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Invasive Thymoma: Postoperative Mediastinal Irradiation, and Low-Dose Entire Hemithorax Irradiation in Patients with Pleural Dissemination
ORIGINAL ARTICLE
Invasive Thymoma: Postoperative Mediastinal Irradiation, and Low-Dose Entire Hemithorax Irradiation in Patients with Pleural Dissemination Chikao Sugie, MD,* Yuta Shibamoto, MD, PhD,* Chisa Ikeya-Hashizume, MD,* Hiroyuki Ogino, MD,* Shiho Ayakawa, MD,* Natsuo Tomita, MD,* Fumiya Baba, MD,* Hiromitsu Iwata, MD,* Masato Ito, MD,* and Kyota Oda, MD†
Introduction: We evaluated the results of postoperative mediastinal radiotherapy (MRT) for invasive thymoma and low-dose entire hemithorax radiotherapy (EHRT) for pleural dissemination. Methods: Sixty patients were treated with a nearly uniform policy. Generally, we administered 30 to 40 Gy MRT after surgery at 2 Gy daily fractions for Masaoka stage II tumors or suspected residual diseases, and 50 to 55 Gy MRT for stage III tumors and for highlysuspected or macroscopic residual diseases. Since 1992, we have administered EHRT in patients with pleural dissemination, with 11.2 Gy in 7 fractions or 15 to 16 Gy in 10 fractions after removal of disseminated lesions in addition to MRT. We treated 52 patients with MRT alone and 8 with EHRT and MRT. In addition, we gave EHRT to four patients who developed pleural dissemination later. Results: For all 60 patients, the overall and cause-specific survival and local and pleural-dissemination control rates at 5 years were 79, 87, 86, and 69%, respectively. Both Masaoka stage and tumor resectability were associated with prognosis. In stage IVa patients, pleural dissemination control rate was 71% at 3 years after EHRT, whereas it was 49% in patients receiving MRT alone (p ⫽ 0.38). Grade 2 or higher radiation pneumonitis was observed in only 3 of 52 patients (5.8%) undergoing MRT initially. In 12 patients who underwent EHRT, 3 patients (25%) experienced grade 2 or 4 pneumonitis. Conclusions: Postoperative MRT appeared to prevent local recurrence with acceptable toxicity. EHRT is generally safe and may contribute to control of pleural dissemination. Key Words: Invasive thymoma, Mediastinal radiotherapy, Entire hemithorax radiotherapy, Pleural dissemination. (J Thorac Oncol. 2008;3: 75–81) *Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan; and †Department of Radiology, Hokuto Hospital, Obihiro, Hokkaido, Japan. Disclosure: The authors declare no conflict of interest. Address for correspondence to: Chikao Sugie, MD, Department of Radiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 Japan. E-mail: [email protected] Copyright © 2007 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0301-0075
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hymomas deriving from the epithelial cells within the thymic gland are pathologically benign but biologically aggressive,1–3 and so multidisciplinary treatment is often considered necessary. The treatment strategy has often been chosen based on the staging system proposed by Masaoka et al.4,5 The Masaoka stage (shown in Table 1) is considered one of the most important factors predicting prognosis.6 Masaoka stage I–II thymomas are associated with excellent prognosis, and stage III thymoma patients also have favorable prognosis.3 On the other hand, stage IVa patients have poor prognosis because of the difficulty in performing complete resection and giving wide-field radiation therapy. Another important factor predicting survival seems to be the extent of surgery.1,5 Recently, several studies have shown that induction chemotherapy for increasing tumor resectability may improve the prognosis of advanced thymoma patients.1,2 Thymoma is known as a relatively radiosensitive neoplasm, and there seems to be a general agreement that postoperative mediastinal radiotherapy (MRT) should be used in the treatment of invasive thymoma.7,8 For the purpose of improving survival and local control rates in invasive thymomas, we have used postoperative MRT in patients with Masaoka stage II–IVb thymoma, in combination with low-dose entire hemithorax radiotherapy (EHRT) in patients with pleural dissemination. EHRT has been suggested to be a therapeutic and prophylactic radiotherapy technique against pleural dissemination. Uematsu et al.9,10 treated 23 patients with stage II or III thymoma with EHRT plus MRT, and obtained excellent 5-year relapse-free and overall survival rates when compared with those obtained by MRT alone, advocating the efficacy of EHRT. However, there are very few other reports on EHRT, and there have been no prospective studies evaluating EHRT.8 –13 Therefore, the role of EHRT seems to remain controversial. In this study, we investigated the results of treatment in patients who received MRT or MRT plus EHRT at our institution.
PATIENTS AND METHODS Patients A total of 60 patients with thymoma were treated with an almost uniform policy regarding radiotherapy in our insti-
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TABLE 1. Masaoka Stage Stage I Stage II
Stage III Stage IVa Stage IVb
Macroscopically completely encapsulated and microscopically nocapsular invasion 1. Macroscopic invasion into surrounding fatty tissue or mediastinal pleura, or 2. Microscopic invasion into capsule Macroscopic invasion into neighboring organ, ie pericardium, great vessels, or lung Pleural or pericardial dissemination Lymphogenous or hematogenous metastasis
tution between November 1987 and August 2005. There were 23 (38%) men and 37 (62%) women, with a median age of 54 years (range, 21–79 years). We determined Masaoka stage from findings of preoperative computed tomography and pathology at surgery. The stage was I or II in 19 (32%) patients, III in 16 (27%), IVa in 19 (32%), and IVb in 6 (10%). The histopathologic subtype according to the system proposed by Bernatz et al.14 was available in 50 patients, and the subtype according to the new World Health Organization classification proposed in 20003,15 was available in 25. In three patients, no histologic subtype was obtained. The median follow-up term was 56 months (range, 1–209 months).
