Ann Thorac Surg 2008;85:385-389. doi:10.1016/j.athoracsur.2007.08.051
© 2008 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Induction Chemoradiotherapy Followed by Resection for Locally Advanced Masaoka Stage III and IVA Thymic Tumors
Cameron D. Wright, MDa,*,
Noah C. Choi, MDc,
John C. Wain, MDa,
Douglas J. Mathisen, MDa,
Thomas J. Lynch, MDb,
Panos Fidias, MDb
a Division of Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts
b Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
c Division of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
Accepted for publication August 22, 2007.
* Address correspondence to Dr Wright, Massachusetts General Hospital, Thoracic Surgery, Blake 1570, 55 Fruit St, Boston, MA 02114 (Email: wright.cameron{at}mgh.harvard.edu).
 |
Abstract
|
|---|
Background: The treatment of locally advanced thymic tumors is not uniform. Recently, several centers have reported the results of induction chemotherapy followed by resection and then radiation. Our center adopted an alternative strategy and treated locally advanced thymic tumors with induction chemoradiotherapy in an effort to maximize the intensity of the induction therapy.
Methods: A retrospective review was performed of 10 patients with locally advanced thymic tumors treated from 1997 to 2006. Seven patients were clinically staged as Masaoka stage III and 3 as stage IVA. The treatment plan included two cycles of cisplatin and etoposide with concurrent radiation. Patients then had resection followed by postoperative chemotherapy if they were judged to be at high risk for relapse.
Results: Four patients had a partial radiographic response to induction therapy and 6 had no response. Eight patients had a R0 resection and 2 had a R1 resection. Four patients had substantial (>90%) necrosis in the resected specimen. There was no postoperative mortality. Seven patients had two more cycles of chemotherapy. The median follow-up was 41 months. Three patients had recurrences. The 5-year estimated survival was 69% (95% confidence interval: 32% to 100%).
Conclusions: Induction therapy for locally advanced thymic tumors with cisplatin, etoposide, and radiation is well tolerated, with many patients having a partial radiographic response. The majority of patients can undergo a complete resection with this treatment. The survival of these patients compares favorably with those undergoing other induction regimens. Further efforts to maximize the intensity of induction therapy for locally advanced thymic tumors is warranted. We have initiated a multicenter phase 2 clinical trial (NCT00387868) to prospectively test this concept.
|
Introduction
|
|---|
Masaoka stage III and IVA thymic tumors have a relatively high recurrence rate if treated by resection alone [1]. Thymic tumors respond favorably to both radiation and chemotherapy. Previous treatment strategies used adjuvant treatment, either radiation alone or in combination with chemotherapy, to maximize freedom from recurrence. More recently, several groups have reported on an induction strategy using chemotherapy alone, then resection, then radiation, usually followed by more chemotherapy [1–7]. These regimens have been well tolerated, and the results appear better than historical controls [8].
Our center has had a philosophy of using induction chemoradiotherapy for locally advanced thoracic cancers, with favorable results [9, 10]. Pleural implants are the most common site of recurrence after thymoma resection and might be favorably mitigated by perioperative chemotherapy [11]. Pleural recurrences also might be favorably impacted by induction radiation therapy, which can sterilize a sizable portion of the tumor. Preliminary data from our stage III patients suggested that patients who had induction radiation therapy alone had a reduced pleural recurrence rate [12]. Combining these two synergistic modalities might reduce the rate of pleural recurrences. Many reports suggest that a complete resection is the most important prognostic factor for thymomas [11, 13]. Concurrent chemoradiotherapy should allow the most intense induction of the local tumor as that might translate into more complete resections and possibly improved survival. The combination of cisplatin and etoposide is synergistic with radiation, has been extensively studied in lung cancer, and has generally been well tolerated [14]. This chemotherapy regimen is also active in thymic tumors and was chosen as an optimal one to combine with radiation [5, 15]. The early results of this regimen in treating locally advanced, clinically staged Masaoka stage III and IVA thymic tumors are reviewed in this report.
|
Patients and Methods
|
|---|
Patients who had induction chemoradiotherapy followed by resection were retrieved from a prospectively maintained thymoma database. Permission for this study was granted by the Human Studies Committee and individual consent was waived. From December 1997 to July 2006, 10 patients were treated for a locally advanced thymic tumor with induction chemoradiotherapy followed by resection and then adjuvant chemotherapy. During this same period, there were 6 patients with stage III disease who had resection first followed by adjuvant therapy, and 10 patients who had stage IVA disease, of whom 5 had induction chemotherapy alone and 5 had resection followed by adjuvant therapy. Patients were judged to be appropriate for this regimen if they were deemed to have an unresectable thymoma or thymic carcinoma (or one that would likely have an incomplete resection) as judged by a joint consensus of a multimodality thoracic oncology team (thoracic surgery, medical oncology, and radiation oncology) and were candidates for aggressive multimodality treatment. The definition of unresectable is obviously somewhat problematic and difficult to define precisely. Three patients were Masaoka stage 4 and thus were relatively easy to define as poorly resectable. The other patients had computed tomography findings that suggested extensive invasion, large tumors with indistinct borders, or evidence of great vessel invasion, and were clinically staged as stage III. All patients had an initial biopsy that confirmed the suspected thymoma or thymic carcinoma. All patients had an initial chest computed tomography (CT) scan with intravenous contrast, and all patients were encouraged to have positron emission tomography (PET) scans as well.
