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Surgical, Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Systematic Review

Published:November 04, 2022DOI:https://doi.org/10.1016/j.jtho.2022.10.016

      Abstract

      Introduction

      Thymic epithelial tumors are rare and are classified as thymoma, thymic carcinoma, and thymic neuroendocrine tumors. The objective of this systematic review was to evaluate the treatment options for patients with thymic epithelial tumors.

      Methods

      This systematic review was developed by Ontario Health (Cancer Care Ontario)’s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing surgical, radiotherapy, or systemic treatments against any combination of these treatments in patients with thymic epithelial tumors. Meta-analyses were conducted with clinically homogenous studies.

      Results

      A total of 106 studies were included, mainly from observational studies. There was an overall survival benefit with postoperative radiotherapy for patients with thymic carcinoma (hazard ratio = 0.65, 95% confidence interval: 0.47–0.89) and for patients with thymoma (hazard ratio = 0.70, 95% confidence interval: 0.59–0.82), especially for those with a high risk for mortality. Patients with thymic carcinoma or thymoma had a response to chemotherapy. Selection bias affected the results for studies that evaluated neoadjuvant chemotherapy or minimally invasive surgical techniques. Furthermore, the overall survival benefit found for adjuvant chemotherapy may have been confounded by the administration of postoperative radiotherapy.

      Conclusions

      For patients with thymoma or thymic carcinoma, the literature is of low quality and subject to bias. There were overall survival benefits with postoperative radiotherapy. The results of this systematic review were used to inform treatment recommendations in a clinical practice guideline. Future large-scale prospective studies that control for confounders are needed.

      Keywords

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      References

        • de Jong W.K.
        • Blaauwgeers J.L.
        • Schaapveld M.
        • Timens W.
        • Klinkenberg T.J.
        • Groen H.J.
        Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy.
        Eur J Cancer. 2008; 44: 123-130
        • Ahmad U.
        • Yao X.
        • Detterbeck F.
        • et al.
        Thymic carcinoma outcomes and prognosis: results of an international analysis.
        J Thorac Cardiovasc Surg. 2015; 149: 95-101.e102
        • Gaur P.
        • Leary C.
        • Yao J.C.
        Thymic neuroendocrine tumors: a SEER database analysis of 160 patients.
        Ann Surg. 2010; 251: 1117-1121
        • Travis W.D.
        • Brambilla E.
        • Muller-Hermelink H.K.
        • et al.
        Pathology and genetics of tumors of the lung, pleura, thymus and heart.
        in: World Health Organization Classification of Tumours. 2004
        • Masaoka A.
        Staging system of thymoma.
        J Thorac Oncol. 2010; 5: S304-S312
        • Weksler B.
        • Dhupar R.
        • Parikh V.
        • Nason K.S.
        • Pennathur A.
        • Ferson P.F.
        Thymic carcinoma: a multivariate analysis of factors predictive of survival in 290 patients.
        Ann Thorac Surg. 2013; 95: 299-303
        • Gal A.A.
        • Kornstein M.J.
        • Cohen C.
        • Duarte I.G.
        • Miller J.I.
        • Mansour K.A.
        Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study.
        Ann Thorac Surg. 2001; 72: 1179-1182
        • Kondo K.
        • Monden Y.
        Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan.
        Ann Thorac Surg. 2003; 76: 878-885
        • Nakagawa K.
        • Asamura H.
        • Matsuno Y.
        • et al.
        Thymoma: a clinicopathologic study based on the new World Health Organization classification.
        J Thorac Cardiovasc Surg. 2003; 126: 1134-1140
        • Rea F.
        • Marulli G.
        • Girardi R.
        • et al.
        Long-term survival and prognostic factors in thymic epithelial tumours.
        Eur J Cardiothorac Surg. 2004; 26: 412-418
        • Regnard J.F.
        • Magdeleinat P.
        • Dromer C.
        • et al.
        Prognostic factors and long-term results after thymoma resection: a series of 307 patients.