Treatment Radiation therapy was delivered five times a week after Masaoka stage, histopathologic classification and tumor resectability were confirmed by either surgical resection or biopsy. Tumor resectability was defined as shown in Table 2 from grade A (complete resection) to D (biopsy only). The resectability was grade A in 25 (42%) patients, grade B in 20 (33%), grade C in 9 (15%), and grade D in 6 (10%). All
TABLE 2. Tumor Resectability Grade Grade Grade Grade
A B C D
Completely resected Microscopic residual lesion highly suspected Macroscopic residual lesion highly suspected Biopsy only
patients received MRT, without or in combination with EHRT. The radiation doses of MRT were 30 to 40 Gy in 15 to 20 fractions for stage I or II patients, 40 to 46 Gy in 20 to 23 fractions for patients with highly-suspected microscopic residuals, 46 to 50 Gy in 23 to 25 fractions for highlysuspected macroscopic residual diseases, and 50 to 64 Gy in 25 to 32 fractions for gross residual diseases. The average dose of MRT was 41.4 Gy (range, 30 – 64 Gy). EHRT was performed in a total of 12 patients seen in 1992 or later. EHRT was performed after surgical resection of disseminated lesions immediately before or after MRT in seven stage IVa patients with highly-suspected microscopic or macroscopic residuals. Moreover, in one patient with stage II thymoma, whose tumor ruptured into the thoracic cavity during surgery, EHRT was performed before MRT. EHRT was given subsequently against recurrence with pleural dissemination in four initially stage III or IVa patients who had received MRT previously; three initially stage IVa patients received EHRT after surgical removal of the disseminated lesions, and one initially stage III patient received EHRT, followed by boosts to the two disseminated lesions (total 60 Gy) without surgical resection; thus, the pleural disease before EHRT was macroscopic only in this patient, and it was microscopic in the remaining 11 patients. The EHRT dose was 11.2 Gy in 7 fractions in two patients, 15 Gy in 10 fractions in nine, and 16 Gy in 10 fractions in one, with an average dose of 14.1 Gy. These EHRT doses were determined considering the tolerance of the lung and taking previous reports into account.8 –13 We considered that these relatively low doses of radiation would be efficient when the residual tumor cell number was small. For the 12 patients undergoing EHRT, an average total dose to the mediastinum was 44 Gy (range, 30 – 64 Gy). Figure 1 shows representative radiation fields for MRT and EHRT. In 54 patients undergoing tumor resection, 19 (35%) had preoperative corticosteroid therapy, 11 (20%) had postoperative steroid therapy, 3 (6%) had preoperative chemotherapy, 18 (33%) had intraoperative perfusion thermochemotherapy,16 and 3 (6%) had postoperative chemotherapy. In six patients undergoing only biopsy, five (83%) had steroid
FIGURE 1. Representative radiation fields of mediastinal radiotherapy [MRT, (A)] and entire hemithorax radiotherapy [EHRT, (B)].
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therapy, and four (67%) had chemotherapy. Table 3 shows clinical and treatment characteristics of the 60 patients.
Evaluation Overall and relapse-free survival rates and local and pleural-dissemination control rates were calculated from the date of starting radiation therapy. In four patients who received EHRT against pleural dissemination developing after MRT, the time to progression and survival period were respectively measured from the dates of the first MRT and secondary EHRT. Overall and cause-specific survival rates,
TABLE 3. Patient Characteristics Total No. of patients Age (yr) median (range) Gender (male/female) Masaoka stage I, II/III/IVa/IVb Tumor respectability Grade A/B/C/D Myasthenia gravis (Yes/No) Histology Bernatz classification Lymphocytic/ Epithelial Mixed/Spindled/ Unknown WHO classification A/AB/B1/B2/B3/ Unknown Steroid administration Yes/No Chemotherapy Yes/No
HERT ⴙ MRT
MRT
60 54 (21–79) 23/37
52 55 (21–79) 20/32
8 49 (33–63) 3/5
19/16/19/6
18/16/12/6
1/0/7/0
25/20/9/6 10/50
25/15/6/6 9/43
0/5/3/0 1/7
24/5/20/1/10
21/3/17/1/10
3/2/3/0/0
0/2/5/16/2/35
0/2/4/13/0/33
0/0/1/3/2/2
27/33
21/31
6/2
24/36
21/31
3/5
A
B
(%)
100
80
80
80
60
60
60
40
40
40
20
Stage I-II Stage III 20
A
Stage IVa
C
0
50 100 150 Time (months)
B
Stage IVb
P = 0.0046
0 200
0
RESULTS For all 60 patients, the overall survival rate was 79% and the cause-specific survival rate was 87% at 5 years. The local control rate was 86% and pleural-dissemination control rate was 69% at 5 years. Figure 2 shows overall survival curves according to Masaoka stage, tumor resectability, and radiation field (MRT alone or MRT plus EHRT). Overall survival rates differed with Masaoka stage and tumor resectability (p ⫽ 0.048 and 0.0046, respectively), but not with the radiation field. Respective 2- and 5-year survival rates are shown in Table 4. Figure 3 shows survival and local and pleural-dissemination control rates according to Masaoka stage in 52 patients initially receiving MRT alone. For all 52 patients, the 5-year overall and cause-specific survival rates were 80 and 87%, respectively, and local and pleural-dissemination control rates were 84 and 69%, respectively. Cause-specific survival and local and pleural-dissemination control rates differed significantly with Masaoka stage. Figure 4 shows survival and local and dissemination control rates according to the use of EHRT as an initial treatment for stage IVa patients. The pleural-dissemination control rate was relatively high (71% at 3 years) in patients undergoing EHRT, when compared with 49% in those receiving MRT alone, although the difference was not significant (p ⫽ 0.38). Also, overall and cause-specific survival and local control rates did not differ significantly between the two groups. Figure 5 shows overall survival and pleural-dissemination control curves for 12 patients undergoing EHRT. The rates were calculated from the date of starting EHRT. Overall
(%)
100
P = 0.048
local control rate, and dissemination control rate were calculated by the Kaplan–Meier method and differences between these rates were examined using the log-rank test. Radiation pneumonitis was classified according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer acute radiation morbidity scoring criteria using computed tomography in all cases.
C
(%)
100
0
Invasive Thymoma and Patients with Pleural Dissemination
50 100 150 Time (months)
EHRT+MRT
20
MRT
D
P = 0.31
0 200
0
50 100 150 Time (months)
200
Copyright © 2007 by the International Association for the Study of Lung Cancer
FIGURE 2. Overall survival curves according to Masaoka stage (A), tumor resectability (B), and radiation field (with or without EHRT) (C) (n ⫽ 60).
