General Information About Thymoma and Thymic Carcinoma Treatment

Thymoma and thymic carcinoma, collectively termed thymic epithelial tumors (TETs), are relatively rare tumors arising from the thymus. Although infrequent, TETs are the most common tumors of the anterior mediastinum in adults. TETs, particularly thymomas, have unique biological properties and are associated with autoimmune paraneoplastic diseases. TETs have the lowest tumor mutational burden of all solid tumors in adults. All TETs have malignant potential and the ability to metastasize. The clinical behavior of TETs can vary from relatively indolent to aggressive, resulting in a range of clinical outcomes.

Surgery is the main treatment, especially for early-stage disease. Multimodality therapy, including chemotherapy and radiation therapy, is used to treat locally advanced disease, and systemic therapy alone is indicated for metastatic TETs.[1]

Incidence and Mortality

TETs are relatively rare tumors, representing about 0.2% to 1.5% of all malignancies.[2] The overall incidence of thymoma is 0.13 cases per 100,000 person-years, based on data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program.[3] Thymic carcinomas account for approximately 20% of all TETs.[4] The 5-year survival rate is 36% for patients with inoperable, locally advanced carcinoma and 24% for patients with metastatic thymoma and thymic carcinoma.[5]

Autoimmune Paraneoplastic Diseases Associated With Thymoma and Thymic Carcinomas

Autoimmune paraneoplastic diseases are associated with thymoma but rarely with thymic carcinomas.[6,7,8,9]

The occurrence of autoimmune paraneoplastic diseases in patients with thymoma is related to defective negative selection of autoreactive T cells. Decreased expression of AIRE, the autoimmune regulator gene, contributes to this process.[10] Thymoma-associated autoimmune paraneoplastic disease also involves an alteration in circulating T-cell subsets.[11,12] The primary T-cell abnormality may be related to the acquisition of the CD45RA+ phenotype on naive CD4+ T cells during terminal intratumorous thymopoiesis, followed by the export of these activated CD4+ T cells into the circulation.[13]

In addition to T-cell defects, B-cell lymphopenia and the presence of anticytokine antibodies have been observed in patients with thymoma-related immunodeficiency, resulting in an increased risk of developing opportunistic infection.[6,14,15]

The most common autoimmune paraneoplastic diseases associated with thymoma are myasthenia gravis, hypogammaglobulinemia, and autoimmune pure red cell aplasia.

• Myasthenia gravis is the most common autoimmune paraneoplastic disease associated with thymoma. In reported series, approximately 30% to 65% of patients with thymoma have been diagnosed with myasthenia gravis.[7,16,17] Patients with thymoma-associated myasthenia gravis can produce autoantibodies to a variety of neuromuscular antigens, particularly the acetylcholine receptor and titin, a striated muscle antigen.[18,19]
• Thymoma-associated hypogammaglobulinemia (Good syndrome) has a frequency of 5% to 20%, and thymoma-associated autoimmune pure red cell aplasia has a frequency of approximately 4%.[7,14]

A variety of other autoimmune paraneoplastic diseases can be associated with TETs and include virtually any organ system.[7,9]

Thymoma patients with myasthenia gravis or other autoimmune paraneoplastic diseases are typically diagnosed with early-stage disease and are more likely to undergo complete surgical resection than those who do not have autoimmune paraneoplastic diseases.[9,20] Thymectomy may not significantly improve the course of thymoma-associated autoimmune paraneoplastic disease in all cases.[21,22] The presence of autoimmune paraneoplastic disease also does not appear to be an independent prognostic factor in patients with TETs.[9]

Clinical Features

Most patients with thymoma or thymic carcinoma are asymptomatic at diagnosis.[23] About one-third of patients present with symptoms that arise either from the underlying tumor or from the presence of associated autoimmune paraneoplastic diseases. Typical clinical signs and symptoms include cough, dyspnea, chest pain, hoarseness of voice, phrenic nerve palsy, or signs suggestive of superior vena cava syndrome.[24]

Diagnostic and Staging Evaluation

TETs are differentiated from a number of nonthymic neoplasms that can present with mediastinal masses, including the following:[25,26]

• Germ cell tumors.
• Lymphomas.
• Stromal tumors.
• Metastatic tumors.
• Lung cancer.

Nonneoplastic thymic conditions that can present with mediastinal masses include thymic hyperplasia and thymic cysts.

The following tests and procedures may be used to diagnose and stage thymoma and thymic carcinoma:

• Physical examination and history.
• Chest x-ray. Approximately 50% of thymomas are diagnosed when they are localized within the thymic capsule and do not infiltrate surrounding tissues.[23]
• Computed tomography (CT) scan. CT with intravenous contrast is useful in the diagnosis and clinical staging of thymoma. CT is usually accurate in predicting tumor size, location, and invasion into vessels, the pericardium, and the lungs.[27,28]

  The appearance of the tumor on CT may indicate the histological tumor type.[25] In a retrospective study involving 53 patients who underwent thymectomy for TETs, CT indicated that smooth contours with a round shape were most suggestive of type A thymomas, and irregular contours were most suggestive of thymic carcinomas. Calcification was suggestive of type B thymomas. In this study, however, CT was found to be of limited value in differentiating type AB, B1, B2, and B3 thymomas.[29]

• Positron emission tomography (PET) scan. Fluorine F 18-fludeoxyglucose (18F-FDG) PET and thallium single-photon emission CT have been reported in small series for diagnosis and evaluation of therapeutic outcomes in thymic carcinoma.[30,31,32,33] Two small series reported that 18F-FDG uptake was related to the invasiveness of thymic carcinoma.[32,33] This raises the possibility of 18F-FDG PET use for diagnosis, treatment planning, and monitoring for recurrence. The impact of sensitivity and specificity on clinical therapeutic decisions is yet to be defined.
• Magnetic resonance imaging (MRI). MRI can distinguish TETs from other malignant and benign mediastinal lesions. Chemical-shift MRI can help differentiate TETs from thymic hyperplasia and a normal thymus. Cardiac MRI is the preferred modality to evaluate for the presence of myocardial involvement. An MRI can help identify phrenic nerve involvement and is considered superior to CT for assessing chest wall invasion.[34]

Thymic carcinoma can metastasize to regional lymph nodes, bone, liver, or lungs. An evaluation for sites of metastases may be warranted.

Prognostic Factors and Prognosis

The World Health Organization (WHO) pathological classification of tumors of the thymus and stage correlate with prognosis.[25] The degree of invasion or tumor stage is generally thought to be a more important indicator of overall survival (OS).[27,35,36]

Thymoma

Histological classification of thymoma is not sufficient to distinguish biologically indolent thymomas from thymomas that exhibit aggressive clinical behavior. Although some thymoma histological types are more likely to be clinically aggressive, treatment outcome and the likelihood of recurrence appear to correlate more closely with the invasive/metastasizing properties of the tumor cells.[25,35] Therefore, some thymomas that appear to be relatively benign by histological criteria may behave very aggressively. Independent evaluations of both tumor invasiveness (using staging criteria) and tumor histology may be combined to predict the clinical behavior of a thymoma.

