Comparison of Stages I II Thymoma Treated by Complete Resection With or Without Adjuvant Radiation

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1 ORIGINAL ARTICLES: Comparison of Stages I II Thymoma Treated by Complete Resection With or Without Adjuvant Radiation Sunil Singhal, MD, Joseph B. Shrager, MD, David I. Rosenthal, MD, Virginia A. LiVolsi, MD, and Larry R. Kaiser, MD Section of General Thoracic Surgery, Division of Cardiothoracic Surgery, Department of Surgery, and Departments of Radiation Oncology and Pathology and Laboratory Medicine, Philadelphia, Pennsylvania Background. Adjuvant radiation after resection of Masaoka stage II thymoma is widely advocated, but the evidence supporting it is controversial. Studies addressing this issue generally report few patients and lump all patients beyond stage I together in the analysis. Methods. We retrospectively compared outcomes of stage I and II thymomas treated by resection alone with thymomas treated by resection plus radiation. Histology was re-reviewed to confirm pathologic staging and resection margin status. Results. Between February 1992 and 2002, we performed 167 resections for thymoma. Of these, 70 patients were believed to have tumors in stage IIb or less intraoperatively, and all of these patients underwent complete resection. We reviewed the histopathology of 62 of 70 patients. Thirty thymomas demonstrated less than complete transcapsular microscopic invasion (stage I) and 40 thymomas demonstrated microscopic transcapsular invasion or macroscopic invasion into surrounding fatty tissue (stage II). Forty-seven patients underwent surgery without postoperative mediastinal radiotherapy. Dosages in the 23 radiated patients (3 stage I and 20 stage II) consisted of 45 to 55 Gy. Median follow-up was 70.3 months. Stage II patients who were radiated (n 20) and those who were not radiated (n 20) consisted of identical proportions in stages IIa and IIb. Two patients recurred (1 unradiated stage I patient and 1 radiated stage IIb patient). Overall 5-year survival rate was 91%. All who died were free of recurrence at time of death. Log-rank test showed no difference in Kaplan Meier survival curves (p 0.32) between the radiated and unradiated groups. Conclusions. These data support the contention that margin-negative surgical resection alone is sufficient treatment for both stages I and II thymoma. (Ann Thorac Surg 2003;76: ) 2003 by The Society of Thoracic Surgeons Thymoma is an epithelial malignancy arising from the thymus gland, which is usually encapsulated. Complete resection is the cornerstone of therapy. Adjuvant therapy with radiation and chemotherapy has been controversial. Several factors including Masaoka staging, World Health Organization (WHO) classification, and completeness of resection are important prognostic indicators. Clinical staging for thymoma was introduced by Bergh and colleagues [1] in 1978 and was modified by Masaoka and colleagues [2] in 1981 and by Masaoka and colleagues [3] in The currently used modified Masaoka staging system includes one change from the original Masaoka system: complete transgression of the fibrous capsule by the tumor is now required for the tumor to be designated as stage II [4] (Table 1). Stage IIa thymoma designates tumors with transcapsular microscopic invasion. Stage IIb designates tumors with macroscopic invasion of surrounding mediastinal fat or tumor that is Presented at the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31 Feb 2, Address reprint requests to Dr Kaiser, Department of Surgery, Hospital of the University of Pennsylvania, 4 Silverstein Pavilion, 3400 Spruce St, Philadelphia, PA 19104; kaiser@uphs.upenn.edu. grossly adherent to but not through the mediastinal pleura or pericardium. Overall 5-year survival for stage I and stage II thymomas has been quoted at 65% to 100% and 45% to 95%, respectively [5 10]. Apart from the clinical staging represented by the Masaoka system, histologic classification of thymoma has also been proposed. The WHO reached a consensus on histologic classification of thymic epithelial tumors in 1999 [11, 12]. This classification (Table 2) reflects the earlier Müeller-Hermelink and Marx [13] classification, which was based on the morphology of epithelial cells as well as the lymphocyte-to-epithelial cell ratio. Pathologic classification predicts tumor propensity for invasive growth and oncologic behavior and has been proposed for use in conjunction with the Masaoka system to provide complementary prognostic information [6, 8, 9, 14 16]. Despite the Masaoka staging and WHO classifications, the most important prognostic factor in predicting tumor relapse remains completeness of resection [6, 9]. A complete resection predicts better survival than any other modality, including subtotal resections with neoadjuvant or adjuvant chemotherapy or radiotherapy [7 10, 17]. Although surgical excision is the mainstay of treat by The Society of Thoracic Surgeons /03/$30.00 Published by Elsevier Inc doi: /s (03)