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TABLE 4. Survival and Control Rates (%) Overall Survival
Total Masaoka Stage I–II III IVa IVb Tumor resectability A B C D Initial radiation MRT only EHRT⫹MRT Age (yr) ⱖ60 ⬍60 Gender Female Male Myasthenia gravis Yes No Steroid administration Yes No Chemotherapy Yes No
n
2-yr
5-yr
60
95
79
19 16 19 6
100 100 90 83
94 82 64 63
25 20 9 6
96 100 89 83
78 94 76 –– *
52 8
94 100
80 71
21 39
91 97
70 83
37 23
95 96
74 85
10 50
100 94
88 77
27 33
89 100
63 89
24 36
92 97
78 79
p
Cause-specific Survival 2-yr
5-yr
98
87
100 100 95 100
100 89 73 75
100 100 100 83
89 100 86 –– *
98 100
87 83
100 97
92 83
97 100
82 94
100 98
100 84
96 100
72 96
96 100
81 91
0.048
p
Local Control 2-yr
5-yr
92
86
100 94 84 80
100 83 72 80
96 100 88 50
91 100 66 –– *
90 100
84 100
95 90
95 81
89 96
84 90
90 92
90 85
81 100
81 92
83 97
77 92
0.013
0.22
100 61 39 53
92 85 50 80
87 68 0 –– *
84 75
69 75
95 76
89 59
83 82
71 67
80 83
67 70
71 91
61 76
77 86
56 79
0.0011
0.94
0.16
0.43
0.98
0.12
0.57
p 0.0045
0.76
0.14
0.85
100 75 66 100
0.30
0.83
0.21
69
0.16
0.05
0.78
5-yr
83
0.34
0.19
0.13
2-yr
⬍0.00019
0.18
0.22
p 0.079
⬍0.0001
0.0046
Dissemination Control
0.022
0.24
0.17
*Not assessable.
survival and pleural-dissemination control rates were 80 and 66%, respectively, at 3 years. Table 4 summarizes 2- and 5-year survival and control rates according to various prognostic and treatment factors. Overall, Masaoka stage and resectability appeared to be associated with patient prognosis, whereas the other factors did not. In 52 patients receiving MRT alone initially, radiation pneumonitis was grade 3 in one patient, grade 2 in two, and grade 1 in 25. In eight patients receiving EHRT and MRT initially, radiation pneumonitis was grade 4 in one patient, grade 2 in one, and grade 1 in four. In 12 patients undergoing EBRT (including four patients receiving EBRT at intervals after MRT), radiation pneumonitis was grade 4 in one patient, grade 2 in two, and grade 1 in seven. One patient receiving approximately 40 Gy to the spinal cord developed radiation myelopathy. No patient died of adverse effects of radiotherapy.
DISCUSSION Although invasive thymomas are relatively common among mediastinal tumors, their incidence is generally low, and so it is difficult to carry out prospective randomized studies on treatment of invasive thymoma with sufficient
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numbers of patients. We therefore evaluated the efficacy of radiation therapy retrospectively. Masaoka stage and the extent of surgical resection are known to be associated with patient prognosis.1,4,5 In all 60 patients in our study, Masaoka stage and tumor resectability were associated with overall survival rates. Pleural-dissemination control rate was also dependent on Masaoka stage in 52 patients undergoing MRT alone as initial radiotherapy. After MRT, we have obtained favorable survival and local control rates. Local control was excellent in patients with grade A or B resectability, and it was also fair in those with grade C resectability (highly-suspected macroscopic residuals). Overall and cause-specific survival rates for all stages of thymoma patients in the present study compare favorably with those reported previously5,6,13 In view of the acceptable toxicity after MRT, our results would support the usefulness of MRT in the multidisciplinary treatment of thymoma. In completely resected stage I–II thymoma, however, a few studies suggested that radiation therapy might not be necessary.17,18 Although our results of postoperative MRT in stage I–II patients including those with grade B respectability are not inferior to those obtained by surgery alone,17,18
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Journal of Thoracic Oncology • Volume 3, Number 1, January 2008
A
Invasive Thymoma and Patients with Pleural Dissemination
B
(%) 100
(%) 100
80
80
60
60
40
40
Stage I-II
Stage I-II
Stage III
20
Stage III
20
Stage IVa Stage IVb
0
Stage IVa Stage IVb
P =0.16 0
0
50
100
150
0
200
C
P =0.046
50
100
150
200
D (%)
(%) 100
100
80
80
60
60 Stage I-II
40
40
Stage I-II
Stage III
Stage III
20
Stage IVa
20
Stage IVb
Stage IVa
P =0.015
P = 0.0017
Stage IVb
0
0 0
50
100 Time (months)
150
0
200
A
50
100 Time (months)
150
200
FIGURE 3. Overall survival (A), cause-specific survival (B), local control (C), and pleural-dissemination control (D) curves for patients undergoing MRT as an initial radiation treatment (n ⫽ 52).
B
(%) 100
(%) 100
80
80
60
60
40
40 EHRT+MRT
20 0 0
20
EHRT+MRT
20
MRT
P = 0.63
0 40
60
80
100
120
140
160
180
C
MRT
P = 0.71 0
20
40
60
80
100
120
140
160
180
D
(%) 100
(%) 100
80
80
EHRT+MRT
60
60
MRT
40
40 EHRT+MRT
20
20
MRT
P =0.11 0
P = 0.38
0 0
20
40
60
80
100
Time (months)
120
140
160
180
0
20
40
60
80
Time (months)
Copyright © 2007 by the International Association for the Study of Lung Cancer
100
120
FIGURE 4. Overall survival (A), cause-specific survival (B), local control (C), and pleural-dissemination control (D) curves for stage IVa patients undergoing MRT (n ⫽ 12) or MRT ⫹ EHRT (n ⫽ 7).
