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تعداد آیتم قابل مشاهده باقیمانده : -23 مورد

Treatment of thymoma and thymic carcinoma

Treatment of thymoma and thymic carcinoma
Authors:
Avedis Meneshian, MD
Kenneth R Olivier, MD
Julian R Molina, MD, PhD
Section Editors:
Rogerio C Lilenbaum, MD, FACP
Steven E Schild, MD
Eric Vallières, MD, FRCSC
Deputy Editor:
Sonali M Shah, MD
Literature review current through: Apr 2025. | This topic last updated: Mar 21, 2025.

INTRODUCTION — 

Thymic tumors are rare neoplasms that arise in the anterior mediastinum (figure 1). The management of the most common thymic tumors, thymoma and thymic carcinoma, are presented here.

The clinical presentation, diagnosis, and staging of thymoma and thymic carcinoma, and other related topics are discussed separately.

●(See "Clinical presentation, diagnosis, and staging of thymoma and thymic carcinoma".)

●(See "Pathology of mediastinal tumors", section on 'Thymoma'.)

●(See "Pathology of mediastinal tumors", section on 'Thymic carcinoma'.)

●(See "Approach to the adult patient with a mediastinal mass".)

●(See "Thymic neuroendocrine neoplasms".)

LOCALIZED DISEASE — 

For patients with localized thymoma and thymic carcinoma, management options include surgery, preoperative chemotherapy, radiation therapy (RT), and chemoradiation (CRT). There are no randomized clinical trials that provide the optimal management strategy, and data are mostly based on observational studies. It is necessary to obtain multidisciplinary evaluation at a center of excellence with expertise in the management of thymic epithelial malignancies, with input from surgical oncology, medical oncology, and radiation oncology.

Resectable disease

Surgery — For patients with localized, resectable thymoma or thymic carcinoma, we suggest thymectomy and lymph node resection rather than less extensive surgeries or initial treatment with systemic therapy or RT. Surgery offers patients the best chance at curative therapy.

Surgery is the initial treatment for patients with localized thymoma or thymic carcinoma in whom a complete (ie, R0) resection is feasible. Patients in whom an R0 resection is feasible are those with completely encapsulated tumors or those with tumors invading readily resectable structures, such as the mediastinal pleura, pericardium, or adjacent lung. Histopathologic examination of the resection specimen is required for definitive staging and determines whether postoperative RT and/or other additional treatments are necessary. (See 'Postoperative radiation therapy' below.)

Because of the increased surgical risks, patients with myasthenia gravis should be carefully evaluated preoperatively. If signs or symptoms of myasthenia gravis are present, these should be treated prior to surgery, and care should be taken by the anesthesiology team during and after the operation to avoid respiratory failure due to myasthenia gravis. (See "Role of thymectomy in patients with myasthenia gravis", section on 'Perioperative management' and "Overview of the treatment of myasthenia gravis" and "Anesthesia for the patient with myasthenia gravis or Lambert-Eton myasthenic syndrome" and "Anesthesia for patients with an anterior mediastinal mass".)

For most patients, surgical management typically includes total (ie, extended) resection of the thymus and lymph node dissection. Various surgical approaches can be used (eg, traditional median sternotomy, video- or robotic-assisted approaches) and are discussed in more detail separately. (See "Thymectomy", section on 'Procedure'.)

The ability to achieve complete resection of thymoma or thymic carcinoma is determined by the extent of tumor, including the degree of invasion and/or adhesion of the tumor to contiguous structures [1]. Sometimes, resecting the pericardium and accompanying lung parenchyma is required to achieve a complete resection with histologically negative margins. The likelihood of long-term survival depends upon the completeness of surgical resection [1,2]. As an example, in a retrospective study evaluating the long-term outcomes of 228 patients with thymic epithelial tumors after primary surgery, incomplete tumor resection was associated with a high recurrence rate (65 percent) and a poor prognosis [2]. (See 'Prognosis' below.)

Thymomas and thymic carcinomas may be adherent to adjacent structures without being invasive. In such cases, the surgeon should identify the site of adhesion on the resection specimen so the pathologist can take careful sections from that area. An inflammatory fibrous reaction can also lead to the false impression of tumor invasion. The resection specimen should be oriented by the surgeon to identify the exact margins of the resection, which should then be inked. Radiopaque clips should be placed by the surgeon in areas of positive margins (or suspected positive margins) for later identification for possible RT. This ensures the correct sites are irradiated where positive margins exist. (See 'Postoperative radiation therapy' below.)

For those with early-stage resectable thymoma (ie, American Joint Committee on Cancer [AJCC] stage I or Masaoka stage I or II) without myasthenia gravis, total (ie, extended) thymectomy is typically the standard of care. Although the use of partial thymectomy is becoming more frequent, particularly in Asia, many clinicians in the United States consider it to be investigational. (See "Thymectomy", section on 'Extent of resection'.)

Postoperative radiation therapy — For patients with localized thymoma or thymic carcinoma who are treated with surgery, our approach to postoperative therapy is based on the tumor stage.

AJCC stage I thymoma — For patients with American Joint Committee on Cancer (AJCC) stage I (table 1) (Masaoka stage I to II (table 2)) thymoma who are treated with surgery, the selection of postoperative therapy is also based on the presence or absence of high-risk features on postoperative pathology.

●High-risk features – For patients with AJCC stage I (Masaoka stage I to II) thymoma and high-risk features for recurrence on postoperative pathology we suggest postoperative RT rather than surveillance. However, surveillance is also an appropriate alternative given data for postoperative RT in this population are limited. High-risk features for recurrence are defined as invasion into the mediastinal fat or pleura and microscopic or grossly positive surgical margins. Observational studies suggest that this approach reduces the risk of recurrence to that of patients with R0 resections that lack such features [3]. (See 'Posttreatment surveillance' below.)

●No high-risk features – Patients with AJCC stage I (Masaoka stage I to II) thymoma and no high-risk features on postoperative pathology may be offered surveillance. Such patients do not require postoperative RT given the low risk of recurrence and lack of overall survival (OS) benefit with postoperative RT. Patients should be followed with imaging of the chest using contrast-enhanced computed tomography (CT) every 6 to 12 months for two years, then annually until 10 years due to the risk of late recurrences [4]. Gadolinium-enhanced magnetic resonance imaging (MRI) of the chest is an appropriate alternative. (See 'Posttreatment surveillance' below.)

Given the low incidence of thymoma, data for the use of postoperative RT are limited to observational studies. In patients with Masaoka stage I and II thymoma who have achieved a complete resection and have no factors suggesting an increased risk of recurrence, data suggest that the addition of postoperative RT is not associated with improved OS [3,5-8]. As an example, an observational study from the National Cancer Database included over 4000 patients with any-stage thymoma (3031 patients) or thymic carcinoma (1025 patients), half of whom received postoperative RT [3]. In a subgroup analysis of those with Masaoka stage I to IIA thymoma, OS was similar for treatment with surgery followed by postoperative RT compared with surgery alone.

AJCC stage II to IIIA thymoma — For patients with American Joint Committee on Cancer (AJCC) stage II to IIIA (Masaoka stage III) thymoma, we suggest postoperative RT rather than surveillance. Such patients are at higher risk for local recurrence, and this approach is associated with a decreased risk of recurrence and improved OS.

For those with positive surgical margins (R1 resection) or macroscopic residual disease after resection (R2 resection), postoperative RT may be administered with or without concurrent chemotherapy. The decision to administer postoperative RT versus postoperative CRT is variable and is based on institutional practice, tumor stage, extent of residual disease following resection (ie, R1 versus R2 resection), and patient performance status and comorbidities. The selection and dosing of radiosensitizing chemotherapy regimens for CRT are discussed separately. (See 'Dosing and schedule' below.)

Although data are limited, studies suggest that postoperative RT is associated with OS benefit in patients with stage II to III thymoma and positive surgical margins [3].

In addition, surgeons who suspect positive surgical margins should place radiopaque clips in the appropriate areas during the surgery to accurately identify the regions that require postoperative RT. (See "Clinical presentation, diagnosis, and staging of thymoma and thymic carcinoma", section on 'Pathologic considerations'.)

Patients with stage II to III thymoma are at increased risk of recurrence because of the extent of disease. In these patients, most observational series [3,6,9-13], but not all [8,14], suggest that postoperative RT is associated with a decreased risk of recurrence and improved OS. As examples:

●An observational study from the National Cancer Database included over 4000 patients with Masaoka stage I to IIA, IIB, III, or IV thymoma (3031 patients) or thymic carcinoma (1025 patients), half of whom received postoperative RT [3]. For the subgroup of patients with thymoma, postoperative RT was associated with improved OS (hazard ratio [HR] 0.80, 95% CI 0.67-0.96). In subgroup analyses of the entire study population (both thymoma and thymic carcinoma), postoperative RT was associated with the most OS benefit in those with Masaoka stage IIB thymoma, Masaoka stage III disease, or positive surgical margins.

