Long-Term Outcome After Multimodality Treatment for Stage III Thymic Tumors

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1 Long-Term Outcome After Multimodality Treatment for Stage III Thymic Tumors Federico Venuta, MD, Erino A. Rendina, MD, Flavia Longo, MD, Tiziano De Giacomo, MD, Marco Anile, MD, Edoardo Mercadante, MD, Luigi Ventura, Mattia F. Osti, MD, Federico Francioni, MD, and Giorgio F. Coloni, MD Departments of Thoracic Surgery, Oncology, Statistics, and Radiotherapy, University of Rome La Sapienza, Rome, Italy Background. Surgery remains the cornerstone of therapy for thymic tumors, but the optimal treatment for advanced, infiltrative lesions is still controversial. The introduction of multimodality protocols has substantially modified survival and recurrence rate. We reviewed our 13-year prospective experience with multimodality treatment of stage III thymoma and thymic carcinoma. Methods. Since 1989 we have prospectively used a multimodality approach in 45 stage III thymic tumors. Sixteen patients (35%) had myasthenia gravis. Twentythree patients (51%) had pure or predominantly cortical thymoma (group 1), 11 (24.5%) had well-differentiated thymic carcinoma (group 2), and 11 (24.5%) had thymic carcinoma (group 3). Tumors that were not considered radically resectable at preoperative workup underwent biopsy and induction chemotherapy (15 patients, 33%) followed by surgical resection; all patients were referred for adjuvant chemoradiotherapy. Results. No operative mortality was recorded; 1 treatment-related death during adjuvant chemotherapy was observed in group 1. Complete resection was feasible in 91% of patients in groups 1 and 2 and 82% in group 3. The overall 10-year survival was 78%. Ten-year survival for groups 1 and 2 was 90% and 85%, respectively; 8-year survival for group 3 was 56%. During follow-up, tumor recurrence was noted in 3 patients (13%) from group 1, 3 (27%) from group 2, and 3 (27%) from group 3. Conclusions. Multimodality treatment with induction chemotherapy (when required) and adjuvant chemoradiotherapy offers encouraging results for stage III thymic tumors; the outcome is more favorable for cortical thymoma and well-differentiated thymic carcinoma. (Ann Thorac Surg 2003;76: ) 2003 by The Society of Thoracic Surgeons Epithelial tumors of the thymus display a remarkable polymorphism in their clinical presentation: from an indolent, encapsulated mediastinal mass to lesions infiltrating the surrounding structures and producing distant metastases. The degree of aggressiveness can be predicted by clinical staging [1, 2] and by the histogenetic classifications currently available [3 5]. In fact, evidence in the literature [6 11] suggests that cortical thymoma (CT), well-differentiated thymic carcinoma (WDTC), and thymic carcinoma (TC) show a progressively less favorable prognosis. Surgery remains the cornerstone of therapy and complete resection should be considered the gold standard, because debulking has been reported to offer no survival advantage over simple biopsy [12 16]. Stage III thymic tumors are defined according to the Masaoka classification [1] by macroscopic invasion into neighboring organs without metastasizing. In this group of patients complete resection may sometimes be unfeasible and preoperative workup may fail in defining suitable candidates for primary surgery. However, even when no residual tumor is left behind, local and distant Presented at the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31 Feb 2, Address reprint requests to Dr Venuta, Department of Thoracic Surgery, University of Rome La Sapienza, Policlinico Umberto I, V.le del Policlinico, Rome 00161, Italy; sofed@libero.it. recurrences are often observed, with an average 5-year survival of 65% [17]. In our previous experience, without any standard approach to multimodality therapy, we observed a 10-year survival of 47% [18]. Induction treatment and adjuvant protocols may contribute to improve radicality and prognosis [19 22]. For this reason in 1989 we started a prospective multimodality therapy protocol for epithelial tumors of the thymus [22] including stage III lesions; the results of this study are presented hereby. Patients and Methods Since 1989 we have prospectively used a multimodality approach in 45 patients with stage III epithelial thymic tumors (age years; 16 women and 29 men). Patients undergoing biopsy only were excluded from this study. Twenty-three patients (51%) had pure or predominantly CT (group 1); 11 (24.5%) had WDTC (group 2); and 11 (24.5%) had TC (group 3). Sixteen patients (35%) had myasthenia gravis (MG): 11 in group 1 (48%), 3 in group 2 (27%), and 2 in group 3 (18%). One patient with WDTC had systemic lupus erythematosus. Preoperative workup included chest computed tomography scan in all patients and magnetic resonance in 67% to assess the degree of invasion of the surrounding organs. Patients with resectable stage III lesions (invasion of the superior 2003 by The Society of Thoracic Surgeons /03/$30.00 Published by Elsevier Inc doi: /s (03)

