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Ann Thorac Surg 2005;79:1840-1844
© 2005 The Society of Thoracic Surgeons

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Original article: General thoracic

Advanced Stage Thymomas and Thymic Carcinomas: Results of Multimodality Treatments

^a Division of Thoracic Surgery, Cardiac and Thoracic Department, University of Pisa, Pisa, Italy
^b Division of Pathology, Department of Oncology, University of Pisa, Pisa, Italy

Accepted for publication December 28, 2004.

^_* Address reprint requests to Dr Lucchi, Division of Thoracic Surgery, Cardiac and Thoracic Department, University of Pisa, Via Paradisa 2, Pisa 56124, Italy (E-mail: m.lucchi{at}med.unipi.it).

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
BACKGROUND: With the aim of evaluating the results of multidisciplinary approaches, we reviewed our experience in multimodality treatment of advanced stage (III and IVA) thymic tumors.

METHODS: From 1976 to 2003, 56 patients with Masaoka stage III and IVA thymic tumors underwent a multimodality treatment. Thirty-six patients underwent neoadjuvant chemotherapy, surgery, and postoperative radiotherapy; 20 patients were treated by primary surgery and postoperative radiotherapy (n = 12), chemotherapy (n = 1) or chemoradiotherapy (n = 7). The neoadjuvant or adjuvant chemotherapy consisted of three courses of cisplatin, epidoxorubicin, and etoposide every 3 weeks. Adjuvant radiotherapy consisted of 45 Gy for complete resections or 60 Gy for incomplete resections.

RESULTS: The preoperative diagnosis of invasive thymomas was performed in a total of 29 cases: 15 by mediastinotomy, 6 by video-assisted thoracoscopic surgery, and 8 by fine-needle aspiration. In 27 cases no diagnosis was available, but in most of them a thymus-related syndrome was present. Thirty-four patients are still alive (31 disease-free), and 22 have died (2 disease-free). Ten-year survival was 48% and 45.7% for stage III and IVA thymomas, respectively. The presence of myasthenia gravis (p = 0.04) and neoadjuvant chemotherapy (p = 0.004) affected survival significantly.

CONCLUSIONS: The multimodality treatment of stage III and IVA thymic tumors allows a good long-term outcome; the neoadjuvant chemotherapy improves the resectability rate and the survival of both stages of the disease.

	Introduction

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A complete surgical resection is the main target in the treatment of thymomas [1–4]; unfortunately, it is not always achievable in stage III and IVA thymomas because of local invasion of the neighboring organs or the presence of diffuse pleural or pericardial implants [5].

Chemotherapy, at the beginning believed of scanty value [6], was revived and proved to be effective in advanced and metastatic thymic tumors [7–10]. Multimodality strategies [1, 5, 11] became more and more trimodality treatments (surgery, radiotherapy, and chemotherapy) with satisfying results [12–16]; however, which integration is the best has still not been established.

We report our experience with 56 patients, affected by stage III and IVA thymomas, who underwent multimodality treatments with the aim of determining the results of such treatments as regards resectability and survival rates.

	Material and Methods

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We analyzed 56 patients with thymic tumors (of 210 resected during the same period) who underwent a multimodality treatment between 1976 and 2003. The diagnosis of thymic tumor was reviewed and confirmed by our pathologists (F.B., G.F.) according to the World Health Organization classification [17]. Collection of data and follow-up were performed by review of medical charts and phone contact or examination of all patients. There were 35 men and 21 women, with a mean age of 53.3 years (range, 25 to 80 years). Preoperative staging included a complete history and physical examination, chest radiography, bronchoscopy, whole body computed tomography, chest nuclear magnetic resonance in some cases, abdomen ultrasonography, and bone scan.

After 1989 all the patients with clinically radiologically advanced thymic cancer (stage III and IVA), independent of the surgeon’s judgment of resectability, were enrolled in a prospective study of neoadjuvant chemotherapy with surgery and postoperative radiotherapy [12]. The neoadjuvant chemotherapy included three courses of intravenous cisplatin (75 mg/m² on day 1), epirubicin (100 mg/m² on day 1), and etoposide (120 mg/m² on days 1, 3, and 5), repeated every 3 weeks, depending on the patient’s hematologic status and in the absence of heart or general disorders. Restaging was repeated 3 weeks after the third course, and then the patients underwent surgery.

The operations were performed through a median sternotomy (n = 47), a sternothoracotomy (n = 6), and a thoracotomy (n = 3). A complete exeresis of the tumor was always attempted; whenever this proved impossible, the residual tumor was clipped to better define the radiation therapy portals. All patients underwent an extended thymectomy [18]. Preoperative and postoperative staging were performed according to the staging system of Masaoka [19].