        J Thorac Cardiovasc Surg. 1996; 112: 376-384
        • Falkson C.B.
        • Bezjak A.
        • Darling G.
        • et al.
        The management of thymoma: a systematic review and practice guideline.
        J Thorac Oncol. 2009; 4: 911-919
        • Huang J.
        • Ahmad U.
        • Antonicelli A.
        • et al.
        Development of the international thymic malignancy interest group international database: an unprecedented resource for the study of a rare group of tumors.
        J Thorac Oncol. 2014; 9: 1573-1578
        • Nicholson A.G.
        • Detterbeck F.C.
        • Marino M.
        • et al.
        The IASLC/ITMIG thymic Epithelial Tumors Staging Project: proposals for the T Component for the forthcoming (8th) edition of the TNM classification of malignant tumors.
        J Thorac Oncol. 2014; 9: S73-S80
      1. Falkson C, Vella ET, Ellis PM, Maziak DE, Ung YC, Yu E. Surgical, radiation, and systemic treatments of patients with thymic epithelial tumours: a clinical practice guideline [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2022.08.007, accessed November 24, 2022.

        • Shea B.J.
        • Reeves B.C.
        • Wells G.
        • et al.
        AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.
        BMJ. 2017; 358: j4008
        • Sterne J.A.
        • Hernán M.A.
        • Reeves B.C.
        • et al.
        ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
        BMJ. 2016; 355: i4919
        • Sterne J.A.C.
        • Savović J.
        • Page M.J.
        • et al.
        RoB 2: a revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; 366: l4898
      2. Review Manager (RevMan) [Computer Program]. Version 5.4. The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark2020
        • Parmar M.K.
        • Torri V.
        • Stewart L.
        Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.
        Stat Med. 1998; 17: 2815-2834
        • Guyatt G.
        • Oxman A.D.
        • Akl E.A.
        • et al.
        GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
        J Clin Epidemiol. 2011; 64: 383-394
        • Zhang H.A.
        • Lu N.
        • Wang M.
        • Gu X.
        • Zhang D.
        Postoperative radiotherapy for stage I thymoma: a prospective randomized trial in 29 cases.
        Chin Med J (Engl). 1999; 112: 136-138
        • Zhai Y.R.
        • Feng Q.
        • Gao Y.
        • et al.
        THYPORT: postoperative radiotherapy versus surgery alone in Masaoka Stage II thymoma: mid-term result of a prospective randomized study from a Single Center(NCT02014805).
        Int J Radiat Oncol Biol Phys. 2019; 105: E492-E493
        • Hishida T.
        • Asamura H.
        • Yoshida K.
        • et al.
        Clinical features and prognostic impact of coexisting autoimmune disease other than myasthenia gravis in resected thymomas: analysis of a Japanese multi-institutional retrospective database.
        Eur J Cardiothorac Surg. 2021; 59: 641-649
        • Narm K.S.
        • Lee C.Y.
        • Do Y.W.
        • et al.
        Limited thymectomy as a potential alternative treatment option for early-stage thymoma: a multi-institutional propensity-matched study.
        Lung Cancer. 2016; 101: 22-27
        • Rusidanmu A.
        • Huang S.
        • Lv X.
        Is thymomectomy sufficient for non-myasthenic early stage thymoma patients? A retrospective, single center experience.
        Thorac Cancer. 2018; 9: 88-93
        • Sakamaki Y.
        • Oda T.
        • Kanazawa G.
        • Shimokawa T.
        • Kido T.
        • Shiono H.
        Intermediate-term oncologic outcomes after video-assisted thoracoscopic thymectomy for early-stage thymoma.
        J Thorac Cardiovasc Surg. 2014; 148: 1230-1237.e1
        • Zhao M.
        • Yin J.
        • Yang X.
        • et al.
        Nomogram to predict thymoma prognosis: a population-based study of 1312 cases.
        Thorac Cancer. 2019; 10: 1167-1175
        • Onuki T.
        • Ishikawa S.
