Alberto Antonicelli

The Impact of Thymoma Histotype on Prognosis in a Worldwide Database

Introduction: The rarity of thymomas and lack of multi-institutional studies have hampered therapeutic progress for decades. To overcome this, the members of the International Thymic Malignancy Interest Group created a worldwide retrospective database. This database was analyzed regarding the demographic and geographic distribution of thymomas and the impact of different variables on survival and recurrence. Methods: This study analyzed 4221 thymomas diagnosed between 1983 and 2012 with World Health Organization histotype information from the International Thymic Malignancy Interest Group database. Associations to survival and recurrence were studied by univariate and multivariate analyses. Results: Type B2 thymoma is the most common (28%) and type A the least common (12%) histotypes. They are significantly more frequent in Europe and the United States than Asia. Type A and AB occur at significantly higher age than other thymomas (64 and 57 years, respectively). There are no differences in gender distribution. Stage is lower in type A (90% in stages I–II) and AB than B1 to B3 thymomas (38% of type B3 in stage III). In univariate analysis, recurrence is significantly less frequent among stage I/II tumors, in type A and AB (recurrence rates, 1–2%) than B1 to B3 thymomas (2–7%). Multivariate analysis reveals an impact of age, stage, and resection status on survival and recurrence, whereas for histology there is only a significant impact on recurrence. Conclusion: New findings are (1) geographic differences such as a lower incidence of type A and B2 thymoma in Asia; and (2) impact of stage and histology, the latter partially limited to early stage disease, on recurrence.

Development of the International Thymic Malignancy Interest Group International Database: An Unprecedented Resource for the Study of a Rare Group of Tumors

Background: Our knowledge of thymic malignancies has largely been derived from small, single-institution series. Recognition of the need for broad collaboration led to the creation of the International Thymic Malignancy Interest Group (ITMIG) and the development of a large, centralized database to advance knowledge of these rare tumors. Methods: A multidisciplinary Database Committee was convened to define a common set of data elements a priori. Retrospective data were solicited from ITMIG members and collated using standardized fields. Patients with thymoma, thymic carcinoma, or thymic carcinoid were included. Results: Over a 6-month period, 47 institutions spanning 15 countries contributed a total of 6097 cases (mean, 129 [range, 10–1209]). The sex distribution was equal for thymomas, but there was a greater proportion of men with thymic carcinoma and thymic carcinoid (p < 0.0001). Nearly all cases (99%) were treated surgically. WHO type B2 was the most frequent histologic classification among thymomas, whereas squamous was the most common among thymic carcinomas. In total, 38% of patients with thymoma had myasthenia gravis compared with less than or equal to 5% for thymic carcinoma and thymic carcinoid. Median overall survival was 18.9 years (95% confidence interval [CI], 17.4–20.3) for thymoma, 6.8 years (95% CI, 5.5–7.9) for thymic carcinoma, and 7.5 years (95% CI, 6.5–8.5) for thymic carcinoid. Conclusions: The rapid creation of the ITMIG database demonstrates the feasibility of international collaboration for this rare set of malignancies and attests to the engagement of its membership. This database represents the largest collective data set ever assembled and provides an unprecedented resource for research of these tumors.

Impact of Adjuvant Treatment for Microscopic Residual Disease After Non-Small Cell Lung Cancer Surgery

BACKGROUND Incomplete resection of non-small cell lung cancer (NSCLC) portends a dramatic decline in survival. Historically, postoperative radiation and chemotherapy have been offered to treat residual disease at the surgical margins, yet the efficacy is unknown. We examined the survival among incompletely resected NSCLC patients to identify the optimal response to positive NSCLC surgical margins. METHODS The National Cancer Data Base was queried for surgically managed pathologic stage I-III NSCLC between 2003 and 2006 (n = 54,512). The prevalence, predictors, impact, and optimal treatment approaches to positive surgical margins were investigated. RESULTS A positive surgical margin was identified in 3,102 NSCLC patients (5.7% of resections), including 1,688 with microscopically positive (R1) margins (3.1%). Compared with complete resections, patients with R1 resections had a worse 5-year survival; stage pI (62% vs 37%; p < 0.0001), stage pII (41% vs 29%; p < 0.0001), and stage pIII (33% vs 19%; p < 0.0001). Postoperative administration of both chemotherapy and radiation were associated with superior survival compared with surgery alone at all stages; stage pI (44% vs 35%; p = 0.05), stage pII (33% vs 21%; p = 0.0013), and stage pIII NSCLC (30% vs 12%; p < 0.0001). Administration of chemotherapy or radiation alone was less consistently associated with improved outcome in R1 patients. Of note, radiation alone did not improve survival for stage pI patients with R1 resections (26% vs 35%; p = 0.0399). CONCLUSIONS The administration of both chemotherapy and radiation is associated with an improved survival in patients with microscopically positive surgical margins, irrespective of stage. Further study is needed to clarify the optimal stage-specific adjuvant approach to incompletely resected NSCLC.