Radiotherapy to the mediastinal or residual tumor areas was performed using opposite anterior and posterior parallel fields at doses of 45 Gy for complete resections or 60 Gy for incomplete resections delivered for a period of 5 or 6 weeks, respectively. Survival was calculated from the date of the diagnosis until the date of the last follow-up (March 31, 2004). The statistical analysis was performed by the Stat-Soft software. Results are expressed as mean ± standard deviation. Survival curves were estimated by the Kaplan-Meier product-limit method [20] and were compared by using the log-rank test. The ² test was used for comparison between proportions, whereas Fisher’s exact test was used when the cell frequencies were small. In this study, a p value less than 0.05 was considered significant in all comparisons.

	Results

Top Abstract Introduction Material and Methods Results Comment References

 
Thirty-six patients had no thymus-related syndrome, 14 had myasthenia gravis, 4 had red cell aplasia, 1 had hypogammaglobulinemia, and 1 had multiple syndromes (myasthenia gravis, red cell aplasia, thrombocytopenia, and rheumatologic syndrome). The preoperative diagnosis of thymoma was performed in 29 patients: in 15 cases by mediastinotomy, in 6 by video-assisted thoracoscopic surgery, and in 8 by computed tomography or ultrasound biopsy. In 15 cases the myasthenia gravis or red cell aplasia addressed the diagnosis, and in 12 cases we had only a clinical radiologic suspicion. According to the Masaoka staging 40 patients had stage III thymoma, and 16 had stage IVA. The postoperative pathologic diagnosis, reviewed according to the World Health Organization histologic classification, showed 3 type AB thymomas, 7 type B1, 10 type B2, 22 type B3, and 14 type C.

As regards the treatment, 36 patients underwent neoadjuvant chemotherapy, surgery, and postoperative radiotherapy (n = 25) or chemoradiotherapy (n = 11); 20 patients underwent primary surgery and adjuvant therapy consisting of radiotherapy (n = 12), chemoradiotherapy (n = 7), or chemotherapy (n = 1). The total number of courses delivered in the 36 patients who underwent neoadjuvant chemotherapy was 108 (median interval between courses being 23 days). Median granulocyte, platelet, and hemoglobin nadirs were 695/mm³, 132,000/mm³, and 10.6 g/dL, respectively; neutropenic fever occurred in 31 of the 108 courses (28.7%). The most common nonhematologic toxicities were alopecia, nausea or vomiting, and stomatitis, usually mild or moderate. No epirubicin-related cardiotoxicity was recorded during treatment. In 24 patients a major objective response was achieved, although, contrarily, we did not experience any tumoral progression. All patients underwent surgery without major technical difficulties induced by neoadjuvant chemotherapy; there was no postoperative mortality or significant perioperative complication.

The surgical route was a median sternotomy in 47 cases, a sternothoracotomy in 6, and a thoracotomy in 3. The complete resections for stage III disease were 20 of 25 (80%) and 7 of 15 (46.6%) for neoadjuvant and primary surgery groups, respectively; in stage IVA disease the complete resections were 8 of 11 (72.7%) and 2 of 5 (40%), respectively.

Thirty-four patients are still alive (31 disease-free), whereas 22 have died (2 disease-free). Of the 23 patients who experienced recurrence of disease, 10 have been reoperated on (8 for pleural implants and 2 for mediastinal relapse). Of the remaining 13 patients 3 had liver metastases (in 2 the metastases was single and were resected), 2 had bone metastases, 5 had a mediastinal relapse (judged not resectable), and 3 had multiple metastases (lung, liver, and bone).

The overall median survival was 113.2 months (Fig 1), whereas the 10-year survival was 48% and 45.7% for stage III and IVA thymomas, respectively (Fig 2).

View larger version (26K): [in this window] [in a new window]   Fig 1. Overall survival of 56 patients with stage III and IVA thymoma.

View larger version (25K): [in this window] [in a new window]   Fig 2. Survival according to the stage of disease. (NS = not significant.)

View larger version (27K): [in this window] [in a new window]   Fig 3. Survival according to the presence of thymus-related syndromes. (MG = myasthenia gravis.)

View larger version (28K): [in this window] [in a new window]   Fig 4. Survival according to the multimodality treatment (primary surgery versus neoadjuvant chemotherapy).

	Comment

Top Abstract Introduction Material and Methods Results Comment References

 
Although surgery remains the mainstay in the treatment of thymoma [2, 19], the best strategy and which multimodality treatment should be adopted in the more advanced and invasive tumors have yet to be determined. In this study we analyzed 56 patients with stage III and IVA thymic tumors, aiming to compare the results of different multimodality treatments. Despite the fact that the study is not randomized, the series (single-institution experience) is remarkable, and some important concerns can be emphasized. The selection of patients was on the basis of the preoperative workup with computed tomography or magnetic resonance: before 1989 all patients underwent surgery and adjuvant radiotherapy or chemotherapy; after 1989 all patients with clinically radiologically advanced thymic tumors (stage III or IVA) were enrolled in a prospective study of neoadjuvant chemotherapy, surgery, and postoperative radiotherapy [12]. Even though we paid attention to the selection of patients for the above-mentioned study, 7 patients (6 stage III and 1 stage IVA) were operated on primarily because we failed to predict the real staging at the preoperative workup. We inserted the patients in the present analysis believing that the two groups were comparable for oncologic characteristics, and the comparison of the two groups could give important information regarding the controversy about the most effective treatment for advanced-stage thymic tumors.

