Sakata R, Fujii Y, Kuwano H.
Thoracic and cardiovascular surgery in Japan during 2008: annual report by The Japanese Association for Thoracic Surgery.
Gen Thorac Cardiovasc Surg. 2010 Jul;58(7):356-83. doi: 10.1007/s11748-010-0604-0.
Abstract/Text
日本胸腺学会編：縦隔腫瘍取扱い規約第1版、金原出版、2009．.
Okumura M, Marino M, Cilento V, Goren E, Ruffini E, Dibaba D, Ahmad U, Appel S, Bille A, Boubia S, Brambilla C, Cangir AK, Detterbeck F, Falkson C, Fang W, Filosso PL, Giaccone G, Girard N, Guerrera F, Huang J, Infante M, Kim DK, Lucchi M, Marom EM, Nicholson AG, Rami-Porta R, Rimner A, Simone CB 2nd, Asamura H; Members of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee and of the Advisory Boards and Participating Institutions.
The International Association for the Study of Lung Cancer Thymic Epithelial Tumor Staging Project: Proposal for the T Component for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors.
J Thorac Oncol. 2023 Dec;18(12):1638-1654. doi: 10.1016/j.jtho.2023.08.024. Epub 2023 Aug 25.
Abstract/Text
INTRODUCTION: A TNM-based stage classification system of thymic epithelial tumors was adopted for the eighth edition of the stage classification of malignant tumors. The Thymic Domain of the Staging and Prognostics Factor Committee of the International Association for the Study of Lung Cancer developed a new database with the purpose to make proposals for the ninth edition stage classification system. This article outlines the proposed definitions for the T categories for the ninth edition TNM stage classification of thymic malignancies.
METHODS: A worldwide collective database of 11,347 patients with thymic epithelial tumors was assembled. Analysis was performed on 9147 patients with available survival data. Overall survival, freedom-from-recurrence, and cumulative incidence of recurrence were used as outcome measures. Analysis was performed separately for thymomas, thymic carcinomas, and neuroendocrine thymic tumors.
RESULTS: Proposals for the T categories include the following: T1 category is divided into T1a (≤5 cm) and T1b (>5 cm), irrespective of mediastinal pleura invasion; T2 includes direct invasion of the pericardium, lung, or phrenic nerve; T3 denotes direct invasion of the brachiocephalic vein, superior vena cava, chest wall, or extrapericardial pulmonary arteries and veins; and T4 category remains the same as in the eighth edition classification, involving direct invasion of the aorta and arch vessels, intrapericardial pulmonary arteries and veins, myocardium, trachea, or esophagus.
CONCLUSIONS: The proposed T categories for the ninth edition of the TNM classification provide good discrimination in outcome for the T component of the TNM-based stage system of thymic epithelial tumors.
Copyright © 2023. Published by Elsevier Inc.
Ruffini E, Huang J, Cilento V, Goren E, Detterbeck F, Ahmad U, Appel S, Bille A, Boubia S, Brambilla C, Cangir AK, Falkson C, Fang W, Filosso PL, Giaccone G, Girard N, Guerrera F, Infante M, Kim DK, Lucchi M, Marino M, Marom EM, Nicholson AG, Okumura M, Rami-Porta R, Rimner A, Simone CB 2nd, Asamura H; Members of the IASLC Staging and Prognostic Factors Committee and of the Advisory Boards, and Participating Institutions.
The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: Proposal for a Stage Classification for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors.
J Thorac Oncol. 2023 Dec;18(12):1655-1671. doi: 10.1016/j.jtho.2023.09.002. Epub 2023 Sep 9.
Abstract/Text
INTRODUCTION: A TNM-based system for all types of thymic epithelial tumors was introduced in the eighth edition of the TNM classification of thoracic malignancies. The Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, composed of multispecialty international experts, was charged to develop proposals for the ninth edition. This article outlines the proposed definitions for the T, the N, and the M components and their combination into stage groups.
METHODS: A large central database of 11,347 patients with thymic epithelial tumors was assembled thanks to the contribution of the major thymic organizations worldwide and analyses were carried out for the T, the N, and the M components and the stage groups. Overall survival was the outcome measure for patients with completely and incompletely resected tumors, and recurrence for those with complete resection. When the number of patients was sufficient, analyses were performed separately for thymomas, thymic carcinomas, and neuroendocrine thymic tumors.
RESULTS: Tumor size is included in the T1 category as T1a (≤5cm) and T1b (>5 cm); the mediastinal pleura is dropped as a T descriptor; invasion of the lung or phrenic nerve is reclassified as T2 (instead of T3). No changes are proposed for the N and the M components from the eighth edition. The stage groups remain the same.
CONCLUSIONS: The proposed changes for the ninth edition of the TNM classification set the stage for further progress in the future for these rare tumors.
Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.
Okumura M, Yoshino I, Funaki S, Okuda K, Watanabe SI, Tsuboi M, Shimizu K, Date H, Chen-Yoshikawa TF, Nakajima J, Toyooka S, Asamura H.
Long-term outcomes following surgical treatment for thymic epithelial tumor in Japan and an analysis of prognostic factors based on the Japanese Association for Research on the Thymus nationwide database.
Surg Today. 2023 Nov;53(11):1247-1259. doi: 10.1007/s00595-023-02705-w. Epub 2023 Jul 17.
Abstract/Text
PURPOSE: Patients with a thymic epithelial tumor (TET), comprising thymoma, thymic carcinoma (TC), and thymic neuroendocrine neoplasm (TNEN), are rarely encountered. The present study was conducted to determine the recent outcomes of surgical treatment for TET in Japan and clarify the significance of prognostic factors by analyzing a nationwide database created by the Japanese Association for Research on the Thymus (JART).
METHODS: The JART database includes records of 2471 thymoma, 285 TC, and 56 TNEN cases surgically treated between 1991 and 2010. At the time of the final follow-up examination, 439 patients had died, with tumor the cause of death in 188. The disease-specific survival was examined using the Kaplan-Meier method, with Cox's proportional hazards model utilized to determine independent prognostic factors.
RESULTS: The 10-year survival rate according to TNM-based Stage I, II, IIIA, IIIB, IVA, and IVB classification was 98.7%, 76.8%, 85.0%, 68.9%, 66.2%, and 59.8%, respectively. The T factor, M factor, and tumor size were independent prognostic factors in both thymoma and thymic carcinoma cases, while the N factor had tendency to be a prognostic factor in thymoma but not in thymic carcinoma cases. The WHO histological type was an independent factor in thymoma cases.