Both histological classification of thymomas and stage may have independent prognostic significance.[35,36] A few series have reported the prognostic value of the WHO classifications. Two large retrospective analyses, one with 100 thymoma cases and the other with 178 thymoma cases, showed that disease-free survival at 10 years varied (see Table 1).[37,38] In these series, stage and complete resection were significant independent prognostic factors. Another analysis reported on 273 thymoma patients who were treated over a 44-year period. See Table 1 for the 20-year survival rates.[35]

Thymic carcinoma

Thymic carcinomas are usually advanced when diagnosed.[39,40] Thymic carcinomas have a greater propensity for capsular invasion, metastases, and recurrence than thymomas. Patients with thymic carcinoma have worse survival than patients with thymoma (5-year survival rate, 30%–50%).[41] In a retrospective study of 40 patients with thymic carcinoma, the OS rates were 38% for 5 years and 28% for 10 years.[39] In another retrospective study evaluating 43 cases of thymic carcinoma, prognosis was found to depend solely on tumor invasion of the brachiocephalic artery.[40]

Follow-Up After Treatment of Thymoma

Thymoma has been associated with an increased risk of second malignancies. Because of this risk and because thymoma can recur after a long interval, lifelong surveillance should be considered.[22] The measurement of interferon-alpha and interleukin-2 antibodies is helpful in identifying patients with a thymoma recurrence.[42]

In a study of 849 cases between 1973 and 1998, there was an excess risk of subsequent non-Hodgkin lymphoma and soft tissue sarcomas following thymoma.[43] Risk of second malignancy does not appear to be related to thymectomy, radiation therapy, or a clinical history of myasthenia gravis.[22,43,44]

References:

1. Kelly RJ, Petrini I, Rajan A, et al.: Thymic malignancies: from clinical management to targeted therapies. J Clin Oncol 29 (36): 4820-7, 2011.
2. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy of invasive thymoma. J Clin Oncol 8 (8): 1419-23, 1990.
3. Engels EA: Epidemiology of thymoma and associated malignancies. J Thorac Oncol 5 (10 Suppl 4): S260-5, 2010.
4. Carter BW, Benveniste MF, Madan R, et al.: IASLC/ITMIG Staging System and Lymph Node Map for Thymic Epithelial Neoplasms. Radiographics 37 (3): 758-776, 2017 May-Jun.
5. Kondo K, Monden Y: Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 76 (3): 878-84; discussion 884-5, 2003.
6. Levy Y, Afek A, Sherer Y, et al.: Malignant thymoma associated with autoimmune diseases: a retrospective study and review of the literature. Semin Arthritis Rheum 28 (2): 73-9, 1998.
7. Marx A, Willcox N, Leite MI, et al.: Thymoma and paraneoplastic myasthenia gravis. Autoimmunity 43 (5-6): 413-27, 2010.
8. Bernard C, Frih H, Pasquet F, et al.: Thymoma associated with autoimmune diseases: 85 cases and literature review. Autoimmun Rev 15 (1): 82-92, 2016.
9. Padda SK, Yao X, Antonicelli A, et al.: Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database. J Thorac Oncol 13 (3): 436-446, 2018.
10. Kisand K, Lilic D, Casanova JL, et al.: Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol 41 (6): 1517-27, 2011.
11. Hoffacker V, Schultz A, Tiesinga JJ, et al.: Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 96 (12): 3872-9, 2000.
12. Buckley C, Douek D, Newsom-Davis J, et al.: Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol 50 (1): 64-72, 2001.
13. Ströbel P, Helmreich M, Menioudakis G, et al.: Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas. Blood 100 (1): 159-66, 2002.
14. Martinez B, Browne SK: Good syndrome, bad problem. Front Oncol 4: 307, 2014.
15. Burbelo PD, Browne SK, Sampaio EP, et al.: Anti-cytokine autoantibodies are associated with opportunistic infection in patients with thymic neoplasia. Blood 116 (23): 4848-58, 2010.
16. Morgenthaler TI, Brown LR, Colby TV, et al.: Thymoma. Mayo Clin Proc 68 (11): 1110-23, 1993.
17. Souadjian JV, Enriquez P, Silverstein MN, et al.: The spectrum of diseases associated with thymoma. Coincidence or syndrome? Arch Intern Med 134 (2): 374-9, 1974.
18. Voltz RD, Albrich WC, Nägele A, et al.: Paraneoplastic myasthenia gravis: detection of anti-MGT30 (titin) antibodies predicts thymic epithelial tumor. Neurology 49 (5): 1454-7, 1997.
19. Gautel M, Lakey A, Barlow DP, et al.: Titin antibodies in myasthenia gravis: identification of a major immunogenic region of titin. Neurology 43 (8): 1581-5, 1993.
20. Kondo K, Monden Y: Thymoma and myasthenia gravis: a clinical study of 1,089 patients from Japan. Ann Thorac Surg 79 (1): 219-24, 2005.
21. Budde JM, Morris CD, Gal AA, et al.: Predictors of outcome in thymectomy for myasthenia gravis. Ann Thorac Surg 72 (1): 197-202, 2001.
22. Evoli A, Minisci C, Di Schino C, et al.: Thymoma in patients with MG: characteristics and long-term outcome. Neurology 59 (12): 1844-50, 2002.
23. Schmidt-Wolf IG, Rockstroh JK, Schüller H, et al.: Malignant thymoma: current status of classification and multimodality treatment. Ann Hematol 82 (2): 69-76, 2003.
24. Rajan A, Giaccone G: Treatment of advanced thymoma and thymic carcinoma. Curr Treat Options Oncol 9 (4-6): 277-87, 2008.
25. Rosai J: Histological Typing of Tumours of the Thymus. Springer-Verlag, 2nd ed., 1999.
26. Strollo DC, Rosado-de-Christenson ML: Tumors of the thymus. J Thorac Imaging 14 (3): 152-71, 1999.
27. Sperling B, Marschall J, Kennedy R, et al.: Thymoma: a review of the clinical and pathological findings in 65 cases. Can J Surg 46 (1): 37-42, 2003.
28. Rendina EA, Venuta F, Ceroni L, et al.: Computed tomographic staging of anterior mediastinal neoplasms. Thorax 43 (6): 441-5, 1988.
29. Tomiyama N, Johkoh T, Mihara N, et al.: Using the World Health Organization Classification of thymic epithelial neoplasms to describe CT findings. AJR Am J Roentgenol 179 (4): 881-6, 2002.
30. Sasaki M, Kuwabara Y, Ichiya Y, et al.: Differential diagnosis of thymic tumors using a combination of 11C-methionine PET and FDG PET. J Nucl Med 40 (10): 1595-601, 1999.
31. Kageyama M, Seto H, Shimizu M, et al.: Thallium-201 single photon emission computed tomography in the evaluation of thymic carcinoma. Radiat Med 12 (5): 237-9, 1994 Sep-Oct.
32. Adams S, Baum RP, Hertel A, et al.: Metabolic (PET) and receptor (SPET) imaging of well- and less well-differentiated tumours: comparison with the expression of the Ki-67 antigen. Nucl Med Commun 19 (7): 641-7, 1998.
33. Kubota K, Yamada S, Kondo T, et al.: PET imaging of primary mediastinal tumours. Br J Cancer 73 (7): 882-6, 1996.
34. Carter BW, Lichtenberger JP, Benveniste MF: MR Imaging of Thymic Epithelial Neoplasms. Top Magn Reson Imaging 27 (2): 65-71, 2018.
35. Okumura M, Ohta M, Tateyama H, et al.: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94 (3): 624-32, 2002.
36. Chen G, Marx A, Wen-Hu C, et al.: New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 95 (2): 420-9, 2002.
37. Kondo K, Yoshizawa K, Tsuyuguchi M, et al.: WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 77 (4): 1183-8, 2004.
38. Rena O, Papalia E, Maggi G, et al.: World Health Organization histologic classification: an independent prognostic factor in resected thymomas. Lung Cancer 50 (1): 59-66, 2005.
39. Ogawa K, Toita T, Uno T, et al.: Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 94 (12): 3115-9, 2002.
40. Blumberg D, Burt ME, Bains MS, et al.: Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 115 (2): 303-8; discussion 308-9, 1998.
41. Eng TY, Fuller CD, Jagirdar J, et al.: Thymic carcinoma: state of the art review. Int J Radiat Oncol Biol Phys 59 (3): 654-64, 2004.
42. Buckley C, Newsom-Davis J, Willcox N, et al.: Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence? Neurology 57 (9): 1579-82, 2001.
43. Engels EA, Pfeiffer RM: Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 105 (4): 546-51, 2003.
44. Pan CC, Chen PC, Wang LS, et al.: Thymoma is associated with an increased risk of second malignancy. Cancer 92 (9): 2406-11, 2001.