        • Iguchi K.
        • et al.
        Limited thymectomy for stage I or II thymomas.
        Lung Cancer. 2010; 68: 460-465
        • Nakagawa K.
        • Yokoi K.
        • Nakajima J.
        • et al.
        Is thymomectomy alone appropriate for stage I (T1N0M0) thymoma? Results of a propensity-score analysis.
        Ann Thorac Surg. 2016; 101: 520-526
        • Tassi V.
        • Ceccarelli S.
        • Zannori C.
        • et al.
        Could thymomectomy be a reasonable option for non-myasthenic thymoma patients?.
        J Thorac Dis. 2017; 9: 3817-3824
        • Tseng Y.C.
        • Hsieh C.C.
        • Huang H.Y.
        • et al.
        Is thymectomy necessary in nonmyasthenic patients with early thymoma?.
        J Thorac Oncol. 2013; 8: 952-958
        • Agatsuma H.
        • Yoshida K.
        • Yoshino I.
        • et al.
        Video-assisted thoracic surgery thymectomy versus sternotomy thymectomy in patients with thymoma.
        Ann Thorac Surg. 2017; 104: 1047-1053
        • He Z.F.
        • Wu Y.B.
        • Lu D.
        • et al.
        Efficacy and safety of video-assisted thoracic surgery and median sternotomy in the treatment of thymoma-associated myasthenia gravis.
        Int J Clin Exp Med. 2016; 9: 21922-21931
        • Kocer B.
        • Kaplan T.
        • Gunal N.
        • et al.
        Long-term survival after R0 resection of thymoma.
        Asian Cardiovasc Thorac Ann. 2018; 26: 461-466
        • Liu T.J.
        • Lin M.W.
        • Hsieh M.S.
        • et al.
        Video-assisted thoracoscopic surgical thymectomy to treat early thymoma: a comparison with the conventional transsternal approach.
        Ann Surg Oncol. 2014; 21: 322-328
        • Manoly I.
        • Whistance R.N.
        • Sreekumar R.
        • et al.
        Early and mid-term outcomes of trans-sternal and video-assisted thoracoscopic surgery for thymoma.
        Eur J Cardiothorac Surg. 2014; 45: e187-e193
        • Tian W.
        • Sun Y.
        • Wu Q.
        • et al.
        Surgical outcomes of 215 patients with thymic epithelial tumors: A single-center experience.
        Thorac Cancer. 2020; 11: 1840-1847
        • Triviño A.
        • Congregado M.
        • Loscertales J.
        • et al.
        Análisis comparativo del abordaje para el tratamiento del timoma estadio i-ii: VATS versus abordaje convencional [Comparative analysis of video-assisted thoracic surgery versus open resection for early-stage thymoma].
        Cir Esp. 2015; 93: 466-471
        • Yang C.J.
        • Hurd J.
        • Shah S.A.
        • et al.
        A national analysis of open versus minimally invasive thymectomy for stage I to III thymoma.
        J Thorac Cardiovasc Surg. 2020; 160: 555-567.e15
        • Zhang X.
        • Li B.
        • Zou J.
        • et al.
        Perioperative risk factors for occurrence of myasthenia gravis after thymectomy in patients with thymoma.
        Interact Cardiovasc Thorac Surg. 2020; 31: 519-526
        • Odaka M.
        • Tsukamoto Y.
        • Shibasaki T.
        • et al.
        Thoracoscopic thymectomy is a feasible and less invasive alternative for the surgical treatment of large thymomas.
        Interact Cardiovasc Thorac Surg. 2017; 25: 103-108
        • Yuan Z.Y.
        • Gao S.G.
        • Mu J.W.
        • et al.
        Long-term outcomes of 307 patients after complete thymoma resection.
        Chin J Cancer. 2017; 36: 46
        • Jurado J.
        • Javidfar J.
        • Newmark A.
        • et al.
        Minimally invasive thymectomy and open thymectomy: outcome analysis of 263 patients.
        Ann Thorac Surg. 2012; 94: 974-982
        • Lin Q.