As regards the thymus-related syndromes, whose incidence is about 40% in thymic tumors [1], we observed a better survival in patients with myasthenia gravis at the time of diagnosis. It was already demonstrated in previous reports that the presence of myasthenia gravis favorably affected survival [18], but the fact that it remains significant in advanced-stage diseases proves that it is not stage-dependent, and that it is not merely attributable to an earlier diagnosis of the tumor. However, we know that the rate of thymus-related syndrome is very low in type C thymoma (thymic carcinoma), and when we excluded the 14 patients with type C thymoma from the survival analysis, the presence of myasthenia gravis lost its statistical significance.

Indeed, we did not observe any deterioration of myasthenia gravis during chemotherapy or radiotherapy administration; on the contrary, we verified some partial remissions. Such remissions are further evidence of the efficacy of chemotherapy and radiotherapy in thymic tumors and may represent an adjunctive tool to monitor the response to the treatments [21].

The World Health Organization histologic classification system, which may reflect the oncologic behavior of thymoma when all stages are considered [22–24], did not prove to be a statistically significant prognostic factor in stage III and IVA thymomas. However, type B3 and C thymomas were more frequent in advanced disease and showed worse survival rates than other histologic types.

The main goal to achieve in the treatment of thymic cancers is the complete exeresis of the neoplasm, and, on the basis of the experience with other neoplasms, it may be reached by integration of surgery, radiotherapy, and chemotherapy. Theoretically, the primary chemotherapy should reduce the bulky disease, downstage it, and increase the resectability rate. As a matter of fact, neoadjuvant chemotherapy increased the complete resection rate for both stage III and stage IVA disease. Patients with stage III and IVA, altogether, who underwent a radical resection had a more favorable outcome. On the contrary, considering only the patients who underwent neoadjuvant chemotherapy, the radicality of the resection lost its statistical significance. This finding is in contrast with some reports on neoadjuvant chemotherapy [13, 15], and it may be related to the small number of patients in the analysis. However, we also suggest the following hypothesis: even though the radicality of the operation is a prognostic factor whenever we resect an invasive thymic tumor, and this is well reported in the literature [1, 10, 13], after neoadjuvant chemotherapy it may not be so crucial, and the goal of a complete tumoral clearance may be achieved through a multimodality treatment. Moreover, radiotherapy may prove to be more effective after neoadjuvant chemotherapy and surgery, both because of an effect of radiosensibility induced by the chemotherapy and because of a smaller disease mass, and determine a better clearance of the tumoral bed.

Most of the chemotherapy regimens contain cisplatin, and good response rates have been reported. In our preliminary experience [12], we had 2 complete responses with no tumor on postoperative histologic examination; unfortunately, we did not experience any further complete response in the following cases despite having a major response rate of more than 60%. Similarly to us, Kim and colleagues [15] had 3 complete responders in 22 cases of neoadjuvant chemotherapy.

Although induction chemotherapy proved to be effective both at downstaging thymoma and at allowing resectability of tumors initially thought not to be surgical candidates, only a few reports [13, 15], with limited series of patients, focused on the survival rates. Our study provides a comparison between different multimodality treatments in advanced-stage thymic cancers. It confirms our preliminary experience [12], adding more information about the long-term outcome.

With a bigger series and a longer follow-up we have been able to compare patients with stage III and IVA thymic cancers who underwent neoadjuvant chemotherapy, surgery, and chemoradiotherapy to patients who underwent primary surgery and adjuvant chemoradiotherapy. After 1989, all preoperatively estimated invasive thymic tumors underwent neoadjuvant chemotherapy, so that, at least theoretically, patients with a better prognosis, judged as resectable and with less than stage III disease, fell into the group of primary surgery. This consideration emphasizes the results of such a comparison, as a multimodality treatment, including neoadjuvant chemotherapy, appears superior to a multimodality treatment of surgery and adjuvant chemoradiotherapy both in terms of resectability rate and survival. It is not easy to speculate why this happens with a tumor, such as thymoma, with particular biologic characteristics and with a low propensity to metastasize; it may be justified in part by the higher rate of radical resections in the neoadjuvant group, but some factors concerning its biology in respect to the pharmacogenomic and pharmacogenetic, which are still not recognized, may better explain this phenomenon.

In conclusion, in cases of thymic tumor with clinical or radiologic signs of invasiveness or of spreading to surrounding organs, we support a multimodality treatment including a cisplatin-based chemotherapy, surgery, and adjuvant chemoradiotherapy. However, it still cannot be considered a standard treatment until a large, multicenter, randomized study is performed.

	References

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