2 Ann Thorac Surg VENUTA ET AL 2003;76: MULTIMODALITY TREATMENT OF THYMIC TUMORS vena cava, pericardium, or limited invasion of the mediastinal pleura and lung) underwent surgical intervention; all patients with tumors that at preoperative workup were not considered completely resectable due to the extensive invasion of the surrounding organs underwent invasive staging and biopsy (anterior mediastinotomy or video-assisted thoracoscopy), induction (neoadjuvant) chemotherapy, and then surgical resection. No preoperative radiotherapy was administered. In the first 8 patients neoadjuvant chemotherapy included cisplatin (75 mg/m 2 on day 1), epirubicin hydrochloride (100 mg/m 2 on day 1), and etoposide (120 mg/m 2 on days 1, 3, and 5) repeated three times every 3 weeks; in the rest of the patients the induction regimen included cisplatin (50 mg/m 2, adriblastin (50 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) repeated three times every 3 weeks. Computed tomography scan was repeated after induction chemotherapy to evaluate the response: complete remission was described as the complete disappearance of the tumor mass; partial remission was defined as a decrease of 50% or more in the size of the lesion; and stable disease was defined as a regression of less than 50% of the mass with no new lesions appearing and no deterioration of patient performance. After operation patients received adjuvant chemotherapy (same regimen as that provided preoperatively repeated two or three times) and radiotherapy. A dose of 40 Gy was usually administered to patients undergoing complete resection and 50 to 60 Gy in case of incomplete resection; the mediastinum or residual tumor areas were irradiated in 3 to 5 weeks with five fractions per week. In 15 patients (33%) complete resection could not be anticipated at preoperative workup; evidence of unresectability was constituted by invasion of the great vessels, the chest wall and, more frequently, an extended infiltration of the mediastinum that would pose serious problems at the time of surgery. These patients underwent biopsy (8 by thoracoscopy, 7 by anterior mediastinotomy) and induction chemotherapy followed by surgical resection through median sternotomy. The remaining 30 patients underwent primary surgery. The site of infiltration of the surrounding structures in all patients is reported in Table 1. Univariate analysis was performed to assess the prognostic factors on overall survival: the data were analyzed with respect to age ( 50 years or 50 years or older), sex (male or female), histologic classification (CT, WDTC, or Table 1. Site of Infiltration of Surrounding Structures Structure n (%) Lung 23 (51) Pericardium 16 (36) Superior vena cava 9 (20) Left brachiocephalic vein 2 (4.4) Phrenic nerve 5 (11) Ascending aorta 2 (4.4) Main pulmonary artery 3 (6.6) Chest wall 3 (6.6) Table 2. Results of Univariate Analysis Variable Age 0.3 Sex 0.95 Myasthenia gravis 0.8 Induction chemotherapy 0.3 Histology (Group 1 2 versus III) 0.06 Recurrence Completeness of resection 0.3 TC), MG (present or absent), administration of induction chemotherapy (yes or no), completeness of resection (complete or incomplete), and recurrence (yes or no) (Table 2). Survival curves were calculated from the time of diagnosis to death or last follow-up. Actuarial curves were constructed according to the Kaplan Meier method [23]. Disease-free survival and complete continuous remission curves were also calculated. Differences between variables were analyzed with the 2 test and Student s t test. Survival curves were compared with the two-sided log rank test [24] and the Wilcoxon test. Multivariate analysis was performed with the Cox proportional hazard model on overall and disease-free survival (Tables 3 and 4). A probability level (p) of 0.05 was chosen for statistical significance. Statistical analysis was performed using SPSS software (SPSS Inc, Chicago, IL). Results All patients but 3 completed the treatment plan: an 82-year-old woman with CT and MG undergoing complete resection received postoperative radiotherapy only; adjuvant radiotherapy alone was also administered to a patient with CT and MG because the