int J Radiat Oncol Biol Phys 2010;76: Moran CA, Suster S. On the histologic heterogeneity of thymic epithelial neoplasms. Impact of sampling in subtyping and classification of thymomas. Am J Clin Pathol 2000; 114: DISCUSSION DR BILL PUTNAM (Nashville, TN): Thank you, Dr Weksler, for your thoughtful analysis of the effects of postoperative radiation on patients with resected stage III thymoma, a rare disease. You and your colleagues are to be congratulated on limiting your analysis to thymoma alone, as the addition of thymic carcinoma in this population would create unnecessary confusion. As you noted, thymoma, particularly stage III thymoma, is a rare disease with an indolent course and long-term survival. The excellent short-term results following any operation mask the problems of late local recurrence and cancer-specific death often a decade or more later. However, long-term results can be variable, as you demonstrated. Comorbidities, particularly for the many years of follow-up, may adversely affect overall survival, particularly for the older patients, and disease-specific survival would remain an important outcome of the treatment. Only one third of the patients had a radical excision, as you noted in your manuscript, with the others having simple or complete excision. This finding was surprising to me, given the large size and clinical characteristics of invasion into other structures, a clue to the biologic intent of the tumor. Was the survival for the patients with radical resection better than for lesser resection? You also described patients who were only debulked and followed with adjuvant therapy who had the same survival as complete resection. In my opinion, this finding does not justify sloppy or casual surgery. The sins of inadequate surgery cannot be washed away simply with postoperative radiation. A complete resection is indeed the goal. Induction therapy has been used to optimize surgical resectability for other thoracic cancers. In a small prospective series, induction chemotherapy improves the resectability rate, particularly for these larger thymomas. What is the role of induction therapy in patients with clinical characteristics of stage III invasive thymoma? Would this improve the resectability rate? And finally, on Monday morning, when I go into the operating room, resect a pathologic stage III thymoma from a healthy 65-year-old patient, and I achieve a complete resection with negative margins, do I recommend adjuvant therapy for this patient? Thank you for your presentation. DR WEKSLER: Thank you, Dr Putnam, for your kind and thoughtful comments. You did touch upon many of the limitations of the SEER (Surveillance, Epidemiology, and End Results) database. We did not find differences in survival according to the type of surgical procedure performed. So when we plugged in the variables for a simple resection or what the SEER database called radical resection or simple gland resection, we did not find differences in survival in those patient groups. And, again, it is part of the uniformity of criteria and how you define those. I do not know what SEER defines as a radical resection, simple gland resection, et cetera. And those are, unfortunately, not very well explained in the SEER manuals. I agree with you wholeheartedly that the finding that debulking therapy did not affect survival is in no way a justification for a sloppy surgical resection, and I think that we are talking about an indolent disease, and we may not see the effects of a sloppy surgical resection or incomplete resection for many years. I will confess to you my lack of opinion on induction chemotherapy. I can tell you it has been used, and I have used it myself; however, the data to support it is very, very weak, just like the data for radiation therapy. So personally, when I see a very large tumor that I think I would not be able to completely resect, I will offer those patients induction chemotherapy, possibly with radiation therapy. Finally, Monday morning, if I go to the OR (operating room) and I have a healthy patient who has a complete resection of a stage III thymoma with negative margins, I would still offer him radiation therapy postoperatively. Thank you. DR ROBERT J. CERFOLIO (Birmingham, AL): Benny, congratulations a few questions. First of all, the source, the reliability of the data. When I come home from work and I sit down and have dinner and my middle son starts telling me why he didn t get a great grade on the AP physics exam because the test was too long, nobody finished on time, the highest grade was a 60, et cetera the first question I ask is the source of the data, then I try to get more information. So the SEER database worries me a lot. Now, one of the main findings you had here was that the complete resection did not matter that does not make sense to me and that the cancer-specific survival was better than the overall survival. In my own prospective database where I have hired people to follow our patients I can t tell if people die from their cancer or not. An example is a patient we operated on who died a year or two ago in a car accident. We would have said the patient was cancer free, but it turns out that she had an autopsy because it was an MVA, and they found a brain met[astasis]; in fact she may have had a seizure that caused the accident. So we would have said that was a nonrelated cancer death; turned out it was. We have many patients die without autopsies, so even in my own database I can t figure it out. Tell me how the heck you can tell me cancer-specific survival in the SEER database when I can t do it in my own prospective database. DR WEKSLER: All right, let s go by stage. This is like the third encounter of Dr Cerfolio and me in three successive meetings on the SEER database. A few years ago, Dr Detterbeck [was] presenting, and I believe it was in the General Thoracic Surgical Club, on the International Thymic Interest Group, at one point said that sometimes in this rare disease we can learn a lot from one patient. Well, if we can learn a lot from one patient, how much more can we learn from 476 patients? And I think that is the reason that we insist on trying to learn from the SEER database and get better data even if not ideal, but we are doing our best to learn more about this rare disease. The SEER database has a data field called COD, cause of death, and the cause of death is classified in different categories. For example, there is a thymic malignancy cause of death and there are other causes of death, such as lung cancer, MVA, stroke, et cetera, and the data for cancer-specific survival was taken from this particular data field. So everybody that died from thymic malignancy was assumed to have a cancer-specific death and the others

8 Ann Thorac Surg WEKSLER ET AL 2012;93: ADJUVANT RADIATION FOR THYMOMA were excluded. And, again, I spent I believe two or three paragraphs in the manuscript discussing the limitations of the SEER database, which are many. I still think that in rare diseases like this one, looking at the SEER database is justified considering the lack of other good options that we have to study the data. DR CERFOLIO: I understand your point, but I submit to you that you carefully consider the accuracy of the person who is checking off that column, I wouldn t hang my hat on it at all DR PUTNAM: Perhaps I could offer a suggestion here. The National Cancer Database is a unique resource that is provided by the American College of Surgeons Commission on Cancer, and it has an excellent registry base throughout the United States. All approved cancer programs in the United States enter patients data into this database and the registrars are very well trained. So one option would be to validate this finding through another appropriate database such as the National Cancer Database. GENERAL THORACIC DR WEKSLER: But I am not sure I will hang my hat on my own database manager in Pittsburgh. DR WEKSLER: That is an excellent idea. Thank you. Notice From the American Board of Thoracic Surgery Regarding Trainees and Candidates for Certification Who Are Called to Military Service Related to the War on Terrorism The Board appreciates the concern of those who have received emergency calls to military service. They may be assured that the Board will exercise the same sympathetic consideration as was given to candidates in recognition of their special contributions to their country during the Vietnam conflict and the Persian Gulf conflict with regard to applications, examinations, and interruption of training. If you have any questions about how this might affect you, please call the Board office at (312) John H. Calhoon, MD Chair The American Board of Thoracic Surgery 2012 by The Society of Thoracic Surgeons Ann Thorac Surg 2012;93: /$36.00 Published by Elsevier Inc