- Email: [email protected]
Multimodality Therapy for Locally Advanced Thymomas: State of the Art or Investigational Therapy?
EDITORIAL
Multimodality Therapy for Locally Advanced Thymomas: State of the Art or Investigational Therapy? James Huang, MD, Gregory J. Riely, MD, Kenneth E. Rosenzweig, MD, and Valerie W. Rusch, MD Thoracic Service, Department of Surgery, Thoracic Oncology Service, Department of Medicine, and Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
B
ecause thymic tumors are uncommon and can have a relatively indolent course, there is debate regarding the optimal treatment for patients with these tumors. Our management of patients with thymic tumors has been derived from a small, retrospective series of patients given heterogeneous treatments. Early stage and complete resection are consistently associated with better outcomes [1, 2]. Surgical resection is recommended as the first, and often only, therapy in most patients with a well-circumscribed thymic tumor that is clearly resectable. The optimal management of locally advanced thymic tumors that invade the adjacent organs or have spread to the pleural space is less clear. See page 385 In this issue, Wright and colleagues [3] reviewed their experience with 10 patients who had Masaoka stage III or IVA thymomas or thymic carcinomas and who were treated over a 10-year period with preoperative concurrent chemoradiation followed by resection. Using an induction regimen of cisplatin and etoposide with concurrent radiation, they were able to achieve an impressive R0 resection rate of 80%, with no postoperative mortalities and a 5-year estimated overall survival of 69%. A 40% radiographic partial response rate was observed in these 10 patients who completed all of the therapy. Induction chemotherapy with a variety of chemotherapy regimens given without concurrent RT for treatment of locally advanced thymic tumors has been reported by a number of groups. Resectability rates in these series have ranged from 25% to 76%, and survival rates have been reported to be as high as 90% at 10 years [4 –7]. The rate of pathologic complete responses averaged just 13%. Similarly, at least two prospective studies of preoperative chemotherapy have been reported resulting in a 57% to 76% R0 resection rate and up to a 95%, 5-year survival [8]. This report by Wright and colleagues is the first to examine induction therapy with both chemotherapy and radiation. Because thymic tumors are sensitive to both chemotherapy and radiation, it is reasonable to expect a Address correspondence to Dr Rusch, Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room C-868, New York, NY 10021; e-mail: [email protected].
© 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
higher response rate and a potentially higher rate of complete resections using this combined approach. Induction chemoradiation using similar chemotherapy regimens have been studied and have shown to be feasible in the management of stage III nonsmall cell lung cancer [9, 10]. However, preoperative chemoradiation can limit treatment in important ways. By combining with radiation, the type of chemotherapy given and the dose delivered are often altered. Giving combined chemotherapy and radiation therapy also increases toxicity. Finally, there is an increased risk of morbidity associated with surgery in an irradiated field. A major complication of acute respiratory distress syndrome in 1 patient in this series seems directly attributable to the combined induction therapy. The authors concede that in cases of large tumors that are greater than 15 cm, withholding preoperative radiation may be appropriate to minimize pulmonary toxicity. Achieving a complete resection remains the key to treatment, and the possibility of extended resections including caval resection or even extrapleural pneumonectomy should not deter surgeons from doing so, if that is what is necessary to obtain a R0 resection in the appropriate patient. Thymoma patients are usually younger and more fit than patients with lung or esophageal cancer, and they can often tolerate intensive multimodality therapy and extended resections safely. One series reported 12 resections of thymomas invading the superior vena cava without any significant morbidity or mortality and confirmed that complete resection remained the most significant prognosticating factor [11]. Given the extent of these tumors, optimal exposure often requires more than the standard sternotomy, and a hemi-clamshell or even clamshell approach may provide the best access. Stage IVa thymomas offer a particularly difficult challenge. Despite the presence of disease metastatic to the pleura, these lesions are still oftentimes amenable to resection. In cases of extensive pleural disease, several institutions including the authors and our own have now reported small series of extrapleural pneumonectomy for stage IVa disease with excellent outcomes and low morbidity [12, 13]. In cases requiring a concomitant extrapleural pneumonectomy, our institution has used a sternotomy for the mediastinal dissection, followed imAnn Thorac Surg 2008;85:365–7 • 0003-4975/08/$34.00 doi:10.1016/j.athoracsur.2007.10.098
366
EDITORIAL HUANG ET AL MULTIMODALITY THERAPY FOR LOCALLY ADVANCED THYMOMAS