●An observational study from the Surveillance, Epidemiology, and End Results (SEER) database evaluated 529 patients with thymoma, most of whom (65 percent) received postoperative RT. In this study, postoperative RT was associated with superior OS (76 versus 66 percent) and disease-free survival (91 versus 81 percent) at seven years [9]. Subgroup analyses suggested that the OS benefit was limited to patients with Masaoka stage III or IV disease.

●An observational database study from the International Thymic Malignancy Interest Group included 1263 patients with Masaoka stage II or III thymoma, most (55 percent) of whom were treated with postoperative RT [10]. Postoperative RT was associated with improved OS at five years (95 versus 90 percent) and at 10 years (86 versus 79 percent). In subgroup analysis, this OS benefit was observed in patients with either Masaoka stage II or III disease.

AJCC stage I to IIIA thymic carcinoma — For patients with American Joint Committee on Cancer (AJCC) stage I to IIIA (Masaoka stage I to III) thymic carcinoma who undergo a complete (R0) resection, we suggest postoperative RT rather than surveillance. Postoperative RT is associated with reduced risk of local recurrence, and most observational data also suggest an OS advantage [3,6,8-11,14-16]. Patients with resected thymic carcinoma are also generally higher risk of local recurrence than those with resected thymoma.

An observational study from the National Cancer Database included over 4000 patients with Masaoka stage I to IIA, IIB, III, or IV thymoma (3031 patients) or thymic carcinoma (1025 patients), half of whom received postoperative RT [3]. For the subgroup of patients with thymic carcinoma, postoperative RT was associated with improved OS (HR 0.80, 95% CI 0.67-0.96). In subgroup analyses of the entire study population (both thymoma and thymic carcinoma), most OS benefit was seen in those with stage III disease or positive margins.

For those with positive surgical margins or macroscopic residual disease after resection, we suggest postoperative CRT rather than postoperative RT alone. Although there is limited evidence for adjuvant CRT in this population [16], the rationale is that such patients are at higher risk of disease recurrence and benefit from the addition of concurrent chemotherapy to RT. Selection and dosing of radiosensitizing chemotherapy regimens for CRT are discussed separately. (See 'Dosing and schedule' below.)

In a retrospective study, 632 patients with resected stage IIB and III thymic carcinoma treated with resection were either observed or treated with various postoperative therapies including adjuvant RT alone, adjuvant chemotherapy alone, or adjuvant CRT. Among the 176 patients with stage IIB disease, adjuvant therapy was associated with improved OS (HR 0.42); however, in a subgroup analysis, this OS benefit was seen only in those with positive surgical margins and not among those with R0 resection. By contrast, among those with stage III disease, adjuvant therapy was associated with improved OS (HR 0.63), regardless of surgical margin status [16]. Adjuvant CRT was also associated with improved OS in those with stage III disease but not in those with stage IIB disease. By contrast, adjuvant RT was not associated with improved OS in either those with stage II or stage III disease.

RT technique, dosing, and schedule — Intensity-modulated radiation therapy (IMRT) is the most common RT technique used to treat thymoma and thymic carcinoma. Although proton beam RT has been evaluated in thymoma and thymic carcinoma [17,18], it is not available at most institutions. The potential benefit of proton beam RT is the delivery of decreased RT doses to the adjacent normal tissues (esophagus, lungs, and heart). (See "Radiation therapy techniques in cancer treatment".)

Postoperative RT is generally administered at 45 to 54 Gy in 1.8 to 2 Gy daily fractions over five weeks to the tumor bed and immediately adjacent mediastinum. For patients with gross residual disease present following a partial resection, RT is administered at doses up to 60 Gy in 2 Gy daily fractions [4].

For patients receiving postoperative CRT, RT dosing and radiosensitizing agents are discussed separately. (See 'Dosing and schedule' below.)

Toxicities — Potential RT-related toxicities include esophagitis, pneumonitis and pulmonary fibrosis, pericarditis, and, very rarely, radiation myelitis. Late radiation sequelae include radiation lung fibrosis in the lung included in the high-dose area and a small risk of constrictive pericarditis if a very large volume of heart was included in the RT field. Other potential late complications include acceleration of coronary artery disease, cardiac events such as myocardial infarcts, and second cancers in the RT field. These late complications are of concern to young patients who have many decades of expected survival after treatment of their thymic tumors. (See "Radiation-induced lung injury" and "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

Potentially resectable disease

Approach to therapy — For patients with localized thymoma or thymic carcinoma and potentially resectable disease, we suggest initial therapy with preoperative chemotherapy rather than upfront surgery or RT, as this approach offers a chance for prolonged OS. Potentially resectable disease is defined as tumor invasion into the innominate vein, phrenic nerve(s), heart, or great vessels that is not feasible to resect upfront but could be rendered resectable with preoperative therapy to reduce tumor burden [19]. The selection of the preoperative chemotherapy regimen is discussed separately. (See 'Preoperative systemic therapy' below.)

Our approach to patients with potentially resectable thymoma or thymic carcinoma is as follows:

●Patients who will receive preoperative chemotherapy require a biopsy to establish the diagnosis of thymic neoplasm is required prior to treatment. (See "Clinical presentation, diagnosis, and staging of thymoma and thymic carcinoma", section on 'Tissue diagnosis'.)

●Patients who complete preoperative chemotherapy should be evaluated for surgery.

•Patients whose disease is rendered resectable following preoperative chemotherapy should have surgery. (See 'Surgery following preoperative systemic therapy' below.)

•Patients who undergo a complete resection should receive postoperative RT. (See 'Postoperative radiation therapy' above.)

•For patients where a complete resection cannot be accomplished following preoperative chemotherapy, we offer maximum debulking, if technically feasible, followed by postoperative RT. This approach may control residual disease and provide long-term disease-free survival for some patients. For those with thymic carcinoma and residual disease after surgery, adjuvant (ie, postoperative) chemotherapy may also be administered.

•For patients who remain unresectable following preoperative chemotherapy, options include definitive CRT or palliative systemic therapy used to treat metastatic disease. (See 'Definitive chemoradiation' below and 'Metastatic thymic carcinoma' below.)

Preoperative systemic therapy — Preoperative systemic therapy can be used for patients with potentially resectable thymoma or thymic carcinoma to reduce tumor bulk, improve the chances of surgical resection, and prolong OS [20]. In one meta-analysis of observational studies that included 266 patients with advanced thymic epithelial tumors treated with induction systemic therapy, the pooled rate of response to induction therapy and complete resection was 59 and 73 percent. Pooled 5- and 10-year OS following induction therapy was 87 and 76 percent, respectively.

Various regimens are available for use in the preoperative setting for thymomas and thymic carcinomas, but the optimal regimen has not been established in randomized trials. Additionally, the use of some preoperative regimens is extrapolated from studies of advanced unresectable or metastatic thymoma and thymic carcinoma.

Selection of therapy — For patients with potentially resectable thymoma, we suggest preoperative systemic therapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) rather than other systemic regimens. CAP results in the best clinical outcomes for thymomas and is also extrapolated from data on this regimen in the metastatic setting [21]. Appropriate alternatives include carboplatin plus paclitaxel and cisplatin plus etoposide. (See 'Cyclophosphamide, doxorubicin, and cisplatin' below.)

For patients with potentially resectable thymic carcinoma, we suggest carboplatin plus paclitaxel rather than other systemic regimens. Carboplatin plus paclitaxel results in good objective response rates (ORRs) in thymic carcinoma and is better tolerated than other regimens. This approach is also extrapolated from data on carboplatin plus paclitaxel in the metastatic setting [22,23]. Appropriate alternatives include CAP and cisplatin plus etoposide. (See 'Carboplatin plus paclitaxel' below.)

Cyclophosphamide, doxorubicin, and cisplatin — For patients with thymic epithelial tumors (thymoma or thymic carcinoma) who are receiving CAP in the preoperative setting, we administer cyclophosphamide at 500 mg/m2 intravenous [IV] day 1, doxorubicin at 50 mg/m2 IV day 1, and cisplatin at 50 mg/m2 IV on day 1, every three weeks [21]. We administer four cycles in the preoperative setting, although some patients may require up to six cycles to achieve an appropriate tumor response.

In patients with thymoma, CAP offers the best clinical outcomes including high ORRs (over 40 percent [24-28]). The use of CAP for thymic carcinoma in the preoperative setting is extrapolated from data in advanced and metastatic thymoma [21]. Supporting data and toxicities for this regimen are discussed separately. (See 'Cyclophosphamide, doxorubicin, and cisplatin' below.)