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(%) 100
tion). The fact that one of the patients receiving EHRT developed severe radiation pneumonitis indicates safer treatment is more ideal. Moreover, recent studies cautioned the risk of radiation pneumonitis when large volumes of lungs were irradiated with relatively low doses.23–25 So we are planning “whole pleural radiation ” with an intensity-modulated radiation therapy technique26 using helical tomotherapy27 to reduce the lung dose, in place of EHRT.
80 60 40
CONCLUSIONS Overall survival
20
Dissemination control rate
0 0
20
40
60 80 Time (months)
100
120
140
FIGURE 5. Overall survival and pleural dissemination control curves for patients undergoing EHRT (n ⫽ 12).
the role of MRT should be further clarified in this group of patients. EHRT appeared to be feasible in terms of safety. In 12 patients who received EHRT, one patient developed grade 4 radiation pneumonitis, but this appeared to be in part related to operative procedure. The remaining 11 patients did not have severe complications. No patients died of complications after EHRT. Uematsu et al.9,10 reported the safety of EHRT with 10 to 16 Gy in 10 to 16 fractions. In the present study, EHRT with doses up to 15 Gy given in 10 fractions seems to be generally safe. Uematsu et al.9,10 reported 100% relapsefree survival at 3 years after EHRT plus MRT in stage II or III patients. Although most of our 12 patients undergoing EHRT had pleural dissemination, they had a relatively high pleural-dissemination control rate of 66% at 3 years after EHRT. Although it is difficult to draw definite conclusions from the present study comprising the small patient number, it may be possible that EHRT contributes to improved dissemination control rates when it is given after macroscopic total removal of disseminated lesions. Combined multidisciplinary treatment of advanced thymomas is a topic in recent years. Several studies indicate that induction chemotherapy to optimize surgical resectability and consolidation chemotherapy to control residual disease may improve the prognosis of patients with advanced thymomas.1,2,19 –22 In the present study, EHRT appeared to play a role in eradicating pleural dissemination in patients with stage IVa thymoma, but the patients who received EHRT did not undergo intensive chemotherapy. Cure may be achieved more effectively in patients with pleural dissemination when EHRT plus MRT and induction or consolidation chemotherapy are given in combination with surgery. However, it is feared that the risk of severe complications might increase in patients who undergo both EHRT and chemotherapy. Therefore, we suggest that patients who should undergo EHRT and induction or consolidation chemotherapy need to be selected carefully by applying eligibility criteria (e.g., age, performance status, adequate bone marrow reserve, liver and renal func-
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Postoperative MRT appeared to play a role in preventing local recurrence with acceptable toxicity. EHRT with doses up to 15 Gy appeared to be generally safe, but caution should be made with respect to occurrence of high-grade toxicity. EHRT may possibly improve outcome for stage IVa disease or recurrence with pleural dissemination. We will try to clarify in future collaborative studies whether EHRT contributes to control of pleural dissemination and improvement of survival rate. It is expected that new radiation technique like intensity-modulated radiation therapy would improve the outcome by increasing the dose and reducing the possibility of radiation pneumonitis. At present, we recommend EHRT for patients with nonextensive dissemination and good postoperative pulmonary function in the combined multidisciplinary treatment. REFERENCES 1. Bretti S, Berutti A, Loddo C, et al. Multimodal management of stages III–IVa malignant thymoma. Lung Cancer 2004;44:69 –77. 2. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 2004;44:369 –379. 3. Rena O, Papalia E, Maggi G, et al. World health organization histologic classification: an independent prognostic factor in resected thymomas. Lung Cancer 2005;50:59 – 66. 4. Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48: 2485–2492. 5. Wilkins KB, Sheikh E, Green R, et al. Clinical and pathologic predictors of survival in patients with thymoma. Ann Surg 1999;230:562–574. 6. Strobel P, Bauer A, Puppe B, et al. Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol 2004;22:1501–1509. 7. Pollack A, Komaki R, Cox JD, et al. Thymoma: treatment and prognosis. Int J Radiat Oncol Biol Phys 1992;23:1037–1043. 8. Urgesi A, Monetti U, Rossi G, et al. Role of radiation therapy in locally advanced thymoma. Radiother Oncol 1990;19:273–280. 9. Uematsu M, Yoshida H, Kondo M, et al. Entire hemithorax irradiation following complete resection in patients with stage II–III invasive thymoma. Int J Radiat Oncol Biol Phys 1996;35:357–360. 10. Uematsu K, Kondo M. A proposal for treatment of invasive thymoma. Cancer 1986:1979 –1984. 11. Ariaratnam LS, Kalnicki S, Mincer F, et al. The management of malignant thymoma with radiation therapy. Int J Radiat Oncol Biol Phys 1979;5:77– 80. 12. Evans WK, Thompson DM, Simpson WJ, et al. Combination chemotherapy in invasive thymoma. Cancer 1980;46:1523–1527. 13. Zhu G, He S, Fu X, et al. Radiotherapy and prognostic factors for thymoma: a retrospective study of 175 patients. Int J Radiat Oncol Biol Phys 2004;60:1113–1119. 14. Bernatz PE, Harrison EG, Clagett OT. Thymoma: a clinicopathologic study. J Thorac Cardiovasc Surg 1961;42:424 – 444. 15. Kondo K, Yoshizawa K, Tsuyuguchi M, et al. WHO histologic classi-
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fication is a prognostic indicator in thymoma. Ann Thorac Surg 2004; 77:1183–1188. Refaely Y, Simansky DA, Paley M, et al. Resection and perfusion thermochemotherapy: a new approach for the treatment of thymic malignancies with pleural spread. Ann Thorac Surg 2001;72:366 –370. Singhal S, Shrager JB, Rosenthal DI, et al. Comparison of stages I–II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg 2003;76:1635–1641. 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;31:109 –113. Yokoi K, Matsunaga H, Nakahara R, et al. Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J Thorac Oncol 2007;2:73–78. Lucchi M, Melfi F, Dini P, et al. Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up. J Thorac Oncol 2006;1:308 –313. Loehrer PJ, Kim KM, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. J Clin Oncol 1994;12:1164 –1168.