mediately by a posterolateral thoracotomy for the pleural component with good success. The use of induction chemoradiotherapy not only limits dose of induction chemotherapy, but also the ability to give radiation in the adjuvant setting, which may be more critical in the event of incomplete resections. Although the authors report an 80% R0 resection rate, 70% of the patients subsequently received postoperative chemotherapy due to close margins or high grade tumor histology. Would some of these patients have received adjuvant radiation instead had they not already been radiated? The median follow-up in this series was about 3.5 years. Long-term follow-up is required, as late recurrences are a known factor in thymic tumors with relapses occurring as late as 7 years after treatment or more [14, 15]. Despite the sensitivity of thymoma to radiation, the best use of radiotherapy remains controversial. In the preoperative setting, radiation offers potential synergism with concurrent induction chemotherapy, but at the expense of increased toxicity and surgical morbidity. In the postoperative setting, there remains no consensus on whether or not adjuvant radiation is of any benefit in completely resected thymoma. Most recurrences occur locally in the pleural space [12] and not necessarily in the treatment portal. However, most studies in the literature do not reflect current techniques of therapy. Modern three-dimensional conformal planning and intensity modulated radiation therapy-based planning offer the potential for higher dosages with less toxicity. In the particular case where extensive pleural disease necessitates an extrapleural pneumonectomy, we have been able to proceed with high-dose hemithoracic radiation without the intervening lung in place, analogous to current strategies with mesothelioma at our institution [16]. Whether these new strategies prove to be of benefit remains to be determined. Whereas 2 patients in this series had greater than 99% tumor necrosis on the resection specimen, even with concurrent radiotherapy the overall radiographic response rate was just 40%, emphasizing that better systemic therapy is needed to improve response rates and ultimately reduce the risk of recurrence. Thymoma has been found to respond to several different cytotoxic regimens, but none are clearly superior to the others. Recent studies have identified potential molecular targets in thymoma. As in many tumor types, EGFR has been shown to be over-expressed in thymoma [17] and some clinical responses to EGFR inhibitors have been observed [18 –20]. c-KIT has received much attention in the treatment of gastrointestinal stromal tumors and has been found to be over-expressed in thymic carcinoma [21–23]. Although a recent report detailed a clinical response to imatinib, results of a prospective study in patients with thymic carcinoma are pending [24]. Clinical responses have been observed to other tyrosine kinase inhibitors, including dasatinib, as well [25]. Other studies have found upregulation of cyclooxygenase-2 (COX-2) in thymic tumors raising the possibility of a separate therapeutic avenue [26]. By incorporating newer therapies
Ann Thorac Surg 2008;85:365–7
into trials of induction therapy, one can evaluate the molecular changes that occur after treatment. These future efforts are critically dependent on a standardized approach to pathologic evaluation. The importance of a rigorous evaluation, paying close attention to all margins, the presence of invasion versus adherence to adjacent structures, the determination of the degree of treatment effect, and the presence of nodal metastases is critical to improving our understanding of this disease and requires close collaboration between the thoracic surgeon and pathologist. Wright and colleagues appear to have used the 1999 World Health Organization (WHO) thymic tumor classification. An updated 2004 WHO classification allows more accurate histological subtyping which is key to designing prospective trials, because of the influence of histology on chemotherapy response and survival [27]. This article by Wright and colleagues add to our understanding of the optimal treatment of patients with locally advanced thymic tumors. Patients presenting with locally advanced thymic tumors should be staged with a contrast-enhanced computed tomography, FDG-PET, and at least a core biopsy. If no clinical trial is available, induction therapy including chemotherapy plus or minus concurrent radiation should be followed by surgery with every effort made to achieve a complete resection, including extended resection if necessary. Decisions on adjuvant therapies should be based on histology and resection margins. Adjuvant radiation seems most appropriate in the setting of incomplete resections or close margins. Because thymic tumors can have an indolent course, annual follow-up computed tomographic scans are mandatory for at least 10 years, if not lifelong. For years, clinicians have called for prospective trials to validate strategies for the management of thymic tumors. Although two small prospective trials have been performed, there is a paucity of clinical trial options for these patients. As such, our practices are mostly informed by conclusions drawn from single-institution retrospective data. The limited numbers of cases mandate a collaborative effort among multiple institutions. Wright and colleagues are to be commended for moving their retrospective data forward by initiating a prospective trial to validate their approach. Let this be just the beginning. The authors thank Dr William Travis, Department of Pathology, Memorial Sloan-Kettering Cancer Center for his critical review, and Melody Owens for her expert assistance in manuscript preparation.
