- Email: [email protected]
Induction Therapy For Locally Advanced Thymoma
MALIGNANCIES
OF THE
THYMUS
Induction Therapy For Locally Advanced Thymoma Gregory J. Riely, MD,* and James Huang, MD†
Abstract: Thymomas are the most frequently encountered tumors of the mediastinum and often present with either localized or locally advanced disease. The prognosis in thymoma has been consistently shown to correspond to the invasiveness of the tumor (as represented by the Masaoka stage of the tumor) and the completeness of surgical resection. Because treatment with a variety of different chemotherapy regimens has demonstrated radiographic response rates greater than 50% in patients with advanced thymoma, a number of investigators have explored the use of preoperative (induction, neoadjuvant) therapy for patients with locally advanced thymoma. In this review, we summarize the published experience with preoperative therapy for thymoma and discuss ongoing clinical trials exploring multimodality therapy for treatment of locally advanced thymoma. Key Words: Thymoma, Thymic carcinoma, Chemotherapy, Epidermal growth factor receptor. (J Thorac Oncol. 2010;5: S323–S326)
A
lthough rare in the general population, thymomas are the most frequently encountered tumors of the mediastinum and often present with either localized or locally advanced disease. The prognosis in thymoma has been consistently shown to correspond to the invasiveness of the tumor (as represented by its Masaoka stage) and the completeness of surgical resection.1–3 Approximately 50% of patients with thymoma have a completely encapsulated tumor without evidence of invasion. Stage I and II thymomas are generally managed with surgery, and complete resection for such small tumors can be generally anticipated. Patients with completely resected stage I and II thymomas have 10-year survivals estimated at more than 80%. However, some patients with thymoma present with more advanced disease with local invasion or spread to the pleura. Because thymomas are located in the mediastinum, local invasion of the mediastinum and great vessels can present a daunting challenge complete resection. Given the clear prognostic benefit of *Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; †Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York. Disclosure: Memorial Sloan-Kettering Cancer Center has received research support from Bristol-Myers Squibb, distributor of cetuximab. Address correspondence: Gregory J. Riely, MD, PhD, Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0510-0323
complete surgical resection in such patients, a number of investigators have explored the role of preoperative therapy for optimal management of locally advanced thymoma.
SURGICAL RESECTION OF LOCALLY ADVANCED THYMOMA Achieving a complete resection remains the key to treatment of thymoma, but for patients with locally advanced disease and with disease involving the pleura (stage IVa), complete resections can require extensive surgical resections. Given the large areas encompassed by these tumors, optimal exposure often requires more than the standard sternotomy, and a hemiclamshell or even clamshell approach may provide the best access. Thymoma patients are typically younger and more fit than patients with lung or esophageal cancer and can often tolerate such extended resections. 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 prognostic factor.4 Stage IVA thymomas offer a particularly difficult challenge. Despite the presence of disease metastatic to the pleura, these lesions are still often amenable to resection. However, whether surgical resection of metastatic disease improves overall outcome has not been prospectively established. In cases of extensive pleural disease, several institutions including our own have now reported small series of extrapleural pneumonectomy for stage IVA disease with excellent outcomes and low morbidity.5–7 Nonetheless, achieving a complete resection in these cases remains challenging and resection rates in these series ranged from 60 to 67%.