2 1636 SINGHAL ET AL Ann Thorac Surg POSTOPERATIVE RADIATION FOR STAGES I II THYMOMA 2003;76: Table 1. Masaoka Clinical Staging of Thymoma as of Most Recent (1994) Modifications Masaoka Stage Stage I Stage II Stage III Stage IV ment, adjuvant radiation (RT) has been advocated by many. However the complications of RT are not trivial. Surgery alone for encapsulated (Masaoka stage I) thymoma is becoming an accepted practice; however some groups continue to radiate even these patients [8 10, 17 19]. Many groups favor RT for completely resected stage II patients [8 10, 17 19]. Others believe that recurrence after complete resection in stage II is rare and only select cases should be radiated [17, 20, 21]. Many studies addressing this issue lump all patients who are in stages II IV together as invasive thymoma and present results for the entire group [1, 18, 22, 23]. Furthermore, we believe that none of these studies take into account the modified Masaoka staging or WHO histopathologic classification. This makes it impossible to determine whether postoperative RT is truly indicated in all patients with stage II disease, which is the only group of patients with invasive disease that are likely to have been completely resected. A recent report from Massachusetts General Hospital presents their 27-year experience with specific stage II patients [24], which is a study very similar to our own. Our goal was to separate stage I and II patients and to evaluate the necessity for adjuvant RT in these patients by retrospectively examining outcome in those who did and did not receive adjuvant RT. Material and Methods Diagnostic Criteria Macroscopically and microscopically, completely encapsulated (tumor invading into but not through the capsule is also included in this stage) A. Microscopic transcapsular invasion B. Macroscopic invasion into surrounding fatty tissue or grossly adherent to but not through mediastinal pleura or pericardium Macroscopic invasion into neighboring organs (ie, pericardium, great vessels, or lung) A. Without invasion of great vessels B. With invasion of great vessels A. Pleural or pericardial dissemination B. Lymphogenous or hematogenous metastasis This study was approved by the Institutional Review Board of the University of Pennsylvania. Table 2. World Health Organization Pathologic Classification of Thymoma Type Type A Type AB Type B1 Type B2 Type B3 Histologic Description Medullary thymoma Mixed thymoma Predominantly cortical thymoma Cortical thymoma Well-differentiated thymic carcinoma Patient Population and Initial Evaluation Between February 1992 and 2002, 167 patients underwent surgical resection of thymoma at the University of Pennsylvania Medical Center. We reviewed the records of these patients to extract information including clinical characteristics (age 50 years or 50 years and gender), clinical presentation (myasthenia gravis [MG], local symptoms, incidental findings), preoperative studies, surgical approach (median sternotomy, transcervical thymectomy, video-assisted thoracoscopic surgery, thoracotomy), postoperative complications, pathologic report, and available long-term follow-up information. Pathologic Review Operative notes were reviewed to determine intraoperative suspicion of invasion, gross tumor extension into adjacent structures, and completeness of resection. Pathology reports were obtained for all patients. Slides on 62 of 71 patients were believed to have stage I or II intraoperatively and were available and reviewed by a single pathologist (VL). One of the cases was excluded from the analysis because the tumor was totally necrotic and inaccessible. There was complete agreement between the initial histologic examination and the rereview on margin status and degree of capsular invasion. The tumors were classified retrospectively into the five WHO histopathologic classification subtypes (Table 2). Clinical Staging Staging was based on the surgical and pathologic criteria described by Masaoka and colleagues [2] in 1981 and was modified by Masaoka and colleagues [3] in 1994 (Table 1). Staging was retrospectively performed based on the re-review of the pathology and operative notes of the surgeon in the 61 patients in whom re-review was possible. Although pathology was only available for 61 patients on re-review, we chose to use all 70 patients in our final analysis because there was close agreement of the original pathologic description and re-review. Table 3. Characteristics of 70 Stage I and Stage II Patients Undergoing Surgery Alone Versus Surgery and Adjuvant Radiation Surgery Alone (n 47) Surgery and Radiation (n 23) Demographics Range of age Median age Female 32 (69.6%) 7 (30.4%) Presenting complaint Local symptoms 11 (23.4%) 8 (34.8%) Myasthenia gravis 18 (38.2%) 5 (21.7%) Asymptomatic 18 (38.2%) 10 (43.4%) Masaoka stage I 27 (57%) 3 (13%) II 20 (43%) 20 (87%)