        • Zhang Y.
        • Yang L.
        Single-center retrospective analysis of 162 cases with thymoma complicating myasthenia gravis.
        J BUON. 2017; 22: 741-745
        • Marulli G.
        • Comacchio G.M.
        • Schiavon M.
        • et al.
        Comparing robotic and trans-sternal thymectomy for early-stage thymoma: a propensity score-matching study.
        Eur J Cardiothorac Surg. 2018; 54: 579-584
        • Allakhverdiev A.
        • Davydov M.
        • Allakhverdieva G.
        • Akhmedov P.
        Thoracoscopic thymectomy - the method of choise in surgical treatment of non-invasive thymomas.
        Ann Med Surg (Lond). 2018; 42: 29-34
        • Fadayomi A.B.
        • Iniguez C.E.B.
        • Chowdhury R.
        • et al.
        Propensity score adjusted comparison of minimally invasive versus open thymectomy in the management of early stage thymoma.
        Thorac Cardiovasc Surg. 2018; 66: 352-358
        • He Z.
        • Zhu Q.
        • Wen W.
        • Chen L.
        • Xu H.
        • Li H.
        Surgical approaches for stage I and II thymoma-associated myasthenia gravis: feasibility of complete video-assisted thoracoscopic surgery (VATS) thymectomy in comparison with trans-sternal resection.
        J Biomed Res. 2013; 27: 62-70
        • Maniscalco P.
        • Tamburini N.
        • Quarantotto F.
        • Grossi W.
        • Garelli E.
        • Cavallesco G.
        Long-term outcome for early stage thymoma: comparison between thoracoscopic and open approaches.
        Thorac Cardiovasc Surg. 2015; 63: 201-205
        • Mu J.W.
        • Chen G.Y.
        • Sun K.L.
        • et al.
        Application of video-assisted thoracic surgery in the standard operation for thoracic tumors.
        Cancer Biol Med. 2013; 10: 28-35
        • 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
        • Ye B.
        • Li W.
        • Ge X.X.
        • et al.
        Surgical treatment of early-stage thymomas: robot-assisted thoracoscopic surgery versus transsternal thymectomy.
        Surg Endosc. 2014; 28: 122-126
        • Chao Y.K.
        • Liu Y.H.
        • Hsieh M.J.
        • et al.
        Long-term outcomes after thoracoscopic resection of stage I and II thymoma: A propensity-matched study.
        Ann Surg Oncol. 2015; 22: 1371-1376
        • Cheng Y.J.
        • Kao E.L.
        • Chou S.H.
        Videothoracoscopic resection of stage II thymoma: prospective comparison of the results between thoracoscopy and open methods.
        Chest. 2005; 128: 3010-3012
        • Chung J.W.
        • Kim H.R.
        • Kim D.K.
        • et al.
        Long-term results of thoracoscopic thymectomy for thymoma without myasthenia gravis.
        J Int Med Res. 2012; 40: 1973-1981
        • Kimura T.
        • Inoue M.
        • Kadota Y.
        • et al.
        The oncological feasibility and limitations of video-assisted thoracoscopic thymectomy for early-stage thymomas.
        Eur J Cardiothorac Surg. 2013; 44: e214-e218
        • Odaka M.
        • Akiba T.
        • Yabe M.
        • et al.
        Unilateral thoracoscopic subtotal thymectomy for the treatment of stage I and II thymoma.
        Eur J Cardiothorac Surg. 2010; 37: 824-826
        • Tian W.
        • Li X.
        • Tong H.
        • et al.
        Surgical effect and prognostic factors of myasthenia gravis with thymomas.
        Thorac Cancer. 2020; 11: 1288-1296
        • Tagawa T.
        • Yamasaki N.
        • Tsuchiya T.
        • et al.
        Thoracoscopic versus transsternal resection for early stage thymoma: long-term outcomes.
        Surg Today. 2014; 44: 2275-2280
        • Guerrera F.
        • Rendina E.A.
