Real-world outcomes of radiation therapy-based multimodal therapy in thymic epithelial tumors: A single-center retrospective analysis

Abstract

Thymic epithelial tumors (TETs) are rare malignancies with diverse histologic subtypes and complex clinical behavior, necessitating a multidisciplinary approach to care. We conducted a retrospective analysis of 52 patients with TETs treated at a tertiary cancer center, including 41 with thymoma and 11 with thymic carcinoma. The median age was 50 years for thymoma and 56 years for thymic carcinoma. Paraneoplastic syndromes, particularly myasthenia gravis, were more frequent in thymoma (46.3%) than in thymic carcinoma (9.1%). Most patients presented with advanced-stage disease (stage IIIA or higher accounted for 75.7% of thymoma cases and 72.8% of thymic carcinoma cases). Neoadjuvant chemotherapy was administered to 26.8% of thymoma cases and 27.3% of thymic carcinoma cases. Surgical resection was performed in 90.2% of thymoma and 63.6% of thymic carcinoma patients, with complete resection (R0) achieved in 83.8% and 71.4%, respectively. Post-operative radiotherapy (RT) was widely utilized, delivered via volumetric-modulated arc therapy or tomotherapy. Four patients with stage IVA thymoma received hyperthermic intrathoracic chemotherapy after cytoreductive surgery. At a median follow-up of 6 years, the 5-year overall survival for thymoma and thymic carcinoma was 70.0% and 30.7%, respectively, while the 5-year progression-free survival for thymoma and thymic carcinoma was 85.1% and 26%, respectively. Relapse occurred in 17.1% of thymoma and 63.6% of thymic carcinoma patients. Despite the predominance of advanced-stage disease and large tumor burden at presentation, an aggressive, multimodal treatment approach—including high rates of R0 resection, advanced RT techniques (e.g., volumetric modulated arc therapy, tomotherapy), multiline systemic therapy, and selective hyperthermic intrathoracic chemotherapy—demonstrates potential to improve treatment outcomes. Recurrence is the strongest predictor of mortality in both thymoma and thymic carcinoma.

Keywords

Thymoma / Thymic carcinoma / Thymic epithelial tumors / Myasthenia gravis / Multidisciplinary / Radiation / Post-operative radiotherapy

References

[1] Jackson MW, Palma DA, Camidge DR, et al. The impact of postoperative radiotherapy for thymoma and thymic carcinoma. J Thorac Oncol. 2017; 12(4):734-744. doi: 10.1016/j.jtho.2017.01.002

[2] Riely GJ, Wood DE, Loo BW, et al. Thymomas and thymic carcinomas, version 2.2025, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2025; 23(6):255-269. doi: 10.6004/jnccn.2025.0027

[3] Chen L, Li Y, Dong X, et al. The value of postoperative radiotherapy in thymoma patients with myasthenia gravis. Radiother Oncol. 2023;183:109644. doi: 10.1016/j.radonc.2023.109644

[4] Rich AL. Epidemiology of thymoma. J Thorac Dis. 2020; 12(12):7531-7535. doi: 10.21037/jtd-2019-thym-02

[5] Roden AC, Ahmad U, Cardillo G, et al. Thymic carcinomas-a concise multidisciplinary update on recent developments from the thymic carcinoma working group of the international thymic malignancy interest group. J Thorac Oncol. 2022; 17(5):637-650. doi: 10.1016/j.jtho.2022.01.021

[6] Marx A, Chan JKC, Chalabreysse L, et al. The 2021 WHO classification of tumors of the thymus and mediastinum: What is new in thymic epithelial, germ cell, and mesenchymal tumors? J Thorac Oncol. 2022; 17(2):200-213. doi: 10.1016/j.jtho.2021.10.010

[7] Zhang Y, Lin D, Aramini B, et al. Thymoma and thymic carcinoma: Surgical resection and multidisciplinary treatment. Cancers (Basel). 2023; 15(7):1953. doi: 10.3390/cancers15071953

[8] Girard N, Ruffini E, Marx A, Faivre-Finn C, Peters S; ESMO Guidelines Committee. Thymic epithelial tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26(Suppl 5):v40-v55. doi: 10.1093/annonc/mdv277

[9] Rathod S, Munshi A, Paul S, Ganesh B, Prabhash K, Agarwal JP. Thymoma: First large Indian experience. Indian J Cancer. 2014; 51:109-112. doi: 10.4103/0019-509X.138144

[10] Chowdhary RL, Chufal KS, Ismail M, et al. Intuitive evaluation of contemporary management strategies in thymoma - the largest Indian experience. Rep Pract Oncol Radiother. 2023; 28(4):454-464. doi: 10.5603/RPOR.a2023.0050

[11] Gerber TS, Strobl S, Marx A, Roth W, Porubsky S. Epidemiology of thymomas and thymic carcinomas in the United States and Germany,1999-2019. Front Oncol. 2024;13:130889. doi: 10.3389/fonc.2023.1308989