CONCLUSION: The significance of pathology and TNM classification as prognostic factors was confirmed.
© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.
TravisWD, Brambilla E, Müller-Hermelink HK, Harris CC. WHO Classification of Tumours. Pathology and Genetics of Tumours of Lung, Pleura, Thymus and Heart. IARC Press, Lyon, 2004.
Kondo K, Monden Y.
Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan.
Ann Thorac Surg. 2003 Sep;76(3):878-84; discussion 884-5. doi: 10.1016/s0003-4975(03)00555-1.
Abstract/Text
BACKGROUND: Surgery remains the mainstay of treatment for thymic epithelial tumors, and radiation and chemotherapy also have been applied widely as adjuvant and palliative procedures.
METHODS: We compiled records of 1,320 patients with thymic epithelial tumors who were treated from 1990 to 1994 in 115 institutes certified as special institutes for general thoracic surgery by The Japanese Association for Chest Surgery.
RESULTS: Patients with stage I thymoma were treated with only surgery, and patients with stage II and III thymoma and thymic carcinoid underwent surgery and additional radiotherapy. Patients with stage IV thymoma and thymic carcinoma were treated with radiation or chemotherapy. The Masaoka clinical stage is an excellent predictor of the prognosis of thymoma and thymic carcinoma, but not thymic carcinoid. In stage III and IV thymoma, the 5-year survival rates of total resection, subtotal resection, and inoperable groups were 93%, 64%, and 36%, respectively. On the other hand, in thymic carcinoma, the 5-year survival rates of total resection, subtotal resection, and inoperable groups were 67%, 30%, and 24%, respectively. Prophylactic mediastinal radiotherapy could not prevent local recurrences effectively in patients with totally resected stage II and III thymoma. Adjuvant therapy including radiation or chemotherapy did not improve the prognosis in patients with totally resected III and VI thymoma and thymic carcinoma.
CONCLUSIONS: Total resection is the most important factor in the treatment of thymic epithelial tumors. There is value in debulking surgery in invasive thymoma, but not in thymic carcinoma. We doubt that adjuvant therapy is valuable for patients with totally resected invasive thymoma and thymic carcinoma.
Hishida T, Nomura S, Yano M, Asamura H, Yamashita M, Ohde Y, Kondo K, Date H, Okumura M, Nagai K; Japanese Association for Research on the Thymus (JART).
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 Mar;49(3):835-41. doi: 10.1093/ejcts/ezv239. Epub 2015 Jun 26.
Abstract/Text
OBJECTIVES: Thymic carcinoma is a rare thymic malignancy. The purpose of this study was to evaluate the prognostic impact of clinicopathological variables and perioperative therapy for surgically treated thymic carcinoma using a nationwide database.
METHODS: Of 2835 patients with surgically treated thymic epithelial tumours collected from 32 Japanese institutions, a total of 306 patients with thymic carcinomas, excluding neuroendocrine tumours, were enrolled in this retrospective study. Multivariable Cox regression analyses were performed for overall (OS) and recurrence-free survival (RFS) after R0 resection.
RESULTS: Of 306 patients, 228 (75%) patients presented with Masaoka stage III-IV. Squamous cell carcinoma was the most common histological type (n = 216, 71%). R0 resection was performed in 181 (61%) patients, R1 in 46 (16%), R2 sub-total (≥80% tumour resection) in 43 (14%) and R2 non-resection in 27 (9%). The 5-year OS rate was 61%. Prognostic factors for OS were Masaoka stage and resection status. R0 resection was associated with most improved OS; however, both R1 and R2 sub-total resection resulted in superior OS compared with R2 non-resection [hazard ratio (95% confidence interval) for R0, R1 and R2 sub-total, 0.27 (0.15-0.48), 0.40 (0.22-0.74) and 0.38 (0.20-0.72), respectively]. Histological type and perioperative therapy did not affect OS, whereas tumour size and postoperative radiotherapy were associated with improved RFS after R0 resection.
CONCLUSIONS: R0 resection is essential for prolonged OS for surgically treated thymic carcinoma, but maximal debulking surgery might be beneficial and worth evaluating for advanced disease deemed difficult for R0 resection. The benefit of postoperative radiotherapy after R0 resection should also be evaluated prospectively.
© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
Yamada Y, Yoshino I, Nakajima J, Miyoshi S, Ohnuki T, Suzuki M, Nagayasu T, Iwasaki A, Okumura M; Japanese Association for Research of the Thymus.
Surgical Outcomes of Patients With Stage III Thymoma in the Japanese Nationwide Database.
Ann Thorac Surg. 2015 Sep;100(3):961-7. doi: 10.1016/j.athoracsur.2015.04.059. Epub 2015 Jul 7.
Abstract/Text
BACKGROUND: To investigate the clinical characteristics and therapeutic outcomes of patients who underwent surgery for stage III thymoma in Japan.
METHODS: Using the Japanese nationwide database, which contains the records of 2,835 patients with thymic epithelial tumors who underwent treatment between 1991 and 2010, we extracted and analyzed the records of those who underwent surgery for stage III thymoma.
RESULTS: A total of 310 patients (170 males, 140 females; median age, 58 years) were analyzed. Involved sites were the lung in 194 (62.6%), the pericardium in 151 (48.7%), the great vessels in 126 (40.6%), the phrenic nerve in 84 (27.1%), and the chest wall in 7 (2.3%). Complete resection (R0) was achieved in 247 (79.7%) cases. Induction therapies were administered to 42 (13.5%) patients, and postoperative therapies were administered to 147 (47.4%). In R0 cases, 68 (27.5%) experienced recurrence. The pleural space was the most frequent site of recurrence (46; 18.6%). The 10-year overall and disease-free (in R0) survival rates were 80.2% and 51.6%, respectively. Multivariate analyses revealed that age (p = 0.002), male sex (p = 0.017), induction therapy (p < 0.001), and type B histology (p = 0.037) were independent adverse predictors for overall survival. Chest wall invasion was the only independent adverse predictor for disease-free survival, although the factor analysis was marginal for overall survival.
CONCLUSIONS: The outcomes of surgery for patients with stage III thymoma were favorable unless chest wall invasion was present; however, the role of complete resection and appropriate multimodal treatment plan require further investigation.
Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
Nakamura S, Kawaguchi K, Fukui T, Hakiri S, Ozeki N, Mori S, Goto M, Hashimoto K, Ito T, Yokoi K.