postoperative course was complicated with pulmonary embolism. One treatment-related death during postoperative chemotherapy (brain hemorrhage in a patient with severe thrombocytopenia) was observed in group 1; this patient did not receive adjuvant radiotherapy. No major complications were observed during induction chemotherapy. Nonhematologic toxicity was usually mild and included stomatitis, alopecia, nausea, and vomiting. Esophagitis developed in 1 patient after postoperative radiotherapy. Treatment Response Fifteen patients (33%) received neoadjuvant chemotherapy (9 [39%] in group 1, 2 [18%] in group 2, and 4 [36%] in group 3); at postinduction computed tomography scan 2 patients (13.3%) had complete response, 8 (53.3%) had Table 3. Multivariate Analysis Using Cox Proportional Hazard Model for Overall Survival HR Coefficient p Histology Recurrence HR hazard ratio p GENERAL THORACIC

3 1868 VENUTA ET AL Ann Thorac Surg MULTIMODALITY TREATMENT OF THYMIC TUMORS 2003;76: Table 4. Multivariate Analysis Using the Cox Proportional Hazard Model for Disease-Free Survival HR Coefficient p Histology TTR 40 months TTR 40 months HR hazard ratio; TTR time to relapse. partial response, and 5 (33.3%) had stable disease; however, only 1 (7%) had complete histologic remission. No progression of the disease was observed during induction chemotherapy. Tumor downstaging to stage II occurred in 3 patients (20%): regression of chest wall invasion in 2 and lung involvement in 1 (preinduction staging was confirmed by anterior mediastinotomy and thoracoscopy); at operation they presented only capsular infiltration. Complete surgical resection was feasible in 91% of patients in groups 1 and 2 and in 82% of group 3. Two patients (13%) had incomplete resection after induction chemotherapy: radiologic evidence of invasion of the great vessels (ascending aorta and main pulmonary artery in both) was confirmed at anterior mediastinotomy before induction chemotherapy; extended full-thickness tumor invasion of the vessels was still present at operation and was the reason for incomplete resection in both. Mediastinal invasion in 3 additional patients was too extended to allow complete resection, and only debulking could be performed. No operative mortality was observed. Major complications after surgery were observed in 3 patients (6.7%) and included sternal dehiscence, pulmonary embolism, and recurrent bilateral pleural effusions; the first 2 patients previously received induction chemotherapy, the latter had CT associated with systemic lupus erythematosus and pleural effusions before the operation (multiple pleural biopsies proved negative for neoplastic invasion). No patient was lost to follow-up. The mean follow-up was months (2 to 170 months); the mean follow-up for patients still alive at the last follow-up was months (range 6 to 170 months). The 10-year actuarial survival in all patients was 78% (Fig 1), whereas the cumulative disease-free survival was 53% (Fig 2). Overall and disease-free survival curves for the 3 groups are reported in Figures 3 and 4. The diagnosis of TC significantly affected survival. Ten-year survival for patients receiving complete resection was 80% compared with 60% for patients with incomplete resection (p 0.3). Survival for patients receiving induction chemotherapy was 90% compared with 71% for patients undergoing primary surgery (p 0.2). The results of univariate and multivariate analysis are reported in Tables 2, 3, and 4. Recurrence During follow-up 9 patients (20%) had tumor recurrence at a mean of months after surgery: 3 (13%) in group 1, 3 (27%) in group 2, and 3 (27%) in group 3. Four Fig 1. Overall survival. (Pts patients.) of these patients previously received induction chemotherapy. Intrathoracic sites of recurrence were the lung (8 patients), pleura (3 patients), and mediastinum (1 patient). Extrathoracic metastases were cerebral and spinal in one case each (22%) and were associated, respectively, with pulmonary and pleural metastases. In 2 patients the pleural and lung recurrence could be resected; the spinal recurrence was resected by the neurosurgeons. All patients with recurrence underwent additional chemoradiotherapy. The early onset of recurrence ( 40 months after surgery) had a negative impact on prognosis (Figures 5 and 6) as confirmed by multivariate analysis (Table 4). Five patients (11%) died of their disease at a mean of months after the operation; 3 patients died from causes not related to the tumor (pulmonary embolism, myocardial infarction, and brain hemorrhage) at a mean Fig 2. Cumulative disease-free survival. (Pts patients.)