3 Ann Thorac Surg SINGHAL ET AL 2003;76: POSTOPERATIVE RADIATION FOR STAGES I II THYMOMA 1637 Table 4. Breakdown of World Health Organization Histologic Subtype for Each Masaoka Stage in Our Series Masaoka Stage World Health Organization Histologic Classification A AB B1 B2 B3 Undetermined % Radiated Stage I 5 (0) 3 (0) 9 (1) 6 (2) 2 (0) 5 (0) 10.0 Stage IIa 1 (1) 0 (0) 1 (0) 0 (0) 0 (0) 4 (2) 50.0 Stage IIb 4 (2) 4 (3) 14 (6) 9 (4) 3 (2) 0 (0) 50.0 Values without ( ) indicate total number of patients in each clinical and pathological stage. Values in ( ) indicate patients in each category who underwent postoperative irradiation. Adjuvant RT The decision to refer patients for adjuvant RT was based on the surgeon s subjective assessment of the risk of recurrence. Treatment regimens for patients who underwent RT at our institution were reviewed for total doses, dose fractionation, and complications. Follow-Up Patients were contacted by telephone. In cases where patients could not be reached, their primary care doctor or neurologist was contacted to update their care. Follow-up information was obtained on 69 patients. Fifty-six patients (81%) were followed up with chest roentgenogram or computed tomographic scan. Further follow-up was left to the discretion of their referring physician. Statistical Methods Indicators including histologic type (medullary, mixed, predominantly cortical, cortical, and well-differentiated), Masaoka stage, treatment, and morbidity were analyzed with respect to recurrence and survival. Fischer s exact test (categorical data) and the Student s t test (noncategorical data) were used to compare the mean value of the variables of the groups studied as appropriate. A p value less than 0.05 was considered to represent statistical significance for all tests. Survival was calculated from the date of surgery. The Kaplan-Meier method was used to estimate the time to recurrence or death. The log-rank test was used to compare Kaplan Meier survival curves. Results Patient Characteristics Between 1992 and 2002, 167 patients underwent surgical resection for thymoma. Seventy patients were pathologically and surgically staged as Masaoka stages I or II. Clinical characteristics of these patients are shown in Table 3. Histopathologic and Clinical Staging Tumor size was recorded in 52 patients. The average thymoma measured 5.3 cm in diameter (range, 1 cm 11.5 cm). Patients were classified according to the WHO classification [11, 12]. Patients presented with type A(n 10), type B1 (n 24), type B2 (n 15), type B3 (n 5), and type AB (n 7) (Table 4). Negative margins were obtained in all 70 patients. There were 30 of 167 (18.0%) Masaoka stage I patients and 40 of 167 (24.0%) stage II patients (Table 4). Of the 30 stage I patients, 17 were completely encapsulated and 13 demonstrated microinvasion into the capsule. In the stage II patients, 6 of 40 (15%) demonstrated transcapsular invasion (stage IIa) and 34 of 40 (85%) had pleural involvement or fatty tissue penetration (stage IIb). Surgical Results The majority of patients underwent a total thymectomy through a median sternotomy (n 42; 60%) or a transcervical approach (n 19; 27%) (Table 5). Seven patients underwent operations by thoracotomy, and 2 patients had video-assisted thoracoscopic surgery. Most patients after the mid-1990s who had not undergone prior chest surgery and who had tumors less than 4 cm had operations attempted by a transcervical approach [25]. It was believed that all patients had a complete resection at the time of surgery and that the pleural reflections were routinely dissected as part of the procedure. There were no perioperative mortalities. Morbidity included one seroma that required percutaneous drainage, one wound infection that required reexploration for drainage, two postoperative atrial fibrillations, one bradycardia, and one postoperative acute renal failure that required temporary dialysis. One patient had an intraoperative ventricular tachycardia that required chemical cardioversion. Radiotherapy Twenty-three of 70 patients (33%) were managed with postoperative RT (Table 6). Three patients in the stage I group were treated with RT. Of the 40 stage II patients, an equal number (n 20) received surgery with and without RT. Furthermore, an identical percentage of stage IIa (3 of 6 patients) and stage IIb (17 of 34 patients) received radiation. The treatment volume at the Hospital of the Table 5. Procedure Performed for Resection of Thymoma Surgery Alone (n 47) Surgery Radiation Therapy (n 23) Transcervical thymectomy 13 6 Median sternotomy Thoracotomy 6 1 a Video-assisted thorascopic surgery 2 a 0 a Denotes single recurrence in this group.