Multimodality therapy for thymoma patients with pleural dissemination.
Gen Thorac Cardiovasc Surg. 2019 Jun;67(6):524-529. doi: 10.1007/s11748-018-01054-7. Epub 2019 Feb 6.
Abstract/Text
BACKGROUND: Although multidisciplinary treatment is recommended for patients with advanced stage and recurrent thymoma, a detailed treatment strategy remains controversial. We have performed a multimodality therapy of induction chemotherapy (CAMP therapy: cisplatin, doxorubicin, and methylprednisolone) combined with surgery for those patients. We now conducted a retrospective study for investigating the results of this multimodality therapy for thymoma patients with pleural dissemination.
PATIENTS AND METHODS: Between 2003 and 2017, 201 patients underwent surgical resection for thymomas. Twenty-six of them received induction CAMP therapy followed by surgery, and 19 of them with pleural dissemination were enrolled in this study. Those cohort were divided into 2 groups by employing surgical procedures: extrapleural pneumonectomy (EPP) group (n = 10) and resection of plural dissemination (RPD) group (n = 9).
RESULTS: The median age of all patients was 49 years. Based on the WHO classification, the histological diagnoses of those thymomas were as follows: Type B1 (n = 1), Type B2 (n = 13), and Type B3 (n = 5). Seven patients were complicated with myasthenia gravis (MG). Clinical stage of the 13 primary cases based on the Masaoka classification were stage IV, and the remaining six cases had recurrent pleural dissemination after surgery. Partial response in induction CAMP therapy was obtained in 78.9% (n = 15) of the patients. Adverse events (Grade 4) occurred in 2 patients (10.5%). Postoperative complications (Grade 4) were observed in 2 patients (10.5%). In all of the enrolled patients, the five-year overall survival rate (5Y-OS) and 5-year progression-free survival rate (5Y-PFS) were 76.7% and 55.1%, respectively. In the EPP group, 5Y-OS and 5Y-PFS were 83.3% and 83.3%, respectively, and in the RPD group, 70.0% and 29.6%, respectively.
CONCLUSIONS: Multidisciplinary treatment using induction CAMP therapy and surgical resection for thymoma patients with pleural dissemination was effective and feasible. Because of the low recurrent rate of disease, young patients with good cardiopulmonary function and well-controlled MG might be good candidates for EPP.
Kaba E, Ozkan B, Erus S, Duman S, Cimenoglu B, Toker A.
Role of Surgery in the Treatment of Masaoka Stage IVa Thymoma.
Ann Thorac Cardiovasc Surg. 2018 Feb 20;24(1):6-12. doi: 10.5761/atcs.oa.17-00108. Epub 2017 Dec 8.
Abstract/Text
PURPOSE: To analyze the role of surgery in patients with Masaoka stage IVa thymoma treated with multimodality therapy.
METHODS: Of 191 patients undergoing surgery for thymoma in our department between January 2002 and December 2015, 39 (20.4%) had Masaoka stage IVa. Histopathological tumor type, myasthenic status of the Osserman-Genkins score, Masaoka stage at the first surgery, neoadjuvant treatment, number and type of surgeries, and survival rates were recorded.
RESULTS: Thymoma B2 was the most common histopathological tumor type (n = 16, 41%). Twenty-six (66.7%) patients underwent primary surgeries for Masaoka stage IVa thymoma, whereas nine (23.1%) underwent secondary surgeries and four (10.3%) underwent tertiary surgeries for pleural or pericardial recurrences. Median survival was 132 ± 25 (82-181; 95% confidence interval [CI]) months. Overall 3-, 5-, and 10-year survival rates were 93%, 93%, and 56%, respectively.
CONCLUSION: Surgical treatment should be considered as a completion modality to oncological therapy and has the potential to provide long-term survival of Masaoka stage IVa in patients with thymoma. The type of surgery should be determined based on the invasiveness of the lesion.
Huang J, Rizk NP, Travis WD, Seshan VE, Bains MS, Dycoco J, Downey RJ, Flores RM, Park BJ, Rusch VW.
Feasibility of multimodality therapy including extended resections in stage IVA thymoma.
J Thorac Cardiovasc Surg. 2007 Dec;134(6):1477-83; discussion 1483-4. doi: 10.1016/j.jtcvs.2007.07.049. Epub 2007 Oct 26.
Abstract/Text
OBJECTIVE: Extended resections for advanced-stage thymomas are not commonly performed because of the potential morbidity in the face of unclear survival or palliative benefit. We reviewed our experience with multimodality treatment for Masaoka stage IVA thymomas for feasibility and outcomes.
METHODS: We conducted a retrospective review of a single-institution surgical database. Data included patient demographics, preoperative staging and treatment, perioperative events, pathologic findings, and postoperative outcomes.
RESULTS: During the period from 1996 to 2006, 18 patients who had Masaoka stage IVA thymoma underwent surgical resection. All patients received preoperative chemotherapy. Four patients with extensive pleural involvement underwent concomitant extrapleural pneumonectomy and postoperative hemithoracic radiation. Complete resection was achieved in 12 (67%) patients. There was no operative mortality. With a median follow-up of 32.2 months (range 1.4-129.9 months), 3-year, 5-year, and 10-year survivals were 91%, 78%, and 65%, respectively, and median survival has not yet been reached.
CONCLUSION: Multimodality therapy including extended surgical resection can be performed in select patients with stage IVA thymoma with low morbidity and mortality and can result in excellent long-term survival.
Mendogni P, Toker A, Moser B, Trancho FH, Aigner C, Bravio IG, Novoa NM, Molins L, Costardi L, Voltolini L, Ardò NP, Verdonck B, Ampollini L, Zisis C, Barmin V, Enyedi A, Ruffini E, Van Raemdonck D, Thomas PA, Weder W, Rocco G, Brunelli A, Detterbeck FC, Venuta F, Falcoz PE, Tosi D, Bonitta G, Nosotti M; European Association of Thoracic Surgeons (ESTS) Thymic Working Group.
Surgical resection of Masaoka stage III thymic epithelial tumours with great vessels involvement: a retrospective multicentric analysis from the European Society of Thoracic Surgeons thymic database.
Eur J Cardiothorac Surg. 2022 Sep 2;62(4). doi: 10.1093/ejcts/ezac021.
Abstract/Text
OBJECTIVES: The aim of this study was to analyse the outcomes of an international cohort of patients affected by Masaoka stage III thymic epithelial tumours with vascular involvement and treated by surgery.