        • Venuta F.
        • et al.
        Does the World Health Organization histological classification predict outcomes after thymomectomy? Results of a multicentre study on 750 patients.
        Eur J Cardiothorac Surg. 2015; 48: 48-54
        • Liou D.Z.
        • Ramakrishnan D.
        • Lui N.S.
        • Shrager J.B.
        • Backhus L.M.
        • Berry M.F.
        Does size matter? A national analysis of the utility of induction therapy for large thymomas.
        J Thorac Dis. 2020; 12: 1329-1341
        • Yamada Y.
        • Yoshino I.
        • Nakajima J.
        • et al.
        Surgical outcomes of patients with stage III thymoma in the Japanese nationwide database.
        Ann Thorac Surg. 2015; 100: 961-967
        • Hakiri S.
        • Fukui T.
        • Mori S.
        • et al.
        Clinicopathologic features of thymoma with the expression of programmed death ligand 1.
        Ann Thorac Surg. 2019; 107: 418-424
        • Kumar A.
        • Pulle M.V.
        • Asaf B.B.
        • et al.
        Surgical and oncological outcomes in locally advanced thymoma.
        Indian J Surg Oncol. 2021; 12: 350-357
        • Song S.H.
        • Suh J.W.
        • Yu W.S.
        • et al.
        The role of postoperative radiotherapy in stage II and III thymoma: a Korean multicenter database study.
        J Thorac Dis. 2020; 12: 6680-6689
        • Bian D.
        • Zhou F.
        • Yang W.
        • et al.
        Thymoma size significantly affects the survival, metastasis and effectiveness of adjuvant therapies: a population based study.
        Oncotarget. 2018; 9: 12273-12283
        • Song J.S.
        • Kim D.
        • Kwon J.H.
        • Kim H.R.
        • Choi C.M.
        • Jang S.J.
        Clinicopathologic significance and immunogenomic analysis of programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) expression in thymic epithelial tumors.
        Front Oncol. 2019; 9: 1055
        • Lucchi M.
        • Melfi F.
        • Dini P.
        • et al.
        Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up.
        J Thorac Oncol. 2006; 1: 308-313
        • Rea F.
        • Marulli G.
        • Di Chiara F.
        • et al.
        Multidisciplinary approach for advanced stage thymic tumors: long-term outcome.
        Lung Cancer. 2011; 72: 68-72
        • Khorfan R.
        • Bharat A.
        • Odell D.D.
        Management and long-term outcomes of advanced stage thymoma in the United States.
        Ann Thorac Surg. 2021; 111: 223-230
        • Fornasiero A.
        • Daniele O.
        • Ghiotto C.
        • et al.
        Chemotherapy for invasive thymoma: a 13-year experience.
        Cancer. 1991; 68: 30-33
        • Kunitoh H.
        • Tamura T.
        • Shibata T.
        • et al.
        A phase-II trial of dose-dense chemotherapy in patients with disseminated thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9605).
        Br J Cancer. 2009; 101: 1549-1554
        • Loehrer Sr., A.P.J.
        • Kim K.
        • Aisner S.C.
        • 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: 1164-1168
        • Loehrer Sr., P.J.
        • Wang W.
        • Johnson D.H.
        • Aisner S.C.
        • Ettinger D.S.
        Eastern Cooperative Oncology Group Phase II Trial. 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: 293-299
        • Rajan A.
        • Carter C.A.
        • Berman A.
        • et al.
        Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2014; 15: 191-200
        • Zucali P.A.
        • 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: 342-349
        • Wu K.L.
        • Mao J.F.
        • Chen G.Y.
        • Fu X.L.
        • Qian H.
        • Jiang G.L.
        Prognostic predictors and long-term outcome of postoperative irradiation in thymoma: a study of 241 patients.
        Cancer Invest. 2009; 27: 1008-1015
        • Bian D.
        • Zhao L.
        • Zhang X.
        • et al.
        Immunohistochemistry biomarker TP53 expression predicts the survival of thymomas.