4 1638 SINGHAL ET AL Ann Thorac Surg POSTOPERATIVE RADIATION FOR STAGES I II THYMOMA 2003;76: Table 6. Recurrences According to Postoperative Therapy and Masaoka Staging Stage I Stage IIa Stage IIb Surgery alone 1/27 0/3 0/17 Surgery and 0/3 0/3 1/17 radiation University of Pennsylvania for postoperative RT varied. The minimum volume was the operative bed with at least 2 cm margins on the gross tumor bed, and the maximum volume included a much larger mediastinal field. Adjuvant total doses were 45 to 54Gy in 25 to 30 fractions. Recurrence and Survival The median follow-up time after surgery was 70.3 months. Six patients died of other causes. No patients had any sign of thymoma recurrence at time of death. The overall 5-year survival rates for patients was 94% for stage I disease and 90% for stage II disease. Twenty-three (33%) stage I and stage II patients received RT with one recurrence (1.4%). Forty-seven (67%) stage I and stage II patients did not receive RT and suffered one recurrence (1.4%) (Table 6). There was no statistical difference (p 0.32; log-rank test) between the Kaplan-Meier survival curves of those patients treated with surgical excision alone and those treated with surgery plus RT (Fig 1). Similarly, if one evaluates stage II patients separately there is no difference between the survival curve of radiated and unradiated patients (p 0.72; log-rank test) (Fig 2). There were two recurrences. One recurrence was a drop metastasis to the diaphragm in a patient with stage I (4 cm) type A thymoma who had been treated 3 years Fig 1. Kaplan-Meier survival curves demonstrate no statistical difference (p 0.32; log-rank test) in the entire study group (stages I and II combined) between patients undergoing surgery alone (n 47) and those undergoing surgery and radiation (n 23). (ns not significant; RT adjuvant radiation; XRT radiation therapy.) Fig 2. Kaplan-Meier survival curves demonstrated no statistical difference (p 0.72; log-rank test) between stage II patients undergoing surgery alone (n 20) and those undergoing surgery and radiation (n 20). (ns not significant; RT adjuvant radiation; XRT radiation therapy.) earlier by video-assisted thoracoscopic surgery resection without radiation. The other recurrence was a left upper lobe nodule in a patient who underwent a left thoracotomy 3 years earlier and 50.4 Gy mediastinal postoperative RT for a stage IIb (7.5 cm) type B2 tumor. Both patients underwent re-resection and remain disease free at 62 months and 11 months, respectively. Comment Many thoracic surgeons currently favor postoperative RT for even completely resected stage II thymoma patients. Others believe that recurrence among completely resected stage II patients is rare and that RT is not indicated. Various studies report 5-year survival in these patients ranging from 50% to 90% without RT and 40% to 90% with RT [1, 18, 22, 23]. We set out to shed further light on this issue by examining outcome in patients with completely resected stage I and II thymomas with and without postoperative RT. Our results from this retrospective study suggest that margin-negative surgical resection is sufficient treatment for stage I, IIa, and IIb thymomas (Table 6). Our patients fit the general demographic data that have been previously presented in other larger series. The mean age was 59.4 years. A slightly larger number of patients had myasthenia gravis than the recently cited literature, which was likely due to the fact that our institution is a referral center for myasthenia gravis. Stage I Stage I thymomas have an excellent prognosis after complete resection. Most groups accept that there is no need for RT after surgery for stage I thymomas (Table 7).