References 1. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–92. 2. 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;130:1413–21. 3. Wright CD, Choi NC, Wain JC, Mathisen DJ, Lynch TJ, Fidias P. Induction chemoradiotherapy followed by resec-
Ann Thorac Surg 2008;85:365–7
4. 5. 6. 7. 8.
9.
10.
11. 12. 13. 14.
EDITORIAL HUANG ET AL MULTIMODALITY THERAPY FOR LOCALLY ADVANCED THYMOMAS
tion for locally advanced Masaoka stage III and IVA thymic tumors. Ann Thorac Surg 2008;85:385–9. Rea F, Sartori F, Loy M, et al. Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 1993;106: 543–9. Venuta F, Rendina EA, Longo F, et al. Long-term outcome after multimodality treatment for stage III thymic tumors. Ann Thorac Surg 2003;76:1866 –72. Lucchi M, Ambrogi MC, Duranti L, et al. Advanced stage thymomas and thymic carcinomas: results of multimodality treatments. Ann Thorac Surg 2005;79:1840 – 4. Bretti S, Berruti A, Loddo C, et al. Multimodal management of stages III-IVa malignant thymoma. Lung Cancer 2004;44: 69 –77. Kim ES, Putnam JB, Komaki R, et al. Phase II study of 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 –79. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small cell lung cancer: mature results of Southwest Oncology Group Phase II study 8805. J Clin Oncol 1995;13:1880 –92. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small cell lung carcinomas: long-term results of Southwest Oncology Group trial 9416 (Intergroup trial 0160). J Clin Oncol 2007;25:313– 8. Yagi K, Hirata T, Fukuse T, et al. Surgical treatment for invasive thymoma, especially when the superior vena cava is invaded. Ann Thorac Surg 1996;61:521– 44. Wright CD. Pleuropneumonectomy for the treatment of Masaoka stage IV thymoma. Ann Thorac Surg 2006;82: 1234 –9. Huang J, Rizk NP, Travis WD, et al. Feasbility of multimodality therapy including extended resections in stage IVA thymoma. J Thorac Cardiovasc Surg 2007;134:1477– 84. Ruffini E, Mancuso M, Oliaro A, et al. Recurrence of thymoma: analysis of clinicopathologic features, treatment and outcome. J Thorac Cardiovasc Surg 1997;113:55– 63.
367
15. Regnard J-F, Magdeleinat P, Dromer C, et al. Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 1996;112: 367– 84. 16. Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122:788 –95. 17. Henley JD, Koukoulis GK, Loehrer PJ, Sr. Epidermal growth factor expression in invasive thymoma. J Cancer Res Clin Oncol 2002;128:167–70. 18. Palmieri G, Marino M, Salvatore M, et al. Cetuximab is an active treatment of metastatic and chemorefractory thymoma. Front Biosci 2007;12:757– 61. 19. Farina G, Garassino MC, Gambacorta M, et al. Response of thymoma to cetuximab. Lancet Oncol 2007;8:449 –50. 20. Yamaguchi H, Soda H, Kitazaki T, et al. Thymic carcinoma with epidermal growth factor receptor gene mutations. Lung Cancer 2006;52:261–2. 21. Henley JD, Cummings OW, Loehrer PJ, Sr. Tyrosine kinase receptor expression in thymomas. J Cancer Res Clin Oncol 2004;130:222– 4. 22. Pan C-C, Chen PC-H, Chiang H. KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas. J Pathol 2004;202:375– 81. 23. Nakagawa K, Matsuno Y, Kunitoh H, et al. Immunohistochemical KIT (CD117) expression in thymic epithelial tumors. Chest 2005;128:140 – 4. 24. Ströbel P, Hartmann M, Jakob A, et al. Thymic carcinoma with overexpression of mutated KIT and the response to Imatinib. N Engl J Med 2004;350:2625– 6. 25. Chuah C, Lim TH, Lim AS, et al. Dasatanib induces a response in malignant thymoma. J Clin Oncol 2006;24:e56 – 8. 26. Rieker RJ, Joos S, Mechtersheimer G, et al. COX-2 upregulation in thymomas and thymic carcinomas. Int J Cancer 2006;119:2063–70. 27. Müller-Hermelink HK, Ströbel P, Zettl A, et al. Combined thymic epithelial tumours. In: Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, eds. Pathology and genetics: tumours of the lung, pleura, thymus and heart (WHO classification of tumours). Lyon, France: IARC Press; 2004: 196 –201.