Invasive Thymoma and Patients with Pleural Dissemination
22. Lucchi M, Ambrogi MC, Duranti L, et al. Advanced stage thymomas and thymic carcinomas: results of multimodality treatments. Ann Thorac Surg 2005;79:1840 –1844. 23. Allen AM, Czerminska M, Janne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys. 2006;65:640 – 645 24. Yorke ED, Jackson A, Rosenzweig KE, et al. Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study. Int J Radiat Oncol Biol Phys 2005;63:672– 682. 25. Seppenwoolde Y, Lebesque JV, Jaeger KD, et al. Comparing different NTCP models that predict the incidence of radiation pneumonitis. Int J Radiat Oncol Biol Phys 2003;55:724 –735. 26. Zhu XR, Prado K, Liu HH, et al. Intensity-modulated radiation therapy for mesothelioma: impact of multileaf collimator leaf width and pencil beam size on planning quality and delivery efficiency. Int J Radiat Oncol Biol Phys 2005;62:1525–1534. 27. Florino C, Dell’Oca I, Pierelli A, et al. Significant improvement in normal tissue sparing and target coverage for head and neck cancer by means of helical tomotherapy. Radiother Oncol 2006;78:276 –282.
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Invasive Thymoma: Postoperative Mediastinal Irradiation, and Low-Dose Entire Hemithorax Irradiation in Patients with Pleural Dissemination Chikao Sugie, MD,* Yuta Shibamoto, MD, PhD,* Chisa Ikeya-Hashizume, MD,* Hiroyuki Ogino, MD,* Shiho Ayakawa, MD,* Natsuo Tomita, MD,* Fumiya Baba, MD,* Hiromitsu Iwata, MD,* Masato Ito, MD,* and Kyota Oda, MD†
Introduction: We evaluated the results of postoperative mediastinal radiotherapy (MRT) for invasive thymoma and low-dose entire hemithorax radiotherapy (EHRT) for pleural dissemination. Methods: Sixty patients were treated with a nearly uniform policy. Generally, we administered 30 to 40 Gy MRT after surgery at 2 Gy daily fractions for Masaoka stage II tumors or suspected residual diseases, and 50 to 55 Gy MRT for stage III tumors and for highlysuspected or macroscopic residual diseases. Since 1992, we have administered EHRT in patients with pleural dissemination, with 11.2 Gy in 7 fractions or 15 to 16 Gy in 10 fractions after removal of disseminated lesions in addition to MRT. We treated 52 patients with MRT alone and 8 with EHRT and MRT. In addition, we gave EHRT to four patients who developed pleural dissemination later. Results: For all 60 patients, the overall and cause-specific survival and local and pleural-dissemination control rates at 5 years were 79, 87, 86, and 69%, respectively. Both Masaoka stage and tumor resectability were associated with prognosis. In stage IVa patients, pleural dissemination control rate was 71% at 3 years after EHRT, whereas it was 49% in patients receiving MRT alone (p ⫽ 0.38). Grade 2 or higher radiation pneumonitis was observed in only 3 of 52 patients (5.8%) undergoing MRT initially. In 12 patients who underwent EHRT, 3 patients (25%) experienced grade 2 or 4 pneumonitis. Conclusions: Postoperative MRT appeared to prevent local recurrence with acceptable toxicity. EHRT is generally safe and may contribute to control of pleural dissemination. Key Words: Invasive thymoma, Mediastinal radiotherapy, Entire hemithorax radiotherapy, Pleural dissemination. (J Thorac Oncol. 2008;3: 75–81) *Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan; and †Department of Radiology, Hokuto Hospital, Obihiro, Hokkaido, Japan. Disclosure: The authors declare no conflict of interest. Address for correspondence to: Chikao Sugie, MD, Department of Radiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 Japan. E-mail: [email protected] Copyright © 2007 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0301-0075
T
hymomas deriving from the epithelial cells within the thymic gland are pathologically benign but biologically aggressive,1–3 and so multidisciplinary treatment is often considered necessary. The treatment strategy has often been chosen based on the staging system proposed by Masaoka et al.4,5 The Masaoka stage (shown in Table 1) is considered one of the most important factors predicting prognosis.6 Masaoka stage I–II thymomas are associated with excellent prognosis, and stage III thymoma patients also have favorable prognosis.3 On the other hand, stage IVa patients have poor prognosis because of the difficulty in performing complete resection and giving wide-field radiation therapy. Another important factor predicting survival seems to be the extent of surgery.1,5 Recently, several studies have shown that induction chemotherapy for increasing tumor resectability may improve the prognosis of advanced thymoma patients.1,2 Thymoma is known as a relatively radiosensitive neoplasm, and there seems to be a general agreement that postoperative mediastinal radiotherapy (MRT) should be used in the treatment of invasive thymoma.7,8 For the purpose of improving survival and local control rates in invasive thymomas, we have used postoperative MRT in patients with Masaoka stage II–IVb thymoma, in combination with low-dose entire hemithorax radiotherapy (EHRT) in patients with pleural dissemination. EHRT has been suggested to be a therapeutic and prophylactic radiotherapy technique against pleural dissemination. Uematsu et al.9,10 treated 23 patients with stage II or III thymoma with EHRT plus MRT, and obtained excellent 5-year relapse-free and overall survival rates when compared with those obtained by MRT alone, advocating the efficacy of EHRT. However, there are very few other reports on EHRT, and there have been no prospective studies evaluating EHRT.8 –13 Therefore, the role of EHRT seems to remain controversial. In this study, we investigated the results of treatment in patients who received MRT or MRT plus EHRT at our institution.
PATIENTS AND METHODS Patients A total of 60 patients with thymoma were treated with an almost uniform policy regarding radiotherapy in our insti-
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TABLE 1. Masaoka Stage Stage I Stage II
Stage III Stage IVa Stage IVb
Macroscopically completely encapsulated and microscopically nocapsular invasion 1. Macroscopic invasion into surrounding fatty tissue or mediastinal pleura, or 2. Microscopic invasion into capsule Macroscopic invasion into neighboring organ, ie pericardium, great vessels, or lung Pleural or pericardial dissemination Lymphogenous or hematogenous metastasis
tution between November 1987 and August 2005. There were 23 (38%) men and 37 (62%) women, with a median age of 54 years (range, 21–79 years). We determined Masaoka stage from findings of preoperative computed tomography and pathology at surgery. The stage was I or II in 19 (32%) patients, III in 16 (27%), IVa in 19 (32%), and IVb in 6 (10%). The histopathologic subtype according to the system proposed by Bernatz et al.14 was available in 50 patients, and the subtype according to the new World Health Organization classification proposed in 20003,15 was available in 25. In three patients, no histologic subtype was obtained. The median follow-up term was 56 months (range, 1–209 months).