5 Ann Thorac Surg SINGHAL ET AL 2003;76: POSTOPERATIVE RADIATION FOR STAGES I II THYMOMA 1639 Table 7. Masaoka Stage I Results From Several Institutions Using Postoperative Radiation or No Adjuvant Therapy Institution Treatment n Outcomes Reference Fox Chase Cancer Center, Surgery alone 42 67% (5-yr survival) Curran, 1988 [19] Hospital of the University of Pennsylvania, Medical College of Virginia Massachusetts General Hospital Surgery alone % (5-yr survival) Quintanilla-Martinez, 1994 [6] MD Anderson Surgery alone 6 One recurrence Pollack, 1992 [18] Surgery and radiation 5 One recurrence Memorial Sloan Kettering Surgery alone 25 95% (5-yr survival) Blumberg, 1995 [5] 86% (10-yr survival) Osaka University Medical School Surgery alone 12 One recurrence Nakahara, 1988 [7] Surgery and radiation 38 No recurrence Tohoku University Surgery alone % (10-yr) Fujimura, 1987 [23] Ryukyus School of Medicine Surgery and radiation % (10-yr) Ogawa, 2002 [28] In the Memorial Sloan Kettering experience, 25 stage I patients underwent complete resection with one recurrence and 95% 5-year survival and 86% 10-year survival rates [5]. Fujimura and colleagues [23] reported no recurrences in 31 stage I thymomas after total resection alone. Ten-year survival rate was 74.3%. The Massachusetts General Hospital experience between 1939 and 1990 included 52 stage I patients who were all treated with thymectomy alone. No patient relapsed or died of thymoma [6]. In 1988, Curran and colleagues [19] reported no recurrences in 43 stage I thymomas after total resection, with only 1 patient receiving neoadjuvant RT. Despite a relapse-free survival of 100%, the 5-year survival was only 67% due to a high frequency of severe myasthenia gravis in this patient population. In the MD Anderson experience, between 1962 and 1987, Pollack and colleagues [18] presented 11 stage I patients who underwent total resection (5 patients who received postoperative RT [50 Gy] and 6 who did not). There were two recurrences (one in each group). A series from Osaka University Medical School presented 38 stage I patients, 26 who underwent RT, and 12 who were not radiated [7, 26]. There were no recurrences in the radiated group, but one recurrence (8%) in the nonradiated group. Our data reinforces the trend to refrain from radiating patients with completely resected stage I thymoma. We document a single recurrence in 27 stage I patients treated by resection alone and no significant difference between patients treated by resection alone versus resection plus RT. Stage II For stage II thymomas, the results in the literature do not give clear guidelines about indications for postoperative RT therapy. Adjuvant radiation therapy has been used postoperatively by most surgeons when an incomplete resection is performed. For completely resected stage II tumors, whereas a few studies have argued against RT [5, 20, 27], most studies have advocated postoperative therapy [10, 19, 28]. If one is inclined to radiate, the experience of the Massachusetts General Hospital indicates that the addition of histologic subtyping is a reasonable approach to fine-tuning this decision [6]. Several authors have felt that RT should follow surgery. In the experience of Curran and colleagues [19], 19 patients underwent complete resection for stage II thymoma. No further pathologic elaboration was available. One patient received postoperative RT. One third of patients (6 of 18) who did not receive RT experienced local recurrence. No relapse was noted in the patient who was radiated. The authors concluded that resection without RT was inadequate. However, statistical analysis was not possible because only 1 patient underwent surgery without RT. A series from Osaka University Medical School reported a 29% (2 of 7) recurrence rate for patients with resected stage II thymomas who did not undergo adjuvant RT, as compared with 8% (2 of 25) in those who received postoperative RT. They concluded RT was indicated for any patient who had any capsular microinvasion. Margin status was not assessed [10]. Ogawa and colleagues [28] presented 61 Masoaka stage II patients who underwent postoperative mediastinal RT. Despite all patients receiving RT, 6 patients (10%) still experienced recurrence (2 mediastinal and 4 pleural). Their conclusion was that RT prevents mediastinal recurrence for patients with completely resected thymoma but is insufficient to avoid pleural-based recurrence. Other authors have felt adjuvant RT should be performed only with certain caveats or not at all. A report from Memorial Sloan Kettering described 26 stage II thymoma patients between 1949 and 1993 who underwent complete resection, 17 of whom received adjuvant RT and 9 of whom were without RT. Recurrence rates (p 0.21) and survival rates (p 0.14) of the two groups were similar [5]. Ruffini and colleagues [27] from University of Torino presented an interesting report of 58 stage II patients, 13 of whom underwent adjuvant RT. Four patients (31%) recurred despite adjuvant RT, and 2 patients (4%) recurred without postoperative treatment. They demonstrated with statistical significance (p 0.02) that the effect of postoperative RT was potentially harmful. However, they admitted to a possible selection bias