        Gland Surg. 2020; 9: 291-299
        • Eralp Y.
        • Aydiner A.
        • Kizir A.
        • Kaytan E.
        • Oral E.N.
        • Topuz E.
        Resectable thymoma: treatment outcome and prognostic factors in the late adolescent and adult age group.
        Cancer Invest. 2003; 21: 737-743
        • Jackson M.W.
        • Palma D.A.
        • Camidge D.R.
        • et al.
        The impact of postoperative radiotherapy for thymoma and thymic carcinoma.
        J Thorac Oncol. 2017; 12: 734-744
        • Mou H.
        • Liao Q.
        • Hou X.
        • Chen T.
        • Zhu Y.
        Clinical characteristics, risk factors, and outcomes after adjuvant radiotherapy for patients with thymoma in the United States: analysis of the Surveillance, Epidemiology, and End Results (SEER) Registry (1988–2013).
        Int J Radiat Biol. 2018; 94: 495-502
        • 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: 1008-1016
        • 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: 1785-1792
        • Singhal S.
        • Shrager J.B.
        • Rosenthal D.I.
        • LiVolsi V.A.
        • Kaiser L.R.
        Comparison of stages I–II thymoma treated by complete resection with or without adjuvant radiation.
        Ann Thorac Surg. 2003; 76: 1635-1642
        • Tang E.K.
        • Chang J.M.
        • Chang C.C.
        • et al.
        Prognostic factor of completely resected and pathologic T3 N0 M0 thymic epithelial tumor.
        Ann Thorac Surg. 2021; 111: 1164-1173
        • Yan J.
        • Liu Q.
        • Moseley J.N.
        • et al.
        Adjuvant radiotherapy for stages II and III resected thymoma: A single-institutional experience.
        Am J Clin Oncol. 2016; 39: 223-227
        • Berman A.T.
        • Litzky L.
        • Livolsi V.
        • et al.
        Adjuvant radiotherapy for completely resected stage 2 thymoma.
        Cancer. 2011; 117: 3502-3508
        • 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 the literature.
        J Thorac Dis. 2020; 12: 7518-7530
        • Chen Y.D.
        • Feng Q.F.
        • Lu H.Z.
        • et al.
        Role of adjuvant radiotherapy for stage II thymoma after complete tumor resection.
        Int J Radiat Oncol Biol Phys. 2010; 78: 1400-1406
        • D’Angelillo R.M.
        • Trodella L.
        • Ramella S.
        • et al.
        Novel prognostic groups in thymic epithelial tumors: assessment of risk and therapeutic strategy selection.
        Int J Radiat Oncol Biol Phys. 2008; 71: 420-427
        • Fan C.
        • Feng Q.
        • Chen Y.
        • et al.
        Postoperative radiotherapy for completely resected Masaoka stage III thymoma: a retrospective study of 65 cases from a single institution.
        Radiat Oncol. 2013; 8: 199
        • Häfner M.F.
        • Roeder F.
        • Sterzing F.
        • et al.
        Postoperative radiotherapy of patients with thymic epithelial tumors (TET): a retrospective analysis of outcome and toxicity.
        Strahlenther Onkol. 2015; 191: 133-140
        • Lee K.H.
        • Noh J.M.
        • Ahn Y.C.
        • et al.
        Patterns of failure following postoperative radiation therapy based on “tumor bed with margin” for stage II to IV type C thymic epithelial tumor.
        Int J Radiat Oncol Biol Phys. 2018; 102: 1505-1513
        • Tomita N.
        • Okuda K.
        • Ogawa Y.
        • et al.
        Relationship between radiation doses to heart substructures and radiation pneumonitis in patients with thymic epithelial tumors.
        Sci Rep. 2020; 1011191
        • Fernandes A.T.
        • Shinohara E.T.
        • Guo M.
        • et al.
        The role of radiation therapy in malignant thymoma: a surveillance, epidemiology, and end results database analysis.
        J Thorac Oncol. 2010; 5: 1454-1460
        • Lim Y.J.