METHODS: Study design was the observational multicentre retrospective cohort study. Data were extracted from the European Society of Thoracic Surgeons thymic database; additional variables were collected. Inclusion criteria were as follows: stage III (Masaoka-Koga) thymic epithelial tumours; surgery with radical intention; clinical or pathological great vessels involvement; and radiologically suspected or diagnosed intraoperatively. Outcome items were analysed.
RESULTS: Sixty-five patients submitted to surgery from 2001 to 2017 fulfilled inclusion criteria. Thymoma and thymic carcinoma patients did not differ for demographics and clinical characteristics. The majority of great vessel treated were superior vena cava or innominate veins (72.3%). Eleven patients (16.9%) had postoperative cardiopulmonary complications; vascular stenosis was observed in 3 patients (4.6%). The multivariable Cox analysis for disease-free survival showed an increased hazard of recurrence for thymic carcinoma (hazard ratio = 3.59; 95% confidence interval: 1.66-7.78, P = 0.001). The 1-, 3-, 5- and 10-year overall survival rates were 0.86, 0.84, 0.81, and 0.53, respectively. There was no significant difference in overall survival according to resection status or between thymoma and thimic carcinoma. The univariable Cox regression model did not show an increased hazard of death for myasthenic patients considering all resection status and for patients who received neoadjuvant therapy.
CONCLUSIONS: We observed that clinical outcomes of patients treated for stage III thymic epithelial tumours with vascular involvement are satisfactory suggesting to increase the confidence in dealing with these complex surgeries. Complete resection should be achieved, even though extensive vascular reconstructions are required.
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
Ahmad U, Yao X, Detterbeck F, Huang J, Antonicelli A, Filosso PL, Ruffini E, Travis W, Jones DR, Zhan Y, Lucchi M, Rimner A.
Thymic carcinoma outcomes and prognosis: results of an international analysis.
J Thorac Cardiovasc Surg. 2015 Jan;149(1):95-100, 101.e1-2. doi: 10.1016/j.jtcvs.2014.09.124. Epub 2014 Oct 5.
Abstract/Text
OBJECTIVES: The objectives of this collaborative study were to characterize patients with thymic carcinoma, their treatment patterns, and association with overall survival (OS) and recurrence-free survival (RFS).
METHODS: Clinical, pathologic, treatment, and follow-up information were analyzed. OS and RFS were the primary outcome measures.
RESULTS: In 1042 cases of thymic carcinoma, 42 (5%) patients had pathologic Masaoka stage I, 138 (17%) had stage II, 370 (45%) had stage III, and 274 (33%) had stage IV disease. Overall, 166 patients (22%) underwent induction chemotherapy and 48 (6%) had preoperative radiation therapy. An R0 resection was performed in 447 cases (61%), R1 in 102 cases (14%), and R2 in 184 cases (25%). Squamous cell carcinoma was the predominant histologic subtype (n = 560; 79%). Adjuvant chemotherapy was administered to 237 (31%) patients, and 449 (60%) received adjuvant radiation therapy. The median OS was 6.6 years (95% confidence interval [CI], 5.8-8.3) and the cumulative incidence of recurrence at 5 years was 35% (95% CI, 30%-40%). In univariate analysis, early Masaoka stage, R0 resection, chemotherapy, and radiation therapy were associated with OS. Early Masaoka stage and R0 resection were also associated with RFS. On multivariable analysis, R0 resection and radiation therapy were associated with prolonged OS. Radiation therapy and male gender were associated with prolonged RFS.
CONCLUSIONS: R0 resection and radiation therapy are associated with improved OS, whereas radiation therapy and male gender are associated with longer RFS.
Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Ko R, Shukuya T, Okuma Y, Tateishi K, Imai H, Iwasawa S, Miyauchi E, Fujiwara A, Sugiyama T, Azuma K, Muraki K, Yamasaki M, Tanaka H, Takashima Y, Soda S, Ishimoto O, Koyama N, Morita S, Kobayashi K, Nukiwa T, Takahashi K; North East Japan Study Group.
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 Oct;23(10):1210-1217. doi: 10.1634/theoncologist.2017-0586. Epub 2018 Mar 22.
Abstract/Text
BACKGROUND: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma.
MATERIALS AND METHODS: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group.
RESULTS: A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model.
CONCLUSION: The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients.
IMPLICATIONS FOR PRACTICE: Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.
© AlphaMed Press 2018.
Tateishi K, Ko R, Shukuya T, Okuma Y, Watanabe S, Kuyama S, Murase K, Tsukita Y, Ashinuma H, Nakagawa T, Uematsu K, Nakao M, Mori Y, Kaira K, Mouri A, Miyabayashi T, Sakashita H, Matsumoto Y, Tanigawa T, Koizumi T, Morita S, Kobayashi K, Nukiwa T, Takahashi K; North East Japan Study Group.
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 Apr;25(4):e668-e674. doi: 10.1634/theoncologist.2019-0593. Epub 2019 Nov 26.
Abstract/Text
BACKGROUND: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma.
MATERIAL AND METHODS: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records.
RESULTS: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively).
CONCLUSION: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study.
IMPLICATIONS FOR PRACTICE: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.
© AlphaMed Press 2019.
Okuma Y, Ko R, Shukuya T, Tateishi K, Imai H, Iwasawa S, Miyauchi E, Kojima T, Fujita Y, Hino T, Yamanda S, Suzuki T, Fukuizumi A, Sakakibara T, Harada T, Morita S, Kobayashi K, Nukiwa T, Takahashi K; North East Japan Study Group.
Prognostic factors for patients with metastatic or recurrent thymic carcinoma receiving palliative-intent chemotherapy.
Lung Cancer. 2020 Oct;148:122-128. doi: 10.1016/j.lungcan.2020.08.014. Epub 2020 Aug 20.
Abstract/Text
BACKGROUND: Thymic malignancies are a model of rare cancer. However, little clinical data is available based on the large database. We aimed to clarify the prognostic factors, particularly the metastatic sites, for thymic malignancies using one of the largest, representative, multi-institutional databases, the NEJ023 database.
PATIENTS AND METHODS: Patients with Stage IVA/IVB or recurrent thymic carcinoma were enrolled between 1995 and 2014. Clinicopathologic information was evaluated, and the patients were subdivided according to the metastatic organs of involvement (serosal dissemination, liver, lymph node, pulmonary, and bone metastasis). A Kaplan-Meier analysis and multivariate Cox regression were used to evaluate survival.