[12] Nakajima J, Okumura M, Yano M, et al. Myasthenia gravis with thymic epithelial tumour: A retrospective analysis of a Japanese database. Eur J Cardiothorac Surg. 2016;49:1510-1515. doi: 10.1093/ejcts/ezv380

[13] Lin L, Li Y, Huang Y, et al. Investigating the impact of tumor size on survival outcomes in thymoma and thymic carcinoma patients using the SEER database. Sci Rep. 2024; 14(1):27680. doi: 10.1038/s41598-024-79186-5

[14] Kumar N, Kumar R, Bera A, et al. Thymoma: Clinical experience from a tertiary care institute from North India. J Cancer Res Ther. 2013;9:235-239. doi: 10.4103/0973-1482.113364

[15] Khandelwal A, Sholl LM, Araki T, Ramaiya NH, Hatabu H, Nishino M. Patterns of metastasis and recurrence in thymic epithelial tumours: Longitudinal imaging review in correlation with histologic subtypes. Clin Radiol. 2016; 71(10):1010-1017. doi: 10.1016/j.crad.2016.05.007

[16] Vladislav T, Jain RK, Alvarez R, et al. Extrathoracic metastases of thymic origin: A review of 35 cases. Mod Pathol. 2012; 25:370-377. doi: 10.1038/modpathol.2011.178

[17] Weis CA, Yao X, Deng Y, et al. The impact of thymoma histotype on prognosis in a worldwide database. J Thorac Oncol. 2015; 10(2):367-372. doi: 10.1097/JTO.0000000000000393

[18] Guleria P, Parshad R, Malik PS, Ray R, Panday RM, Jain D. Histotyping of Indian thymomas: A clinicopathologic study from North India. Indian J Med Res. 2019; 150(2):153-160. doi: 10.4103/ijmr.IJMR_530_18

[19] Liou DZ, Berry MF, Brown LM, et al. The society of thoracic surgeons expert consensus document on the surgical management of thymomas. J Thorac Dis. 2019; 11(7):2695-2699. doi: 10.1016/j.athoracsur.2024.04.013

[20] Du X, Cui J, Yu X, Yu L. Risk factor analysis of thymoma resection and its value in guiding clinical treatment. Cancer Med. 2023; 12(12):13408-13414. doi: 10.1002/cam4.6043

[21] Brascia D, De Palma A, Schiavone M, et al. Lymph nodes involvement and lymphadenectomy in thymic tumors: Tentative answers for unsolved questions. Cancers (Basel). 2021; 13(20):5085. doi: 10.3390/cancers13205085

[22] Da Nobrega Oliveira REN, De Andrade Pontual Peres C, Oliveira AC, et al. Efficacy of cytoreductive surgery and hyperthermic intrathoracic chemotherapy (HITHOC) in thymic neoplasia: A systematic review and single-arm meta-analysis. Ann Surg Oncol. 2025; 32(3):1670-1678. doi: 10.1245/s10434-024-16547-4

[23] Tateishi Y, Horita N, Namkoong H, Enomoto T, Takeda A, Kaneko T. 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(4):677-685. doi: 10.1016/j.jtho.2020.12.023

[24] Rea F, Marulli G, Di Chiara F, et al. Multidisciplinary approach for advanced stage thymic tumors: Long-term outcome. Lung Cancer. 2011; 75:68-72. doi: 10.1016/j.lungcan.2010.07.006

[25] Lu CF, Yu L, Jing Y, Zhang YF, Ke J. Value of adjuvant radiotherapy for thymoma with myasthenia gravis after extended thymectomy. Chin Med J (Engl). 2018;131:927-932. doi: 10.4103/0366-6999.229894

[26] Lin L, Li Y, Huang Y, et al. Evaluation of the role of postoperative radiotherapy in locally invasive thymoma: A propensity-matched study based on the SEER database. PLoS One. 2023; 18(4):e0283192. doi: 10.1371/journal.pone.0283192

[27] Rico M, Flamarique S, Casares C, et al. GOECP/SEOR radiotherapy guidelines for thymic epithelial tumours. World J Clin Oncol. 2021; 12(4):195-216. doi: 10.5306/wjco.v12.i4.195

[28] Marcuse F, Peeters S, Herman K, et al. Optimal delineation of the clinical target volume for thymomas in the post-resection setting: A multicenter study. Radiother Oncol. 2021; 165:8-13. doi: 10.1016/j.radonc.2021.10.007

[29] Rahi MS, Parekh J, Pednekar P, et al. Radiation-induced lung injury-current perspectives and management. Clin Pract. 2021; 11(3):410-429. doi: 10.3390/clinpract11030056

[30] Moiseenko V, Craig T, Bezjak A, Van Dyk J. Dose-volume analysis of lung complications in the radiation treatment of malignant thymoma: A retrospective review. Radiother Oncol. 2003; 67(3):265-274. doi: 10.1016/S0167-8140(03)00003-3