4 Ann Thorac Surg VENUTA ET AL 2003;76: MULTIMODALITY TREATMENT OF THYMIC TUMORS 1869 GENERAL THORACIC Fig 3. Survival according to grouping by histology. (Pts patients.) follow-up of months after the operation. Four patients with recurrence are still alive. Comment The optimal treatment for epithelial thymic tumors has long been debated; outcome is related to a number of variables: staging, histology, completeness of resection, and recurrence of the disease [25], the effects of which may potentially affect long-term survival even years after a successful operation. Early stage (I and II) tumors can always be completely resected; this goal may be more difficult to achieve for stage III lesions. Invasion of the surrounding structures, even if extended resections can Fig 4. Disease-free survival according to grouping. (Pts patients.) Fig 5. Survival plotted according to the onset of recurrence. (Pts patients.) often be performed, may pose additional problems. At preoperative workup it can be difficult to ascertain if complete resection is feasible; computed tomography, magnetic resonance, and invasive staging may help to select patients for primary surgery; however, incomplete resections are not rare and are usually considered an unfavorable prognostic factor [12, 14, 15, 26]. Stage III tumors also shows a relatively high recurrence rate: up to 57% in the absence of any postoperative treatment [27]. The optimal treatment at this advanced stage has yet to be defined. Complete resection, postoperative control of residual tumor, and prevention of local and distant recurrence should be pursued if cure rather than prolonged survival is to be achieved. Without a standardized induction or adjuvant treatment we have previously able to achieve a 47% 10-year survival [18, 22]. To improve these results we designed a multimodality approach [22]. When complete resection cannot be anticipated at preoperative workup, induction chemotherapy is administered to reduce the size of the tumor and the extent of infiltration. Preinduction histology is extremely important because chemotherapy can be so effective that sometimes no tumor is found in the surgical specimen. In our experience, adequate histologic material can be easily obtained with multiple biopsies through a minimally invasive approach; this policy may also help correct staging. Induction chemotherapy yields good local control by shrinking the tumor mass and reducing infiltration. This resulted in a complete resection rate of 87% in the group of patients undergoing induction therapy; this achievement is important because at preoperative workup complete resection was judged to be not feasible among these patients. However, true downstaging was possible only in 3 of our patients. Neoadjuvant chemotherapy usually results in dense fibrosis involving the structures at the site of infiltration and could make the

5 1870 VENUTA ET AL Ann Thorac Surg MULTIMODALITY TREATMENT OF THYMIC TUMORS 2003;76: Fig 6. Complete continuous remission curve. (Pts patients.) dissection more difficult. For this reason en bloc resection may be sometimes required even if true neoplastic invasion is not histologically proven. The administration of induction chemotherapy allowed the achievement of complete resection in patients otherwise not suitable for primary surgery; this group of patients showed a benefit in survival (90% versus 70% at 10 years), although the difference did not reach statistical significance, probably due to the small size of the group. The multimodality approach was always completed by postoperative therapy, as suggested by other authors [19 21]. Epithelial thymic tumors are radiosensitive, and radiation therapy is generally accepted after partial resection; however, the definitive evidence of its efficacy is hard to define because there are no prospective trials, and results from retrospective series are usually affected by the small number of patients in the nonirradiated group [13, 28 31]. The benefit of radiation therapy in patients with completely resected invasive thymic tumors is even more difficult to assess. Most of the studies retrospectively address a mixed population of tumors: stage II, III, and even IV lesions are often considered together and extrapolating the results for each of these categories can be difficult. In addition, histology poses several problems: many reports are referred to old nonhistogenetic classifications and often consider both thymoma and thymic carcinoma together without comparing the results. Although the treatment protocol for these histologic subsets