The patients had to be fit and met the following standards: Zubrod score less than 2, absolute neutrophil count greater than 1,500, platelet count greater than 100,000, total bilirubin and aspartate aminotransferase/alanine aminotransferase less than 1.5 normal, creatinine clearance greater than 50 mL/min, no previous chest radiation, and the surgeon judged the patient to be a candidate for resection (after induction therapy). The chemotherapy was cisplatin 33 mg/m2 daily x 3 and etoposide (VP16) at a dose of 100 mg/m2 daily x 3. Two cycles were planned 3 to 4 weeks apart. Radiation was given concurrently with chemotherapy using a three-dimensional conformal or intensity-modulated radiation therapy–based plan. The radiation target dose goal was 40 to 45 Gy but was adjusted downward for huge tumors. Two to 4 weeks after completion of preoperative chemoradiation, the tumor was reevaluated by a chest CT and PET scan. When patients were judged to have recovered from induction therapy (4 to 8 weeks), they underwent surgical resection with a goal of a complete resection (R0), to include the tumor and all attached structures, the thymus, and all pleural implants if present. Postoperative chemotherapy (cisplatin and etoposide) was planned for patients with incomplete resections and those judged to be at high risk for recurrence (close margins, World Health Organization B3 or C histology). Patients were then serially followed by chest CT scans every 6 months. Survival was estimated by the method of Kaplan-Meier, and the first day of treatment was used as the start date.
|
Results
|
|---|
Ten patients were treated with this regimen. The characteristics of these patients can be seen in Table 1. Females predominated. All patients were symptomatic. Three had evidence of great vessel invasion on the initial CT, 3 had pleural metastases on the initial CT, and 7 were thought to be at least Masaoka stage III and poorly or unresectable based on CT characteristics. Eight of the 10 tumors were greater than 8 cm on the initial CT scan. Six patients had pretreatment PET scans, and all tumors were PET positive. All patients completed two cycles of cisplatin/etoposide chemotherapy and the concurrent radiotherapy. There were no patients who started this regimen who failed to complete the therapy or failed to go on for resection. The radiographic response based on the CT scan was 40% with a partial response and 60% with stable disease using response evaluation criteria in solid tumors (RECIST) [16]. No patients progressed on induction treatment. Six patients had before and after PET scans; 4 went from positive to negative and 2 went from positive to decreased activity.
All 10 patients underwent resection; 8 had an R0 resection and 2 had a R1 resection. Three patients required superior vena cava resection and reconstruction with a polytetrafluoroethylene (PTFE) graft. One patient required pleuropneumonectomy for extensive invasion of the lung (nearly complete replacement) and confluent pleural disease. Two patients required pleurectomy for pleural metastases. Other structures resected included lung (7), pericardium (9), phrenic nerve (4). Two patients had an incomplete resection, 1 owing to chest wall invasion from pleural disease and 1 owing to invasion of the main pulmonary artery. Both patients had all gross tumor resected and were thought to be R1 resections. Only 1 patient had stage changed from what was thought clinically based upon the CT scan and what was found at pathologic review. Two patients had complications after surgery. One patient had tamponade after pleuropneumonectomy with pericardial resection and PTFE reconstruction. She required reexploration and removal of the PTFE pericardial reconstruction and then did well. Another patient who had evidence of low-grade treatment-related pneumonitis after induction therapy had acute respiratory distress syndrome after resection and required prolonged ventilation; he required a tracheosotomy but eventually fully recovered. The median length of stay was 7 days (range, 4 to 90). There were no postoperative deaths. Seven patients had two more cycles of postoperative chemotherapy based upon the pathology report. All prescribed chemotherapy was received by the patients after operation.