        • Song C.
        • Kim J.S.
        Improved survival with postoperative radiotherapy in thymic carcinoma: a propensity-matched analysis of Surveillance, Epidemiology, and End Results (SEER) database.
        Lung Cancer. 2017; 108: 161-167
        • Yuan Z.Y.
        • Gao S.G.
        • Mu J.W.
        • et al.
        Prognostic value of preoperative neutrophil-lymphocyte ratio is superior to platelet-lymphocyte ratio for survival in patients who underwent complete resection of thymic carcinoma.
        J Thorac Dis. 2016; 8: 1487-1496
        • Cheng Y.J.
        Videothoracoscopic resection of encapsulated thymic carcinoma: retrospective comparison of the results between thoracoscopy and open methods.
        Ann Surg Oncol. 2008; 15: 2235-2238
        • 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: 541-548
        • Bakhos C.T.
        • Salami A.C.
        • Kaiser L.R.
        • Petrov R.V.
        • Abbas A.E.
        Thymic neuroendocrine tumors and thymic carcinoma: demographics, treatment, and survival.
        Innovations (Phila). 2020; 15: 468-474
        • Hishida T.
        • Nomura S.
        • Yano M.
        • et al.
        Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese nationwide database study.
        Eur J Cardiothorac Surg. 2016; 49: 835-841
        • 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
        • Miura Y.
        • Kaira K.
        • Sakurai R.
        • et al.
        Prognostic effect of class III β-tubulin and topoisomerase-II in patients with advanced thymic carcinoma who received combination chemotherapy, including taxanes or topoisomerase-II inhibitors.
        Oncol Lett. 2017; 14: 2369-2378
        • Agatsuma T.
        • Koizumi T.
        • Kanda S.
        • et al.
        Combination chemotherapy with doxorubicin, vincristine, cyclophosphamide, and platinum compounds for advanced thymic carcinoma.
        J Thorac Oncol. 2011; 6: 2130-2134
        • Ko R.
        • Shukuya T.
        • Okuma Y.
        • et al.
        Prognostic factors and efficacy of first-line chemotherapy in patients with advanced thymic carcinoma: a retrospective analysis of 286 patients from NEJ023 study.
        Oncologist. 2018; 23: 1210-1217
        • 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
        • Kim H.S.
        • Lee J.Y.
        • Lim S.H.
        • et al.
        A prospective phase II study of cisplatin and cremophor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors.
        J Thorac Oncol. 2015; 10: 1800-1806
        • Song Z.
        • Yu X.
        • Zhang Y.
        Chemotherapy and prognosis in advanced thymic carcinoma patients.
        Clinics (Sao Paulo). 2015; 70: 775-780
        • Xu J.P.
        • Hao X.Z.
        • Zhang X.R.
        • Yang S.
        • Shi Y.K.
        Efficacy and safety of the combination of paclitaxel and platinum in advanced thymic carcinoma.
        Thorac Cancer. 2016; 7: 222-225
        • Yang X.
        • Zhuo M.
        • Shi A.
        • et al.
        Optimal first-line treatment for advanced thymic carcinoma.
        Thorac Cancer. 2019; 10: 2081-2087
        • Fan X.W.
        • Yang Y.
        • Wang H.B.
        • et al.
        Intensity modulated radiation therapy plus etoposide/cisplatin for patients with limited advanced unresectable thymic epithelial tumors: a prospective phase 2 study.
        Int J Radiat Oncol Biol Phys. 2020; 107: 98-105
        • 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-e674
        • Okuma Y.
        • Goto Y.
        • Ohyanagi F.
        • et al.
        Phase II trial of S-1 treatment as palliative-intent chemotherapy for previously treated advanced thymic carcinoma.
        Cancer Med. 2020; 9: 7418-7427
        • Wang C.L.
        • Gao L.T.
        • Lu C.X.
        S-1 salvage chemotherapy for stage IV thymic carcinoma: A study of 44 cases.