Cellular Classification and Molecular Characteristics of Thymoma and Thymic Carcinomas

The histological classification of thymic epithelial tumors (TETs) is largely based on the third edition of the World Health Organization (WHO) classification of tumors of the lung, pleura, thymus, and heart, published in 2004. The fourth edition of the WHO classification, published in 2015, contains refined histological and immunohistochemical diagnostic criteria and is the most widely accepted cellular classification of TETs.[1,2] Thymomas arise from the thymic epithelium and consist of epithelial cells mixed with varying proportions of immature T cells. Thymic carcinomas are epithelial tumors with overt cytological atypia and without organotypic (i.e., thymus-like) features.

Thymoma

The epithelial component of thymomas exhibit no or minimal overt atypia and retain histological features specific to the normal thymus.[1] Immature nonneoplastic lymphocytes are present in variable numbers depending on the histological type of thymoma.

Table 2, Table 3, Table 4, Table 5, and Table 6 describe morphologic, molecular, and clinical characteristics of various subtypes of thymoma.

Thymic Carcinoma

Thymic carcinoma is a TET that exhibits a definite cytological atypia and a set of histological features no longer specific to the thymus but similar to histological features observed in carcinomas of other organs. Unlike type A and B thymomas, thymic carcinomas lack immature lymphocytes. Any lymphocytes that are present are mature and usually admixed with plasma cells.[1]

The characteristics of thymic carcinoma subtypes are described in Table 7.

Molecular Characteristics of Thymoma and Thymic Carcinomas

TETs have the lowest mutational burden of all adult cancers. Multiplatform analyses have revealed four molecular subtypes that are associated with survival and WHO histological subtypes. Mutations in HRAS, NRAS, TP53, and GTF2I have been observed. Targetable mutations are uncommon. Tumor overexpression of muscle autoantigens and increased aneuploidy have also been identified and provide a molecular link between thymoma and myasthenia gravis.[6]

References:

1. Travis WD, Brambilla E, Burke E, et al.: WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. International Agency for Research on Cancer, 2015.
2. Marx A, Chan JK, Coindre JM, et al.: The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes. J Thorac Oncol 10 (10): 1383-95, 2015.
3. Hirabayashi H, Fujii Y, Sakaguchi M, et al.: p16INK4, pRB, p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma. Int J Cancer 73 (5): 639-44, 1997.
4. Sasaki H, Kobayashi Y, Tanahashi M, et al.: Ets-1 gene expression in patients with thymoma. Jpn J Thorac Cardiovasc Surg 50 (12): 503-7, 2002.
5. Rajan A, Girard N, Marx A: State of the art of genetic alterations in thymic epithelial tumors. J Thorac Oncol 9 (9 Suppl 2): S131-6, 2014.
6. Radovich M, Pickering CR, Felau I, et al.: The Integrated Genomic Landscape of Thymic Epithelial Tumors. Cancer Cell 33 (2): 244-258.e10, 2018.
7. Travis W, Brambilla E, Müller-Hermelink H, et al., eds.: Pathology and Genetics of Tumours of the Lung, Pleura, and Thymus. IARC Press, 2004. World Health Organization Classification of Tumours.
8. Marx A, Chan J, Coindre J-M, et al.: The 2015 WHO classification of tumors of the thymus: continuity and changes. J Thorac Oncol 10 (10): 1383–95, 2015.

Stage Information for Thymoma and Thymic Carcinoma

Evaluating the invasiveness of a thymoma involves the use of staging criteria that indicate the presence and degree of contiguous invasion, the presence of tumor implants, and lymph node or distant metastases regardless of histological type. The staging system, proposed by Masaoka in 1981 and modified by Koga in 1994, is most commonly used, with the modified system being recommended by the International Thymic Malignancies Interest Group (ITMIG) (see Table 8).[1,2] To establish consistency in the staging of thymic epithelial tumors (TETs), the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) adopted a new TNM (tumor, node, metastasis) classification system developed by the International Association for the Study of Lung Cancer (IASLC) and ITMIG.[3,4,5]

AJCC Stage Groupings and TNM Definitions

When the Masaoka staging system was applied to a series of 85 surgically treated patients with thymoma, its value in determining prognosis was confirmed, with 5-year survival rates of 96% for stage I disease, 86% for stage II disease, 69% for stage III disease, and 50% for stage IV disease.[1] In a large, retrospective study involving 273 patients with thymoma, 20-year survival rates (as defined by freedom from tumor death) according to the Masaoka staging system were reported to be 89% for stage I disease, 91% for stage II disease, 49% for stage III disease, and 0% for stage IV disease.[6]