can be identical, results should be kept separate; in fact it is now clearly demonstrated that CT, WDTC, and TC (B2, B3, and C categories of the new WHO classification) are usually more aggressive, present at a more advanced stage, and show a less favorable prognosis along with the decrease of histologic differentiation. Despite conflicting data, the vast majority of authors support the administration of adjuvant radiation therapy for patients with invasive tumors after complete resection [1, 12, 32, 33]. However, even after adjuvant mediastinal irradiation, recurrence is not infrequent (Table 5) [13, 14, 16, 25, 29, 34 39]. In this subset of patients local recurrence may occur, but the most common pattern of failure after complete resection and mediastinal irradiation is represented by pleural dissemination or lung metastases [1, 25, 30, 36, 40]. This complication, which may appear years after surgical resection, is more frequent when the primary thymic tumor invades the pleura, suggesting that some patients may already have latent microscopic pleural dissemination at the time of surgery [26]. Extrathoracic metastases are unusual but not rare [41 43], and occurred in 2 of our patients (4.4%). Recurrence is more frequent in patients with thymic carcinoma and is associated with a negative affect on survival, even if resection is sometimes still feasible [25]. Early onset of recurrence ( 40 months after surgery) should be considered a negative prognostic factor and should probably be interpreted as a partial resistance to the drugs currently used; rescue therapy should be performed with different drugs. Table 5. Survival and Recurrence Rates in Patients With Stage III Thymoma and Thymic Carcinoma Author (Year) Patients (n) 5-Year Survival Rate (%) Recurrence Rate (%) Histology Postop. Radiotherapy Kruger (1988) Thymoma Yes Curran (1988) Thymoma Yes/no Nakahara (1988) Thymoma Yes Urgesi (1990) Thymoma Yes Jackson (1991) Thymoma Yes Hanjuda (1992) Thymoma Yes Latz (1997) Thymoma carcinoma Yes Gripp (1998) Thymoma Yes Wilkins (1999) Thymoma carcinoma Yes/no Myojin (2000) Thymoma carcinoma Yes/no Lardinois (2000) Thymoma carcinoma Yes/no Ogawa (2002) Thymoma Yes

6 Ann Thorac Surg VENUTA ET AL 2003;76: MULTIMODALITY TREATMENT OF THYMIC TUMORS Conclusions Comparing previous reports and our previous experience, the outcome of our study is encouraging. Multimodality therapy contributed to improve survival, especially for patients with CT and WDTC (80% and 90%, respectively, at 10 years); we experienced a 10-year survival rate of less than 50% before using this protocol [18, 22]. Distant metastases still occur and have a detrimental effect on prognosis, especially when they occur early during follow-up; however, their incidence can be considered acceptable, especially for CT, given the stage of the primary tumor. Thymic carcinoma still represents an aggressive entity that is difficult to cure. We thank Paola Fazi, MD, for her invaluable help in reviewing the manuscript. References 1. Masaoka A, Monden Y, Nakahara K, Tanaka T. Follow up study of thymoma with special reference to their clinical stage. 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7 1872 VENUTA ET AL Ann Thorac Surg MULTIMODALITY TREATMENT OF THYMIC TUMORS 2003;76: Lardinois D, Rechsteiner R, Lang RH, et al. Prognostic relevance of Masaoka and Muller-Hermelink classification in patients with thymic tumors. Ann Thorac Surg 2000;69: Ogawa K, Toita T, Kakinohana Y, Kamata M, Koja K, Genga K. Postoperative radiation therapy for completely resected invasive thymoma: prognostic value of pleural invasion for intrathoracic control. Jpn J Clin Oncol 1999;29: Batata M, Martini N, Huvos A, et al. Thymomas: clinicopathologic features, therapy and prognosis. Cancer 1974;34: Chainian AP, Bhardwaj S, Meyer RJ, et al. Treatment of invasive or metastatic thymoma: report of eleven cases. Cancer 1981;47: Couture MM, Mountain CF. Thymoma. Semin Surg Oncol 1990;6: DISCUSSION DR LARRY R. KAISER (Philadelphia, PA): Federico, I enjoyed the paper very much. I just had a few questions for you. You mentioned in those cases that you considered unresectable that you do a biopsy and then treat them with induction therapy prior to operation. What about the patients who you do consider to be resectable? Do you make a preoperative diagnosis in those patients? What criteria do you use to determine whether someone has a resectable tumor? DR VENUTA: Thank you, Larry, for your comments and questions. Histology should always be obtained before induction chemotherapy. Preoperative radiological