Carboplatin plus paclitaxel — For patients with thymic epithelial tumors (thymoma or thymic carcinoma) who are receiving carboplatin plus paclitaxel in the preoperative setting, we administer carboplatin at area under the curve (AUC) of 5 and paclitaxel at 200 mg/m2 IV on day 1 every three weeks. Paclitaxel may be dose-reduced to 175 mg/m2 for patients who are anticipated to not tolerate the toxicities of the higher dose (eg, age, comorbidities, preexisting underlying neuropathy). For most patients, we administer four cycles of chemotherapy in the preoperative setting, although some patients may require up to six cycles to achieve an appropriate tumor response.

In thymic carcinomas, carboplatin plus paclitaxel results in ORRs of up to 36 percent [29-33] and is better tolerated than other regimens, such as CAP. The use of carboplatin plus paclitaxel for thymic epithelial tumors in the preoperative setting is also extrapolated from data in advanced unresectable and metastatic thymoma and thymic carcinoma [22,23]. Although these studies suggested higher doses of both chemotherapy agents, lower doses of both agents are also effective and better tolerated in our clinical experience. Supporting data and toxicities for this regimen are discussed separately. (See 'Carboplatin plus paclitaxel' below.)

Carboplatin plus paclitaxel in combination with ramucirumab, an antiangiogenic agent, is also effective in patients with metastatic thymic carcinoma [34], but this regimen has not been evaluated in the preoperative setting. (See 'Carboplatin plus paclitaxel and ramucirumab' below.)

Cisplatin plus etoposide — For patients with thymoma and thymic carcinoma who are receiving cisplatin plus etoposide in the preoperative therapy, cisplatin is administered at 60 mg/m2 IV on day 1 and etoposide is administered at 120 mg/m2 IV days 1 to 3 every three weeks for four to six cycles. The use of cisplatin plus etoposide in the preoperative setting is extrapolated from data in advanced and metastatic thymoma [35]. Supporting data and toxicities for this regimen are discussed separately. (See 'Cyclophosphamide, doxorubicin, and cisplatin' below.)

Regimens less preferred or not used — Some systemic regimens are less preferred or no longer used to treat thymic epithelial tumors in the preoperative setting due to toxicity and/or complexity of administration. These include CAP with prednisone [36]; cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC) [37]; and etoposide, ifosfamide, and cisplatin (VIP) [38].

Surgery following preoperative systemic therapy — ORRs with preoperative chemotherapy and preoperative RT have ranged from 70 to 100 percent. Resectability rates following preoperative chemotherapy vary between 36 and 69 percent [36,39,40].

Aggressive surgical approaches in cases of locoregional tumor extension have ranged from pleurectomy to extrapleural pneumonectomy. It is controversial as to whether such aggressive surgical strategies prolong disease-free survival in thymic carcinomas.

For patients with phrenic nerve involvement, resection of tumor extending along one or both phrenic nerves is challenging since iatrogenic phrenic nerve injury can result in hemidiaphragm paralysis and impaired respiratory function. The risk of respiratory morbidity is greater with bilateral phrenic nerve involvement. In patients with tumor extending along one or both phrenic nerves, the risk of respiratory compromise following phrenic nerve division should be estimated preoperatively by measuring baseline respiratory function (with pulmonary function tests) and the degree to which the phrenic nerve contributes to this function (with a fluoroscopic or ultrasonographic sniff test). Subsequent management is described separately. (See "Thymectomy", section on 'Pulmonary function testing' and "Thymectomy", section on 'Handling the phrenic nerves'.)

Unresectable disease

Definitive chemoradiation — For patients with localized, unresectable thymoma or thymic carcinoma, we suggest definitive CRT rather than RT alone or systemic therapy. This approach is mainly extrapolated from data in advanced unresectable non-small cell lung cancer. (See "Management of stage III non-small cell lung cancer".)

Patients with localized unresectable thymoma or thymic carcinoma fall into at least one of the following categories:

●Patients with localized disease who are ineligible for surgery due to age, performance status, or significant comorbidities.

●Patients with AJCC stage IIIB thymoma or thymic carcinoma. Such patients typically have unreconstructable great vessel, myocardial, tracheal, or esophageal involvement, or otherwise technically unresectable disease.

●Select patients with AJCC stage IVA (Masaoka Stage IVA) thymoma or thymic carcinoma (those with localized disease and nodal metastases, with or without limited metastatic disease to the pleura or pericardium).

For patients with initially unresectable disease whose tumors are converted to potentially resectable with definitive CRT, it is reasonable to evaluate select patients for debulking surgery, as this approach improves long-term survival outcomes [41]. (See 'Surgery following preoperative systemic therapy' above.)

Patients who complete definitive CRT and are not candidates for further debulking surgery may proceed to posttreatment surveillance. In thymoma and thymic carcinoma, it is unknown whether other consolidative systemic therapy is effective following definitive CRT. (See 'Posttreatment surveillance' below.)

Dosing and schedule — For patients with thymoma or thymic carcinoma who are receiving definitive chemoradiation, we suggest weekly dosing of carboplatin (AUC of 2) plus paclitaxel (45 mg/m2) concurrently with RT for radiosensitization rather than other regimens. Cisplatin plus etoposide (PE) is also an acceptable alternative.

The use of concurrent carboplatin plus paclitaxel with RT is mainly extrapolated from studies in stage III non-small cell lung cancer [42]. The use of concurrent PE with RT is extrapolated from studies of thymoma and thymic carcinoma in the preoperative setting [40] and stage III non-small cell lung cancer [43]. We offer a total RT dose of 60 Gy in 30 daily fractions, also extrapolating from advanced lung cancer [4]. Further details on these CRT regimens in non-small cell lung cancer are discussed separately. (See "Management of stage III non-small cell lung cancer", section on 'Choice of chemotherapy' and "Management of stage III non-small cell lung cancer", section on 'Administration of radiation'.)

RECURRENT DISEASE

Localized resectable recurrent disease — For most patients with isolated resectable recurrences and no distant metastases, we suggest surgical resection rather than systemic therapy. Patients who undergo a complete surgical resection may be evaluated for postoperative radiation therapy (RT), if feasible to deliver. (See 'Postoperative radiation therapy' above.)

For the rare patient with a limited number of resectable and unresectable foci of disease (eg, local recurrences in the thymic bed and/or within the pleural cavity where an R0 resection is unattainable), we offer a combination of surgery for the resectable foci and stereotactic body radiotherapy (SBRT) for the unresectable foci [44]. Such aggressive local therapies may result in prolonged overall survival (OS) in carefully selected patients with a localized recurrent lesion (eg, a "drop" pleural metastasis).

Surgical resection of recurrent disease is associated with prolonged OS and offers the patients the chance of curative therapy [45-47]. As an example, in an observational series of 395 patients with thymoma or thymic carcinoma, 67 patients experienced tumor recurrence [45]. Of these 67 patients, 22 patients (33 percent) underwent re-resection of localized recurrent disease. OS following the second surgery varied depending upon the histology of the primary tumor; among those with World Health Organization B1, B2, and B3 tumors, five-year OS were 100, 56, and 60 percent, respectively (table 3).

Unresectable recurrent disease — For patients with unresectable recurrences, options include definitive chemoradiation (CRT) [48] or SBRT [44]. (See 'Definitive chemoradiation' above.)

Patients with recurrent disease that is widespread and metastatic are treated with systemic therapy and/or palliative RT. (See 'Metastatic thymic carcinoma' below.)

METASTATIC THYMOMA — 

For patients with advanced unresectable or metastatic thymoma, systemic therapy is the treatment of choice. Patients are encouraged to enroll in clinical trials, where available. (See 'Investigational approaches' below.)

Initial therapy — For patients with advanced unresectable or metastatic thymomas, we suggest initial treatment with cyclophosphamide, doxorubicin, and cisplatin (CAP) rather than other systemic regimens. (See 'Cyclophosphamide, doxorubicin, and cisplatin' below.)

Appropriate alternatives include carboplatin plus paclitaxel and cisplatin plus etoposide. (See 'Carboplatin plus paclitaxel' below and 'Cisplatin plus etoposide' below.)

Cyclophosphamide, doxorubicin, and cisplatin — CAP is the preferred option for initial therapy in patients with metastatic thymoma. In patients with thymoma, CAP results in the best clinical outcomes, including high objective response rates (ORRs; over 40 percent) [21,24-28].

For patients with metastatic thymic epithelial tumors (thymoma or thymic carcinoma), we administer cyclophosphamide at 500 mg/m2 intravenous [IV] day 1, doxorubicin at 50 mg/m2 IV day 1, and cisplatin at 50 mg/m2 IV on day 1, every three weeks for up to eight cycles (typically four to six cycles of chemotherapy) [21].

In a United States Intergroup trial, 29 patients with thymoma and one patient with thymic carcinoma, which was either metastatic or locally progressive, were treated with CAP every three weeks for up to eight cycles. At a median follow-up of three years, for all 30 patients, the objective and complete response rates were 50 and 10 percent, respectively. Median overall survival (OS) was 38 months [21]. The most common grade 1 to 2 toxicities with CAP were gastrointestinal such as nausea/vomiting (76 percent) and diarrhea (17 percent), mucositis (30 percent), genitourinary (43 percent), and neurologic (40 percent). Grade 3 to 4 toxicities included nausea and vomiting (10 percent), mucositis, and paresthesias (3 percent each). Four patients developed nadir white blood cell count less than 1000/microliter (14 percent), and one patient was hospitalized with febrile neutropenia.