The TNM staging system, applicable to thymoma and thymic carcinoma, is based on a large, global database of more than 10,000 subjects, as opposed to smaller series of fewer than 100 patients that were used to develop older staging systems. The TNM system also benefits from rigorous statistical analysis of a large pool of data and input from a multidisciplinary panel of experts. The rate of disease recurrence was 5% in patients with stage I disease, 18% for stage II disease, 32% for stage III disease, 59% for stage IVA disease, and 49% for stage IVB disease. The death rate was 7% in patients with stage I disease, 16% for stage II disease, 18% for stage III disease, 30% for stage IVA disease, and 33% for stage IVB disease.[5]

References:

1. Masaoka A, Monden Y, Nakahara K, et al.: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48 (11): 2485-92, 1981.
2. Koga K, Matsuno Y, Noguchi M, et al.: A review of 79 thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int 44 (5): 359-67, 1994.
3. Thymus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 423–9.
4. Carter BW, Benveniste MF, Madan R, et al.: IASLC/ITMIG Staging System and Lymph Node Map for Thymic Epithelial Neoplasms. Radiographics 37 (3): 758-776, 2017 May-Jun.
5. Detterbeck FC, Stratton K, Giroux D, et al.: The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 9 (9 Suppl 2): S65-72, 2014.
6. Okumura M, Ohta M, Tateyama H, et al.: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94 (3): 624-32, 2002.

Treatment Option Overview for Thymoma and Thymic Carcinoma

The primary treatment for patients with thymoma or thymic carcinoma is surgical resection with en bloc resection for invasive tumors, if possible.[1,2,3] Depending on tumor stage, multimodality treatment options—including the use of radiation therapy and chemotherapy with or without surgery—may be used.[4,5] The optimal strategy for induction therapy, which minimizes operative morbidity and mortality and optimizes resectability rates and ultimately survival, remains unknown. A review of the management of thymic epithelial tumors has been published.[1]

Capecitabine and Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[6,7] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[6,7,8] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles.[9,10,11]DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[12] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[13]

References:

1. Girard N, Ruffini E, Marx A, et al.: Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 (Suppl 5): v40-55, 2015.
2. Ruffini E, Filosso PL, Guerrera F, et al.: Optimal surgical approach to thymic malignancies: New trends challenging old dogmas. Lung Cancer 118: 161-170, 2018.
3. Cameron RB, Loehrer Sr, Marx A: Neoplasms of the mediastinum. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 700-12.
4. 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 11 (10): 1785-92, 2016.
5. Rajan A, Giaccone G: Chemotherapy for thymic tumors: induction, consolidation, palliation. Thorac Surg Clin 21 (1): 107-14, viii, 2011.
6. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021.
7. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016.
8. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021.
9. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018.
10. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018.
11. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022.
12. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022.
13. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023.

Treatment of Thymoma

For patients presenting with a mediastinal mass that is highly suspicious for an early-stage thymic epithelial tumor (TET) and is potentially completely resectable, surgical resection is the preferred initial treatment.[1] Under these circumstances, surgical resection serves as a diagnostic and therapeutic procedure. Complete resection of the tumor can be achieved in nearly all patients with stage I and stage II TETs.

Postoperative radiation therapy (PORT) is associated with survival benefit and is generally recommended for patients with stage II or stage III disease.[2] Patients with stage IVA disease are usually offered multimodality therapy consisting of induction chemotherapy followed by surgery (if the disease is considered resectable) and PORT.[3,4,5,6] Patients with stage IVB disease are treated with definitive chemotherapy.[7,8,9,9,10] Surgery and radiation therapy usually do not have a role as primary treatment modalities for advanced disease.

Stage I and Stage II Thymoma

Treatment options for stages I and II thymoma

Treatment options for stage I and stage II thymoma (operable disease) include the following:

1. Surgery (stage I).
2. Surgery with or without PORT (stage II).

Surgery (stage I)

Excellent long-term survival can be obtained after complete surgical excision for patients with a pathological stage I thymoma. There appears to be no benefit to adjuvant radiation therapy after complete resection of encapsulated noninvasive tumors.[1,11]

Surgery with or without PORT (stage II)

For patients with stage II thymomas with pathologically demonstrated capsular invasion, adjuvant radiation therapy after complete surgical excision has been considered a standard of care, despite the lack of prospective clinical trials.[12,13] Most studies use 40 Gy to 70 Gy with a standard fractionation scheme (1.8–2.0 Gy per fraction).

The role and risks of adjuvant radiation therapy for patients with completely resected stage II thymomas need further study. To avoid the potential morbidity and costs associated with thoracic radiation, PORT may be reserved for stage II patients when adjacent organs are within a few millimeters or involve the surgical margin (close or positive surgical margins), as determined by both pathological and intraoperative findings.

Evidence (surgery followed by PORT):

1. Data were obtained from a clinical study of 1,320 Japanese patients.[14] Patients with stage I thymoma were treated with surgery only, and patients with stage II thymoma underwent surgery and additional radiation therapy.
   • Prophylactic mediastinal radiation therapy did not appear to prevent local recurrences effectively in patients with totally resected stage II thymoma.
2. Some, but not all, retrospective clinical studies show improved local control and survival with the addition of PORT.[2,14,15,16,17][Level of evidence C3]
3. Other retrospective studies have found no outcome difference in patients treated with or without PORT after complete resection of the thymic tumor.[18,19,20,21]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Stage III and Stage IV Thymoma

Treatment options for operable or potentially operable stages III and IV thymoma

Advances in imaging techniques have resulted in more accurate staging of TETs. However, on occasion, stage III thymoma may be difficult to identify before surgery, and invasion of adjacent mediastinal structures may be identified only at the time of surgery.

Surgical resection with curative intent should be considered for all patients deemed to have resectable stage III thymoma after the initial work-up. PORT is offered to all patients, regardless of surgical margin status, because it is associated with longer overall survival (OS).[2]

Combined-modality treatment consisting of induction chemotherapy followed by surgery and radiation therapy should be considered for all patients with unresectable stage III thymoma. The optimal strategy for induction therapy, which optimizes resectability rates and ultimately survival, is not defined. However, commonly used induction chemotherapy regimens include combinations of cisplatin, doxorubicin, and cyclophosphamide, or cisplatin and etoposide. Rates of response to induction chemotherapy ranged from 79% to 100%, with subsequent resectability rates of 36% to 69%.[3,4,5,6,7,22,23,24,25]

Treatment options for operable or potentially operable stage III and stage IV thymoma include the following:

1. Surgery followed by PORT.
2. Induction chemotherapy followed by surgery and radiation therapy.

Evidence (treatment of stage III and IV operable or potentially operable thymoma):