One patient has been lost to follow-up at 36 months after she returned to Saudi Arabia. The median follow-up is 41 months. Three patients have recurred: 1 in the mediastinum, 1 in the pleura alone, and 1 in the pleura and abdominal lymph nodes. Two of these patients died of disease despite additional chemotherapy. One patient had additional chemotherapy and resection of pleural disease and remains free of disease. The Kaplan-Meier estimated 5-year survival is 69% (95% confidence interval: 32% to 100%).
|
Comment
|
|---|
The treatment of locally advanced thymic tumors has changed to an induction strategy with chemotherapy followed by resection, then radiation therapy to improve upon the earlier strategy of resection followed by radiation (Table 2) [1–7]. The results with induction therapy seem improved compared with earlier series. While the partial clinical response rates are relatively high, the complete clinical response rates and the pathologic complete response rates (13%) are not. The R0 resection rates in these series range from 25% to 76%, with an average of 59%. Survival rates in three series that report long-term survival vary from 70% to 95% at 5 years.
Our center has had a philosophy of intense induction therapy for thoracic cancers in an effort to maximize the chance of an R0 resection. Concurrent chemoradiotherapy allows radiation-chemotherapy interactions that may potentiate radiation effects and enhance a complete resection. It would also seem that the greater the tumor was harmed by induction treatment that there would be less chance of pleural seeding during the resection, potentially resulting in fewer pleural recurrences. Preoperative radiation allows more precise radiation planning because the initial tumor volume is undisturbed, unlike with adjuvant treatment in which the important margins of treatment have all been distorted. The disadvantages of induction chemoradiotherapy include the reduced dose intensity of chemotherapy (to allow concurrent radiation), the increased toxicity of combined therapy, and the more difficult surgery after chemoradiotherapy. The argument for induction chemoradiotherapy is more straightforward to make, with a smaller stage III tumor that is, for example, invading the great veins where one knows a complete resection will be hard to achieve. Likewise, with a smaller stage IVA tumor with minimal pleural disease, it makes sense to maximize upfront therapy to try to achieve a complete resection and rely on adjuvant chemotherapy for the pleural disease. The real challenge is in large tumors where the radiation fields include a substantial portion of lung. Each case must be individualized, and very large tumors (>15 cm) probably should just have chemotherapy as an induction treatment. How these important considerations affect the results in locally advanced thymomas is hard to state with certainty. The rarity of this tumor makes the study of it quite difficult and large randomized trials to decide optimal treatment essentially impossible. We are left with the reports of centers that are interested in these rare thoracic tumors. It is interesting to note that, of the seven series (only 7 to 25 patients in each series) that report on induction chemotherapy for locally advanced thymomas, three had about 1 patient in a year and four had about 2 patients in a year, emphasizing just how uncommon this clinical problem is.
Our results seem generally in line with the induction chemotherapy strategy reports (Table 2). The resection rate was 100% and the R0 resection rate was 80%. The PET scans did not seem to correlate well with either the CT response or the pathologic response but the numbers are too small to draw firm conclusions. Patients tolerated postoperative chemotherapy well, with all prescribed therapy delivered. Only 2 patients had a near-complete pathologic response (>99% necrosis) and another 2 had only microscopic residual disease (>90% necrosis). It remains to be seen if an excellent pathologic response translates into a favorable prognosis as for other thoracic cancers, as the numbers are again too small. The 5-year survival of 69% is encouraging given the advanced thymomas these patients presented with. One patient had substantial toxicty that was attributed to the induction chemoradiotherapy associated pneumonitis leading to acute respiratory distress syndrome. In retrospect, we should have delayed his operation to allow further resolution of his treatment-related pneumonitis. The toxicity of the regimen was not excessive, as our length of stay (median, 7 days) was similar to that of our entire database of patients (median, 6 days) and there were no postoperative deaths.
There are several limitations of our study. Treatment was not by protocol but was an in-house "formula" that was designed by trial and error based upon the literature and our experience with other thoracic cancers. Selection for treatment was somewhat surgeon/oncologist/radiation oncologist dependent with 6 other Masaoka stage III thymomas having resection first and 10 other Masaoka stage IVA thymomas having induction chemotherapy (4) or resection first (6). Thus, there was some degree of selection bias that is difficult to quantitate retrospectively. Two patients had their induction treatment elsewhere under our supervision and advice, but not by us. One patient was, unfortunately, lost to follow-up.