CHEMOTHERAPY IN THYMOMA Since treatment with a variety of different chemotherapy regimens has demonstrated radiographic response rates greater than 50%, a number of investigators have explored the use of preoperative therapy for patients with locally advanced thymoma. The two largest intergroup trials studying chemotherapy in patients with advanced or metastatic thymoma found response rates of 50% for regimens of cisplatin, doxorubicin, and cyclophosphamide and 56% for regimens of cisplatin and etoposide.8,9 Median survival times in these trials ranged from 3 to 4 years and 5-year survivals were estimated at 32 to 50%. Both regimens were well tolerated. Toxicities were mild and primarily hematologic, with roughly half of the patients having grade III or IV leukopenia with either regimen. Cyclophosphamide and PE remain the most frequently used chemotherapy regimens in
Journal of Thoracic Oncology • Volume 5, Number 10, Supplement 4, October 2010
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Journal of Thoracic Oncology • Volume 5, Number 10, Supplement 4, October 2010
Riely and Huang
TABLE 1. Induction Therapy for Thymoma Author
No. of Patients
Bretti et al.20
25
Lucchi et al.21 Venuta et al.22 Berruti et al.11
25 15 6
Jacot et al.23 Macchiarini et al.13 Kim et al.12
5 7 22
Rea et al.24
16
Wright et al.15 Kunitoh et al.14
10 21
Chemotherapy Etoposide, cisplatin or doxorubicin, cisplatin, vincristine, cyclophosphamide Cisplatin, epirubicin, etoposide Cisplatin, epirubicin, etoposide Doxorubicin, cisplatin, vincristine, cyclophosphamide Cisplatin, doxorubicin, cyclophosphamide Cisplatin, epirubicin, etoposide Cisplatin, doxorubicin, cyclophosphamide, prednisone Doxorubicin, cisplatin, vincristine, cyclophosphamide Etoposide, cisplatin, radiation therapy Cisplatin, vincristine, doxorubicin, etoposide
Response (CR ⴙ PR)
Complete Resection
Pathologic Complete Response
18/25
11/25
2/25
20 10/15 5/6
1/6
1/15 0
4/5 7/7 17/22
1/5 4/7 16/21
6/16a
16/16
11
5/16
4/10 13/21
8/10 9/21
4/10b 3/21
⬎80% necrosis. ⬎90% necrosis. CR, complete response; PR, partial response. a b
advanced thymoma. More recently, investigators from the Eastern Cooperative Oncology Group have reported their evaluation of paclitaxel and carboplatin.10 In this trial of 24 patients with thymoma, the response rate was 33%, suggesting that this newer regimen may not offer greater benefit for patients with thymoma.
PREOPERATIVE CHEMOTHERAPY IN THYMOMA There is evidence that a multimodality approach incorporating chemotherapy or chemoradiotherapy before surgery may improve resectability and outcomes in locally advanced thymoma (Table 1). These scattered reports are a mixture of disparate, sometimes outdated regimens with small numbers, and some with some series dating back over two decades. However, at least four groups have reported prospective clinical trials exploring multimodality therapy for locally advanced thymoma.11–14 Berruti et al. conducted a prospective clinical trial of cisplatin, doxorubicin, vincristine, and cyclophosphamide in patients with stage III and IVa thymoma. They observed that five of six patients had a partial response and then went on to surgery. Despite this high response rate, only one patient achieved a complete surgical resection, the goal of induction therapy. The largest prospective clinical trial reported in this setting was conducted between 1990 and 2000 at the M.D. Anderson Cancer Center, where patients with locally advanced thymoma received induction cisplatin, doxorubicin, cyclophosphamide, and prednisone, followed by surgery, radiation, and consolidation chemotherapy. In that study, 17 of 22 patients had a radiographic response after chemotherapy and six of 16 patients were found to have greater than 80% tumor necrosis at the time of surgical resection. Finally, most recently, Kunitoh et al.14 reported the results of the Japan Clinical Oncology Group evaluation of weekly, dose dense chemotherapy followed by surgery for patients with locally advanced thymoma. In this study, the investigators observed a
S324
62% response rate and 14% complete pathologic response rate. These trials emphasize that prospective phase 2 trials for patients with locally advanced thymoma are feasible.
IMPROVING ON INDUCTION THERAPY FOR THYMOMA BY ADDITION OF RADIOTHERAPY TO CHEMOTHERAPY Radiation therapy is used to treat thymoma in patients who cannot undergo complete surgical resection and is a common component of postoperative therapy for patients with locally advanced disease. In a variety of diseases, combining radiation therapy with chemotherapy has been demonstrated to improve response rates and increase the rate of cure for potentially unresectable disease (e.g., stage III non-small cell lung cancer, rectal cancer). This approach, retrospectively reviewed by Wright et al.,15 has been associated with a 40% rate of more than 90% tumor necrosis after combined cisplatin, etoposide, and radiation therapy for patients with locally advanced thymoma. To prospectively explore the value of incorporating radiation therapy into conventional chemotherapy treatment plan for locally advanced thymoma, Korst and colleagues are conducting a phase 2 trial of cisplatin, etoposide, and concurrent radiotherapy for patients with locally advanced thymoma (NCT00387868). This trial rigorously defines tumor characteristics that make patients eligible for enrollment, including tumor more than 8 cm in size, those between 5 and 8 cm with multifocal calcification, heterogeneous appearance, irregular borders or great vessel invasion or encirclement, or tumors less than 5 cm with great vessel invasion or encirclement. The primary endpoint of this clinical trial is complete pathologic response. After surgical resection, based on the findings at the time of surgery, patients are treated with observation, additional chemotherapy, or additional concurrent chemoradiotherapy (Figure 1).