RESULTS: Two hundred and seventy-nine patients with metastases and a predominantly squamous histology (66.7%) were included. Most patients (53.0%) had serosal dissemination, whereas 26.5%, 21.9%, 19.7%, and 15.8% had pulmonary, lymph node, bone and liver metastases, respectively. Over a median follow-up time of 21.5 months, the median overall survival (mOS) was 30.7 months. When the subjects were grouped according to involved metastatic sites, patients with more than 3 involved metastatic organs had the worst survival outcome. Among patients with isolated involvement, those with bone metastasis had the poorest survival, followed by patients with liver metastasis. Subjects with hypoalbuminemia also had poor survival outcomes. When patients treated with platinum and anthracycline-containing pharmacotherapy were compared with those treated with platinum and non-anthracycline-containing pharmacotherapy, no significant difference was observed. Bone metastasis (P = 0.0005), liver metastasis (P = 0.047), and hypoalbuminemia (P = 0.0021) were identified as prognostic factors in a multivariate analysis.
CONCLUSION: The site of metastatic involvement affects the survival outcomes of patients with thymic carcinoma, and this result may reflect the sensitivity of metastatic sites to pharmacotherapy. As a next step, controlling liver metastasis with pharmacotherapy could help to improve the prognosis of patients with thymic carcinoma.
Copyright © 2020 Elsevier B.V. All rights reserved.
Yokoi K, Matsuguma H, Nakahara R, Kondo T, Kamiyama Y, Mori K, Miyazawa N.
Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone.
J Thorac Oncol. 2007 Jan;2(1):73-8. doi: 10.1097/JTO.0b013e31802bafc8.
Abstract/Text
BACKGROUND AND OBJECTIVES: Advanced invasive thymomas are not usually manageable by surgical resection and radiotherapy. We reviewed our experience with a multidisciplinary approach and evaluated chemotherapy in the treatment of invasive thymoma.
PATIENTS AND METHODS: Seventeen consecutive patients with invasive thymoma were treated with multimodality therapy consisting of chemotherapy, surgery, and/or radiotherapy. Four patients had stage III disease with superior vena cava invasion, nine had stage IVa disease, and four had stage IVb disease. The chemotherapy regimen consisted of cisplatin, doxorubicin, and methylprednisolone (CAMP). Chemotherapy was administered in a neoadjuvant setting to the 14 patients and in an adjuvant setting to the remaining three patients. Surgical resection was intended in all patients. After those treatments, chemotherapy and/or radiation therapy were performed.
RESULTS: All but one of the 14 patients with induction chemotherapy responded to the CAMP therapy, and the response rate was 92.9%. Seven of these patients underwent complete remission after surgical resection and chemoradiotherapy, and the others underwent partial remission. All three patients treated with surgical resection and then chemotherapy with or without radiotherapy also achieved complete remission. Tumor progression after multimodality therapy occurred in 10 patients. After retreatment, eight of these patients were alive at the time of analysis, with a median survival time after recurrence of 30 months. The 5- and 10-year overall survival rates for all patients were both 80.7%. The major side effect of CAMP therapy was acceptable neutropenia.
CONCLUSIONS: CAMP therapy was highly effective for invasive thymomas, and the multimodality therapy containing this chemotherapy brought about good disease control in the majority of patients. We believe that this multidisciplinary treatment with CAMP therapy, surgery, and radiotherapy is a justifiable initial treatment for patients with advanced invasive thymoma. Furthermore, appropriate treatments are essential for the long-term survival of patients with recurrences after multimodality therapy.
Fornasiero A, Daniele O, Ghiotto C, Piazza M, Fiore-Donati L, Calabró F, Rea F, Fiorentino MV.
Chemotherapy for invasive thymoma. A 13-year experience.
Cancer. 1991 Jul 1;68(1):30-3. doi: 10.1002/1097-0142(19910701)68:1<30::aid-cncr2820680106>3.0.co;2-4.
Abstract/Text
From 1977 to 1990, 37 patients with Stage III or IV invasive thymoma (20 men and 17 women; median age, 40 years of age) were referred for chemotherapy to the Padova Medical Oncology Department. All patients initially received the same regimen (50 mg/m2 of cisplatin and 40 mg/m2 of doxorubicin intravenously (IV) on day 1, 0.6 mg/m2 of vincristine IV on day 3, and 700 mg/m2 of cyclophosphamide IV on day 4 [ADOC]), recycling at monthly intervals. No life-threatening side effects were noted. The overall clinical response rate (complete response plus partial response) was 91.8%, with 43% complete remissions. Median duration of response and survival were 12 months (range, 2 to 96+ months) and 15 months (range, 5 to 96+ months), respectively. Seven of the 16 complete remissions were pathologically confirmed at subsequent thoracotomy. Other chemotherapy combinations and radiation therapy have been applied as second-line treatment, achieving only minimal responses. In the opinion of the authors, such chemotherapy deserves evaluation for adjuvant and neo-adjuvant treatment of invasive (and/or inoperable) thymoma due to the high complete response rate and overall response rate.
Hirai F, Yamanaka T, Taguchi K, Daga H, Ono A, Tanaka K, Kogure Y, Shimizu J, Kimura T, Fukuoka J, Iwamoto Y, Sasaki H, Takeda K, Seto T, Ichinose Y, Nakagawa K, Nakanishi Y; West Japan Oncology Group.
A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L.
Ann Oncol. 2015 Feb;26(2):363-8. doi: 10.1093/annonc/mdu541. Epub 2014 Nov 17.
Abstract/Text
BACKGROUND: Thymic carcinoma (TC) is an exceptionally rare tumor, which has a very poor prognosis differing from thymoma. Till date, there has been no report of any results of clinical trials focusing on TC. The role of non-anthracycline-based chemotherapy has not been elucidated since the previous studies included a relatively small number of TC patients. This single-arm study evaluated carboplatin and paclitaxel (CbP) in chemotherapy-naive patients with advanced TC.
PATIENTS AND METHODS: The study treatment consisted of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) every 3 weeks for a maximum of six cycles. The primary end point was objective response rate (ORR) by independent review. The secondary end points included overall survival (OS), progression-free survival (PFS), and safety. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05.