6 1640 SINGHAL ET AL Ann Thorac Surg POSTOPERATIVE RADIATION FOR STAGES I II THYMOMA 2003;76: toward patients who were selected for RT based on what appeared to be clinically advanced disease. The Massachusetts General Hospital experience presented 32 stage II patients who underwent thymectomy [6]. Seven of them received postoperative RT. In stage II patients, one of the 16 minimally invasive (stage IIa) tumors recurred, compared with 3 of 16 grossly invasive (stage IIb) tumors. Two of seven patients (28.3%) who had received postoperative RT treatment relapsed at 6 and 16 years, and 2 of 24 patients (8%) who had received no RT treatment relapsed at 5 and 13 years. Similar to our study, the Massachusetts General Hospital group attempted to correlate the pathologic extent of disease and histologic classification with outcome [6]. There was no clear effect of RT on outcome. However, none of the 12 patients with medullary or mixed thymoma relapsed, whereas 4 of 19 patients with predominantly cortical (2 of 13) or well-differentiated thymic carcinoma (2 of 6) relapsed. On the basis of these results, they recommended that stage II medullary and mixed thymomas be spared adjuvant therapy but that stage II cortical thymomas receive a postoperative treatment regimen. Recently, the Massachusetts General Hospital updated its 27 year experience and presented 49 completely resected stage II patients [24]. Fourteen stage II patients underwent postoperative RT and 35 did not. The addition of adjuvant RT did not alter local or distant recurrence rates. Disease-specific survival at 10 years in stage II patients was 100% with and without RT (p 0.87). Our results, with no significant difference between recurrence rates in 40 stage II thymomas treated by resection alone or resection plus RT, adds to the data suggesting that resection alone is sufficient treatment even for stage II. The fact that we had equal proportions of patients treated with and without RT in stages IIa and IIb suggests that the substage within stage II is not critical in determining the need for adjuvant treatment. Our low overall recurrence rate (2 of 70 patients) makes it impossible to comment regarding the influence of histologic typing by the WHO classification on the need for adjuvant treatment. However, it is worth noting that our single recurrence in stage II was in a patient with a WHO type B2 tumor. Limitations We acknowledge several limitations to our study. First, the length of follow-up in this study is relatively short. Thymoma has a known potential to recur beyond 10 years and our average follow-up time is 70.3 months. Notably, the most recent Massachusetts General Hospital study, which arrived at similar conclusions, had a mean follow-up of 90 months (range, 1 to 336 months) [24]. Another potential concern is that the selection of which patients should undergo RT was based at least partly upon surgeon preference. This bias is common to all retrospective studies addressing this issue. It would tend to select RT for those tumors that seem more aggressive in some way, which is not accounted for in the current clinicopathologic staging and classification systems. However, even after retrospective restaging, and the fact that equal proportions of stage IIa and IIb tumors underwent radiotherapy, and that tumor size was similar in the radiated and unradiated groups (5.2 cm vs 5.4 cm; p 0.9, not significant), the facts support the contention that the radiated and unradiated groups were closely matched. Conclusion In this series, which is only one of two studies critically examining the role of RT in margin-negative stage II thymoma, we identify no benefit of adjuvant RT. Because thymoma is an indolent disease with a low rate of recurrence, we believe that patients with stage II thymomas should not be recommended to undergo RT. We believe that these patients may be safely followed by serial radiographic examination. Ideally this issue should be resolved by a prospective study randomizing stage II patients to postoperative radiation versus observation. However, it is unlikely that such a trial will ever be satisfactorily completed given the small number of patients involved and the long-term follow-up that would be required. References 1. Bergh NP, Gatzinsky P, Larsson S, Lundin P, Ridell B. Tumors of the thymus and thymic region: I. Clinicopathological studies on thymomas. Ann Thorac Surg 1978;25: Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48: Masaoka A, Yamakawa Y, Niwa H, et al. Thymectomy and malignancy. Eur J Cardiothorac Surg 1994;8: Koga K, Matsuno Y, Noguchi M, et al. A review of 79 thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int 1994;44: Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995;60:908 13; discussion, Quintanilla-Martinez L, Wilkins EW Jr, Choi N, Efird J, Hug E, Harris NL. Thymoma: histologic subclassification is an independent prognostic factor. Cancer 1994;74: Nakahara K, Ohno K, Hashimoto J, et al. Thymoma: results with complete resection and adjuvant postoperative irradiation in 141 consecutive patients. J Thorac Cardiovasc Surg 1988;95: Wilkins EW Jr, Grillo HC, Scannell JG, Moncure AC, Mathisen DJ. Role of staging in prognosis and management of thymoma. Ann Thorac Surg 1991;51: Verley JM, Hollmann KH. Thymoma: a comparative study of clinical stages, histologic features, and survival in 200 cases. Cancer 1985;55: Monden Y, Nakahara K, Iioka S, et al. Recurrence of thymoma: clinicopathological features, therapy, and prognosis. Ann Thorac Surg 1985;39: Rosai J, Sobin LH. Histological typing of tumours of the thymus. In: International histological classification of tumours. New York: Springer, Okumura M, Ohta M, Tateyama H, et al. The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 2002;94: Muller-Hermelink HK, Marx A. Pathological aspects of malignant and benign thymic disorders. Annals of Medicine 1999;31: Okumura M, Ohta M, Miyoshi S, et al. Oncological signifi-