        J Thorac Dis. 2019; 11: 2816-2821
        • Cho J.
        • Kim H.S.
        • Ku B.M.
        • 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
        • 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
        • 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
        • Fu H.
        • Gu Z.T.
        • Fang W.T.
        • et al.
        Long-term survival after surgical treatment of thymic carcinoma: a retrospective analysis from the Chinese Alliance for Research of thymoma database.
        Ann Surg Oncol. 2016; 23: 619-625
        • Kim S.
        • Bull D.A.
        • Hsu C.H.
        • Hsu C.C.
        The role of adjuvant therapy in advanced thymic carcinoma: a national cancer database analysis.
        Ann Thorac Surg. 2020; 109: 1095-1103
        • Mao Y.
        • Wu S.
        Treatment and survival analyses of completely resected thymic carcinoma patients.
        Onco Targets Ther. 2015; 8: 2503-2507
        • Song Z.
        • Zhang Y.
        Outcomes after surgical resection of thymic carcinoma: a study from a single tertiary referral centre.
        Eur J Surg Oncol. 2014; 40: 1523-1527
        • Wang Y.
        • Xu L.
        • Du T.
        • Gao Y.
        • Wu Z.
        • Luo D.
        A nomogram predicting recurrence and guiding adjuvant radiation for thymic carcinoma after resection.
        Ann Thorac Surg. 2018; 106: 257-263
        • Zhao Y.
        • Zhao H.
        • Hu D.
        • Fan L.
        • Shi J.
        • Fang W.
        Surgical treatment and prognosis of thymic squamous cell carcinoma: a retrospective analysis of 105 cases.
        Ann Thorac Surg. 2013; 96: 1019-1024
        • Wen J.
        • Chen J.
        • Chen D.
        • et al.
        Evaluation of the prognostic value of surgery and postoperative radiotherapy for patients with thymic neuroendocrine tumors: a propensity-matched study based on the SEER database.
        Thorac Cancer. 2018; 9: 1603-1613
        • Fang W.
        • Filosso P.L.
        • Roden A.C.
        • et al.
        Clinicopathological features and current treatment outcomes of neuroendocrine thymic tumours.
        Eur J Cardiothorac Surg. 2021; 59: 1004-1013
        • Bian D.
        • Qi M.
        • Hu J.
        • et al.
        The comparison of predictive factors regarding prognoses and invasion of thymic neuroendocrine tumors preoperatively and postoperatively.
        J Thorac Dis. 2018; 10: 1657-1669
        • Fiorelli A.
        • Natale G.
        • Freda C.
        • Santini M.
        Is thymomectomy equivalent to complete thymectomy in non-myasthenic patients with early-stage thymoma?.
        Interact Cardiovasc Thorac Surg. 2019; 28: 399-403
        • Yang Y.
        • Dong J.
        • Huang Y.
        Thoracoscopic thymectomy versus open thymectomy for the treatment of thymoma: a meta-analysis.
        Eur J Surg Oncol. 2016; 42: 1720-1728
        • Lim Y.J.
        • Kim E.
        • Kim H.J.
        • et al.
        Survival impact of adjuvant radiation therapy in Masaoka stage II to IV thymomas: a systematic review and meta-analysis.
        Int J Radiat Oncol Biol Phys. 2016; 94: 1129-1136
        • Hamaji M.
        • Shah R.M.
        • Ali S.O.
        • Bettenhausen A.
        • Lee H.S.
        • Burt B.M.
        A meta-analysis of postoperative radiotherapy for thymic carcinoma.
        Ann Thorac Surg. 2017; 103: 1668-1675
        • Hamaji M.
        • Ali S.O.
        • Burt B.M.
        A meta-analysis of induction therapy for advanced thymic epithelial tumors.
        Ann Thorac Surg. 2015; 99: 1848-1856
        • Berghmans T.
        • Durieux V.
        • Holbrechts S.
        • et al.
        Systemic treatments for thymoma and thymic carcinoma: A systematic review.
        Lung Cancer. 2018; 126: 25-31