Carboplatin plus paclitaxel — Carboplatin plus paclitaxel is another option for initial therapy in patients with metastatic thymoma. The dosing of this regimen for thymic epithelial tumors is discussed separately. (See 'Carboplatin plus paclitaxel' below.)

In an open-label, single-arm phase II trial, 46 patients with previously untreated, advanced unresectable thymoma or thymic carcinoma were treated with carboplatin (area under the curve [AUC] of 6) plus paclitaxel (225 mg/m2) every three weeks for a maximum of six cycles [22]. At a median follow-up of 59 months, among the 21 patients with thymoma, objective responses were seen in nine patients (ORR of 43 percent), including three complete responses and six partial responses. The outcomes for patients with metastatic thymic carcinoma in this study are discussed separately. (See 'Carboplatin plus paclitaxel' below.)

Cisplatin plus etoposide — Cisplatin plus etoposide is another option for initial therapy in patients with metastatic thymoma.

For patients with metastatic thymic epithelial tumors (thymoma or thymic carcinoma), cisplatin is administered at 60 mg/m2 IV on day 1 and etoposide is administered at 120 mg/m2 IV days 1 to 3 every three weeks for four to six cycles [35].

In a European Organisation for Research and Treatment of Cancer (EORTC) study, 16 patients with recurrent or metastatic thymoma received etoposide plus cisplatin every three weeks [35]. The median of six cycles were administered per patient. Objective responses were seen in nine patients (56 percent), including five complete and four partial responses. Median progression-free survival (PFS) and OS were 2.2 and 4.3 years, respectively.

Second-line therapy — For patients with metastatic thymoma who progress on platinum-based chemotherapy, we offer second-line therapy with agents not previously received. Options for include gemcitabine with or without capecitabine [49,50], pemetrexed [51], octreotide with or without prednisone for somatostatin receptor positive thymomas [52], etoposide [53], ifosfamide [54], fluorouracil (FU) plus leucovorin [55], and paclitaxel [56]. Everolimus is also effective in relapsed thymoma but is associated with severe toxicity (pneumonitis) [57].

Regimens less preferred or not used — CAP plus prednisone [36]; etoposide, ifosfamide, and cisplatin (VIP) [38]; and cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC) [37] are less preferred regimens for metastatic thymoma due to toxicity and the complexity of administration.

We do not offer immunotherapy to those with metastatic thymoma, as high rates of immune-related adverse events (irAEs) have been reported in these patients [58-62]. (See "Overview of toxicities associated with immune checkpoint inhibitors".)

As an example, in a nonrandomized phase II trial, 33 patients with thymic tumors refractory to platinum-based chemotherapy received pembrolizumab [58]. Grade ≥3 irAEs rates were higher for those with thymoma relative to those with thymic carcinoma (71 versus 15 percent), with toxicities including myasthenia gravis, myocarditis, and hepatitis. These findings led investigators to halt the inclusion of patients with thymoma or previous autoimmune disease in the trial. Full outcomes for this trial are discussed separately. (See 'Pembrolizumab' below.)

METASTATIC THYMIC CARCINOMA — 

For patients with advanced unresectable or metastatic thymic carcinoma, systemic therapy is the treatment of choice. Patients are encouraged to enroll in clinical trials, where available. (See 'Investigational approaches' below.)

Initial therapy

Carboplatin plus paclitaxel and ramucirumab — For patients with advanced unresectable or metastatic thymic carcinomas, we suggest initial treatment with carboplatin plus paclitaxel and ramucirumab rather than other systemic regimens. In a nonrandomized phase II trial, this regimen resulted in high objective response rates (ORRs) and durable overall survival (OS) and was well-tolerated [34]. For those who are ineligible for ramucirumab (an antiangiogenic agent) or have central nervous system metastases, appropriate alternatives include carboplatin plus paclitaxel, cyclophosphamide, doxorubicin, and cisplatin (CAP), and cisplatin plus etoposide. (See 'Carboplatin plus paclitaxel' below and 'Cyclophosphamide, doxorubicin, and cisplatin' above and 'Cisplatin plus etoposide' below.)

We administer carboplatin at area under the curve (AUC) of 5 on day 1, paclitaxel at 200 mg/m2 intravenous (IV) on day 1, and ramucirumab at 10 mg/kg on day 1 every three weeks for a maximum of six cycles, followed by maintenance therapy with ramucirumab alone at 10 mg/kg every three weeks until progressive disease or unacceptable toxicity [34].

In an open-label, single-arm phase II trial (RELEVANT) of 52 patients with treatment-naive advanced thymic carcinoma (14 percent with Masaoka stage IVA disease and 86 percent with Masaoka stage IVB disease) who received carboplatin plus paclitaxel plus ramucirumab, the ORR was 58 percent [34]. At a median follow-up of 32 months, median progression-free survival (PFS) and OS were 18 and 43 months. The grade ≥3 toxicity rate was 47 percent. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Carboplatin plus paclitaxel — Carboplatin plus paclitaxel is another option for initial therapy in patients with metastatic thymic carcinoma. Although comparative randomized trials are lacking, carboplatin plus paclitaxel has good ORRs in thymic carcinoma (up to 36 percent) [29-33] and is generally associated with less toxicity than other regimens used for metastatic thymic epithelial tumors.

For patients with metastatic thymic epithelial tumors (thymoma or thymic carcinoma), we administer carboplatin at AUC of 5 and paclitaxel at 200 mg/m2 IV on day 1 every three weeks for between four to six cycles of chemotherapy. Paclitaxel may be dose-reduced to 175 mg/m2 for patients who are anticipated to not tolerate the toxicities of the higher dose (eg, age, comorbidities, preexisting underlying neuropathy). Although studies in metastatic thymic epithelial tumors used higher doses of both chemotherapy agents [22,23], lower doses of both agents are also effective and better tolerated in our clinical experience.

Data for this regimen in metastatic thymic carcinoma are as follows:

●In an open-label, single-arm phase II trial, 46 patients with previously untreated, advanced unresectable thymoma or thymic carcinoma were treated with carboplatin (AUC of 6) plus paclitaxel (225 mg/m2) every three weeks for a maximum of six cycles [22]. At a median follow-up of 59 months, among the 23 patients with thymic carcinoma, objective responses were seen in five patients (ORR of 22 percent), all of which were partial responses. The outcomes in this study for those with metastatic thymoma are discussed separately. (See 'Carboplatin plus paclitaxel' above.)

●Similar results were also seen in another phase II trial of 39 patients with advanced thymic carcinoma who received carboplatin (AUC of 6) and paclitaxel (200 mg/m2) every three weeks for a maximum of six cycles [23]. In preliminary results, objective responses were seen in 14 patients (ORR of 36 percent). Median PFS and OS were eight months and not reached, respectively.

Carboplatin plus paclitaxel is generally well-tolerated, with most patients experiencing grade 1 to 2 toxicity [22]. Grade 3 to 4 toxicities included neutropenia (24 percent), sensory neuropathy (13 percent), and febrile neutropenia (4 percent). One patient developed nonlymphocytic leukemia approximately 14 months after completing therapy.

Cisplatin plus etoposide — Cisplatin plus etoposide is another option for initial therapy in patients with metastatic thymic carcinoma, extrapolating from data in metastatic thymoma [35]. Further details are discussed separately. (See 'Cisplatin plus etoposide' above.)

Second-line therapy

Pembrolizumab — For patients with thymic carcinoma who progress on platinum-based chemotherapy and have no history of autoimmune disease, we suggest second-line therapy with single-agent pembrolizumab rather than other systemic agents. In clinical trials, pembrolizumab demonstrated durable responses in patients with thymic carcinoma, which may be more pronounced in those whose tumors express programmed cell death 1 ligand 1 [63-65]. These patients should be carefully monitored for possible severe immune-related adverse events (irAEs), including myocarditis, myasthenia gravis, and hepatitis.

For patients with thymic carcinoma and autoimmune disease, we do not offer pembrolizumab. In such patients, appropriate alternatives include an antiangiogenic agent or other systemic agents used in later-line therapy. (See 'Antiangiogenic agents' below and 'Later-line therapy' below.)

Pembrolizumab is an accepted option in patients with thymic carcinoma refractory to initial chemotherapy, based on nonrandomized phase II data [58,64,65]. There are no randomized trials directly comparing immunotherapy with other subsequent-line regimens, such as chemotherapy. Data for pembrolizumab are as follows:

●In one phase II study, 40 patients with thymic carcinoma were managed with pembrolizumab for up to two years [64,65]. All patients had widespread disease and had received at least one prior systemic therapy. There were nine objective responses (23 percent), including one complete response. Responses were relatively durable, with a median duration of approximately three years and five-year OS of 18 percent [65]. Severe irAEs were seen in six cases, including two with myocarditis.