Copyright © 2010 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 5, Number 10, Supplement 4, October 2010
Induction Therapy for Locally Advanced Thymoma
FIGURE 1. Schema of induction chemoradiation trial.
FIGURE 2. Schema of cetuximab, cisplatin, doxorubicin, and cyclophosphamide induction chemotherapy trial.
IMPROVING ON INDUCTION THERAPY FOR THYMOMA BY ADDITION OF TARGETED THERAPIES In many advanced malignancies, significant improvements in response rate and overall survival have been observed after the addition of biologic therapies suggesting that by incorporating this approach, we may improve outcomes for patients with thymoma. Staining for epidermal growth factor receptor (EGFR) by immunohistochemistry is observed in a high percentage of thymomas across all histologic types and stages of disease.16 However, activating EGFR mutations are rare with only two exon 21 mutations found in 29 thymic tumors analyzed.17 Cetuximab is a monoclonal antibody directed against EGFR that has demonstrated activity in patients with colorectal cancer, squamous cell cancer of the head and neck, and non-small cell lung cancer. Moreover, two separate reports documenting clinical responses to cetuximab in patients with advanced thymoma support the concept that EGFR inhibition is a promising therapeutic avenue.18,19 Partial responses were observed in three patients who had metastatic disease and had progressive disease after at least two lines of prior therapy. In two patients, a reduction in fluorodeoxyglucose uptake by positron emission tomography was noted as well. Taken together, these data suggest that incorporation of cetuximab with chemotherapy in patients with locally advanced thymoma may improve the radiographic and pathologic response rates and rate of complete resections. To explore the incorporation of cetuximab into a preoperative chemotherapy regimen, there is an ongoing phase II clinical trial of cetuximab with cisplatin, doxorubicin, and cyclophosphamide in patients with locally advanced thymoma (Figure 2) (NCT01025089). This clinical trial aims to enroll a total of 28 patients and uses the primary endpoint of pathologic complete response rate. Of note, only patients with thymoma are included and all patients with thymic carcinoma are excluded from this clinical trial. To prospectively evaluate the role of cetuximab alone in these patients with locally advanced thymoma, patients receive an initial 4 weeks of cetuximab before beginning chemotherapy combined with cetuximab. Computed tomography scans will assess response to cetuximab by itself as well as to cetuximab in combination with chemotherapy. All patients will undergo surgical resec-
tion with a goal of complete resection. Additional exploratory endpoints include evaluating the role of positron emission tomography scan for identification of sites of disease and predicting response to therapy and outcomes, pathologic predictors of response to chemotherapy and cetuximab. Given the importance of complete resection in the optimal management of thymoma, ongoing studies hope to define the most active combinations of therapy for further validation in clinical trials. Prospective clinical trials are the model for how we should proceed for evaluating therapy for locally advanced thymomas. The described ongoing clinical trials will teach us about the value of incorporating radiation therapy or EGFR-targeted therapy into preoperative therapy for thymoma. Results of ongoing prospective clinical trials for patients with advanced thymoma will also lead to new hypotheses for therapeutic approaches in treatment of locally advanced thymoma. Induction therapy studies provide a unique opportunity for evaluating tissue biomarkers to better understand tumor biology and predict response to the therapies that are currently being evaluated. REFERENCES 1. Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995;60:908 – 913; discussion 914. 2. 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. 3. 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. 4. 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;61:521–524. 5. Huang J, Riely GJ, Rosenzweig KE, et al. Multimodality therapy for locally advanced thymomas: state of the art or investigational therapy? Ann Thorac Surg 2008;85:365–367. 6. Ishikawa Y, Matsuguma H, Nakahara R, et al. Multimodality therapy for patients with invasive thymoma disseminated into the pleural cavity: the potential role of extrapleural pneumonectomy. Ann Thorac Surg 2009; 88:952–957. 7. Wright CD, Kessler KA. Surgical treatment of thymic tumors. Semin Thorac Cardiovasc Surg 2005;17:20 –26. 8. Giaccone G, Ardizzoni A, Kirkpatrick A, et al. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814 – 820.
