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      Neoadjuvant therapy for thymic neoplasms reduces tumor volume per 3D-reconstructed images but does not improve the complete resection rate

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          Abstract

          Objectives

          Complete resection of thymic neoplasms is important for achieving a favorable prognosis; however, the efficacy of neoadjuvant therapy remains controversial. We investigated the effect of induction therapy on complete resection and survival using 3-dimensionally reconstructed images to measure tumor volume.

          Methods

          Eighty-nine patients who underwent surgical resection for Masaoka-Koga stage III–IV thymic neoplasms between January 2000 and December 2013 were enrolled, including 71 and 18 in the primary surgery and neoadjuvant therapy groups, respectively. Baseline characteristics, postoperative outcomes, and survival rates were analyzed. Moreover, baseline and post-neoadjuvant therapy tumor volumes were compared among patients in the neoadjuvant group.

          Results

          Adjacent mediastinal structure invasion was significantly rarer in the primary surgery group than in the neoadjuvant group (1.27±1.09 vs. 2.61±1.42, p<0.001). On subgroup analysis of patients who underwent neoadjuvant therapy, tumor volumes decreased significantly from 206.08±132.32 cm 3 to 81.25±71.24 cm 3 post-therapy (p = 0.001). Interestingly, only the pre-neoadjuvant tumor volume was significantly associated with complete resection, while the post-neoadjuvant volume was not (p = 0.012 and p = 0.458, respectively). Moreover, despite significantly reduced tumor volumes, patients in the neoadjuvant therapy group did not exhibit significantly different R0 resection rates (odds ratio 1.490, p = 0.581) or overall survival (p = 0.285) compared to those in the primary surgery group.

          Conclusions

          Neoadjuvant therapy does not significantly influence the R0 resection rate or overall survival relative to primary surgery. Nevertheless, it may by useful for patients planning surgical resection because it significantly reduces the presurgical tumor volume and extent of invasion.

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          Most cited references9

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          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.

          To evaluate tumor resectability after induction chemotherapy and to determine disease-free and overall survival rates of patients with locally advanced unresectable thymoma that received a multimodal treatment regimen. Twenty-two patients (9 men, 13 women) with histologically confirmed invasive thymoma were treated with a multidisciplinary regimen consisting of three courses of induction chemotherapy, surgical resection, and radiation therapy, followed by three courses of consolidation chemotherapy. The median age was 47 years (range, 25-70). Eleven patients had stage III disease, 10 patients, stage IVA, and one patient, IVB. The most common histologic type was lymphocytic. Induction chemotherapy consisted of 500 mg/m(2) of cyclophosphamide on day 1; doxorubicin (20 mg/m(2) per day) on days 1-3 via continuous infusion (a total of 60 mg/m(2)); cisplatin (30 mg/m(2) per day) on days 1-3 (a total of 90 mg/m(2)); and prednisone (100 mg per day) on days 1-5. This cycle was repeated three times at 3-4-week intervals. Patients then underwent surgery for tumor resection and received radiotherapy. Consolidation chemotherapy given at 80% of the induction chemotherapy doses of cyclophosphamide, doxorubicin, and cisplatin and 100% of the dose of prednisone was then repeated every 3-4 weeks for a total of three courses. Induction chemotherapy produced major responses in 17 (77%) of the 22 patients including 3 (14%) complete responses (CR) and 14 (63%) partial responses (PR). Twenty-one patients underwent surgical exploration: 16 (76%) had complete resection and 5 (24%) had incomplete resection; one patient refused surgery. All 22 patients received radiation therapy. Nineteen of 22 patients completed the planned therapy, and all but one had completed consolidation chemotherapy at the time of analysis. With a median follow-up time of 50.3 months, 18 of the 19 patients who completed the multidisciplinary approach were disease-free. Of the 22 patients originally registered, 20 were alive at the time of analysis (one patient died of endocarditis, and one died of recurrent disease). The overall survival rate was 95% at 5 years (95% confidence interval (CI), 0.87-1.0) and 79% at 7 years (95% CI, 0.55-1.0). The progression-free survival rates were 77% at 5 years (95% CI, 0.58-1.0) and 77% at 7 years (95% CI, 0.58-1.0). The major side effect from induction and consolidation chemotherapy was myelosuppression. Nine patients experienced grade III/IV neutropenia, which included neutropenic fever in two patients, and grade III thrombocytopenia in two patients. The most common nonhematologic side effects were fatigue, nausea and vomiting, and decreased appetite. One patient experienced acute respiratory distress syndrome after surgical resection and required a prolonged hospitalization. No patients developed cardiac toxic effects, and no surgical mortality occurred. The use of induction chemotherapy to optimize surgical resectability of thymoma followed by radiation therapy and consolidation chemotherapy lead to good control of residual disease and high overall survival rates. We believe that this combined multidisciplinary approach prolongs lives and may cure locally advanced unresectable malignant thymomas. Future prospective multi-institutional studies are needed to further verify or define the best treatment for this patient population.
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            Induction chemoradiotherapy followed by resection for locally advanced Masaoka stage III and IVA thymic tumors.