●In a nonrandomized phase II trial, 33 patients with thymic tumors refractory to platinum-based chemotherapy received pembrolizumab [58]. Partial responses were seen in 5 of 26 patients (19 percent) with thymic carcinoma and two of seven patients (29 percent) with thymoma. Median PFS was approximately six months for both groups, and duration of response was approximately 10 months for the entire study population. Pembrolizumab was well-tolerated for thymic carcinoma (grade ≥3 irAEs rates of 15 percent) but poorly tolerated for thymomas. (See 'Regimens less preferred or not used' above.)

Antiangiogenic agents — For patients with thymic carcinoma who progress on platinum-based chemotherapy and progress on (or are ineligible for) immunotherapy, options include sunitinib or lenvatinib. These antiangiogenic agents inhibit multiple tyrosine kinases, including vascular endothelial growth factor and c-KIT.

●Sunitinib – Sunitinib is an option for second-line therapy in thymic carcinoma [66,67]. In a single-arm, open-label phase II trial, 41 patients with thymic carcinoma or thymoma refractory to platinum-based chemotherapy were treated with sunitinib 50 mg daily in six-week cycles (four weeks on and two weeks off treatment) [66]. At a median follow-up of 17 months, partial responses were seen in 6 of 23 patients with thymic carcinoma (26 percent) and 1 of 16 patients with thymoma (6 percent). Grade ≥3 toxicities included lymphocytopenia fatigue, mucositis (20 percent each), and decreased left ventricular ejection fraction (8 percent). One patient died of potential treatment-related cardiac arrest.

●Lenvatinib – Lenvatinib is an option for second-line therapy in thymic carcinoma. In a single-arm, open-label phase II trial (REMORA) conducted in Japan, 42 patients with thymic carcinoma refractory to platinum-based chemotherapy were treated with lenvatinib 24 mg once daily [68]. After a median follow-up of approximately 16 months, partial responses were seen in 16 patients (38 percent), and stable disease was seen in 24 patients (57 percent). Common treatment-related adverse events included hypertension, diarrhea, hand-foot syndrome, proteinuria, hypothyroidism, and thrombocytopenia.

Later-line therapy — For treatment-refractory thymic carcinoma, options for later-line therapy, if not previously received, include gemcitabine with or without capecitabine [49,50], avelumab plus axitinib (if no prior immunotherapy) [69], etoposide [53], ifosfamide [54], pemetrexed [51], fluorouracil (FU) plus leucovorin [55], and paclitaxel [56].

Regimens less preferred or not used — CAP plus prednisone [36]; etoposide, ifosfamide, and cisplatin (VIP) [38]; and cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC) [37] are less preferred regimens for metastatic thymic carcinoma due to toxicity and the complexity of administration.

There is no clear role for single-agent nivolumab or single-agent avelumab in patients with relapsed or metastatic thymic carcinoma, as clinical trials evaluating these agents showed limited activity and significant toxicity [70,71].

Everolimus is not routinely used due to severe toxicity (pneumonitis) despite initial studies that suggest some efficacy in relapsed thymic carcinoma [57].

PALLIATIVE RADIATION THERAPY — 

For patients with metastatic thymoma and thymic carcinoma, radiation therapy (RT) is an appropriate option for those who require palliation of thoracic symptoms. The optimal approach to palliative RT in metastatic thymic epithelial tumors is not established, and treatment should be individualized to the needs of the patient [72]. For patients with metastatic thymoma, RT can be used for palliation and possibly as curative therapy in oligometastatic disease using either standard fractionated therapy or stereotactic body radiotherapy (SBRT). In patients with metastatic thymic carcinoma, RT should be restricted to palliation of local symptoms with noncurative intent.

INVESTIGATIONAL APPROACHES — 

Other agents have been evaluated in the treatment of metastatic thymoma and thymic carcinoma, but their use remains investigational. Clinical trials (www.clinicaltrials.gov) are encouraged, where available.

●Combination therapy – Various combination regimens of chemotherapy, immune checkpoint inhibitors, and antiangiogenic therapy have been investigated in patients with thymic carcinoma. Regimens under investigation as initial therapy in thymic carcinoma include platinum-based chemotherapy plus immunotherapy [73]. Regimens under investigation as later-line therapy in thymoma and thymic carcinoma include avelumab plus axitinib [69] and lenvatinib plus pembrolizumab [74].

●KIT inhibitors – Although KIT mutations are seen in less than 10 percent of thymic carcinomas, the frequency of c-KIT overexpression ranges between 46 to 80 percent [75,76]. Imatinib has shown activity in case reports of thymic carcinomas with KIT exon 9 mutations but not for tumors that are unselected for or lack KIT mutations [77,78]. Sorafenib has shown activity in thymic carcinomas independent of KIT mutations, with a disease control rate of 80 percent in one observational series [79].

●GFT2I inhibitors – A potential target of clinical interest is the single nucleotide mutation in the GFT2I gene (L424H), which is expressed in approximately 39 percent of type A and AB thymomas [76]. However, no GFT2I inhibitors are clinically available.

PROGNOSIS — 

The main prognostic factors for thymoma and thymic carcinoma are disease stage and the complete resectability of the tumor. (See "Clinical presentation, diagnosis, and staging of thymoma and thymic carcinoma", section on 'Staging system'.)

Tumor histology has also been found to have prognostic value, with a major distinction between thymomas and thymic carcinomas. Thymomas usually are slow-growing tumors, whereas thymic carcinomas are more aggressive and are associated with a poorer prognosis [55,80]. (See "Pathology of mediastinal tumors", section on 'Thymoma' and "Pathology of mediastinal tumors", section on 'Thymic carcinoma'.)

Masaoka staging system — Various studies in thymoma and thymic carcinoma suggest that higher disease stage using the Masaoka staging system (table 2) is associated with worsened prognosis [2,81]. As an example, in an observational series of 379 patients with thymoma or thymic carcinoma treated with surgical resection, five- and 10-year overall survival (OS) was 96 and 89 percent for patients with Masaoka stage I disease; 95 and 90 percent for those with Masaoka stage II disease, and 85 and 73 percent for those with Masaoka stage III disease. By contrast, in another observational study, 10-year OS was 47 percent for patients with Masaoka stage IV disease [2]. Of note, these studies did not distinguish OS outcomes between thymomas and thymic carcinomas.

AJCC staging system — The impact of disease stage using the ninth version of the AJCC staging system on prognosis was illustrated in a global observational series of 11,347 patients with thymoma (figure 2) or thymic carcinoma (figure 3) [82]. Higher disease stage was consistently associated with a progressively worsened prognosis, with an increasing proportion of recurrences and deaths for both patients with thymomas (over 20 years of follow-up) and those with thymic carcinomas (over 10 years of follow-up).

POSTTREATMENT SURVEILLANCE — 

Long-term posttreatment surveillance is necessary to monitor for recurrent disease and second cancers. For patients with recurrent disease detected on surveillance, early intervention may be more feasible and effective. (See 'Recurrent disease' above and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)

For patients who have completed therapy for thymoma and thymic carcinoma, our approach to posttreatment surveillance is consistent with guidelines from the National Comprehensive Cancer Network [4]:

●Resected Masaoka stage I thymoma or thymic carcinoma – We obtain a contrast-enhanced CT of the chest every 6 to 12 months for two years, then annually until five years for thymic carcinoma, and until 10 years for thymoma.

●More advanced thymoma – We obtain a contrast-enhanced CT of the chest every six months for two years, then annually until 10 years.

●More advanced thymic carcinoma – We obtain a contrast-enhanced CT of the chest every three to six months for two years and then annually until five years.

Recurrence of thymoma may not become apparent for years (even decades) after initial treatment. As an example, in an observational series of 126 patients with resected thymoma, recurrences were seen in 24 patients [83]. The time to recurrence ranged from 4 to 175 months (mean, 68 months). Common sites of recurrence were pleural, local disease, or distant metastases (22, 6, and 5 cases, respectively).

Patients with thymoma are also at risk for developing subsequent cancers, which have been reported in 17 to 28 percent of patients with thymoma following thymectomy [84-89]. The most common second cancers observed include non-Hodgkin lymphoma, gastrointestinal cancers, and soft tissue sarcomas [87].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thymomas and thymic carcinomas".)

SUMMARY AND RECOMMENDATIONS

●General principles – Thymic tumors are rare neoplasms that arise in the anterior mediastinum (figure 1). The most common thymic tumors are thymomas and thymic carcinomas. (See 'Introduction' above.)

●Localized resectable disease – For patients with localized thymoma and thymic carcinoma, it is necessary to obtain multidisciplinary evaluation at a center of excellence with expertise in the management of thymic epithelial malignancies, with input from surgical oncology, medical oncology, and radiation oncology. (See 'Localized disease' above.)