Multimodality Therapy for Locally Advanced Thymomas: State of the Art or Investigational Therapy? James Huang, MD, Gregory J. Riely, MD, Kenneth E. Rosenzweig, MD, and Valerie W. Rusch, MD Thoracic Service, Department of Surgery, Thoracic Oncology Service, Department of Medicine, and Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
B
ecause thymic tumors are uncommon and can have a relatively indolent course, there is debate regarding the optimal treatment for patients with these tumors. Our management of patients with thymic tumors has been derived from a small, retrospective series of patients given heterogeneous treatments. Early stage and complete resection are consistently associated with better outcomes [1, 2]. Surgical resection is recommended as the first, and often only, therapy in most patients with a well-circumscribed thymic tumor that is clearly resectable. The optimal management of locally advanced thymic tumors that invade the adjacent organs or have spread to the pleural space is less clear. See page 385 In this issue, Wright and colleagues [3] reviewed their experience with 10 patients who had Masaoka stage III or IVA thymomas or thymic carcinomas and who were treated over a 10-year period with preoperative concurrent chemoradiation followed by resection. Using an induction regimen of cisplatin and etoposide with concurrent radiation, they were able to achieve an impressive R0 resection rate of 80%, with no postoperative mortalities and a 5-year estimated overall survival of 69%. A 40% radiographic partial response rate was observed in these 10 patients who completed all of the therapy. Induction chemotherapy with a variety of chemotherapy regimens given without concurrent RT for treatment of locally advanced thymic tumors has been reported by a number of groups. Resectability rates in these series have ranged from 25% to 76%, and survival rates have been reported to be as high as 90% at 10 years [4 –7]. The rate of pathologic complete responses averaged just 13%. Similarly, at least two prospective studies of preoperative chemotherapy have been reported resulting in a 57% to 76% R0 resection rate and up to a 95%, 5-year survival [8]. This report by Wright and colleagues is the first to examine induction therapy with both chemotherapy and radiation. Because thymic tumors are sensitive to both chemotherapy and radiation, it is reasonable to expect a Address correspondence to Dr Rusch, Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room C-868, New York, NY 10021; e-mail: [email protected].
© 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
higher response rate and a potentially higher rate of complete resections using this combined approach. Induction chemoradiation using similar chemotherapy regimens have been studied and have shown to be feasible in the management of stage III nonsmall cell lung cancer [9, 10]. However, preoperative chemoradiation can limit treatment in important ways. By combining with radiation, the type of chemotherapy given and the dose delivered are often altered. Giving combined chemotherapy and radiation therapy also increases toxicity. Finally, there is an increased risk of morbidity associated with surgery in an irradiated field. A major complication of acute respiratory distress syndrome in 1 patient in this series seems directly attributable to the combined induction therapy. The authors concede that in cases of large tumors that are greater than 15 cm, withholding preoperative radiation may be appropriate to minimize pulmonary toxicity. Achieving a complete resection remains the key to treatment, and the possibility of extended resections including caval resection or even extrapleural pneumonectomy should not deter surgeons from doing so, if that is what is necessary to obtain a R0 resection in the appropriate patient. Thymoma patients are usually younger and more fit than patients with lung or esophageal cancer, and they can often tolerate intensive multimodality therapy and extended resections safely. One series reported 12 resections of thymomas invading the superior vena cava without any significant morbidity or mortality and confirmed that complete resection remained the most significant prognosticating factor [11]. Given the extent of these tumors, optimal exposure often requires more than the standard sternotomy, and a hemi-clamshell or even clamshell approach may provide the best access. Stage IVa thymomas offer a particularly difficult challenge. Despite the presence of disease metastatic to the pleura, these lesions are still oftentimes amenable to resection. In cases of extensive pleural disease, several institutions including the authors and our own have now reported small series of extrapleural pneumonectomy for stage IVa disease with excellent outcomes and low morbidity [12, 13]. In cases requiring a concomitant extrapleural pneumonectomy, our institution has used a sternotomy for the mediastinal dissection, followed imAnn Thorac Surg 2008;85:365–7 • 0003-4975/08/$34.00 doi:10.1016/j.athoracsur.2007.10.098
366
EDITORIAL HUANG ET AL MULTIMODALITY THERAPY FOR LOCALLY ADVANCED THYMOMAS