            The treatment of locally advanced thymic tumors is not uniform. Recently, several centers have reported the results of induction chemotherapy followed by resection and then radiation. Our center adopted an alternative strategy and treated locally advanced thymic tumors with induction chemoradiotherapy in an effort to maximize the intensity of the induction therapy. A retrospective review was performed of 10 patients with locally advanced thymic tumors treated from 1997 to 2006. Seven patients were clinically staged as Masaoka stage III and 3 as stage IVA. The treatment plan included two cycles of cisplatin and etoposide with concurrent radiation. Patients then had resection followed by postoperative chemotherapy if they were judged to be at high risk for relapse. Four patients had a partial radiographic response to induction therapy and 6 had no response. Eight patients had a R0 resection and 2 had a R1 resection. Four patients had substantial (>90%) necrosis in the resected specimen. There was no postoperative mortality. Seven patients had two more cycles of chemotherapy. The median follow-up was 41 months. Three patients had recurrences. The 5-year estimated survival was 69% (95% confidence interval: 32% to 100%). Induction therapy for locally advanced thymic tumors with cisplatin, etoposide, and radiation is well tolerated, with many patients having a partial radiographic response. The majority of patients can undergo a complete resection with this treatment. The survival of these patients compares favorably with those undergoing other induction regimens. Further efforts to maximize the intensity of induction therapy for locally advanced thymic tumors is warranted. We have initiated a multicenter phase 2 clinical trial (NCT00387868) to prospectively test this concept.
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              Long-term outcome after multimodality treatment for stage III thymic tumors.

              Surgery remains the cornerstone of therapy for thymic tumors, but the optimal treatment for advanced, infiltrative lesions is still controversial. The introduction of multimodality protocols has substantially modified survival and recurrence rate. We reviewed our 13-year prospective experience with multimodality treatment of stage III thymoma and thymic carcinoma. Since 1989 we have prospectively used a multimodality approach in 45 stage III thymic tumors. Sixteen patients (35%) had myasthenia gravis. Twenty-three patients (51%) had pure or predominantly cortical thymoma (group 1), 11 (24.5%) had well-differentiated thymic carcinoma (group 2), and 11 (24.5%) had thymic carcinoma (group 3). Tumors that were not considered radically resectable at preoperative workup underwent biopsy and induction chemotherapy (15 patients, 33%) followed by surgical resection; all patients were referred for adjuvant chemoradiotherapy. No operative mortality was recorded; 1 treatment-related death during adjuvant chemotherapy was observed in group 1. Complete resection was feasible in 91% of patients in groups 1 and 2 and 82% in group 3. The overall 10-year survival was 78%. Ten-year survival for groups 1 and 2 was 90% and 85%, respectively; 8-year survival for group 3 was 56%. During follow-up, tumor recurrence was noted in 3 patients (13%) from group 1, 3 (27%) from group 2, and 3 (27%) from group 3. Multimodality treatment with induction chemotherapy (when required) and adjuvant chemoradiotherapy offers encouraging results for stage III thymic tumors; the outcome is more favorable for cortical thymoma and well-differentiated thymic carcinoma.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 March 2019
                2019
                : 14
                : 3
                : e0214291
                Affiliations
                [1 ] Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
                [2 ] Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
                Baylor College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9309-8235
                http://orcid.org/0000-0003-3490-2195
                http://orcid.org/0000-0003-2767-6505
                Article
                PONE-D-18-29859
                10.1371/journal.pone.0214291
                6435136
                30913241
                e004edee-0bfa-4145-953c-cab97a971ef9
                © 2019 Suh et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 October 2018
                : 11 March 2019
                Page count
                Figures: 3, Tables: 5, Pages: 10
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Surgical Resection
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Surgical Oncology
                Tumor Resection
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Oncology
                Surgical Oncology
                Tumor Resection
                Medicine and Health Sciences
                Oncology
                Clinical Oncology
                Surgical Oncology
                Tumor Resection
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Surgical Resection
                Tumor Resection
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Surgical Oncology
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Oncology
                Surgical Oncology
                Medicine and Health Sciences
                Oncology
                Clinical Oncology
                Surgical Oncology
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Neoplasms
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Minimally Invasive Surgery
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Lung and Intrathoracic Tumors
                Thymic Tumors
                Custom metadata
                According to the ‘Personal Information Protection Act’ of Korea, retrospective medical records research is not possible without the informed consent of the subject to use the information. For this reason, data are not available, even upon request. For clarification regarding these restrictions, please contact our Ethics Committee via irb@ 123456yuhs.ac , or 82-2-2228-0453.

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