•Surgery – For patients with localized, resectable thymoma or thymic carcinoma, we suggest thymectomy and lymph node resection rather than less-extensive surgeries or initial treatment with systemic therapy or radiation therapy (RT) (Grade 2C). Surgery offers patients the best chance at curative therapy. (See 'Surgery' above.)

•Postoperative therapy for thymoma – For patients with localized thymoma or thymic carcinoma who are treated with surgery, our approach to postoperative therapy is based on the tumor stage. (See 'Postoperative radiation therapy' above.)

-AJCC stage I – For patients with American Joint Committee on Cancer (AJCC) stage I (Masaoka stage I to II) thymoma and high-risk features for recurrence on postoperative pathology we suggest postoperative RT rather than surveillance (Grade 2C). However, surveillance is an appropriate alternative as data for postoperative RT in this population are limited. High-risk features for recurrence are defined as invasion into the mediastinal fat or pleura and microscopic or grossly positive surgical margins. Patients without high-risk features may be offered surveillance and do not require postoperative radiation. (See 'AJCC stage I thymoma' above.)

-AJCC stage II to IIIA – For patients with AJCC stage II to IIIA (Masaoka stage III) thymoma, we suggest postoperative RT rather than surveillance (Grade 2C). For those with positive surgical margins (R1 resection) or macroscopic residual disease (R2 resection), postoperative RT may be administered with or without concurrent chemotherapy, with the decision based on institutional practice, tumor stage, R1 versus R2 resection, and patient performance status and comorbidities. (See 'AJCC stage II to IIIA thymoma' above.)

•Postoperative therapy for thymic carcinoma – For patients with AJCC stage I to IIIA (Masaoka stage I to III) thymic carcinoma who undergo a complete (R0) resection, we suggest postoperative RT rather than surveillance (Grade 2C). For patients with R1 or R2 resection, we suggest postoperative chemoradiation (CRT) rather than postoperative RT alone (Grade 2C), although there is limited evidence for this approach. (See 'AJCC stage I to IIIA thymic carcinoma' above.)

●Potentially resectable disease – For patients with localized thymoma or thymic carcinoma and potentially resectable disease, we suggest initial therapy with preoperative chemotherapy rather than upfront surgery or RT (Grade 2C), as this approach offers a chance for prolonged overall survival (OS). Potentially resectable disease is defined as tumor invasion into the innominate vein, phrenic nerve(s), heart, or great vessels that is not feasible to resect upfront but could be rendered resectable with preoperative therapy to reduce tumor burden. (See 'Potentially resectable disease' above.)

•Thymoma – For patients with potentially resectable thymoma, we suggest cyclophosphamide, doxorubicin, and cisplatin (CAP) rather than other systemic regimens (Grade 2C), as this regimen results in the best outcomes, including objective response rates (ORRs), for thymomas. Appropriate alternatives include carboplatin plus paclitaxel and cisplatin plus etoposide. (See 'Selection of therapy' above and 'Cyclophosphamide, doxorubicin, and cisplatin' above.)

•Thymic carcinoma – For patients with potentially resectable thymic carcinoma, we suggest carboplatin plus paclitaxel rather than other systemic regimens (Grade 2C), as this regimen results in the best ORRs for thymic carcinoma and is better tolerated than other regimens. Appropriate alternatives include CAP and cisplatin plus etoposide. (See 'Selection of therapy' above and 'Carboplatin plus paclitaxel' above.)

•Management after preoperative systemic therapy – Patients who complete preoperative systemic therapy should be evaluated for surgery. (See 'Approach to therapy' above.)

●Unresectable disease – For patients with localized, unresectable thymoma or thymic carcinoma, we suggest definitive CRT rather than RT alone or systemic therapy (Grade 2C). (See 'Definitive chemoradiation' above and "Management of stage III non-small cell lung cancer".)

•Dosing and schedule for CRT – For patients who are receiving definitive CRT, we suggest weekly dosing of carboplatin (area under the curve [AUC] of 2) plus paclitaxel (45 mg/m2) concurrently with RT for radiosensitization rather than other regimens (Grade 2C). Cisplatin plus etoposide (PE) is also an acceptable alternative. (See 'Dosing and schedule' above and "Management of stage III non-small cell lung cancer", section on 'Choice of chemotherapy' and "Management of stage III non-small cell lung cancer", section on 'Administration of radiation'.)

●Metastatic thymoma

•Initial therapy – For patients with advanced unresectable or metastatic thymomas, we suggest initial treatment with CAP rather than other systemic regimens (Grade 2C). (See 'Cyclophosphamide, doxorubicin, and cisplatin' above.)

Appropriate alternatives include carboplatin plus paclitaxel and cisplatin plus etoposide. (See 'Carboplatin plus paclitaxel' above and 'Cisplatin plus etoposide' above.)

•Second-line therapy – For patients with metastatic thymoma who progress on platinum-based chemotherapy, we offer second-line therapy with agents not previously received. Options include gemcitabine with or without capecitabine, octreotide with or without prednisone for somatostatin receptor positive thymomas, and pemetrexed, among other agents. (See 'Second-line therapy' above.)

•No immunotherapy for metastatic thymoma – We do not offer immunotherapy to patients with metastatic thymoma due to the high rates of immune-related adverse events (irAEs) including myasthenia gravis, myocarditis, and hepatitis. (See 'Regimens less preferred or not used' above.)

●Metastatic thymic carcinoma

•Initial therapy – For patients with advanced unresectable or metastatic thymic carcinomas, we suggest initial treatment with carboplatin plus paclitaxel and ramucirumab rather than other systemic regimens (Grade 2C), as this regimen results in high ORRs, durable OS, and is well-tolerated. (See 'Carboplatin plus paclitaxel and ramucirumab' above.)

For those who are ineligible for ramucirumab or have central nervous system metastases, appropriate alternatives include carboplatin plus paclitaxel, CAP, and cisplatin plus etoposide. (See 'Carboplatin plus paclitaxel' above and 'Cisplatin plus etoposide' above and 'Cyclophosphamide, doxorubicin, and cisplatin' above.)

•Second-line therapy

-Pembrolizumab – For patients with metastatic thymic carcinoma who progress on platinum-based chemotherapy and have no history of autoimmune disease, we suggest second-line therapy with single-agent pembrolizumab rather than other systemic agents (Grade 2C). (See 'Pembrolizumab' above.)

-Antiangiogenic agents – For those who progress on platinum-based chemotherapy and progress on (or are ineligible for) immunotherapy, options include sunitinib or lenvatinib. (See 'Antiangiogenic agents' above.)

•Later-line therapy – Options for later-line therapy, if not previously received, include gemcitabine with or without capecitabine, avelumab plus axitinib (if no prior immunotherapy), etoposide, ifosfamide, pemetrexed, fluorouracil (FU) plus leucovorin, and paclitaxel.

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Andrea Bezjak, BMedSc, MDCM, MSc, FRCPC, Giuseppe Giaccone, MD, PhD, and James R Jett, MD, who contributed to earlier versions of this topic review.