mediately by a posterolateral thoracotomy for the pleural component with good success. The use of induction chemoradiotherapy not only limits dose of induction chemotherapy, but also the ability to give radiation in the adjuvant setting, which may be more critical in the event of incomplete resections. Although the authors report an 80% R0 resection rate, 70% of the patients subsequently received postoperative chemotherapy due to close margins or high grade tumor histology. Would some of these patients have received adjuvant radiation instead had they not already been radiated? The median follow-up in this series was about 3.5 years. Long-term follow-up is required, as late recurrences are a known factor in thymic tumors with relapses occurring as late as 7 years after treatment or more [14, 15]. Despite the sensitivity of thymoma to radiation, the best use of radiotherapy remains controversial. In the preoperative setting, radiation offers potential synergism with concurrent induction chemotherapy, but at the expense of increased toxicity and surgical morbidity. In the postoperative setting, there remains no consensus on whether or not adjuvant radiation is of any benefit in completely resected thymoma. Most recurrences occur locally in the pleural space [12] and not necessarily in the treatment portal. However, most studies in the literature do not reflect current techniques of therapy. Modern three-dimensional conformal planning and intensity modulated radiation therapy-based planning offer the potential for higher dosages with less toxicity. In the particular case where extensive pleural disease necessitates an extrapleural pneumonectomy, we have been able to proceed with high-dose hemithoracic radiation without the intervening lung in place, analogous to current strategies with mesothelioma at our institution [16]. Whether these new strategies prove to be of benefit remains to be determined. Whereas 2 patients in this series had greater than 99% tumor necrosis on the resection specimen, even with concurrent radiotherapy the overall radiographic response rate was just 40%, emphasizing that better systemic therapy is needed to improve response rates and ultimately reduce the risk of recurrence. Thymoma has been found to respond to several different cytotoxic regimens, but none are clearly superior to the others. Recent studies have identified potential molecular targets in thymoma. As in many tumor types, EGFR has been shown to be over-expressed in thymoma [17] and some clinical responses to EGFR inhibitors have been observed [18 –20]. c-KIT has received much attention in the treatment of gastrointestinal stromal tumors and has been found to be over-expressed in thymic carcinoma [21–23]. Although a recent report detailed a clinical response to imatinib, results of a prospective study in patients with thymic carcinoma are pending [24]. Clinical responses have been observed to other tyrosine kinase inhibitors, including dasatinib, as well [25]. Other studies have found upregulation of cyclooxygenase-2 (COX-2) in thymic tumors raising the possibility of a separate therapeutic avenue [26]. By incorporating newer therapies
Ann Thorac Surg 2008;85:365–7
into trials of induction therapy, one can evaluate the molecular changes that occur after treatment. These future efforts are critically dependent on a standardized approach to pathologic evaluation. The importance of a rigorous evaluation, paying close attention to all margins, the presence of invasion versus adherence to adjacent structures, the determination of the degree of treatment effect, and the presence of nodal metastases is critical to improving our understanding of this disease and requires close collaboration between the thoracic surgeon and pathologist. Wright and colleagues appear to have used the 1999 World Health Organization (WHO) thymic tumor classification. An updated 2004 WHO classification allows more accurate histological subtyping which is key to designing prospective trials, because of the influence of histology on chemotherapy response and survival [27]. This article by Wright and colleagues add to our understanding of the optimal treatment of patients with locally advanced thymic tumors. Patients presenting with locally advanced thymic tumors should be staged with a contrast-enhanced computed tomography, FDG-PET, and at least a core biopsy. If no clinical trial is available, induction therapy including chemotherapy plus or minus concurrent radiation should be followed by surgery with every effort made to achieve a complete resection, including extended resection if necessary. Decisions on adjuvant therapies should be based on histology and resection margins. Adjuvant radiation seems most appropriate in the setting of incomplete resections or close margins. Because thymic tumors can have an indolent course, annual follow-up computed tomographic scans are mandatory for at least 10 years, if not lifelong. For years, clinicians have called for prospective trials to validate strategies for the management of thymic tumors. Although two small prospective trials have been performed, there is a paucity of clinical trial options for these patients. As such, our practices are mostly informed by conclusions drawn from single-institution retrospective data. The limited numbers of cases mandate a collaborative effort among multiple institutions. Wright and colleagues are to be commended for moving their retrospective data forward by initiating a prospective trial to validate their approach. Let this be just the beginning. The authors thank Dr William Travis, Department of Pathology, Memorial Sloan-Kettering Cancer Center for his critical review, and Melody Owens for her expert assistance in manuscript preparation.