Induction chemoradiotherapy with concurrent radiation and cisplatin with etoposide for locally advanced thymomas is well tolerated, causes a partial radiographic response in many patients, and results in substantial necrosis of the tumor in many patients. Most patients can have a complete resection. The 5-year survival is 69% with this regimen. Further improvements need to be made to enhance the intensity of induction therapy for advanced thymomas while minimizing toxicity. We have initiated a multicenter phase 2 clinical trial (NCT00387868 [17]) based upon this concept along with four other centers to test this strategy in a prospective fashion.
|
References
|
|---|
- Venuta F, Rendina EA, Longo F, et al. Long term outcome after multimodality treatment for stage III thymic tumors Ann Thorac Surg 2003;76:1866-1872.[Abstract/Free Full Text]
- Macchiarini P, Chella A, Ducci F, et al. Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma Cancer 1991;68:706-713.[Medline]
- Rea F, Sartori F, Loy M, et al. Chemotherapy and operation for invasive thymoma J Thorac Cardiovasc Surg 1993;106:543-549.[Abstract]
- Kim ES, Putnam JB, Komacki 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.[Medline]
- Bretti S, Berruti A, Loddo C, et al. Multimodal management of stages III-IVA malignant thymoma Lung Cancer 2004;44:69-77.[Medline]
- Lucchi M, Ambrogi M, Duranti L, et al. Advanced stage thymomas and thymic carcinomas: results of multimodality treatments Ann Thorac Surg 2005;79:1840-1844.[Abstract/Free Full Text]
- Jacot W, Quantin X, Valette S, et al. Multimodality treatment program in invasive thymic epithelial tumor Am J Clin Oncol 2005;28:5-7.[Medline]
- Evans TL, Lynch TJ. Role of chemotherapy in the management of advanced thymic tumors Sem Thorac Cardiovasc Surg 2005;17:41-50.[Medline]
- Choi NC, Carey RW, Daly W, et al. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small cell lung cancer J Clin Oncol 1997;15:712-722.[Abstract/Free Full Text]
- Wright CD, Menard MT, Wain JC, et al. Induction chemoradiation compared to induction radiation for lung cancer invading the superior sulcus Ann Thorac Surg 2002;73:1541-1544.[Abstract/Free Full Text]
- 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;130:1413-1421.[Abstract/Free Full Text]
- Myojin M, Choi NC, Wright CD, et al. Stage III thymoma: patterns of failure after surgery and postoperative radiotherapy and its implications for further study Int J Radiat Oncol Biol Phys 2000;46:927-933.[Medline]
- Detterbeck FC. Thymic tumors Ann Thorac Surg 2004;77:1860-1869.[Abstract/Free Full Text]
- 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;25:313-318.[Abstract/Free Full Text]
- Giaccone G, Ardizzoni A, Kirkpatrick A, et al. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymomaA phase II study of the European Organization for Research and Treatment of Cancer. Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814-820.[Abstract/Free Full Text]
- Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors J Natl Cancer Inst 2000;92:205-216.[Abstract/Free Full Text]
- Available at: http://www.ClinicalTrials.gov (NCT 00387868). Accessed June 1, 2007.
Related Article
-
Multimodality Therapy for Locally Advanced Thymomas: State of the Art or Investigational Therapy?
- James Huang, Gregory J. Riely, Kenneth E. Rosenzweig, and Valerie W. Rusch
Ann. Thorac. Surg. 2008 85: 365-367.
[Extract]
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
F. Venuta, M. Anile, D. Diso, D. Vitolo, E. A. Rendina, T. De Giacomo, F. Francioni, and G. F. Coloni
Thymoma and thymic carcinoma
Eur. J. Cardiothorac. Surg.,
January 1, 2010;
37(1):
13 - 25.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Luzzi, A. Campione, A. Gorla, G. Vassallo, A. Bianchi, A. Biggi, and A. Terzi
Role of fluorine-flurodeoxyglucose positron emission tomography/computed tomography in preoperative assessment of anterior mediastinal masses
Eur. J. Cardiothorac. Surg.,
September 1, 2009;
36(3):
475 - 479.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Huang, N. P. Rizk, W. D. Travis, G. J. Riely, B. J. Park, M. S. Bains, J. Dycoco, R. M. Flores, R. J. Downey, and V. W. Rusch
Comparison of patterns of relapse in thymic carcinoma and thymoma
J. Thorac. Cardiovasc. Surg.,
July 1, 2009;
138(1):
26 - 31.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tomaszek, D. A. Wigle, S. Keshavjee, and S. Fischer
Thymomas: Review of Current Clinical Practice.
Ann. Thorac. Surg.,
June 1, 2009;
87(6):
1973 - 1980.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. E. Cohn
Successful Long-Term Outcome in Locally Advanced Masaoka IVA Thymoma With Induction Chemotherapy Followed by Complete Resection and Adjuvant Radiotherapy
Ann. Thorac. Surg.,
November 1, 2008;
86(5):
1725 - 1725.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. D. Wright
Reply
Ann. Thorac. Surg.,
November 1, 2008;
86(5):
1725 - 1725.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Huang, G. J. Riely, K. E. Rosenzweig, and V. W. Rusch
Multimodality Therapy for Locally Advanced Thymomas: State of the Art or Investigational Therapy?
Ann. Thorac. Surg.,
February 1, 2008;
85(2):
365 - 367.
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