7 Ann Thorac Surg SINGHAL ET AL 2003;76: POSTOPERATIVE RADIATION FOR STAGES I II THYMOMA 1641 cance of WHO histological thymoma classification. A clinical study based on 286 patients. Jpn J Thorac Cardiovasc Surg 2002;50: Schneider PM, Fellbaum C, Fink U, Bollschweiler E, Prauer HW. Prognostic importance of histomorphologic subclassification for epithelial thymic tumors. Ann Surg Oncol 1997; 4: McCart JA, Gaspar L, Inculet R, Casson AG. Predictors of survival following surgical resection of thymoma. Journ Surg Oncol 1993;54(Suppl): Maggi G, Giaccone G, Donadio M, et al. Thymomas: a review of 169 cases, with particular reference to results of surgical treatment. Cancer 1986;58: Pollack A, Komaki R, Cox JD, et al. Thymoma: treatment and prognosis. Int J Radiat Oncol Biol Phys 1992;23: 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: Urgesi A, Monetti U, Rossi G, Ricardi U, Casadio C. Role of radiation therapy in locally advanced thymoma. Radiother Oncol 1990;19: Cohen DJ, Ronnigen LD, Graeber GM, et al. Management of patients with malignant thymoma. J Thorac Cardiovasc Surg 1984;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. Federation Nationale des Centres de Lutte Contre le Cancer. Radiother Oncol 1995;34: Fujimura S, Kondo T, Handa M, Shiraishi Y, Tamahashi N, Nakada T. Results of surgical treatment for thymoma based on 66 patients. J Thorac Cardiovasc Surg 1987;93: Mangi AA, Wright CD, Allan JS, et al. Adjuvant radiation therapy for stage II thymoma. Ann Thorac Surg 2002;74: Deeb ME, Brinster CJ, Kucharzuk J, Shrager JB, Kaiser LR. Expanded indications for transcervical thymectomy in the management of anterior mediastinal masses. Ann Thorac Surg 2001;72: Moreno EA, Aguayo AJL, Parrilla PP, Sola PJ, Garcia LF, Jimenez BA. Prognostic factors of thymomas. Eur J Surg Oncol 1995;21: Ruffini E, Mancuso M, Oliaro A, et al. Recurrence of thymoma: analysis of clinicopathologic features, treatment, and outcome. J Thorac Cardiovasc Surg 1997;113: Ogawa K, Uno T, Toita T, et al. Postoperative radiotherapy for patients with completely resected thymoma: a multiinstitutional, retrospective review of 103 patients. Cancer 2002;94: DISCUSSION DR CAMERON D. WRIGHT (Boston, MA): Doctor Singhal and coauthors are to be complimented for an excellent presentation, and I would like to thank them for sending me the manuscript well in advance. The role of radiation therapy in thymoma is an important one and the decision should not be relegated to the radiation oncologist. Indeed, the thoracic surgeon should strive to reassert control over all decision-making for induction or adjuvant treatment for their patients, because we understand the disease best. We must continue to diagnose, decide on the appropriate treatment, order appropriate induction or adjuvant therapy, and follow our patients both for the sake of our patients and to maintain our role as thoracic surgical oncologists. Thymoma is a radiation-sensitive tumor and we all agree with its role for incomplete resections. I believe, as do the authors, that its role as an adjuvant treatment is overrated and often ill-advised. Radiation comes at a cost to the patient, with early complications, such as radiation pneumonitis occurring in about 8% of these patients, which occasionally can be life-threatening. Numerous underreported late complications of mediastinal radiation are well known to cardiothoracic surgeons, and these include esophageal strictures and cancers, pericardial disease, and radiation-induced coronary disease. Furthermore, radiation is costly, believe it or not, even more so than surgical treatment. Last, mediastinal radiation does not prevent pleural recurrences, which is the most common mode of failure after thymoma treatment. The enthusiasm and history of adjuvant radiation therapy is difficult to elucidate, but I think it relates mostly to three factors: tight resection margins, sometimes poorly conceived and performed resections, which may include inadequate incisional approaches, preliminary or intraoperative biopsies, non-total thymectomy, and insufficient en bloc resections, and a relinquishing of decision- making to either the medical or radiation oncologist. As noted, our group recently analyzed and reported on this same subject and came up with the same conclusions as the authors. I have three questions for Dr Singhal. One, why were three stage I patients radiated? If we use lung cancer as an example, we never radiate stage I lung cancer patients after a complete resection, and in fact the meta-analysis suggests that those patients do worse. Two, there was obvious selection bias in this series among the stage II patients, with