Treatment Radiation therapy was delivered five times a week after Masaoka stage, histopathologic classification and tumor resectability were confirmed by either surgical resection or biopsy. Tumor resectability was defined as shown in Table 2 from grade A (complete resection) to D (biopsy only). The resectability was grade A in 25 (42%) patients, grade B in 20 (33%), grade C in 9 (15%), and grade D in 6 (10%). All
TABLE 2. Tumor Resectability Grade Grade Grade Grade
A B C D
Completely resected Microscopic residual lesion highly suspected Macroscopic residual lesion highly suspected Biopsy only
patients received MRT, without or in combination with EHRT. The radiation doses of MRT were 30 to 40 Gy in 15 to 20 fractions for stage I or II patients, 40 to 46 Gy in 20 to 23 fractions for patients with highly-suspected microscopic residuals, 46 to 50 Gy in 23 to 25 fractions for highlysuspected macroscopic residual diseases, and 50 to 64 Gy in 25 to 32 fractions for gross residual diseases. The average dose of MRT was 41.4 Gy (range, 30 – 64 Gy). EHRT was performed in a total of 12 patients seen in 1992 or later. EHRT was performed after surgical resection of disseminated lesions immediately before or after MRT in seven stage IVa patients with highly-suspected microscopic or macroscopic residuals. Moreover, in one patient with stage II thymoma, whose tumor ruptured into the thoracic cavity during surgery, EHRT was performed before MRT. EHRT was given subsequently against recurrence with pleural dissemination in four initially stage III or IVa patients who had received MRT previously; three initially stage IVa patients received EHRT after surgical removal of the disseminated lesions, and one initially stage III patient received EHRT, followed by boosts to the two disseminated lesions (total 60 Gy) without surgical resection; thus, the pleural disease before EHRT was macroscopic only in this patient, and it was microscopic in the remaining 11 patients. The EHRT dose was 11.2 Gy in 7 fractions in two patients, 15 Gy in 10 fractions in nine, and 16 Gy in 10 fractions in one, with an average dose of 14.1 Gy. These EHRT doses were determined considering the tolerance of the lung and taking previous reports into account.8 –13 We considered that these relatively low doses of radiation would be efficient when the residual tumor cell number was small. For the 12 patients undergoing EHRT, an average total dose to the mediastinum was 44 Gy (range, 30 – 64 Gy). Figure 1 shows representative radiation fields for MRT and EHRT. In 54 patients undergoing tumor resection, 19 (35%) had preoperative corticosteroid therapy, 11 (20%) had postoperative steroid therapy, 3 (6%) had preoperative chemotherapy, 18 (33%) had intraoperative perfusion thermochemotherapy,16 and 3 (6%) had postoperative chemotherapy. In six patients undergoing only biopsy, five (83%) had steroid
FIGURE 1. Representative radiation fields of mediastinal radiotherapy [MRT, (A)] and entire hemithorax radiotherapy [EHRT, (B)].
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Journal of Thoracic Oncology • Volume 3, Number 1, January 2008
therapy, and four (67%) had chemotherapy. Table 3 shows clinical and treatment characteristics of the 60 patients.
Evaluation Overall and relapse-free survival rates and local and pleural-dissemination control rates were calculated from the date of starting radiation therapy. In four patients who received EHRT against pleural dissemination developing after MRT, the time to progression and survival period were respectively measured from the dates of the first MRT and secondary EHRT. Overall and cause-specific survival rates,
TABLE 3. Patient Characteristics Total No. of patients Age (yr) median (range) Gender (male/female) Masaoka stage I, II/III/IVa/IVb Tumor respectability Grade A/B/C/D Myasthenia gravis (Yes/No) Histology Bernatz classification Lymphocytic/ Epithelial Mixed/Spindled/ Unknown WHO classification A/AB/B1/B2/B3/ Unknown Steroid administration Yes/No Chemotherapy Yes/No
HERT ⴙ MRT
MRT
60 54 (21–79) 23/37
52 55 (21–79) 20/32
8 49 (33–63) 3/5
19/16/19/6
18/16/12/6
1/0/7/0
25/20/9/6 10/50
25/15/6/6 9/43
0/5/3/0 1/7
24/5/20/1/10
21/3/17/1/10
3/2/3/0/0
0/2/5/16/2/35
0/2/4/13/0/33
0/0/1/3/2/2
27/33
21/31
6/2
24/36
21/31
3/5
A
B
(%)
100
80
80
80
60
60
60
40
40
40
20
Stage I-II Stage III 20
A
Stage IVa
C
0
50 100 150 Time (months)
B
Stage IVb
P = 0.0046
0 200
0
RESULTS For all 60 patients, the overall survival rate was 79% and the cause-specific survival rate was 87% at 5 years. The local control rate was 86% and pleural-dissemination control rate was 69% at 5 years. Figure 2 shows overall survival curves according to Masaoka stage, tumor resectability, and radiation field (MRT alone or MRT plus EHRT). Overall survival rates differed with Masaoka stage and tumor resectability (p ⫽ 0.048 and 0.0046, respectively), but not with the radiation field. Respective 2- and 5-year survival rates are shown in Table 4. Figure 3 shows survival and local and pleural-dissemination control rates according to Masaoka stage in 52 patients initially receiving MRT alone. For all 52 patients, the 5-year overall and cause-specific survival rates were 80 and 87%, respectively, and local and pleural-dissemination control rates were 84 and 69%, respectively. Cause-specific survival and local and pleural-dissemination control rates differed significantly with Masaoka stage. Figure 4 shows survival and local and dissemination control rates according to the use of EHRT as an initial treatment for stage IVa patients. The pleural-dissemination control rate was relatively high (71% at 3 years) in patients undergoing EHRT, when compared with 49% in those receiving MRT alone, although the difference was not significant (p ⫽ 0.38). Also, overall and cause-specific survival and local control rates did not differ significantly between the two groups. Figure 5 shows overall survival and pleural-dissemination control curves for 12 patients undergoing EHRT. The rates were calculated from the date of starting EHRT. Overall
(%)
100
P = 0.048
local control rate, and dissemination control rate were calculated by the Kaplan–Meier method and differences between these rates were examined using the log-rank test. Radiation pneumonitis was classified according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer acute radiation morbidity scoring criteria using computed tomography in all cases.