RESULTS: Forty patients from 21 centers were enrolled for this study from May 2008 to November 2010. Of the 39 patients evaluable for analysis, 36 were pathologically diagnosed by independent review, and 97% patients were eventually TC. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval 21%-53%; P = 0.031). The median PFS was 7.5 (6.2-12.3) months, while OS did not reach the median value. Major adverse event was grade 3-4 neutropenia in 34 patients (87%). There was no treatment-related death.
CONCLUSIONS: In this largest trial with TC, CbP showed promising efficacy in advanced TC when compared with anthracycline-based chemotherapy, which is the current standard treatment of thymic neoplasm. Our results established that CbP, one of the standard treatments for non-small-cell lung cancer, might be an option as a chemotherapy regimen for TC.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Inoue A, Sugawara S, Harada M, Kobayashi K, Kozuki T, Kuyama S, Maemondo M, Asahina H, Hisamoto A, Nakagawa T, Hotta K, Nukiwa T.
Phase II study of Amrubicin combined with carboplatin for thymic carcinoma and invasive thymoma: North Japan Lung Cancer group study 0803.
J Thorac Oncol. 2014 Dec;9(12):1805-9. doi: 10.1097/JTO.0000000000000362.
Abstract/Text
BACKGROUND: There has been no standard chemotherapy for advanced or recurrent thymic malignancies including thymic carcinoma (TC) and invasive thymoma (IT), though platinum and anthracycline have been reported as effective agents for the treatment of these diseases. The objective of this study was to evaluate the efficacy and safety of the combination of amrubicin (AMR), a new anthracycline agent, and carboplatin (CBDCA) in patients with advanced thymic malignancies.
METHODS: Patients with histologically confirmed thymic malignancies received AMR (35 mg/m, days 1-3) and CBDCA (area under the curve 4.0, day 1) every 3 weeks. Patients who had received previous chemotherapy were treated with a reduced dose of AMR (30 mg/m). The primary end point was objective response rate (ORR), and secondary endpoints were progression-free survival, overall survival, and toxicity profile.
RESULTS: From December 2008 to October 2012, 51 patients (33 TC and 18 IT) were enrolled. The median number of treatment cycles was four in each group. The ORR and progression-free survival were 30% (95% confidence interval, 14-46) and 7.6 months in the TC group, and 17% (95% confidence interval, 0-34) and 7.6 months in the IT group, respectively. The ORR of TC patients without previous chemotherapy (n = 19) was 42%. Although grade 3 or 4 hematological toxicities were common including neutropenia (82%) and febrile neutropenia (22%), these were transient and manageable. Nonhematological toxicities were moderate and no treatment-related death was observed.
CONCLUSIONS: The combination of AMR with CBDCA was active for TC with acceptable toxicity, although it was not effective for IT. Further investigation of this regimen for advanced TC is warranted.
Proto C, Ganzinelli M, Manglaviti S, Imbimbo M, Galli G, Marabese M, Zollo F, Alvisi MF, Perrino M, Cordua N, Borea F, de Vincenzo F, Chella A, Cappelli S, Pardini E, Ballatore Z, Lucarelli A, Ambrosini E, Giuliano M, Pietroluongo E, Mulargiu C, Fabbri A, Prelaj A, Occhipinti M, Brambilla M, Mazzeo L, Beninato T, Vigorito R, Ruggirello M, Greco FG, Calareso G, Miliziano D, Rulli E, De Simone I, Torri V, de Braud FGM, Pasello G, De Placido P, Berardi R, Petrini I, Zucali P, Garassino MC, Lo Russo G.
Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).
Ann Oncol. 2024 Sep;35(9):817-826. doi: 10.1016/j.annonc.2024.06.002. Epub 2024 Jun 8.
Abstract/Text
BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC.
PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out.
RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3.
CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.
Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.
Sato J, Satouchi M, Itoh S, Okuma Y, Niho S, Mizugaki H, Murakami H, Fujisaka Y, Kozuki T, Nakamura K, Nagasaka Y, Kawasaki M, Yamada T, Machida R, Kuchiba A, Ohe Y, Yamamoto N.
Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial.
Lancet Oncol. 2020 Jun;21(6):843-850. doi: 10.1016/S1470-2045(20)30162-5.
Abstract/Text
BACKGROUND: Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma.
METHODS: This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777.
FINDINGS: Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events.
INTERPRETATION: The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma.
FUNDING: Center for Clinical Trials, Japan Medical Association.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Gbolahan OB, Porter RF, Salter JT, Yiannoutsos C, Burns M, Chiorean EG, Loehrer PJ Sr.
A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma.
J Thorac Oncol. 2018 Dec;13(12):1940-1948. doi: 10.1016/j.jtho.2018.07.094. Epub 2018 Aug 16.
Abstract/Text
INTRODUCTION: Thymoma and thymic carcinoma (TC) are neoplastic diseases with reported chemosensitivity to a broad range of agents. However, because of the rarity of these diseases, few prospective trials have been conducted in patients with advanced thymic malignancies. We conducted a prospective phase II trial to evaluate the clinical activity of pemetrexed, a multitargeted antifolate agent, in previously treated patients with thymoma and TC.
METHODS: A total of 27 previously treated patients (16 with thymoma and 11 with TC) with advanced, unresectable disease were treated with pemetrexed, 500 mg/m2, intravenously every 3 weeks for a maximum of six cycles or until undue toxicity or progressive disease. All patients received folic acid, vitamin B12, and steroid prophylaxis.
RESULTS: The median number of cycles administered was 6 (range 1-6). Nine patients with a total of 14 events had grade 3 toxicities; no grade 4 toxicities were noted. In 26 fully evaluable patients, two complete and three partial responses (according to the Response Evaluation Criteria in Solid Tumors) were documented (all in patients with stage IVA thymoma, except for one partial response with stage IVA TC). A total of 14 patients completed the full six cycles of treatment, 7 patients progressed while undergoing therapy, 5 patients discontinued therapy because of intolerance, and 1 patient discontinued therapy because of progressive Morvan syndrome. The median progression-free survival time for all patients was 10.6 months (12.1 months for those with thymoma versus 2.9 months for those with TC). With 23 deaths at data cutoff, the median overall survival time was 28.7 months (46.4 months for those with thymoma versus 9.8 months for those with TC).
CONCLUSIONS: Pemetrexed is an active agent in this heavily pretreated population of patients with recurrent thymic malignancies, especially thymoma.
Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Hellyer JA, Gubens MA, Cunanan KM, Padda SK, Burns M, Spittler AJ, Riess JW, San Pedro-Salcedo M, Ramchandran KJ, Neal JW, Wakelee HA, Loehrer PJ Sr.
Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies.
Lung Cancer. 2019 Nov;137:71-75. doi: 10.1016/j.lungcan.2019.09.015. Epub 2019 Sep 18.
Abstract/Text
OBJECTIVES: There are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor.
MATERIALS AND METHODS: This was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40 mg/m2 IV days 1-3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35 mg/m2 for the final 15 patients.
RESULTS: A total of 33 patients (14 T/19 TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%-32.8%; T = 4/14 (29%), TC = 2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient.
CONCLUSION: Amrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.
Copyright © 2019 Elsevier B.V. All rights reserved.
Okuma Y, Goto Y, Ohyanagi F, Sunami K, Nakahara Y, Kitazono S, Kudo K, Tambo Y, Kanda S, Yanagitani N, Horiike A, Horinouchi H, Fujiwara Y, Nokihara H, Yamamoto N, Nishio M, Ohe Y, Hosomi Y.
Phase II trial of S-1 treatment as palliative-intent chemotherapy for previously treated advanced thymic carcinoma.
Cancer Med. 2020 Oct;9(20):7418-7427. doi: 10.1002/cam4.3385. Epub 2020 Aug 19.
Abstract/Text
Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival following palliative-intent chemotherapy. Sunitinib, everolimus, and pembrolizumab have been proposed as active agents based on previous phase II trials. In this phase II study, TC patients previously treated with platinum-based chemotherapy were enrolled. The patients received S-1 orally twice daily at a dose of 40-60 mg/m2 for 4 weeks, followed by 2 weeks off until the progression of the disease or the presence of unacceptable toxicities. The primary endpoint was the objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size of 26 patients was planned to reject the ORR of 10% under the expectation of 30% with a power of 0.80 and a type I error of 0.05 (one-sided). Twenty-six patients were recruited between 2013 and 2016; 23 patients had squamous cell carcinoma and 10 had an ECOG performance status of 0. One patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (90% confidence interval [CI], 18.3-46.9) and an 80.8% disease control rate (90% CI, 65.4-90.3). The median PFS was 4.3 months (95% CI, 2.3-10.3 months) and median OS was 27.4 months (95% CI, 16.6-34.3). Adverse events of grade ≥ 3 included neutropenia (12%), skin rash (8%), elevated alanine aminotransferase, and fatigue (4%). No treatment-related death was observed. S-1 confirmed clinical activity with tolerability in patients with previously treated TC. (UMIN000010736).
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Kurokawa K, Shukuya T, Greenstein RA, Kaplan BG, Wakelee H, Ross JS, Miura K, Furuta K, Kato S, Suh J, Sivakumar S, Sokol ES, Carbone DP, Takahashi K.
Genomic characterization of thymic epithelial tumors in a real-world dataset.
ESMO Open. 2023 Oct;8(5):101627. doi: 10.1016/j.esmoop.2023.101627. Epub 2023 Sep 12.
Abstract/Text
BACKGROUND: Thymic epithelial tumors (TETs) are rare neoplasms arising in the mediastinum, including thymic carcinomas and thymomas. Due to their rarity, little is known about the genomic profiles of TETs. Herein, we investigated the genomic characteristics of TETs evaluated in a large comprehensive genomic profiling database in a real-world setting.
METHODS: We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the United States and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. Samples profiled were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also evaluated.
RESULTS: A total of 794 patients were collected in our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), and CDKN2A (5.8%) in thymoma. TMB-high (≥10 mutations/Mb) and MSI were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Within C-CAT data, CDKN2A (38.5%), TP53 (36.5%) and CDKN2B (30.8%) were also frequently altered in thymic carcinoma, while alterations of TSC1, SETD2 and LTK (20.0% each) were found in thymoma.
CONCLUSIONS: To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB and MSI status of TETs were investigated. Potential targets for treatment previously unbeknownst in TETs are identified in this study, entailing newfound opportunities to advance therapeutic development.
Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Giaccone G, Kim C, Thompson J, McGuire C, Kallakury B, Chahine JJ, Manning M, Mogg R, Blumenschein WM, Tan MT, Subramaniam DS, Liu SV, Kaplan IM, McCutcheon JN.
Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study.
Lancet Oncol. 2018 Mar;19(3):347-355. doi: 10.1016/S1470-2045(18)30062-7. Epub 2018 Jan 26.
Abstract/Text
BACKGROUND: Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma.
METHODS: We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis.
FINDINGS: 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity.
INTERPRETATION: Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential.
FUNDING: Merck & Co.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Giaccone G, Kim C.
Durable Response in Patients With Thymic Carcinoma Treated With Pembrolizumab After Prolonged Follow-Up.
J Thorac Oncol. 2021 Mar;16(3):483-485. doi: 10.1016/j.jtho.2020.11.003. Epub 2020 Nov 25.
Abstract/Text
Here, we present an update of a phase 2 study of pembrolizumab in patients with advanced thymic carcinoma who failed previous therapies. Duration of response was approximately 3 years, and median survival was in excess of 2 years with a 5-year survival rate of 18%. The higher than expected incidence of severe autoimmune disorders (15%) did not substantially increase with a longer follow-up. Pembrolizumab induces durable responses in patients with thymic carcinoma. Careful selection of patients and monitoring of toxicities are warranted.
Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Remon J, Villacampa G, Facchinetti F, Di Maio M, Marcuse F, Tiseo M, Hochstenbag M, Hendriks LEL, Besse B.
Immune checkpoint blockers in patients with unresectable or metastatic thymic epithelial tumours: A meta-analysis.
Eur J Cancer. 2023 Feb;180:117-124. doi: 10.1016/j.ejca.2022.12.005. Epub 2022 Dec 12.
Abstract/Text
BACKGROUND: For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice.
METHODS: We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy.
RESULTS: Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3-26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6-34.6) and 66.9% (95% CI: 59.6-75.2%), respectively. The incidence of grade 3-5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma.
CONCLUSIONS: Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Burt BM, Nguyen D, Groth SS, Palivela N, Ripley RT, Makris KI, Farjah F, Cornwell L, Massarweh NN.
Utilization of Minimally Invasive Thymectomy and Margin-Negative Resection for Early-Stage Thymoma.
Ann Thorac Surg. 2019 Aug;108(2):405-411. doi: 10.1016/j.athoracsur.2019.03.010. Epub 2019 Apr 3.