  1. Davenport E, Malthaner RA. The role of surgery in the management of thymoma: a systematic review. Ann Thorac Surg 2008; 86:673.
  2. Ströbel P, Bauer A, Puppe B, et al. Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol 2004; 22:1501.
  3. Jackson MW, Palma DA, Camidge DR, et al. The Impact of Postoperative Radiotherapy for Thymoma and Thymic Carcinoma. J Thorac Oncol 2017; 12:734.
  4. National Comprehensive Cancer Network guidelines http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on July 10, 2024).
  5. Utsumi T, Shiono H, Kadota Y, et al. Postoperative radiation therapy after complete resection of thymoma has little impact on survival. Cancer 2009; 115:5413.
  6. Forquer JA, Rong N, Fakiris AJ, et al. Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease. Int J Radiat Oncol Biol Phys 2010; 76:440.
  7. Singhal S, Shrager JB, Rosenthal DI, et al. Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg 2003; 76:1635.
  8. Omasa M, Date H, Sozu T, et al. Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: the Japanese Association for Research on the Thymus Database Study. Cancer 2015; 121:1008.
  9. Lim YJ, Kim HJ, Wu HG. Role of Postoperative Radiotherapy in Nonlocalized Thymoma: Propensity-Matched Analysis of Surveillance, Epidemiology, and End Results Database. J Thorac Oncol 2015; 10:1357.
  10. Rimner A, Yao X, Huang J, et al. Postoperative Radiation Therapy Is Associated with Longer Overall Survival in Completely Resected Stage II and III Thymoma-An Analysis of the International Thymic Malignancies Interest Group Retrospective Database. J Thorac Oncol 2016; 11:1785.
  11. Boothe D, Orton A, Thorpe C, et al. Post-operative Radiation Therapy in Locally Invasive Malignancies of the Thymus: Patterns of Care and Survival. Int J Radiat Oncol Biol Phys 2017; 98:229.
  12. Ruffini E, Detterbeck F, Van Raemdonck D, et al. Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database. J Thorac Oncol 2014; 9:541.
  13. Tateishi Y, Horita N, Namkoong H, et al. Postoperative Radiotherapy for Completely Resected Masaoka/Masaoka-Koga Stage II/III Thymoma Improves Overall Survival: An Updated Meta-Analysis of 4746 Patients. J Thorac Oncol 2021; 16:677.
  14. Myojin M, Choi NC, Wright CD, et al. Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study. Int J Radiat Oncol Biol Phys 2000; 46:927.
  15. Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 2015; 149:95.
  16. Kim S, Bull DA, Hsu CH, Hsu CC. The Role of Adjuvant Therapy in Advanced Thymic Carcinoma: A National Cancer Database Analysis. Ann Thorac Surg 2020; 109:1095.
  17. Parikh RR, Rhome R, Hug E, et al. Adjuvant Proton Beam Therapy in the Management of Thymoma: A Dosimetric Comparison and Acute Toxicities. Clin Lung Cancer 2016; 17:362.
  18. Mercado CE, Hartsell WF, Simone CB 2nd, et al. Proton therapy for thymic malignancies: multi-institutional patterns-of-care and early clinical outcomes from the proton collaborative group and the university of Florida prospective registries. Acta Oncol 2019; 58:1036.
  19. Hayes SA, Huang J, Golia Pernicka J, et al. Radiographic Predictors of Resectability in Thymic Carcinoma. Ann Thorac Surg 2018; 106:242.
  20. Hamaji M, Ali SO, Burt BM. A meta-analysis of induction therapy for advanced thymic epithelial tumors. Ann Thorac Surg 2015; 99:1848.
  21. Loehrer PJ Sr, Kim K, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 1994; 12:1164.
  22. Lemma GL, Lee JW, Aisner SC, et al. Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 2011; 29:2060.
  23. Hirai F, Yamanaka T, Taguchi K. A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L. Ann Oncol 2015; 26; 2S.
  24. Merveilleux du Vignaux C, Dansin E, Mhanna L, et al. Systemic Therapy in Advanced Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort. J Thorac Oncol 2018; 13:1762.
  25. Kondo K. Optimal therapy for thymoma. J Med Invest 2008; 55:17.
  26. Okuma Y, Saito M, Hosomi Y, et al. Key components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2015; 141:323.
  27. Rajan A, Giaccone G. Chemotherapy for thymic tumors: induction, consolidation, palliation. Thorac Surg Clin 2011; 21:107.
  28. Schmitt J, Loehrer PJ Sr. The role of chemotherapy in advanced thymoma. J Thorac Oncol 2010; 5:S357.
  29. Lemma GL, Lee JW, Aisner SC, et al. Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 2011; 29:2060.
  30. Hirai F, Yamanaka T, Taguchi K, et al. A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L. Ann Oncol 2015; 26:363.
  31. Furugen M, Sekine I, Tsuta K, et al. Combination chemotherapy with carboplatin and paclitaxel for advanced thymic cancer. Jpn J Clin Oncol 2011; 41:1013.
  32. Igawa S, Murakami H, Takahashi T, et al. Efficacy of chemotherapy with carboplatin and paclitaxel for unresectable thymic carcinoma. Lung Cancer 2010; 67:194.
  33. Maruyama R, Suemitsu R, Okamoto T, et al. Persistent and aggressive treatment for thymic carcinoma. Results of a single-institute experience with 25 patients. Oncology 2006; 70:325.
  34. Proto C, Ganzinelli M, Manglaviti S, et al. Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671). Ann Oncol 2024; 35:817.
  35. 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.
  36. 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.
  37. Fornasiero A, Daniele O, Ghiotto C, et al. Chemotherapy for invasive thymoma. A 13-year experience. Cancer 1991; 68:30.
  38. Loehrer PJ Sr, Jiroutek M, Aisner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 2001; 91:2010.
  39. Huang J, Rizk NP, Travis WD, et al. Feasibility of multimodality therapy including extended resections in stage IVA thymoma. J Thorac Cardiovasc Surg 2007; 134:1477.
  40. Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg 2014; 147:36.
  41. Modh A, Rimner A, Allen PK, et al. Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study. Am J Clin Oncol 2016; 39:120.
  42. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 2005; 23:5883.
  43. Albain KS, Crowley JJ, Turrisi AT 3rd, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol 2002; 20:3454.
  44. Hao XJ, Peng B, Zhou Z, Yang XQ. Prospective Study of Stereotactic Body Radiation Therapy for Thymoma and Thymic Carcinoma: Therapeutic Effect and Toxicity Assessment. Sci Rep 2017; 7:13549.
  45. Okumura M, Shiono H, Inoue M, et al. Outcome of surgical treatment for recurrent thymic epithelial tumors with reference to world health organization histologic classification system. J Surg Oncol 2007; 95:40.
  46. Lucchi M, Davini F, Ricciardi R, et al. Management of pleural recurrence after curative resection of thymoma. J Thorac Cardiovasc Surg 2009; 137:1185.
  47. Hamaji M, Ali SO, Burt BM. A meta-analysis of surgical versus nonsurgical management of recurrent thymoma. Ann Thorac Surg 2014; 98:748.
  48. Komaki R, Gomez DR. Radiotherapy for thymic carcinoma: adjuvant, inductive, and definitive. Front Oncol 2014; 3:330.
  49. Palmieri G, Merola G, Federico P, et al. Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs). Ann Oncol 2010; 21:1168.
  50. Palmieri G, Buonerba C, Ottaviano M, et al. Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial. Future Oncol 2014; 10:2141.
  51. Gbolahan OB, Porter RF, Salter JT, et al. A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma. J Thorac Oncol 2018; 13:1940.
  52. Loehrer PJ Sr, Wang W, Johnson DH, et al. Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial. J Clin Oncol 2004; 22:293.
  53. Bluthgen MV, Boutros C, Fayard F, et al. Activity and safety of oral etoposide in pretreated patients with metastatic or recurrent thymic epithelial tumors (TET): A single-institution experience. Lung Cancer 2016; 99:111.
  54. Highley MS, Underhill CR, Parnis FX, et al. Treatment of invasive thymoma with single-agent ifosfamide. J Clin Oncol 1999; 17:2737.
  55. Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art. J Clin Oncol 1999; 17:2280.
  56. Tateishi K, Ko R, Shukuya T, et al. Clinical Outcomes of Second-Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study. Oncologist 2020; 25:e668.
  57. Zucali PA, De Pas T, Palmieri G, et al. Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy. J Clin Oncol 2018; 36:342.
  58. Cho J, Kim HS, Ku BM, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol 2019; 37:2162.
  59. Lara MS, Afify A, Ellis MP, et al. Immune Checkpoint Inhibitor-Induced Myasthenia Gravis in a Patient with Advanced NSCLC and Remote History of Thymoma. Clin Lung Cancer 2019; 20:e489.
  60. Zekeridou A, Lennon VA. Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy. Mayo Clin Proc 2019; 94:1865.
  61. Remon J, Villacampa G, Facchinetti F, et al. Immune checkpoint blockers in patients with unresectable or metastatic thymic epithelial tumours: A meta-analysis. Eur J Cancer 2023; 180:117.
  62. Fenioux C, Abbar B, Boussouar S, et al. Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis. Nat Med 2023; 29:3100.
  63. Arunachalam A, Zhang I, Zhao B, et al. Efficacy and safety of treatments for advanced thymic carcinoma after failure of first-line platinum-based chemotherapy: A systematic literature review and meta-analysis. Lung Cancer 2023; 176:132.
  64. Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 2018; 19:347.
  65. Giaccone G, Kim C. Durable Response in Patients With Thymic Carcinoma Treated With Pembrolizumab After Prolonged Follow-Up. J Thorac Oncol 2021; 16:483.
  66. Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol 2015; 16:177.
  67. Remon J, Girard N, Mazieres J, et al. Sunitinib in patients with advanced thymic malignancies: Cohort from the French RYTHMIC network. Lung Cancer 2016; 97:99.
  68. Sato J, Satouchi M, Itoh S, et al. Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial. Lancet Oncol 2020; 21:843.
  69. Conforti F, Zucali PA, Pala L, et al. Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2022; 23:1287.
  70. Katsuya Y, Horinouchi H, Seto T, et al. Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study. Eur J Cancer 2019; 113:78.
  71. Rajan A, Heery CR, Thomas A, et al. Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma. J Immunother Cancer 2019; 7:269.
  72. Angrisani A, Houben R, Marcuse F, et al. "Radiotherapy for thymic epithelial tumors: What is the optimal dose? A systematic review.". Clin Transl Radiat Oncol 2022; 34:67.
  73. Zhang B, Liu Y, Chen Z, et al. Chemotherapy versus chemotherapy plus immune checkpoint inhibitors for the first-line treatment of unresectable thymic carcinoma: A multicenter retrospective study. Int J Cancer 2024; 155:710.
  74. Remon Masip J, Bironzo P, Girard N. Lenvatinib plus pembrolizumab in pretreated advanced B3-thymoma and thymic carcinoma: PECATI, single arm phase II clinical trial. Ann Oncol 2024; 35;S2.
  75. Girard N, Shen R, Guo T, et al. Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas. Clin Cancer Res 2009; 15:6790.
  76. Radovich M, Pickering CR, Felau I, et al. The Integrated Genomic Landscape of Thymic Epithelial Tumors. Cancer Cell 2018; 33:244.
  77. Ströbel P, Hartmann M, Jakob A, et al. Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J Med 2004; 350:2625.
  78. Palmieri G, Marino M, Buonerba C, et al. Imatinib mesylate in thymic epithelial malignancies. Cancer Chemother Pharmacol 2012; 69:309.
  79. Pagano M, Sierra NM, Panebianco M, et al. Sorafenib efficacy in thymic carcinomas seems not to require c-KIT or PDGFR-alpha mutations. Anticancer Res 2014; 34:5105.
  80. Gripp S, Hilgers K, Wurm R, Schmitt G. Thymoma: prognostic factors and treatment outcomes. Cancer 1998; 83:1495.
  81. Chiappetta M, Lococo F, Pogliani L, et al. Masaoka-Koga and TNM Staging System in Thymic Epithelial Tumors: Prognostic Comparison and the Role of the Number of Involved Structures. Cancers (Basel) 2021; 13.
  82. Ruffini E, Huang J, Cilento V, et al. The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: Proposal for a Stage Classification for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors. J Thorac Oncol 2023; 18:1655.
  83. Haniuda M, Kondo R, Numanami H, et al. Recurrence of thymoma: clinicopathological features, re-operation, and outcome. J Surg Oncol 2001; 78:183.
  84. Pan CC, Chen PC, Wang LS, et al. Thymoma is associated with an increased risk of second malignancy. Cancer 2001; 92:2406.
  85. Wilkins KB, Sheikh E, Green R, et al. Clinical and pathologic predictors of survival in patients with thymoma. Ann Surg 1999; 230:562.
  86. Souadjian JV, Enriquez P, Silverstein MN, Pépin JM. The spectrum of diseases associated with thymoma. Coincidence or syndrome? Arch Intern Med 1974; 134:374.
  87. Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003; 105:546.
  88. Xu BY, Pirskanen R, Lefvert AK. Antibody dependent cell-mediated cytotoxicity--an additional mechanism in human autoimmune myasthenia gravis. J Neuroimmunol 1999; 99:183.
  89. Welsh JS, Wilkins KB, Green R, et al. Association between thymoma and second neoplasms. JAMA 2000; 283:1142.
Topic 4619 Version 64.0