1. Data were obtained from a large clinical study of 1,320 Japanese patients.[14] Patients with stage III and stage IV thymoma underwent surgery and multimodality therapy with surgical resection followed by adjuvant therapy consisting of radiation therapy and/or chemotherapy.
   • The Masaoka clinical stage was found to correlate well with prognosis of thymoma and thymic carcinoma.
   • For patients with stage III or stage IV thymoma, the 5-year survival rates were 93% for patients treated with total resection, 64% for patients treated with subtotal resection, and 36% for patients whose disease was inoperable. These data highlight the prognostic significance of achieving complete surgical resection of the tumor.
   • Prophylactic mediastinal radiation therapy did not appear to prevent local recurrences effectively in patients with totally resected stage III thymoma.
   • Adjuvant therapy, including radiation and/or chemotherapy did not appear to improve the prognosis in patients with totally resected stage III or stage IV thymoma.
2. In a large retrospective study, 1,334 patients diagnosed with malignant thymoma and treated between 1973 and 2005 were identified in a Surveillance, Epidemiology, and End Results (SEER) Program database.[25]
   • At a relatively short median follow-up of 65 months, radiation therapy did not appear to increase the risk of cardiac mortality or secondary malignancy.
   • In patients with stage III and stage IV disease (after excluding patients surviving less than 4 months to account for surgical mortality), the routine use of PORT did not appear to improve long-term survival.
3. In a retrospective study, 476 patients with stage III thymoma who underwent surgical resection were identified using the SEER database. PORT was administered to 322 patients (67.6%).[26]
   • Patients who received PORT had a median OS of 127 months (95% confidence interval [CI], 100.9–153.1) compared with 105 months (95% CI, 76.9–133.1) in patients treated with surgery alone (P = .038).
   • Disease-specific survival was significantly improved in patients receiving PORT compared with patients undergoing surgery alone (P = .049).
4. Different published series have reported long-term survival rates following induction chemotherapy and surgery, with or without radiation therapy and consolidation chemotherapy. The rates have ranged from 50% at 4 years to 77% at 7 years, with 10-year rates of 86% for stage III patients and 76% for stage IV patients.[5,22,23,27]
5. Similar survival rates have been reported with preoperative radiation therapy without chemotherapy, particularly if great vessels are involved. Results showed a 5-year OS rate of 77% and a 10-year OS rate of 59%.[28,29]

Treatment options for inoperable stages III and IV thymoma

Treatment options for patients with inoperable stage III and stage IV thymoma include the following:

1. Chemotherapy.
2. Chemotherapy followed by radiation therapy.
3. Chemotherapy followed by surgery (if operable) and radiation therapy.

The role of surgical debulking for patients with either stage III or stage IVA disease is controversial. Phase II data suggest that prolonged survival can be accomplished with chemotherapy and radiation therapy alone in many patients who present with locally advanced or even metastatic thymoma.[24] The value of surgery may be questioned if complete or, at the very least, near-complete extirpation cannot be accomplished.

Evidence (treatment of stage III and IV inoperable thymoma):

1. An intergroup trial conducted in the United States reported a predicted 5-year OS rate of 52% in 26 patients who received the PAC chemotherapy regimen (cisplatin, doxorubicin, cyclophosphamide) followed by radiation therapy without surgery.[24]
2. In a series of 30 patients with stage IV or locally progressive recurrent tumor after radiation therapy, the PAC regimen was given.[7][Level of evidence C3]
   • A 50% response rate was achieved, including three complete responses.
   • The median duration of response was 12 months.
   • The 5-year survival rate was 32%.
3. The ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide) was given to 37 patients.[8][Level of evidence C3]
   • A 92% response rate (34 of 37 patients) was achieved, including complete responses in 43% of patients.
4. A study of combined chemotherapy with cisplatin and etoposide reported the following:[30][Level of evidence C3]
   • A 56% response rate (9 of 16 patients) was achieved.
   • There was a median response duration of 3.4 years and a median survival of 4.3 years.
5. Patients with invasive thymoma or thymic carcinoma were treated with four cycles of etoposide, ifosfamide, and cisplatin (VIP) at 3-week intervals.[9][Level of evidence C3]
   • Nine of 28 evaluable patients had partial responses (32%; 95% CI, 16%–52%).
   • The median follow-up was 43 months (range, 12.8–52.3).
   • The median duration of response was 11.9 months (range, <1–26).
   • The median OS was 31.6 months.
   • The 1-year survival rate was 89% and the 2-year survival rate was 70%, based on Kaplan-Meier estimates.
   • These results appear to be inferior to other combinations.
6. A phase II study evaluated the activity of a combination of carboplatin and paclitaxel in 46 patients with unresectable TETs, including 21 patients with unresectable thymoma.[10][Level of evidence C3]
   • Nine of 21 patients with thymoma had objective responses (42.9%; 90% CI, 24.5%–62.8%).
   • The median duration of response in patients with thymoma was 16.9 months (95% CI, 3.1–22.0).
   • The median progression-free survival for the thymoma cohort was 16.7 months (95% CI, 7.2–19.8); median OS was not reached after median follow-up of 59.4 months.

References:

