ED15.02 Chemotherapy and Targeted Therapies of Thymic Malignancies

Abstract

Thymic malignancies represent a heterogeneous group of rare thoracic cancers. The histopathological classification distinguishes thymomas from thymic carcinomas. Thymomas are further subdivided into different types (so-called A, AB, B1, B2, and B3) based upon the atypia of tumor cells, the relative proportion of the associated non-tumoral lymphocytic component, and resemblance to the normal thymic architecture. Thymic carcinomas are similar to their extra-thymic counterpart, the most frequent subtype being squamous cell carcinoma. The management of thymic epithelial tumors is a paradigm of multidisciplinary collaboration. The treatment strategy is primarily based on the resectability of the tumor. If complete resection is deemed not to be achievable upfront based on imaging studies, what is the case in Masaoka-Koga stage III/IVA tumors (classified as stage IIIA/IIIB/IVA in the 2015 IASLC-ITMIG TNM proposed system), after a biopsy is performed, primary/induction chemotherapy is administered, part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy. Cases not eligible for local treatment receive definitive chemotherapy. Primary/induction chemotherapy is then standard in non-resectable advanced thymic epithelial tumors. Cisplatin-based combination regimens should be administered; combinations of cisplatin, adriamycin, and cyclophosphamide, and cisplatin and etoposide are the most usually used. Primary chemoradiotherapy with platin and etoposide is an option, especially for thymic carcinomas. Usually 2-4 cycles are administered before imaging is performed to reassess resectability of the tumor. Surgery should be offered to patients for whom complete resection is thought to be ultimately achievable; extended resection may be required. Hyperthermic intrapleural chemotherapy, as well as extra-pleural pneumonectomy may be discussed in case of stage IVA tumor. Postoperative radiotherapy is usually delivered. When the patient is not deemed to be a surgical candidate - either because R0 resection is not thought to be achievable, or because of poor performance status or co-existent medical condition, definitive radiotherapy is recommended part of a sequential chemoradiotherapy strategy. Combination with chemotherapy (including cisplatin, etoposide chemotherapy and a total dose of radiation of 60 Gy) may be considered as well. Chemotherapy should be offered as the single modality treatment in advanced, non-resectable, non-irradiable or metastatic (stage IVB) thymic epithelial tumor to improve tumor-related symptoms the aim is to improve tumor-related symptoms through obtention of tumor response, while prolonged survival is uncertain. Cisplatin-based combination regimen should be administered. No randomized studies have been conducted, and it is unclear which regimens are best; multi-agent combination regimens and anthracycline-based regimens appear to have improved response rates compared to others, especially the etoposide, ifosfamide and cisplatin combination. Combinations of cisplatin, adriamycin, and cyclophosphamide is preferred. Combination of carboplatin and paclitaxel is an option for thymic carcinoma. Surgery or radiotherapy is possible in rare and selected cases with unknown survival benefit. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Complete resection of recurrent lesions represents a major predictor of favorable outcome, and surgery is then recommended in case of resectable lesion. In non-resectable recurrences, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. The re-administration of a previously effective regimen has to be considered, especially in case of previous response, late occurring recurrence, and for anthracyclins, a patient in a good medical condition and not having received cumulative doses precluding the safe delivery of at least 3 additional cycles. Preferred regimens for second-line treatment include carboplatin plus paclitaxel, and platin plus etoposide; capecitabine plus gemcitabine is an option. These regimens were evaluated in dedicated phase II trials. Options for subsequent lines include pemetrexed, oral etoposide. In patients with octreoscan-positive thymoma, not eligible to receive additional chemotherapy, octreotide alone or with prednisone may represent a valuable option. The use of targeted agents may be done in an off-label setting in advanced thymic malignancies. While KIT is overexpressed in 80% of thymic carcinomas, KIT gene mutations are found only in 9% of cases, consisting of mutations observed in other malignancies (V560del, L576P) or mutations unique to thymic carcinomas (H697Y, D820E). Responses and possibly prolonged survival was reported with the use KIT inhibitors - imatinib, sunitinib, or sorafenib -, mostly in single-case observations. Non-pretreated reported KIT mutants are not uniformly sensitive to imatinib, based on the clinical and/or the preclinical evidence in thymic carcinoma and/or other KIT-mutant malignancies. KIT sequencing (exons 9-17) is an option for refractory thymic carcinomas in the setting of possible access to off-label use of such inhibitors. KIT inhibitors also potently inhibiting other kinases, including Vascular Endothelial Growth Factor Receptors and Platelet-Derived Growth Factor Receptors activated in thymic malignancies. A phase II trial recently demonstrated the efficacy of sunitinib in terms of response and disease control rate in thymic epithelial tumors, including thymic carcinomas (ORR 26%; DCR: 91%) and, to a lesser extent, thymomas (ORR:6%; DCR:81%). Sunitinib may then represent an option as second-line treatment for thymic carcinomas, independently from KIT status. There is no clinical data reporting on antitumor efficacy of other antiangiogenic drugs. mTOR is emerging as a potential target in thymic epithelial tumors, following tumor responses observed in phase I trials. Everolimus (10 mg daily) was evaluated in thymic epithelial tumors in a recently reported phase II trial reporting on a 22% response rate, as well as a 93% disease control rate. Everolimus may then represent an option for refractory tumors. Several trials assessing the efficacy of PD-1 checkpoint inhibitors are currently ongoing. A phase II study of pembrolizumab, a fully humanized IgG4 Ab that targets the PD-1 receptor, was recently reported; the study has accrued 30 patients. Four serious autoimmune disorders developed. Out of 30 patients evaluable for response so far the response rate is 24%. The off-label use of checkpoint inhibitors is currently not recommended. Overall, a dramatic improvement in our knowledge of the management of thymic tumors has occurred in the last few years. This improvement has primarily resulted from an increased interest in these rare tumors at some dedicated centers, and from the development of international efforts that succeed in putting together large-volume, top-quality centers all over the world, for databases, translational research, and clinical trials. Thymoma, Thymic carcinoma