Some patients with thymoma and thymic carcinoma present with disease that is unresectable at diagnosis. Neoadjuvant chemotherapy can increase the likelihood of resectable disease for patients who are otherwise eligible for surgery. Potential induction regimens include chemotherapy alone (17, 18), radiation alone (19, 20), and combined chemotherapy and radiation (3). Chemotherapeutic regimens are generally cisplatin-based; regimens used in prior studies have included cyclophosphamide, doxorubicin, cisplatin, and prednisone or cisplatin and etoposide (18, 21). In some cases, patients undergo preoperative radiation therapy and then, after surgical resection, are considered for adjuvant treatment. Radiation therapy in this context can be difficult to deliver without exceeding dose constraints, and the cumulative radiation dose should be considered carefully. As is true for postoperative therapy, preoperative therapy should not include elective nodal regions but rather should encompass the gross area of involvement with an appropriate margin.

Definitive radiation therapy is generally used for patients who are not candidates for surgery because of either the extent of disease at diagnosis or other medical conditions. Because chemotherapy is a known radiation sensitizer, the combination of chemotherapy and radiation is considered most likely to control disease in these circumstances (5, 22–24). A multimodality approach such as trimodality therapy or definitive concurrent chemoradiation in unresectable cases is recommended for thymic carcinoma regardless of disease stage (25). Notably, only one-third of patients with thymic carcinoma are able to undergo a complete resection after such therapy (26). Definitive radiation therapy for unresectable disease is considered analogous to radiation therapy for disease that recurs after surgical resection; for such cases, we recommend radiation doses of 60–66 Gy to encompass gross disease plus a margin for microscopic regions at risk. The corresponding radiation dose when radiation is to be given with chemotherapy as definitive therapy is 54 Gy.

Abundant evidence suggests that long-term survivors of mediastinal radiation therapy are at risk of both acute and chronic cardiac sequelae. With regard to acute effects, the dose and fractionation of the radiation and the volume of heart irradiated all affect the risk of pericarditis and pericardial effusion (41). Given the close physiologic association between perfusion and ventilation, one might expect that radiation to the heart could affect lung function and vice versa. In one clinical study, investigators found that several heart dose-volume variables predicted radiation pneumonitis and that the fit of a model predicting pneumonitis was improved by the incorporation of cardiac variables (42). The risk of cardiac and other side effects is also affected by the exact location of the irradiated field. Short-term surrogates of long-term toxicity such as findings on cardiovascular imaging or biomarker correlates would be helpful for identifying which patients at greatest risk for cardiac events. In the meantime, we recommend the continued use of advanced radiation therapy technologies such as IMRT, proton beam therapy, use of 4D CT-based imaging and treatment planning, and adaptive planning when possible to minimize the dose to mediastinal structures for patients with thymic disease, many of whom will survive for several decades and thus will live to see the long-term consequences of irradiation of these vital organs.

Studies evaluating whether the inclusion of radiation therapy affects disease control and survival in thymic carcinoma are sparse because of the rarity of the disease; indeed, to the best of our knowledge no prospective trials have been done that compare outcomes between patients who have or have not received radiation therapy. Most published retrospective reports have focused on invasive thymoma, with some studies indicating that radiation is beneficial for locally advanced disease after surgery (8, 43–45) and others not demonstrating a clear advantage (46–48). Thymic carcinoma is often analyzed together with locally advanced invasive thymoma in an attempt to increase patient numbers and statistical power. In perhaps the best analysis of this type, a study of 1,320 patients from Japan with thymic malignancies, the authors compared adjuvant regimens in patients with completely resected stage III-IV thymoma and thymic carcinoma (14). They found no significant differences in survival between patients who received adjuvant radiation and those who received no further treatment. A subanalysis of only patients with thymic carcinoma also showed no difference in survival between those who received radiation versus no further treatment; however, that subanalysis did show that patients who received adjuvant chemoradiation for thymic carcinoma had worse outcomes than patients who received either radiation alone or observation. Notably, however, the size of these subgroups was small, with 24 receiving chemoradiation, 33 receiving radiation, and 16 receiving observation. A multivariate analysis of factors predicting survival among 290 patients with thymic carcinoma in the Surveillance, Epidemiology, and End Results database revealed that the extent of surgical excision, Masaoka stage, and race were associated with survival but receipt of radiation was not (49). In a much smaller study of 26 patients, investigators from Taiwan found that surgery and postoperative radiation achieved 5-year local control rates of 77%, but nearly 50% of patients experienced distant metastases (6). Finally, in a study of 14 patients with thymic carcinoma treated at the Gunma Prefectural Cancer Center in Japan, patients who received radiation had better outcomes than those who did not, and those investigators concluded that radiation has an important role in the treatment of thymic carcinoma (50). Clearly large prospective studies are needed to definitively answer this question.

As is true of studies of survival, analyses of patterns of failure after treatment for thymic carcinoma have generally been small and retrospective. In general, thymic carcinoma tends to recur distantly rather than locally, and pleural and extrathoracic metastases tend to drive overall survival (51, 52). For this reason, the development of effective targeted agents will be important in improving treatment outcomes in this disease. However, significant local invasion such as that into the great vessels or heart portends worse locoregional control and progression-free survival (53, 54). Further, both early-stage disease and achievement of complete resection have been shown to be associated with improved prognosis (55, 56), highlighting the role of radiation therapy in maximizing the likelihood of local control and optimizing survival outcomes.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.