Copyright © 2010 by the International Association for the Study of Lung Cancer
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Journal of Thoracic Oncology • Volume 5, Number 10, Supplement 4, October 2010
9. Loehrer PJ Sr, Chen M, Kim K, et al. Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 1997;15:3093– 3099. 10. Lemma GL, Loehrer PJ, Lee JW, et al. A phase II study of carboplatin plus paclitaxel in advanced thymoma or thymic carcinoma: E1C99. J Clin Oncol 2008;26:8018. 11. Berruti A, Borasio P, Roncari A, et al. Neoadjuvant chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide (ADOC) in invasive thymomas: results in six patients. Ann Oncol 1993;4:429 – 431. 12. 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. 13. Macchiarini P, Chella A, Ducci F, et al. Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer. 1991;68:706 –713. 14. Kunitoh H, Tamura T, Shibata T, et al. A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606). Br J Cancer 2010;103:6 –11. 15. Wright CD, Choi NC, Wain JC, et al. Induction chemoradiotherapy
S326
16. 17. 18. 19. 20. 21. 22. 23. 24.
followed by resection for locally advanced Masaoka stage III and IVA thymic tumors. Ann Thorac Surg 2008;85:385–389. Henley JD, Koukoulis GK, Loehrer PJ Sr. Epidermal growth factor receptor expression in invasive thymoma. J Cancer Res Clin Oncol 2002;128:167–170. Yoh K, Nishiwaki Y, Ishii G, et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008;62:316 –320. Farina G, Garassino MC, Gambacorta M, et al. Response of thymoma to cetuximab. Lancet Oncol. 2007;8:449 – 450. Palmieri G, Marino M, Salvatore M, et al. Cetuximab is an active treatment of metastatic and chemorefractory thymoma. Front Biosci 2007;12:757–761. Bretti S, Berruti A, Loddo C, et al. Multimodal management of stages III-IVa malignant thymoma. Lung Cancer 2004;44:69 –77. 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. 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; discussion 1872. Jacot W, Quantin X, Valette S, et al. Multimodality treatment program in invasive thymic epithelial tumor. Am J Clin Oncol 2005;28:5–7. Rea F, Sartori F, Loy M, et al. Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 1993;106:543–549.
Copyright © 2010 by the International Association for the Study of Lung Cancer
OF THE
THYMUS
Induction Therapy For Locally Advanced Thymoma Gregory J. Riely, MD,* and James Huang, MD†
Abstract: Thymomas are the most frequently encountered tumors of the mediastinum and often present with either localized or locally advanced disease. The prognosis in thymoma has been consistently shown to correspond to the invasiveness of the tumor (as represented by the Masaoka stage of the tumor) and the completeness of surgical resection. Because treatment with a variety of different chemotherapy regimens has demonstrated radiographic response rates greater than 50% in patients with advanced thymoma, a number of investigators have explored the use of preoperative (induction, neoadjuvant) therapy for patients with locally advanced thymoma. In this review, we summarize the published experience with preoperative therapy for thymoma and discuss ongoing clinical trials exploring multimodality therapy for treatment of locally advanced thymoma. Key Words: Thymoma, Thymic carcinoma, Chemotherapy, Epidermal growth factor receptor. (J Thorac Oncol. 2010;5: S323–S326)
A
lthough rare in the general population, thymomas are the most frequently encountered tumors of the mediastinum and often present with either localized or locally advanced disease. The prognosis in thymoma has been consistently shown to correspond to the invasiveness of the tumor (as represented by its Masaoka stage) and the completeness of surgical resection.1–3 Approximately 50% of patients with thymoma have a completely encapsulated tumor without evidence of invasion. Stage I and II thymomas are generally managed with surgery, and complete resection for such small tumors can be generally anticipated. Patients with completely resected stage I and II thymomas have 10-year survivals estimated at more than 80%. However, some patients with thymoma present with more advanced disease with local invasion or spread to the pleura. Because thymomas are located in the mediastinum, local invasion of the mediastinum and great vessels can present a daunting challenge complete resection. Given the clear prognostic benefit of *Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; †Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York. Disclosure: Memorial Sloan-Kettering Cancer Center has received research support from Bristol-Myers Squibb, distributor of cetuximab. Address correspondence: Gregory J. Riely, MD, PhD, Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0510-0323
complete surgical resection in such patients, a number of investigators have explored the role of preoperative therapy for optimal management of locally advanced thymoma.