Abstract/Text
BACKGROUND: Minimally invasive thymectomy (MIT) has demonstrated improved short-term outcomes compared with open thymectomy (OT). Although adoption of MIT for thymoma is increasing, oncologic outcomes have not been well characterized.
METHODS: This was a retrospective cohort study of adult patients from the National Cancer Database who underwent MIT or OT for Masaoka stage I to II thymoma between 2010 and 2014. The primary outcome was R0 resection. Secondary outcomes included MIT use, perioperative mortality, and length of stay.
RESULTS: Nine hundred forty-three patients from 395 hospitals underwent thymectomy for stage I to II thymoma. MIT was performed in 31.3% (59.7% robotic, 40.3% thoracoscopic). Over the study period MIT utilization increased from 21.0% to 40.2% (trend test, p < 0.001). R0 resection was achieved in 83.1% of MITs (86.6% stage I, 72.7% stage II) and 79% of OTs (85.5% stage I, 65.8% stage II). In multivariable analyses, the likelihood of incomplete resection (R1/2) was associated with stage II tumors (odds ratio, 2.51) and World Health Organization B3 histology (odds ratio, 3.66). R0 resection was not associated with surgical approach (p = 0.17) and did not vary with tumor size (trend test, p = 0.90). Mortality rates at 30 and 90 days were 0% and 0.5%, respectively. MIT was associated with significantly shorter lengths of stay than OT (-1.03 days [95% confidence interval, -1.68 to -0.38]).
CONCLUSIONS: The use of MIT for resection of early-stage thymoma is increasing and is not associated with lower rates of R0 resection than OT. Reasons for the relatively low rates of R0 resection among all thymectomies requires further investigation, and long-term outcomes data are needed to better define the oncologic effectiveness of MIT.
Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
Kamel MK, Villena-Vargas J, Rahouma M, Lee B, Harrison S, Stiles BM, Abdelrahman AM, Altorki NK, Port JL.
National trends and perioperative outcomes of robotic resection of thymic tumours in the United States: a propensity matching comparison with open and video-assisted thoracoscopic approaches†.
Eur J Cardiothorac Surg. 2019 Oct 1;56(4):762-769. doi: 10.1093/ejcts/ezz111.
Abstract/Text
OBJECTIVES: Despite the recent increased rate of adoption of robotic approaches for the resection of thymic tumours, their use is still limited to large-volume academic centres. To date, a large-scale analysis of the robotic approach has not been performed. We assessed the recent trends and outcomes of robotic thymectomies in the United States compared to those of open and video-assisted thoracoscopic surgical (VATS) approaches.
METHODS: The National Cancer Database was queried for patients who underwent resection for thymic tumours (2010-2014). Predictors of using the robotic approach were estimated by logistic regression analysis. Propensity matching analysis (robotic versus open and robotic versus VATS) was done (1:1-caliper 0.05), controlling for age, gender, comorbidity index, induction treatment, tumour size and tumour extension.
RESULTS: A total of 2558 thymectomies were performed (robotic = 300, VATS = 280, open = 1978). The use of a robotic approach increased from 6% (2010) to 14% (2014). The number of hospitals performing at least 1 robotic thymectomy increased from 22 (2010) to 52 (2014). Independent predictors influencing the choice of a robotic approach included an academic research/integrated cancer programme [odds ratio (OR) 1.66, confidence interval (CI) 1.22-2.27], later year of diagnosis (2014; OR 2.23, CI 1.31-3.80) and a patient's race (Asian) (OR 1.68, CI 1.05-2.69). A robotic approach was less likely to be utilized in midwestern hospitals (OR 0.65, CI 0.42-0.99), in larger tumours (cm) (OR 0.85, CI 0.80-0.90), with invasion of adjacent organs (OR 0.55, CI 0.37-0.82), thymic carcinoma (OR 0.62, CI 0.40-0.97) and following induction chemotherapy (OR 0.22, CI 0.08-0.61). In a propensity-matched analysis, there were no differences in the incidence of positive margins, nodal dissection, 30-day readmission rates and 30-/90-day mortality rates between the groups. However, a robotic approach was associated with fewer conversions compared to VATS, with a trend towards a shorter length of stay compared to an open approach. There were no differences in the 5-year overall survival rate between the matched groups (robotic 93% vs VATS 94%; P = 0.571; robotic 91% vs open 80%; P = 0.094).
CONCLUSIONS: Over a 4-year study period, there was a significant increase in robotic utilization for thymectomies and an increase in the number of hospitals performing the procedure. In a matched analysis, a robotic approach was comparable to a VATS or an open approach. Current trends demonstrate increased robotic utilization for small thymomas with excellent perioperative results.
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
Nagata T, Makutani S, Uchida H, Kichikawa K, Maeda M, Yoshioka T, Anai H, Sakaguchi H, Yoshimura H.
Follow-up results of 71 patients undergoing metallic stent placement for the treatment of a malignant obstruction of the superior vena cava.
Cardiovasc Intervent Radiol. 2007 Sep-Oct;30(5):959-67. doi: 10.1007/s00270-007-9088-4.
Abstract/Text
PURPOSE: To retrospectively clarify the utility of metallic stent placement for the treatment of the malignant obstruction of the superior vena cava (SVC) in 71 patients with VC syndrome (SVCS) on the basis of long-term follow-up data.
MATERIALS AND METHODS: Seventy-one patients underwent stent placement and were followed until death. The applicability of the spiral Z-stent (S-Z-stent) mainly used the initial and follow-up results, stent placement for bilateral BCV obstruction and the value of concurrent anticancer therapy were studied.
RESULTS: The technical success rate was 100%, the initial clinical success rate was 87% (62/71), the primary clinical patency rate was 88% (57/65), and the secondary clinical patency rate was 95% (62/65). The obstruction rate of the stent was 12% (8/65), and an additional stent was useful for relief of recurrent SVCS. Survival of 57 patients in whom there was no recurrence of SVCS until death ranged from 1 week to 29 months (mean, 5.4 months and the S-Z-stent appeared to be suitable for the treatment of the malignant obstruction of SVC. Unilateral stent placement was effective for relief of SVCS with bilateral BCV obstruction. Patients who received concurrent anticancer therapy survived 2 months longer than those who did not.
CONCLUSION: Stent placement is an effective treatment for SVCS. Further, the utility of S-Z-stent for SVCS, an additional stent for recurrence, unilateral stent for patients with bilateral BCV obstruction, and anticancer therapy after stent placement were verified.