workup is always insufficient to define the nature of a mediastinal tumour; moreover, it has been reported in the literature that induction chemotherapy could allow complete response, and we have experienced this in one case. For this reason, at operation, it could be difficult to find the appropriate histology. Invasive staging through thoracoscopy or anterior mediastinotomy could help not only to assess operability, but also histology. Preoperative invasive staging is also indicated to assess operability, even if this endeavor is sometimes difficult, as it is for stage IIIB lung cancer. In 2 patients with invasion of the chest wall we correctly staged them by thoracoscopy proving the infiltration by histology; these tumors were downstaged by induction chemotherapy and turned out to be stage II at the time of operation. Complete resection may be difficult to be anticipated; an assessment is obviously easier at the operative table, with the chest open. For induction chemotherapy we consider patients who have extensive infiltration of the mediastinum and its structures, and patients with an evident invasion of the arterial vessels, such as the ascending aorta or the main pulmonary artery. At operation, the main reason for incomplete resection was invasion of these two vascular structures, persisting after induction chemotherapy; these patients received debulking. In 3 other patients, invasion of the mediastinum was so extended and involved so many structures that complete resection was not feasible; these patients also underwent incomplete resection. DR CAMERON D. WRIGHT (Boston, MA): A great presentation and tremendous results. I have two comments and questions. One, how do you differentiate clinically between stages II and III thymoma to select patients: by preoperative computed tomography or magnetic resonance imaging? What are the subtle differences you found on these scans between resectable and unresectable disease? Obviously that judgment call is difficult to make, but more details about your criteria would help us to better select these patients for induction treatment. Two, we know that thymoma is both a radiation-sensitive and chemotherapy-sensitive tumor, and that complete resection is one of the keys to prolonged survival. Why not combine the two procedures preoperatively? Our personal approach is a combination concurrent chemoradiotherapy followed by resection for these tumors. DR VENUTA: Doctor Wright, thank you for your comments and questions. I will answer the second question first. As you mentioned, thymic tumors are extremely sensitive to radiotherapy with impressive responses in terms of shrinking of the mass. However, we simply do not want to irradiate the operative field, and in particular the sternum, before the operation, even if preoperative radiotherapy has been reported to be effective. Concerning your first question, personally I do not think that staging these tumors as stage II or III preoperatively is so important. It is important to decide if complete resection is feasible, and if not (and these would obviously be stage III), whether induction chemotherapy could be of help. As you mentioned the difference may be subtle and we have no precise criteria, especially in cases in which tumor has invaded the surrounding organs. Obviously with the chest open any decision about resectability would be much easier. Invasive staging could help, as I mentioned earlier to Dr Kaiser. DR ERIC VALLIERES (Seattle, WA): Nice work, Federico. Do you assess tumor size to determine whether a thymic neoplasm is going to be resectable or not? If so, do you have a size limit at which you decide to automatically provide induction therapy? DR VENUTA: Thank you, Eric. I do not believe that size is important for ascertaining the possibility of complete resection. We all know that sometimes huge tumors stay there without invading any structure, and some small tumors are aggressive and infiltrate the vessels. Huge tumors may be more difficult to evaluate radiologically because they may compress the surrounding organs and give a wrong idea of their aggressiveness. A typical difficult situation to judge concerns tumors that slide toward the left, along the pulmonary artery, toward the aortopulmonary window. Size can be an issue to assess prognosis in these cases. It has been described that huge tumors may show a worse prognosis, and we could treat these tumors differently in the future. However, as long as we rely on the Masaoka classification, we do not include dimensions among the criteria for deciding postoperative therapy.