MS08.03 Optimal Management of Metastatic Thymic Carcinoma

Abstract

Thymic carcinoma represents approximately 10-15% of all thymic epithelial tumors, it is more aggressive than thymomas and also somewhat less sensitive to chemotherapy. More often than thymomas, thymic carcinomas are not resectable and therefore the use of systemic therapies and radiation are more often required than in thymomas. In general, the sensitivity of thymic carcinomas to chemotherapy is lower than with thymomas, with response rates usually less than 50% in metastatic disease, and somewhat higher in locally advanced disease. In presence of borderline operable cases, neoadjuvant chemotherapy is indicated, in order to make the tumor more easily operable. Because thymic carcinomas often infiltrate surrounding tissues, radical resection are sometimes not achievable. The use of postoperative radiation is indicated even if margins are clear. Several chemotherapy regimens have been used, and the more commonly employed remain platinum combinations, with or without an anthracycline (mainly doxorubicin). More recently data the combination carboplatin-paclitaxel has been added to the potential chemotherapy regimens and it is often preferred because of its milder toxicity profile. When radiation is planned, the use of doxorubicin is contraindicated, because of the enhanced toxicity. The role of debulking surgery, reoperation and metastasectomy is much more controversial in thymic carcinomas than in thymomas, given the more aggressive behaviour. However, the histological diagnosis sometimes is not paralleled by an aggressive phenotype and individual treatment decisions should always be considered. Unfortunately, thymic carcinoma have the tendency to metastatize wildly to virtually all organs, and brain metastases are all but rare. Complete staging procedures, including brain MRI are therefore indicated in patients with thymic carcinoma. In patients with metastatic disease, chemotherapy is indicated as first line therapy, and the CAP regimen (cisplatin, doxorubicin, cyclophosphamide) or carboplatin-paclitaxel, are the preferred regimens, with response rates in the range of 30-50%. Unfortunately, chemotherapy at this stage is not curative and most patients will require further systemic therapies after failure of chemotherapy. There have been a number of studies in recent years, which have established activity of a few agents, such as sunitinib and pembrolizumab in thymic carcinomas. Both of them are now listed in the NCCN guidelines and have a response rate of about 25%. Pembrolizumab however has a much longer duration of response, albeit the frequency of severe autoimmune disorders is higher than in other diseases in which immune checkpoint inhibitors are used. Further chemotherapy also has some activity, such and the combination gemcitabine-capecitabine and other single agents, with responses in the 20-30% range. The biology of thymic carcinoma does not appear to provide clues to specific treatments, although mutations in epigenetic genes have been found in a significant number of patients. No easily targetable mutations or genetic abnormalities have so far been found. The most common mutation is in the p53 gene, in about 30% of cases, which is not targetable and is associated with a poorer survival. Thymic carcinoma, sunitinib, Pembrolizumab