References

1 : The role of surgery in the management of thymoma: a systematic review.

2 : Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis.

3 : The Impact of Postoperative Radiotherapy for Thymoma and Thymic Carcinoma.

4 : The Impact of Postoperative Radiotherapy for Thymoma and Thymic Carcinoma.

5 : Postoperative radiation therapy after complete resection of thymoma has little impact on survival.

6 : Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease.

7 : Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation.

8 : Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: the Japanese Association for Research on the Thymus Database Study.

9 : Role of Postoperative Radiotherapy in Nonlocalized Thymoma: Propensity-Matched Analysis of Surveillance, Epidemiology, and End Results Database.

10 : Postoperative Radiation Therapy Is Associated with Longer Overall Survival in Completely Resected Stage II and III Thymoma-An Analysis of the International Thymic Malignancies Interest Group Retrospective Database.

11 : Post-operative Radiation Therapy in Locally Invasive Malignancies of the Thymus: Patterns of Care and Survival.

12 : Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database.

13 : Postoperative Radiotherapy for Completely Resected Masaoka/Masaoka-Koga Stage II/III Thymoma Improves Overall Survival: An Updated Meta-Analysis of 4746 Patients.

14 : Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study.

15 : Thymic carcinoma outcomes and prognosis: results of an international analysis.

16 : The Role of Adjuvant Therapy in Advanced Thymic Carcinoma: A National Cancer Database Analysis.

17 : Adjuvant Proton Beam Therapy in the Management of Thymoma: A Dosimetric Comparison and Acute Toxicities.

18 : Proton therapy for thymic malignancies: multi-institutional patterns-of-care and early clinical outcomes from the proton collaborative group and the university of Florida prospective registries.

19 : Radiographic Predictors of Resectability in Thymic Carcinoma.

20 : A meta-analysis of induction therapy for advanced thymic epithelial tumors.

21 : Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group.

22 : Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma.

23 : A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L

24 : Systemic Therapy in Advanced Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort.

25 : Optimal therapy for thymoma.

26 : Key components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy.

27 : Chemotherapy for thymic tumors: induction, consolidation, palliation.

28 : The role of chemotherapy in advanced thymoma.

29 : Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma.

30 : A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L.

31 : Combination chemotherapy with carboplatin and paclitaxel for advanced thymic cancer.

32 : Efficacy of chemotherapy with carboplatin and paclitaxel for unresectable thymic carcinoma.

33 : Persistent and aggressive treatment for thymic carcinoma. Results of a single-institute experience with 25 patients.

34 : Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

35 : 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.

36 : 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.

37 : Chemotherapy for invasive thymoma. A 13-year experience.

38 : Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial.

39 : Feasibility of multimodality therapy including extended resections in stage IVA thymoma.

40 : Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multi-institutional clinical trial.

41 : Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study.

42 : Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol.

43 : Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019.

44 : Prospective Study of Stereotactic Body Radiation Therapy for Thymoma and Thymic Carcinoma: Therapeutic Effect and Toxicity Assessment.

45 : Outcome of surgical treatment for recurrent thymic epithelial tumors with reference to world health organization histologic classification system.

46 : Management of pleural recurrence after curative resection of thymoma.

47 : A meta-analysis of surgical versus nonsurgical management of recurrent thymoma.

48 : Radiotherapy for thymic carcinoma: adjuvant, inductive, and definitive.

49 : Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs).

50 : Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial.

51 : A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma.

52 : Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial.

53 : Activity and safety of oral etoposide in pretreated patients with metastatic or recurrent thymic epithelial tumors (TET): A single-institution experience.

54 : Treatment of invasive thymoma with single-agent ifosfamide.

55 : Thymoma: state of the art.

56 : Clinical Outcomes of Second-Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study.

57 : Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy.

58 : Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial.

59 : Immune Checkpoint Inhibitor-Induced Myasthenia Gravis in a Patient with Advanced NSCLC and Remote History of Thymoma.

60 : Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy.

61 : Immune checkpoint blockers in patients with unresectable or metastatic thymic epithelial tumours: A meta-analysis.

62 : Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

63 : Efficacy and safety of treatments for advanced thymic carcinoma after failure of first-line platinum-based chemotherapy: A systematic literature review and meta-analysis.

64 : Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study.

65 : Durable Response in Patients With Thymic Carcinoma Treated With Pembrolizumab After Prolonged Follow-Up.

66 : Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial.

67 : Sunitinib in patients with advanced thymic malignancies: Cohort from the French RYTHMIC network.

68 : Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial.

69 : Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial.

70 : Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study.

71 : Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma.

72 : "Radiotherapy for thymic epithelial tumors: What is the optimal dose? A systematic review.".

73 : Chemotherapy versus chemotherapy plus immune checkpoint inhibitors for the first-line treatment of unresectable thymic carcinoma: A multicenter retrospective study.

74 : Lenvatinib plus pembrolizumab in pretreated advanced B3-thymoma and thymic carcinoma: PECATI, single arm phase II clinical trial.

75 : Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas.

76 : The Integrated Genomic Landscape of Thymic Epithelial Tumors.

77 : Thymic carcinoma with overexpression of mutated KIT and the response to imatinib.

78 : Imatinib mesylate in thymic epithelial malignancies.

79 : Sorafenib efficacy in thymic carcinomas seems not to require c-KIT or PDGFR-alpha mutations.

80 : Thymoma: prognostic factors and treatment outcomes.

81 : Masaoka-Koga and TNM Staging System in Thymic Epithelial Tumors: Prognostic Comparison and the Role of the Number of Involved Structures.

82 : The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: Proposal for a Stage Classification for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors.

83 : Recurrence of thymoma: clinicopathological features, re-operation, and outcome.

84 : Thymoma is associated with an increased risk of second malignancy.

85 : Clinical and pathologic predictors of survival in patients with thymoma.

86 : The spectrum of diseases associated with thymoma. Coincidence or syndrome?

87 : Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies.

88 : Antibody dependent cell-mediated cytotoxicity--an additional mechanism in human autoimmune myasthenia gravis.

89 : Association between thymoma and second neoplasms.