SURGICAL RESECTION OF LOCALLY ADVANCED THYMOMA Achieving a complete resection remains the key to treatment of thymoma, but for patients with locally advanced disease and with disease involving the pleura (stage IVa), complete resections can require extensive surgical resections. Given the large areas encompassed by these tumors, optimal exposure often requires more than the standard sternotomy, and a hemiclamshell or even clamshell approach may provide the best access. Thymoma patients are typically younger and more fit than patients with lung or esophageal cancer and can often tolerate such extended resections. 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 prognostic factor.4 Stage IVA thymomas offer a particularly difficult challenge. Despite the presence of disease metastatic to the pleura, these lesions are still often amenable to resection. However, whether surgical resection of metastatic disease improves overall outcome has not been prospectively established. In cases of extensive pleural disease, several institutions including our own have now reported small series of extrapleural pneumonectomy for stage IVA disease with excellent outcomes and low morbidity.5–7 Nonetheless, achieving a complete resection in these cases remains challenging and resection rates in these series ranged from 60 to 67%.
CHEMOTHERAPY IN THYMOMA Since treatment with a variety of different chemotherapy regimens has demonstrated radiographic response rates greater than 50%, a number of investigators have explored the use of preoperative therapy for patients with locally advanced thymoma. The two largest intergroup trials studying chemotherapy in patients with advanced or metastatic thymoma found response rates of 50% for regimens of cisplatin, doxorubicin, and cyclophosphamide and 56% for regimens of cisplatin and etoposide.8,9 Median survival times in these trials ranged from 3 to 4 years and 5-year survivals were estimated at 32 to 50%. Both regimens were well tolerated. Toxicities were mild and primarily hematologic, with roughly half of the patients having grade III or IV leukopenia with either regimen. Cyclophosphamide and PE remain the most frequently used chemotherapy regimens in
Journal of Thoracic Oncology • Volume 5, Number 10, Supplement 4, October 2010
S323
Journal of Thoracic Oncology • Volume 5, Number 10, Supplement 4, October 2010
Riely and Huang
TABLE 1. Induction Therapy for Thymoma Author
No. of Patients
Bretti et al.20
25
Lucchi et al.21 Venuta et al.22 Berruti et al.11
25 15 6
Jacot et al.23 Macchiarini et al.13 Kim et al.12
5 7 22
Rea et al.24
16
Wright et al.15 Kunitoh et al.14
10 21
Chemotherapy Etoposide, cisplatin or doxorubicin, cisplatin, vincristine, cyclophosphamide Cisplatin, epirubicin, etoposide Cisplatin, epirubicin, etoposide Doxorubicin, cisplatin, vincristine, cyclophosphamide Cisplatin, doxorubicin, cyclophosphamide Cisplatin, epirubicin, etoposide Cisplatin, doxorubicin, cyclophosphamide, prednisone Doxorubicin, cisplatin, vincristine, cyclophosphamide Etoposide, cisplatin, radiation therapy Cisplatin, vincristine, doxorubicin, etoposide
Response (CR ⴙ PR)
Complete Resection
Pathologic Complete Response
18/25
11/25
2/25
20 10/15 5/6
1/6
1/15 0
4/5 7/7 17/22
1/5 4/7 16/21
6/16a
16/16
11
5/16
4/10 13/21
8/10 9/21
4/10b 3/21
⬎80% necrosis. ⬎90% necrosis. CR, complete response; PR, partial response. a b
advanced thymoma. More recently, investigators from the Eastern Cooperative Oncology Group have reported their evaluation of paclitaxel and carboplatin.10 In this trial of 24 patients with thymoma, the response rate was 33%, suggesting that this newer regimen may not offer greater benefit for patients with thymoma.