one half receiving radiation therapy despite a complete resection status. What was the thought process for selection of radiation in those patients, and would you recommend radiation for those patients or any patients in stage II now? My personal indications for radiation therapy in stage II patients would include those with a preliminary open biopsy, which contaminates the wound; a judgment at the time of surgery that the resection was compromised, and this mostly commonly comes when the tumor is immediately adjacent and is peeled off the phrenic nerve; and most cases of macroscopic invasion with type B3 or well differentiated thymic carcinomas. Three, I wonder about your use of nonstandard incisional approaches in approximately one third of your patients, which limits the ability to do an en bloc resection. Your follow-up period is still very early for an indolent tumor such as thymoma, whereas most tumors, other than B3 tumors, recur after 5 years. You may be underestimating your recurrence rate. The droplet metastasis in the stage I type A patient, for example, was probably due to the non-en bloc resection with intraoperative unrecognized tumor spillage. Why the desire to avoid median sternotomy in these patients? I would like to commend the authors for helping to clarify the role of adjuvant radiation therapy in stage II thymoma. DR SINGHAL: Doctor Wright, thank you for your valuable comments. I will attempt to answer your questions and then I welcome Dr Kaiser to comment further. As you note, 3 patients with Masaoka stage I disease were radiated postoperatively in our study. These patients were radiated based on the decision of their community-based phy-

8 1642 SINGHAL ET AL Ann Thorac Surg POSTOPERATIVE RADIATION FOR STAGES I II THYMOMA 2003;76: sicians who gave them their follow-up care. We hope forums like this will further educate the medical community that radiation is not necessary for Masaoka stage I and II disease. In choosing radiation for our Masaoka stage II patients who were radiated, we acknowledge there may have been a selection bias due to the nonrandomized nature of this study. This may be a tendance to select adjuvant radiation for tumors that are aggressive in some manner that is not accounted for by simple staging and pathology. However, we do not think this is likely to have been a major factor in our results, because first, equal proportions of patients with stage IIa and IIb disease were radiated. Second, the average tumor size between those patients who were radiated and those who were nonradiated was roughly equivalent (5.2 cm vs 5.4 cm, respectively). The decision to radiate was based on the joint decision of the surgeon and radiation oncologist, of course with patient input. As surgeons, we would typically recommend radiation only if we believed that the margins were somehow compromised. This may include, as you mention, those in whom we stripped the tumor off of a phrenic nerve in order to preserve it (a situation in which the margins are necessarily close). We have not routinely radiated those who have had a previous open biopsy, and we have not yet used histologic classification to stratify patients to receive or not receive adjuvant radiation, although there is certainly beginning to be evidence available from Japan, China, and Germany that this may be a reasonable approach. As you know, these studies correlate tumor World Health Organization histopathologic classification and patient prognosis. Because our numbers were small and distributed across various stages, we cannot comment from our data about the role of postoperative radiation with regard to histopathologic classification. However, future studies may push our hand to radiate World Health Organization pathologic type B2 and B3 tumors. With regard to your final question about our use of the transcervical approach for some of these thymomas, 2 years ago we published our 7-year experience performing 121 transcervical thymectomies [1]. At that time we described performing 15 transcervical thymectomies for stage I to III thymomas. Our use of this approach has evolved. We do not take this procedure lightly. We only use the transcervical approach for tumors that are completely encapsulated by preoperative computed tomography and less than 4 cm, although we prefer tumors to be less than 3 cm. If there is any evidence of invasiveness on the computed tomographic scan, we perform the procedure through a median sternotomy. Nevertheless, we have had no recurrences using this approach to date. DR LARRY KAISER (Philadelphia, PA): I really have very little to add to what Dr Singhal has said. I think that Dr Wright correctly asked the question regarding our transcervical approach, and as Dr Singhal said, it is somewhat atypical to use. We are very selective in our criteria; we have published those results. The follow-up period, as Dr Singhal points out, is short. We will continue to follow these patients closely. But I think the routine use of radiation therapy in these patients based on the Massachusetts General Hospital experience and this experience reported today, should not be considered. Reference 1. Shrager JB, Deeb ME, Mick R, et al. Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy. Ann Thorac Surg 2002;74:320 7.