[31] Gomez D, Komaki R. Technical advances of radiation for thymic malignancies. J Thorac Oncol. 2010; 5(Suppl 4):S336-S343. doi: 10.1097/JTO.0b013e3181f20ea2

[32] 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. J Clin Oncol. 1994; 12:1164-1168. doi: 10.1200/JCO.1994.12.6.1164

[33] 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; 13:1762-1770. doi: 10.1016/j.tho.2018.08.005

[34] Theochari K, Rapti K, Kotteas E, et al. Fatal adverse events in two thymoma patients treated with anti-PD-1 immune checkpoint inhibitor and literature review. Lung Cancer. 2019; 135:29-32. doi: 10.1016/j.lungcan.2019.06.015

[35] Argentiero A, Solimando AG, Ungaro V, et al. Case report: Lymphocytosis associated with fatal hepatitis in a thymoma patient treated with anti-PD1: New insight into the immune-related storm. Front Oncol. 2020;10:583781. doi: 10.3389/fonc.2020.583781

[36] 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;26:363-368. doi: 10.1093/annonc/mdu541

[37] 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;21:843-850. doi: 10.1016/S1470-2045(20)30162-5

[38] 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;16:177-186. doi: 10.1016/S1470-2045(14)71181-7

[39] Proto C, Manglaviti S, Lo Russo G, et al. STYLE (NCT03449173): A phase 2 trial of sunitinib in patients with type B3 thymoma or thymic carcinoma in second and further lines. J Thorac Oncol. 2023; 18:1070-1081. doi: 10.1016/j.jtho.2023.04.009

[40] 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; 10:2141-2147. doi: 10.2217/fon.14.144

[41] 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;19:347-355. doi: 10.1016/S1470-2045(18)30062-7

[42] Giaccone G, Kim C. Durable response in patients with thymic carcinoma treated with pembrolizumab after prolonged follow-up. J Thorac Oncol. 2021; 16:483-485. doi: 10.1016/j.jtho.2020.11.003

[43] 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; 37:2162-2170. doi: 10.1200/JCO.2017.77.3184

[44] Conforti F, Zucali PA, Pala L, et al. Avelumab plus axitinib in unresectable or metastatic type B 3 thymomas and thymic carcinomas (CAVEATT): A single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23:1287-1296. doi: 10.1016/S1470-2045(22)00542-3

[45] Conforti F, Pala L, Vivanet G, et al. High-dose continuous-infusion ifosfamide in advanced thymic epithelial tumors: A TYME network study. Lung Cancer. 2023;176:98-102. doi: 10.1016/S1470-2045(22)00542-3.

[46] Hellyer JA, Ouseph MM, Padda SK, Wakelee HA. Everolimus in the treatment of metastatic thymic epithelial tumors. Lung Cancer. 2020; 149:97-102. doi: 10.1016/j.lungcan.2020.09.006

[47] Alothaimeen HS, Memon MA. Treatment outcomes and prognostic factors of malignant thymoma: A single institution experience. Asian Pac J Cancer Prev. 2020; 21(3):653-661. doi: 10.31557/APJCP.2020.21.3.653

[48] Bruni A, Stefani A, Perna M, et al. The role of postoperative radiotherapy for thymomas: A multicentric retrospective evaluation from three Italian centers and review of literature. J Thorac Dis. 2020; 12(12):7518-7530. doi: 10.21037/jtd-2019-thym-09

[49] Yuan ZY, Gao SG, Mu JW, et al. Long-term outcomes of 307 patients after complete thymoma resection. Chin J Cancer. 2017;36:46. doi: 10.1186/s40880-017-0213-8

[50] Liou DZ, Ramakrishnan D, Lui NS, Shrager JB, Backhus LM, Berry MF. Does size matter? A national analysis of the utility of induction therapy for large thymomas. J Thorac Dis. 2020; 12(4):1329-1341. doi: 10.21037/jtd.2020.02.63

[51] Rimner A, Ahmad U, Lobaugh SM, et al. Postoperative radiation therapy for thymic carcinoma: an analysis of the international thymic malignancy interest group/european society of thoracic surgeons database. J Thorac Oncol. 2024; 19(2):233-242. doi: 10.1016/j.jtho.2023.12.011

[52] Tseng YL. Thymic carcinoma: A rare cancer requiring special attention. Formos J Surg. 2011; 44(5):169-175. doi: 10.1016/j.fjs.2011.08.007

[53] Cheng G, Gu C, Song Z. Impact of metastasis site for survival of patients with advanced thymic epithelial tumors. Transl Cancer Res. 2016; 5(5):546-551. doi: 10.21037/tcr.2016.09.35

[54] Bai H, Lyu J, Nie X, et al. Ginsenoside Rg5 enhances the radiosensitivity of lung adenocarcinoma via reducing HSP90-CDC37 interaction and promoting client protein degradation. J Pharm Anal. 2023; 13(11):1296-1308. doi: 10.1016/j.jpha.2023.06.004