1. Maggi G, Casadio C, Cavallo A, et al.: Thymoma: results of 241 operated cases. Ann Thorac Surg 51 (1): 152-6, 1991.
2. 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 11 (10): 1785-92, 2016.
3. Macchiarini P, Chella A, Ducci F, et al.: Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer 68 (4): 706-13, 1991.
4. Rea F, Sartori F, Loy M, et al.: Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 106 (3): 543-9, 1993.
5. Kim ES, Putnam JB, Komaki R, et al.: Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 44 (3): 369-79, 2004.
6. Yokoi K, Matsuguma H, Nakahara R, et al.: Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J Thorac Oncol 2 (1): 73-8, 2007.
7. Loehrer PJ, Kim K, Aisner SC, 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 12 (6): 1164-8, 1994.
8. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy for invasive thymoma. A 13-year experience. Cancer 68 (1): 30-3, 1991.
9. Loehrer PJ, Jiroutek M, Aisner S, et al.: Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 91 (11): 2010-5, 2001.
10. Lemma GL, Lee JW, Aisner SC, et al.: Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 29 (15): 2060-5, 2011.
11. Masaoka A, Monden Y, Nakahara K, et al.: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48 (11): 2485-92, 1981.
12. Pollack A, Komaki R, Cox JD, et al.: Thymoma: treatment and prognosis. Int J Radiat Oncol Biol Phys 23 (5): 1037-43, 1992.
13. Ogawa K, Uno T, Toita T, et al.: Postoperative radiotherapy for patients with completely resected thymoma: a multi-institutional, retrospective review of 103 patients. Cancer 94 (5): 1405-13, 2002.
14. Kondo K, Monden Y: Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 76 (3): 878-84; discussion 884-5, 2003.
15. Ariaratnam LS, Kalnicki S, Mincer F, et al.: The management of malignant thymoma with radiation therapy. Int J Radiat Oncol Biol Phys 5 (1): 77-80, 1979.
16. Penn CR, Hope-Stone HF: The role of radiotherapy in the management of malignant thymoma. Br J Surg 59 (7): 533-9, 1972.
17. Curran WJ, Kornstein MJ, Brooks JJ, et al.: Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 6 (11): 1722-7, 1988.
18. Mangi AA, Wright CD, Allan JS, et al.: Adjuvant radiation therapy for stage II thymoma. Ann Thorac Surg 74 (4): 1033-7, 2002.
19. Singhal S, Shrager JB, Rosenthal DI, et al.: Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg 76 (5): 1635-41; discussion 1641-2, 2003.
20. Thomas CR, Wright CD, Loehrer PJ: Thymoma: state of the art. J Clin Oncol 17 (7): 2280-9, 1999.
21. Berman AT, Litzky L, Livolsi V, et al.: Adjuvant radiotherapy for completely resected stage 2 thymoma. Cancer 117 (15): 3502-8, 2011.
22. Berruti A, Borasio P, Gerbino A, et al.: Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience. Br J Cancer 81 (5): 841-5, 1999.
23. Shin DM, Walsh GL, Komaki R, et al.: A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 129 (2): 100-4, 1998.
24. Loehrer PJ, Chen M, Kim K, et al.: Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 15 (9): 3093-9, 1997.
25. Fernandes AT, Shinohara ET, Guo M, et al.: The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol 5 (9): 1454-60, 2010.
26. Weksler B, Shende M, Nason KS, et al.: The role of adjuvant radiation therapy for resected stage III thymoma: a population-based study. Ann Thorac Surg 93 (6): 1822-8; discussion 1828-9, 2012.
27. 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 1 (4): 308-13, 2006.
28. Yagi K, Hirata T, Fukuse T, et al.: Surgical treatment for invasive thymoma, especially when the superior vena cava is invaded. Ann Thorac Surg 61 (2): 521-4, 1996.
29. Akaogi E, Ohara K, Mitsui K, et al.: Preoperative radiotherapy and surgery for advanced thymoma with invasion to the great vessels. J Surg Oncol 63 (1): 17-22, 1996.
30. Giaccone G, Ardizzoni A, Kirkpatrick A, et al.: Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14 (3): 814-20, 1996.

Treatment of Thymic Carcinoma

Thymic carcinoma is rare, and the optimal treatment is undefined. For patients with clearly resectable well-defined disease, surgical resection is often the initial therapeutic intervention. For patients with clinically borderline or frankly unresectable lesions, neoadjuvant (preoperative) chemotherapy, thoracic radiation therapy, or both have been given.[1] Patients presenting with locally advanced disease are carefully evaluated and undergo multimodality therapy. Patients with poor performance status and high associated operative risks are generally not candidates for these aggressive treatments. Patients with metastatic disease may respond to combination chemotherapy.

Treatment Options for Thymic Carcinoma

Treatment options for patients with operable thymic carcinoma include the following:[2]

1. Surgery (en bloc surgical resection) followed by postoperative radiation therapy (PORT) with or without postoperative chemotherapy.

Treatment options for patients with inoperable thymic carcinoma (stage III and stage IV with vena caval obstruction, pleural involvement, pericardial implants, etc.) include the following:

1. Chemotherapy.
2. Chemoradiation therapy.
3. Chemotherapy followed by surgery (if operable) and radiation therapy.

In most published studies, surgery has been followed by adjuvant radiation therapy.[3,4] A prescriptive dose range has yet to be identified. Most studies use 40 Gy to 70 Gy with a standard fractionation scheme (1.8–2.0 Gy per fraction).

Evidence (surgery followed by PORT with or without postoperative chemotherapy):

1. In the largest series reported, data were obtained from a clinical study of 1,320 Japanese patients.[5] Patients with thymic carcinoma were treated with PORT or chemotherapy.
   • The 5-year survival rates were 67% for patients treated with total resection, 30% for patients treated with subtotal resection, and 24% for patients whose disease was inoperable.
   • Adjuvant therapy, including radiation or chemotherapy, did not appear to improve the prognosis in patients with thymic carcinoma.
2. A multi-institutional retrospective outcome analysis of 186 patients with thymic carcinoma has been reported.[5]
   • The 5-year survival rates for patients with totally resected thymic carcinoma were 81.5% for patients treated with chemotherapy, 46.6% for patients treated with radiation therapy and chemotherapy, 73.6% for patients treated with radiation therapy alone, and 72.2% for patients who received no adjuvant therapy.
   • This study failed to detect a long-term survival benefit in patients treated with subtotal resection or any statistically significant survival augmentation from the addition of adjuvant radiation to surgical resection.
   • The authors stipulated that no definitive conclusions could be made regarding the role of adjuvant radiation therapy in thymic carcinoma because of sample size limitations.

The results of these studies call into question conventional thinking regarding the efficacy of an aggressive multimodality approach that includes debulking, radiation therapy, and cisplatin-based chemotherapy.[6,7,8] While other studies support the addition of adjuvant radiation therapy and chemotherapy, optimum treatment regimens are undetermined.

Chemotherapy is the primary treatment modality for patients with inoperable thymic carcinoma. Most regimens used are similar to those used to treat thymoma and include a platinum compound with or without an anthracycline (PAC [cisplatin, doxorubicin, cyclophosphamide], VIP [etoposide, ifosfamide, and cisplatin], ADOC [doxorubicin, cisplatin, vincristine, cyclophosphamide], cisplatin/etoposide, carboplatin/paclitaxel).[1,9,10,11,12,13,14]

Evidence (chemotherapy):