PREOPERATIVE CHEMOTHERAPY IN THYMOMA There is evidence that a multimodality approach incorporating chemotherapy or chemoradiotherapy before surgery may improve resectability and outcomes in locally advanced thymoma (Table 1). These scattered reports are a mixture of disparate, sometimes outdated regimens with small numbers, and some with some series dating back over two decades. However, at least four groups have reported prospective clinical trials exploring multimodality therapy for locally advanced thymoma.11–14 Berruti et al. conducted a prospective clinical trial of cisplatin, doxorubicin, vincristine, and cyclophosphamide in patients with stage III and IVa thymoma. They observed that five of six patients had a partial response and then went on to surgery. Despite this high response rate, only one patient achieved a complete surgical resection, the goal of induction therapy. The largest prospective clinical trial reported in this setting was conducted between 1990 and 2000 at the M.D. Anderson Cancer Center, where patients with locally advanced thymoma received induction cisplatin, doxorubicin, cyclophosphamide, and prednisone, followed by surgery, radiation, and consolidation chemotherapy. In that study, 17 of 22 patients had a radiographic response after chemotherapy and six of 16 patients were found to have greater than 80% tumor necrosis at the time of surgical resection. Finally, most recently, Kunitoh et al.14 reported the results of the Japan Clinical Oncology Group evaluation of weekly, dose dense chemotherapy followed by surgery for patients with locally advanced thymoma. In this study, the investigators observed a
S324
62% response rate and 14% complete pathologic response rate. These trials emphasize that prospective phase 2 trials for patients with locally advanced thymoma are feasible.
IMPROVING ON INDUCTION THERAPY FOR THYMOMA BY ADDITION OF RADIOTHERAPY TO CHEMOTHERAPY Radiation therapy is used to treat thymoma in patients who cannot undergo complete surgical resection and is a common component of postoperative therapy for patients with locally advanced disease. In a variety of diseases, combining radiation therapy with chemotherapy has been demonstrated to improve response rates and increase the rate of cure for potentially unresectable disease (e.g., stage III non-small cell lung cancer, rectal cancer). This approach, retrospectively reviewed by Wright et al.,15 has been associated with a 40% rate of more than 90% tumor necrosis after combined cisplatin, etoposide, and radiation therapy for patients with locally advanced thymoma. To prospectively explore the value of incorporating radiation therapy into conventional chemotherapy treatment plan for locally advanced thymoma, Korst and colleagues are conducting a phase 2 trial of cisplatin, etoposide, and concurrent radiotherapy for patients with locally advanced thymoma (NCT00387868). This trial rigorously defines tumor characteristics that make patients eligible for enrollment, including tumor more than 8 cm in size, those between 5 and 8 cm with multifocal calcification, heterogeneous appearance, irregular borders or great vessel invasion or encirclement, or tumors less than 5 cm with great vessel invasion or encirclement. The primary endpoint of this clinical trial is complete pathologic response. After surgical resection, based on the findings at the time of surgery, patients are treated with observation, additional chemotherapy, or additional concurrent chemoradiotherapy (Figure 1).
Copyright © 2010 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 5, Number 10, Supplement 4, October 2010
Induction Therapy for Locally Advanced Thymoma
FIGURE 1. Schema of induction chemoradiation trial.
FIGURE 2. Schema of cetuximab, cisplatin, doxorubicin, and cyclophosphamide induction chemotherapy trial.
IMPROVING ON INDUCTION THERAPY FOR THYMOMA BY ADDITION OF TARGETED THERAPIES In many advanced malignancies, significant improvements in response rate and overall survival have been observed after the addition of biologic therapies suggesting that by incorporating this approach, we may improve outcomes for patients with thymoma. Staining for epidermal growth factor receptor (EGFR) by immunohistochemistry is observed in a high percentage of thymomas across all histologic types and stages of disease.16 However, activating EGFR mutations are rare with only two exon 21 mutations found in 29 thymic tumors analyzed.17 Cetuximab is a monoclonal antibody directed against EGFR that has demonstrated activity in patients with colorectal cancer, squamous cell cancer of the head and neck, and non-small cell lung cancer. Moreover, two separate reports documenting clinical responses to cetuximab in patients with advanced thymoma support the concept that EGFR inhibition is a promising therapeutic avenue.18,19 Partial responses were observed in three patients who had metastatic disease and had progressive disease after at least two lines of prior therapy. In two patients, a reduction in fluorodeoxyglucose uptake by positron emission tomography was noted as well. Taken together, these data suggest that incorporation of cetuximab with chemotherapy in patients with locally advanced thymoma may improve the radiographic and pathologic response rates and