References 1. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–92. 2. 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;130:1413–21. 3. Wright CD, Choi NC, Wain JC, Mathisen DJ, Lynch TJ, Fidias P. Induction chemoradiotherapy followed by resec-
Ann Thorac Surg 2008;85:365–7
4. 5. 6. 7. 8.
9.
10.
11. 12. 13. 14.
EDITORIAL HUANG ET AL MULTIMODALITY THERAPY FOR LOCALLY ADVANCED THYMOMAS
tion for locally advanced Masaoka stage III and IVA thymic tumors. Ann Thorac Surg 2008;85:385–9. Rea F, Sartori F, Loy M, et al. Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 1993;106: 543–9. Venuta F, Rendina EA, Longo F, et al. Long-term outcome after multimodality treatment for stage III thymic tumors. Ann Thorac Surg 2003;76:1866 –72. Lucchi M, Ambrogi MC, Duranti L, et al. Advanced stage thymomas and thymic carcinomas: results of multimodality treatments. Ann Thorac Surg 2005;79:1840 – 4. Bretti S, Berruti A, Loddo C, et al. Multimodal management of stages III-IVa malignant thymoma. Lung Cancer 2004;44: 69 –77. Kim ES, Putnam JB, Komaki R, et al. Phase II study of 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 –79. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small cell lung cancer: mature results of Southwest Oncology Group Phase II study 8805. J Clin Oncol 1995;13:1880 –92. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small cell lung carcinomas: long-term results of Southwest Oncology Group trial 9416 (Intergroup trial 0160). J Clin Oncol 2007;25:313– 8. Yagi K, Hirata T, Fukuse T, et al. Surgical treatment for invasive thymoma, especially when the superior vena cava is invaded. Ann Thorac Surg 1996;61:521– 44. Wright CD. Pleuropneumonectomy for the treatment of Masaoka stage IV thymoma. Ann Thorac Surg 2006;82: 1234 –9. Huang J, Rizk NP, Travis WD, et al. Feasbility of multimodality therapy including extended resections in stage IVA thymoma. J Thorac Cardiovasc Surg 2007;134:1477– 84. Ruffini E, Mancuso M, Oliaro A, et al. Recurrence of thymoma: analysis of clinicopathologic features, treatment and outcome. J Thorac Cardiovasc Surg 1997;113:55– 63.
367
15. Regnard J-F, Magdeleinat P, Dromer C, et al. Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 1996;112: 367– 84. 16. Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122:788 –95. 17. Henley JD, Koukoulis GK, Loehrer PJ, Sr. Epidermal growth factor expression in invasive thymoma. J Cancer Res Clin Oncol 2002;128:167–70. 18. Palmieri G, Marino M, Salvatore M, et al. Cetuximab is an active treatment of metastatic and chemorefractory thymoma. Front Biosci 2007;12:757– 61. 19. Farina G, Garassino MC, Gambacorta M, et al. Response of thymoma to cetuximab. Lancet Oncol 2007;8:449 –50. 20. Yamaguchi H, Soda H, Kitazaki T, et al. Thymic carcinoma with epidermal growth factor receptor gene mutations. Lung Cancer 2006;52:261–2. 21. Henley JD, Cummings OW, Loehrer PJ, Sr. Tyrosine kinase receptor expression in thymomas. J Cancer Res Clin Oncol 2004;130:222– 4. 22. Pan C-C, Chen PC-H, Chiang H. KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas. J Pathol 2004;202:375– 81. 23. Nakagawa K, Matsuno Y, Kunitoh H, et al. Immunohistochemical KIT (CD117) expression in thymic epithelial tumors. Chest 2005;128:140 – 4. 24. Ströbel P, Hartmann M, Jakob A, et al. Thymic carcinoma with overexpression of mutated KIT and the response to Imatinib. N Engl J Med 2004;350:2625– 6. 25. Chuah C, Lim TH, Lim AS, et al. Dasatanib induces a response in malignant thymoma. J Clin Oncol 2006;24:e56 – 8. 26. Rieker RJ, Joos S, Mechtersheimer G, et al. COX-2 upregulation in thymomas and thymic carcinomas. Int J Cancer 2006;119:2063–70. 27. Müller-Hermelink HK, Ströbel P, Zettl A, et al. Combined thymic epithelial tumours. In: Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, eds. Pathology and genetics: tumours of the lung, pleura, thymus and heart (WHO classification of tumours). Lyon, France: IARC Press; 2004: 196 –201.