1. A phase II study evaluated the combination of carboplatin and paclitaxel in 46 patients with unresectable thymic epithelial tumors, including 23 patients with unresectable thymic carcinoma.[14][Level of evidence C3]
   • Five of 23 patients with thymic carcinoma had objective responses (21.7%; 90% confidence interval [CI], 9.0%–40.4%).
   • The median duration of response in patients with thymic carcinoma was 4.5 months (95% CI, 3.4–9.9).
   • The median progression-free survival for the thymic carcinoma cohort was 5 months (95% CI, 3.0–8.3) and the median overall survival was 20 months (95% CI, 5.0–43.6) after a median follow-up of 59.4 months.
2. VIP was used in a prospective North American Intergroup trial.[11]
   • Two of 8 patients with thymic carcinoma (25%) had a partial response.
   • The 1-year survival rate for patients with thymic carcinoma was 75% and the 2-year rate was 50%.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Koizumi T, Takabayashi Y, Yamagishi S, et al.: Chemotherapy for advanced thymic carcinoma: clinical response to cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC chemotherapy). Am J Clin Oncol 25 (3): 266-8, 2002.
2. Hsu HC, Huang EY, Wang CJ, et al.: Postoperative radiotherapy in thymic carcinoma: treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 52 (3): 801-5, 2002.
3. 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 121 (7): 1008-16, 2015.
4. Ahmad U, Yao X, Detterbeck F, et al.: Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 149 (1): 95-100, 101.e1-2, 2015.
5. Kondo K, Monden Y: Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 76 (3): 878-84; discussion 884-5, 2003.
6. Ogawa K, Toita T, Uno T, et al.: Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 94 (12): 3115-9, 2002.
7. Greene MA, Malias MA: Aggressive multimodality treatment of invasive thymic carcinoma. J Thorac Cardiovasc Surg 125 (2): 434-6, 2003.
8. Lucchi M, Mussi A, Ambrogi M, et al.: Thymic carcinoma: a report of 13 cases. Eur J Surg Oncol 27 (7): 636-40, 2001.
9. Weide LG, Ulbright TM, Loehrer PJ, et al.: Thymic carcinoma. A distinct clinical entity responsive to chemotherapy. Cancer 71 (4): 1219-23, 1993.
10. Loehrer PJ, Kim K, Aisner SC, 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 12 (6): 1164-8, 1994.
11. Loehrer PJ, Jiroutek M, Aisner S, et al.: Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 91 (11): 2010-5, 2001.
12. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy for invasive thymoma. A 13-year experience. Cancer 68 (1): 30-3, 1991.
13. Giaccone G, Ardizzoni A, Kirkpatrick A, et al.: Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14 (3): 814-20, 1996.
14. Lemma GL, Lee JW, Aisner SC, et al.: Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 29 (15): 2060-5, 2011.

Treatment of Recurrent Thymoma and Thymic Carcinoma

Treatment Options for Recurrent Thymoma and Thymic Carcinoma

Treatment options for recurrent thymoma and thymic carcinoma include the following:

1. Chemotherapy.
2. Biological therapies.
3. Surgery or radiation therapy in carefully selected cases.
4. Pembrolizumab (under clinical evaluation).

Chemotherapy

A number of studies have demonstrated that certain chemotherapy drugs can induce tumor responses as single-agent or combination therapy. These drugs include pemetrexed, gemcitabine, taxanes, capecitabine, or fluorouracil and etoposide. In general, higher response rates have been reported with combinations, however, no randomized trials have been conducted. In most cases of inoperable disease recurrence, single-agent systemic therapy is preferred. Combination chemotherapy can be considered for selected patients who have demonstrated a good response previously, have had a long recurrence-free interval and good performance status, and, in the case of anthracycline-containing regimen, have not received high cumulative doses previously, which can jeopardize safety, especially in relation to cardiac toxicity.[1]

Evidence (single-agent chemotherapy):

1. A phase II trial of pemetrexed (500 mg/m²) was conducted in 27 patients with recurrent thymic epithelial tumors (TETs) (16 patients) and recurrent thymic carcinoma (11 patients).[2]
   • The objective response rate was 19.2% (95% confidence interval [CI], 6.3%–38.1%) (26.7% [95% CI, 7.8%–55.1%] in patients with thymoma and 9.1% [95% CI, 0.2%–41.3%] in patients with thymic carcinoma).
   • The median progression-free survival (PFS) was 10.6 months (12.1 months for patients with thymoma vs. 2.9 months for patients with thymic carcinoma).
   • The median overall survival (OS) was 28.7 months (46.4 months for patients with thymoma vs. 9.8 months for patients with thymic carcinoma).
   • The median duration of response was 4 months in patients with thymoma (range, 3.26–6.28 months) and 3.8 months in the one patient with thymic carcinoma who had a partial response.
2. Six of 16 patients achieved objective responses to octreotide (1.5 mg every day subcutaneously) associated with prednisone (0.6 mg/kg every day orally for 3 months, 0.2 mg/kg every day orally during follow-up).[3]

Evidence (combination chemotherapy):

1. Thirty patients (22 patients with recurrent thymoma and 8 patients with thymic carcinoma) were enrolled in a phase II trial and treated with capecitabine (650 mg/m² twice daily on days 1–14) and gemcitabine (1,000 mg/m² on days 1 and 8 every 3 weeks).[4]
   • Objective responses were observed in 9 of 22 patients (41%) with thymoma and 3 of 8 patients (38%) with thymic carcinoma.
   • After a median follow-up of 18 months (range, 15–22), the median PFS was 11 months (range, 6.5–16.5). The median PFS was 11 months for patients with thymoma and 6 months for patients with thymic carcinoma. The overall median PFS was also 11 months.
   • One-year and 2-year survival rates for the study population were 90% and 66%, respectively.

Biological therapies

Octreotide with or without prednisone may induce responses in patients with octreotide scan–positive thymoma. Objective responses have also been observed with sunitinib and everolimus in patients with recurrent TETs.

Octreotide with or without prednisone

Evidence (octreotide with or without prednisone):

1. In one study, six of 16 patients achieved objective responses to octreotide (1.5 mg every day subcutaneously) associated with prednisone (0.6 mg/kg every day orally for 3 months, 0.2 mg/kg every day orally during follow-up).[3]
2. In a study of octreotide with or without prednisone, two complete responses (5.3%) and ten partial responses (25%) were observed among 42 patients.[5]

Sunitinib

Evidence (sunitinib):

1. Forty-one patients with recurrent TETs (25 thymic carcinoma, 16 thymoma) were enrolled in a phase II trial and treated with sunitinib at a dose of 50 mg per day administered in 6-week cycles (4 weeks on treatment followed by a 2-week break).[6][Level of evidence C3]
   • After a median follow-up of 17 months, 6 of 23 assessable patients with thymic carcinoma (26%; 90% CI, 12.1%–45.3%; 95% CI, 10.2%–48.4%) had an objective response, and 15 patients (65%; 95% CI, 42.7%–83.6%) achieved disease stabilization. Of 16 patients with thymoma, 1 patient (6%; 95% CI, 0.2%–30.2%) had a partial response, and 12 patients (75%; 47.6%–92.7%) had stable disease.
   • The median time to response in the thymic carcinoma cohort was 5.6 months (range, 2.7–13.8), and the median duration of response was 16.4 months (range, 1.4–16.4).
   • The median PFS was 7.2 months (95% CI, 3.4–15.2) for patients with thymic carcinoma and 8.5 months (2.8–11.3) for patients with thymoma.
   • The median OS was not reached for patients with thymic carcinoma and was 15.5 months (95% CI, 12.6–undefined) in patients with thymoma.
   • The estimated OS at 1 year was 78% (95% CI, 58.0%–90.4%) for patients with thymic carcinoma and 86% (60.9%–96.1%) for patients with thymoma.