rate of complete resections. To explore the incorporation of cetuximab into a preoperative chemotherapy regimen, there is an ongoing phase II clinical trial of cetuximab with cisplatin, doxorubicin, and cyclophosphamide in patients with locally advanced thymoma (Figure 2) (NCT01025089). This clinical trial aims to enroll a total of 28 patients and uses the primary endpoint of pathologic complete response rate. Of note, only patients with thymoma are included and all patients with thymic carcinoma are excluded from this clinical trial. To prospectively evaluate the role of cetuximab alone in these patients with locally advanced thymoma, patients receive an initial 4 weeks of cetuximab before beginning chemotherapy combined with cetuximab. Computed tomography scans will assess response to cetuximab by itself as well as to cetuximab in combination with chemotherapy. All patients will undergo surgical resec-
tion with a goal of complete resection. Additional exploratory endpoints include evaluating the role of positron emission tomography scan for identification of sites of disease and predicting response to therapy and outcomes, pathologic predictors of response to chemotherapy and cetuximab. Given the importance of complete resection in the optimal management of thymoma, ongoing studies hope to define the most active combinations of therapy for further validation in clinical trials. Prospective clinical trials are the model for how we should proceed for evaluating therapy for locally advanced thymomas. The described ongoing clinical trials will teach us about the value of incorporating radiation therapy or EGFR-targeted therapy into preoperative therapy for thymoma. Results of ongoing prospective clinical trials for patients with advanced thymoma will also lead to new hypotheses for therapeutic approaches in treatment of locally advanced thymoma. Induction therapy studies provide a unique opportunity for evaluating tissue biomarkers to better understand tumor biology and predict response to the therapies that are currently being evaluated. REFERENCES 1. Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995;60:908 – 913; discussion 914. 2. 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. 3. 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. 4. 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;61:521–524. 5. Huang J, Riely GJ, Rosenzweig KE, et al. Multimodality therapy for locally advanced thymomas: state of the art or investigational therapy? Ann Thorac Surg 2008;85:365–367. 6. Ishikawa Y, Matsuguma H, Nakahara R, et al. Multimodality therapy for patients with invasive thymoma disseminated into the pleural cavity: the potential role of extrapleural pneumonectomy. Ann Thorac Surg 2009; 88:952–957. 7. Wright CD, Kessler KA. Surgical treatment of thymic tumors. Semin Thorac Cardiovasc Surg 2005;17:20 –26. 8. Giaccone G, Ardizzoni A, Kirkpatrick A, et al. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814 – 820.
Copyright © 2010 by the International Association for the Study of Lung Cancer
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Journal of Thoracic Oncology • Volume 5, Number 10, Supplement 4, October 2010
9. Loehrer PJ Sr, Chen M, Kim K, et al. Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 1997;15:3093– 3099. 10. Lemma GL, Loehrer PJ, Lee JW, et al. A phase II study of carboplatin plus paclitaxel in advanced thymoma or thymic carcinoma: E1C99. J Clin Oncol 2008;26:8018. 11. Berruti A, Borasio P, Roncari A, et al. Neoadjuvant chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide (ADOC) in invasive thymomas: results in six patients. Ann Oncol 1993;4:429 – 431. 12. 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. 13. Macchiarini P, Chella A, Ducci F, et al. Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer. 1991;68:706 –713. 14. Kunitoh H, Tamura T, Shibata T, et al. A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606). Br J Cancer 2010;103:6 –11. 15. Wright CD, Choi NC, Wain JC, et al. Induction chemoradiotherapy
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16. 17. 18. 19. 20. 21. 22. 23. 24.
followed by resection for locally advanced Masaoka stage III and IVA thymic tumors. Ann Thorac Surg 2008;85:385–389. Henley JD, Koukoulis GK, Loehrer PJ Sr. Epidermal growth factor receptor expression in invasive thymoma. J Cancer Res Clin Oncol 2002;128:167–170. Yoh K, Nishiwaki Y, Ishii G, et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008;62:316 –320. Farina G, Garassino MC, Gambacorta M, et al. Response of thymoma to cetuximab. Lancet Oncol. 2007;8:449 – 450. Palmieri G, Marino M, Salvatore M, et al. Cetuximab is an active treatment of metastatic and chemorefractory thymoma. Front Biosci 2007;12:757–761. Bretti S, Berruti A, Loddo C, et al. Multimodal management of stages III-IVa malignant thymoma. Lung Cancer 2004;44:69 –77. 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. 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; discussion 1872. Jacot W, Quantin X, Valette S, et al. Multimodality treatment program in invasive thymic epithelial tumor. Am J Clin Oncol 2005;28:5–7. Rea F, Sartori F, Loy M, et al. Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 1993;106:543–549.
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