C
(%)
100
0
Invasive Thymoma and Patients with Pleural Dissemination
50 100 150 Time (months)
EHRT+MRT
20
MRT
D
P = 0.31
0 200
0
50 100 150 Time (months)
200
Copyright © 2007 by the International Association for the Study of Lung Cancer
FIGURE 2. Overall survival curves according to Masaoka stage (A), tumor resectability (B), and radiation field (with or without EHRT) (C) (n ⫽ 60).
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TABLE 4. Survival and Control Rates (%) Overall Survival
Total Masaoka Stage I–II III IVa IVb Tumor resectability A B C D Initial radiation MRT only EHRT⫹MRT Age (yr) ⱖ60 ⬍60 Gender Female Male Myasthenia gravis Yes No Steroid administration Yes No Chemotherapy Yes No
n
2-yr
5-yr
60
95
79
19 16 19 6
100 100 90 83
94 82 64 63
25 20 9 6
96 100 89 83
78 94 76 –– *
52 8
94 100
80 71
21 39
91 97
70 83
37 23
95 96
74 85
10 50
100 94
88 77
27 33
89 100
63 89
24 36
92 97
78 79
p
Cause-specific Survival 2-yr
5-yr
98
87
100 100 95 100
100 89 73 75
100 100 100 83
89 100 86 –– *
98 100
87 83
100 97
92 83
97 100
82 94
100 98
100 84
96 100
72 96
96 100
81 91
0.048
p
Local Control 2-yr
5-yr
92
86
100 94 84 80
100 83 72 80
96 100 88 50
91 100 66 –– *
90 100
84 100
95 90
95 81
89 96
84 90
90 92
90 85
81 100
81 92
83 97
77 92
0.013
0.22
100 61 39 53
92 85 50 80
87 68 0 –– *
84 75
69 75
95 76
89 59
83 82
71 67
80 83
67 70
71 91
61 76
77 86
56 79
0.0011
0.94
0.16
0.43
0.98
0.12
0.57
p 0.0045
0.76
0.14
0.85
100 75 66 100
0.30
0.83
0.21
69
0.16
0.05
0.78
5-yr
83
0.34
0.19
0.13
2-yr
⬍0.00019
0.18
0.22
p 0.079
⬍0.0001
0.0046
Dissemination Control
0.022
0.24
0.17
*Not assessable.
survival and pleural-dissemination control rates were 80 and 66%, respectively, at 3 years. Table 4 summarizes 2- and 5-year survival and control rates according to various prognostic and treatment factors. Overall, Masaoka stage and resectability appeared to be associated with patient prognosis, whereas the other factors did not. In 52 patients receiving MRT alone initially, radiation pneumonitis was grade 3 in one patient, grade 2 in two, and grade 1 in 25. In eight patients receiving EHRT and MRT initially, radiation pneumonitis was grade 4 in one patient, grade 2 in one, and grade 1 in four. In 12 patients undergoing EBRT (including four patients receiving EBRT at intervals after MRT), radiation pneumonitis was grade 4 in one patient, grade 2 in two, and grade 1 in seven. One patient receiving approximately 40 Gy to the spinal cord developed radiation myelopathy. No patient died of adverse effects of radiotherapy.
DISCUSSION Although invasive thymomas are relatively common among mediastinal tumors, their incidence is generally low, and so it is difficult to carry out prospective randomized studies on treatment of invasive thymoma with sufficient
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numbers of patients. We therefore evaluated the efficacy of radiation therapy retrospectively. Masaoka stage and the extent of surgical resection are known to be associated with patient prognosis.1,4,5 In all 60 patients in our study, Masaoka stage and tumor resectability were associated with overall survival rates. Pleural-dissemination control rate was also dependent on Masaoka stage in 52 patients undergoing MRT alone as initial radiotherapy. After MRT, we have obtained favorable survival and local control rates. Local control was excellent in patients with grade A or B resectability, and it was also fair in those with grade C resectability (highly-suspected macroscopic residuals). Overall and cause-specific survival rates for all stages of thymoma patients in the present study compare favorably with those reported previously5,6,13 In view of the acceptable toxicity after MRT, our results would support the usefulness of MRT in the multidisciplinary treatment of thymoma. In completely resected stage I–II thymoma, however, a few studies suggested that radiation therapy might not be necessary.17,18 Although our results of postoperative MRT in stage I–II patients including those with grade B respectability are not inferior to those obtained by surgery alone,17,18
Copyright © 2007 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 3, Number 1, January 2008
A
Invasive Thymoma and Patients with Pleural Dissemination
B
(%) 100
(%) 100
80
80
60
60
40
40
Stage I-II
Stage I-II
Stage III
20
Stage III
20
Stage IVa Stage IVb
0
Stage IVa Stage IVb
P =0.16 0
0
50
100
150
0
200
C
P =0.046
50
100
150
200
D (%)
(%) 100
100
80
80
60
60 Stage I-II
40
40
Stage I-II
Stage III
Stage III
20
Stage IVa
20
Stage IVb
Stage IVa
P =0.015
P = 0.0017
Stage IVb
0
0 0
50
100 Time (months)
150
0
200
A
50
100 Time (months)
150
200
FIGURE 3. Overall survival (A), cause-specific survival (B), local control (C), and pleural-dissemination control (D) curves for patients undergoing MRT as an initial radiation treatment (n ⫽ 52).