Everolimus

Evidence (everolimus):

1. A phase II study included 51 patients with recurrent TETs (32 with thymoma and 19 with thymic carcinoma). Patients received oral everolimus at a dose of 10 mg per day.[7][Level of evidence C3]
   • Objective responses were observed in 3 of 32 patients (9.4%) with thymoma and in 3 of 19 patients (15.8%) with thymic carcinoma.
   • The disease-control rate was 88% (thymoma: 93.8%; thymic carcinoma: 77.8%).
   • After a median follow-up of 25.7 months, the median PFS was 10.1 months (thymoma: 16.6 months; thymic carcinoma: 5.6 months).
   • The median OS was 25.7 months (thymoma: not reached; thymic carcinoma: 14.7 months).

Lenvatinib

Lenvatinib is an orally administered multikinase inhibitor that targets vascular endothelial growth factor receptors, platelet-derived growth factor receptor-alpha, fibroblast growth factor receptors, c-kit, and the RET proto-oncogene.

Evidence (lenvatinib):

1. Forty-two patients with recurrent thymic carcinoma were enrolled in a phase II trial and treated with oral lenvatinib at a dose of 24 mg per day in 4-week cycles until disease progression or development of unacceptable adverse events. The primary end point was objective response rate, assessed by independent central review.[8][Level of evidence C3]
   • Objective responses were observed in 16 of 42 patients (38%; 90% CI, 25.6%–52.0%).
   • The disease-control rate was 95% (95% CI, 83.8%–99.4%).
   • After a median follow-up of 15.5 months, the median time to response was 2.0 months, the median duration of response was 11.6 months (95% CI, 5.8–18.0), the median PFS was 9.3 months (95% CI, 7.7–13.9), and the median OS was not reached (NR) (95% CI, 16.1–NR).
   • The most common treatment-related adverse events were hypertension (88%), palmar-plantar erythrodysesthesia (69%), thrombocytopenia (52%), and diarrhea (50%).
   • All patients required at least one dose reduction due to adverse events. Five dose reductions were permitted in this study (20 mg, 14 mg, 10 mg, 8 mg, 4 mg). There were no treatment-related deaths.
   • Predictive biomarker analysis was not performed as part of this clinical trial.

Surgery

Surgical resection may be repeated, particularly for local recurrences and, in some cases, pleural and pericardial implants. Patients with recurrent thymomas who undergo repeat resection of recurrent disease may have prolonged survival when complete resection is attained.[9] However, only a minority of patients may be candidates for resection.

Evidence (surgery):

1. In a review of 395 patients who underwent resections for TETs, 67 had tumor recurrence and 22 underwent a repeat resection procedure.[10]
   • The 10-year survival rate was 70%.
2. In another study, 30 of 266 patients initially treated by total resection of the tumor had a recurrence; in all 30 patients, surgical resection was attempted.[11] Complete resection of the recurrent tumor was obtained in ten cases.
   • The 5-year survival rate was 48%.
   • The 10-year survival rate was 24%.

Of note, patients in these series may have received chemotherapy and/or radiation therapy in addition to surgery.

Radiation therapy

Postoperative radiation therapy has been used for patients with incomplete resections and for selected patients after complete resections of recurrent thymomas.[9] Radiation therapy is also indicated for palliation of symptoms such as pain due to chest wall invasion, and superior vena cava syndrome.

Pembrolizumab

Pembrolizumab (an anti-programmed death ligand 1 antibody) has been evaluated in patients with recurrent TETs. Immune checkpoint inhibitor therapy is under clinical evaluation and should be used in the context of a clinical trial.

1. Thirty-three patients with refractory or relapsed TETs (26 with thymic carcinoma, 7 with thymoma) were enrolled in a phase II trial of pembrolizumab.[12]
   • Objective responses were observed in 2 of 7 patients with thymoma (28.6%; 95% CI, 8.2%–64.1%) and in 5 of 26 patients with thymic carcinoma (19.2%; 95% CI, 8.5%–37.9%).
   • The median PFS was 6.1 months for both groups.
   • Grade 3 or greater immune-related adverse events were observed in 5 of 7 patients (71.4%) with thymoma and in 4 of 26 patients (15.4%) with thymic carcinoma, including hepatitis (12.1%), myocarditis (9.1%), and myasthenia gravis (6.1%).
2. Forty-one patients with recurrent thymic carcinoma were enrolled in a single-arm phase II study of pembrolizumab.[13]
   • After a median follow-up of 20 months, the objective response rate was 22.5% (95% CI, 10.8%–38.5%).
   • The median duration of response was 22.4 months (95% CI, 12.3–34.7).
   • The median PFS was 4.2 months (95% CI, 2.9–10.3), and the median OS was 24.9 months (15.5–NR).
   • Severe immune-related adverse events were observed in six patients (15%), including two patients (5%) with myocarditis.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Girard N, Ruffini E, Marx A, et al.: Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 (Suppl 5): v40-55, 2015.
2. Gbolahan OB, Porter RF, Salter JT, et al.: A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma. J Thorac Oncol 13 (12): 1940-1948, 2018.
3. Palmieri G, Montella L, Martignetti A, et al.: Somatostatin analogs and prednisone in advanced refractory thymic tumors. Cancer 94 (5): 1414-20, 2002.
4. Palmieri G, Buonerba C, Ottaviano M, et al.: Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial. Future Oncol 10 (14): 2141-7, 2014.
5. Loehrer PJ, Wang W, Johnson DH, et al.: Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group phase II trial. J Clin Oncol 22 (2): 293-9, 2004.
6. 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 16 (2): 177-86, 2015.
7. Zucali PA, 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 36 (4): 342-349, 2018.
8. 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 21 (6): 843-850, 2020.
9. Urgesi A, Monetti U, Rossi G, et al.: Aggressive treatment of intrathoracic recurrences of thymoma. Radiother Oncol 24 (4): 221-5, 1992.
10. Okumura M, Shiono H, Inoue M, et al.: Outcome of surgical treatment for recurrent thymic epithelial tumors with reference to world health organization histologic classification system. J Surg Oncol 95 (1): 40-4, 2007.
11. Ruffini E, Mancuso M, Oliaro A, et al.: Recurrence of thymoma: analysis of clinicopathologic features, treatment, and outcome. J Thorac Cardiovasc Surg 113 (1): 55-63, 1997.
12. 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 37 (24): 2162-2170, 2019.
13. Giaccone G, Kim C, Thompson J, et al.: Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 19 (3): 347-355, 2018.

Latest Updates to This Summary (05 / 23 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment Option Overview for Thymoma and Thymic Carcinoma

Added Capecitabine and Fluorouracil Dosing as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult thymoma and thymic carcinoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Thymoma and Thymic Carcinoma Treatment are:

• Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
• Meredith McAdams, MD (National Cancer Institute)
• Arun Rajan, MD (National Cancer Institute)
• Eva Szabo, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Thymoma and Thymic Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/thymoma/hp/thymoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389476]

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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Last Revised: 2024-05-23