B
(%) 100
(%) 100
80
80
60
60
40
40 EHRT+MRT
20 0 0
20
EHRT+MRT
20
MRT
P = 0.63
0 40
60
80
100
120
140
160
180
C
MRT
P = 0.71 0
20
40
60
80
100
120
140
160
180
D
(%) 100
(%) 100
80
80
EHRT+MRT
60
60
MRT
40
40 EHRT+MRT
20
20
MRT
P =0.11 0
P = 0.38
0 0
20
40
60
80
100
Time (months)
120
140
160
180
0
20
40
60
80
Time (months)
Copyright © 2007 by the International Association for the Study of Lung Cancer
100
120
FIGURE 4. Overall survival (A), cause-specific survival (B), local control (C), and pleural-dissemination control (D) curves for stage IVa patients undergoing MRT (n ⫽ 12) or MRT ⫹ EHRT (n ⫽ 7).
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(%) 100
tion). The fact that one of the patients receiving EHRT developed severe radiation pneumonitis indicates safer treatment is more ideal. Moreover, recent studies cautioned the risk of radiation pneumonitis when large volumes of lungs were irradiated with relatively low doses.23–25 So we are planning “whole pleural radiation ” with an intensity-modulated radiation therapy technique26 using helical tomotherapy27 to reduce the lung dose, in place of EHRT.
80 60 40
CONCLUSIONS Overall survival
20
Dissemination control rate
0 0
20
40
60 80 Time (months)
100
120
140
FIGURE 5. Overall survival and pleural dissemination control curves for patients undergoing EHRT (n ⫽ 12).
the role of MRT should be further clarified in this group of patients. EHRT appeared to be feasible in terms of safety. In 12 patients who received EHRT, one patient developed grade 4 radiation pneumonitis, but this appeared to be in part related to operative procedure. The remaining 11 patients did not have severe complications. No patients died of complications after EHRT. Uematsu et al.9,10 reported the safety of EHRT with 10 to 16 Gy in 10 to 16 fractions. In the present study, EHRT with doses up to 15 Gy given in 10 fractions seems to be generally safe. Uematsu et al.9,10 reported 100% relapsefree survival at 3 years after EHRT plus MRT in stage II or III patients. Although most of our 12 patients undergoing EHRT had pleural dissemination, they had a relatively high pleural-dissemination control rate of 66% at 3 years after EHRT. Although it is difficult to draw definite conclusions from the present study comprising the small patient number, it may be possible that EHRT contributes to improved dissemination control rates when it is given after macroscopic total removal of disseminated lesions. Combined multidisciplinary treatment of advanced thymomas is a topic in recent years. Several studies indicate that induction chemotherapy to optimize surgical resectability and consolidation chemotherapy to control residual disease may improve the prognosis of patients with advanced thymomas.1,2,19 –22 In the present study, EHRT appeared to play a role in eradicating pleural dissemination in patients with stage IVa thymoma, but the patients who received EHRT did not undergo intensive chemotherapy. Cure may be achieved more effectively in patients with pleural dissemination when EHRT plus MRT and induction or consolidation chemotherapy are given in combination with surgery. However, it is feared that the risk of severe complications might increase in patients who undergo both EHRT and chemotherapy. Therefore, we suggest that patients who should undergo EHRT and induction or consolidation chemotherapy need to be selected carefully by applying eligibility criteria (e.g., age, performance status, adequate bone marrow reserve, liver and renal func-
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Postoperative MRT appeared to play a role in preventing local recurrence with acceptable toxicity. EHRT with doses up to 15 Gy appeared to be generally safe, but caution should be made with respect to occurrence of high-grade toxicity. EHRT may possibly improve outcome for stage IVa disease or recurrence with pleural dissemination. We will try to clarify in future collaborative studies whether EHRT contributes to control of pleural dissemination and improvement of survival rate. It is expected that new radiation technique like intensity-modulated radiation therapy would improve the outcome by increasing the dose and reducing the possibility of radiation pneumonitis. At present, we recommend EHRT for patients with nonextensive dissemination and good postoperative pulmonary function in the combined multidisciplinary treatment. REFERENCES 1. Bretti S, Berutti A, Loddo C, et al. Multimodal management of stages III–IVa malignant thymoma. Lung Cancer 2004;44:69 –77. 2. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 2004;44:369 –379. 3. Rena O, Papalia E, Maggi G, et al. World health organization histologic classification: an independent prognostic factor in resected thymomas. Lung Cancer 2005;50:59 – 66. 4. Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48: 2485–2492. 5. Wilkins KB, Sheikh E, Green R, et al. Clinical and pathologic predictors of survival in patients with thymoma. Ann Surg 1999;230:562–574. 6. Strobel P, Bauer A, Puppe B, et al. Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol 2004;22:1501–1509. 7. Pollack A, Komaki R, Cox JD, et al. Thymoma: treatment and prognosis. Int J Radiat Oncol Biol Phys 1992;23:1037–1043. 8. Urgesi A, Monetti U, Rossi G, et al. Role of radiation therapy in locally advanced thymoma. Radiother Oncol 1990;19:273–280. 9. Uematsu M, Yoshida H, Kondo M, et al. Entire hemithorax irradiation following complete resection in patients with stage II–III invasive thymoma. Int J Radiat Oncol Biol Phys 1996;35:357–360. 10. Uematsu K, Kondo M. A proposal for treatment of invasive thymoma. Cancer 1986:1979 –1984. 11. Ariaratnam LS, Kalnicki S, Mincer F, et al. The management of malignant thymoma with radiation therapy. Int J Radiat Oncol Biol Phys 1979;5:77– 80. 12. Evans WK, Thompson DM, Simpson WJ, et al. Combination chemotherapy in invasive thymoma. Cancer 1980;46:1523–1527. 13. Zhu G, He S, Fu X, et al. Radiotherapy and prognostic factors for thymoma: a retrospective study of 175 patients. Int J Radiat Oncol Biol Phys 2004;60:1113–1119. 14. Bernatz PE, Harrison EG, Clagett OT. Thymoma: a clinicopathologic study. J Thorac Cardiovasc Surg 1961;42:424 – 444. 15. Kondo K, Yoshizawa K, Tsuyuguchi M, et al. WHO histologic classi-
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