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

Objectives: The aim of this study was to determine whether postoperative radiation therapy (PORT) is associated with an overall survival (OS) benefit in patients with completely resected Masaoka or Masaoka‐Koga stage II and III thymoma. Methods: All patients with completely resected (R0) stage II or III thymoma were identified in a large database of the International Thymic Malignancy Interest Group. Clinical, pathologic, treatment, and follow‐up information were extracted. OS was the primary end point. A univariate analysis using the log‐rank test was performed, and a multivariate Cox model was created to identify factors associated with OS. Results: Of 1263 patients meeting the selection criteria, 870 (69%) had stage II thymoma. The WHO histologic subtype was A/AB in 360 patients (30%) and B1/B2/B3 in 827 (70%). PORT was given to 55% of patients (n = 689), 15% (n = 180) received chemotherapy, and 10% (n = 122) received both. The 5‐ and 10‐year OS rates for patients having undergone an operation plus PORT were 95% and 86%, respectively, compared with 90% and 79% for patients receiving an operation alone (p = 0.002). This OS benefit remained significant when patients with stage II (p = 0.02) and stage III thymoma (p = 0.0005) were analyzed separately. On multivariate analysis, earlier stage, younger age, absence of paraneoplastic syndrome, and PORT were significantly associated with improved OS. Conclusions: We observed an OS benefit with the use of PORT in completely resected stage II and III thymoma. In the absence of a randomized trial, this represents the most comprehensive analysis of individual patient data and strong evidence in favor of PORT in this patient population.

Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry

Introduction: Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short‐term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database. Methods: The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi‐square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed. Results: A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity‐matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection. Conclusions: The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.

Comparison of surgical approach and extent of resection for Masaoka-Koga Stage I and II thymic tumours in Europe, North America and Asia: an International Thymic Malignancy Interest Group retrospective database analysis†

OBJECTIVES Surgeons at different institutions worldwide choose different types of operations for thymic tumours. It is not known whether these differences affect the outcomes of the patients. METHODS A total of 1430 patients with Masaoka-Koga pathological Stage I-II thymic tumours without myasthenia gravis or pre-treatment were identified from the International Thymic Malignancy Interest Group retrospective database. Outcomes of patients from 3 major continents (Europe, North America and Asia) were compared. RESULTS Patients from the 3 continents were comparable in gender and performance status. More European patients had more paraneoplastic syndromes; North American patients had the smallest tumour sizes and less adjuvant therapy; and Asian patients were younger and had more Stage I disease but higher grade tumours. Partial thymectomy was performed more often in Asian patients (31.7%) than in European (2.4%) and North American (5.4%; P  < 0.001) patients. The median approach (sternotomy/clamshell) was the major approach in Europe (75.3%) and North America (76.6%). In contrast, the median approach was applied significantly less frequently in Asia (45.6%, P  < 0.001); unilateral open (thoracotomy/hemi-clamshell, 23.3%) and minimally invasive approaches (video-assisted thoracoscopic surgery/robot, 31.1%) were used more often with similar rates of complete resection. The 10-year overall survival rate was 82% for Europe, 78% for North America and 90% for Asia ( P  = 0.005), respectively. The 10-year cumulative recurrence rates were similar among the geographic groups (European 0.08, North American 0.07, and Asian 0.06, P  = 0.61). Age was the only independent predictive factor for overall survival ( P  < 0.001, HR = 1.089, 95% CI 1.056-1.123) in multivariable analysis. Types B3 and thymic carcinoma ( P  = 0.003, HR = 3.932, 95% CI 1.615-9.576) were independent risk factors for increased recurrence. CONCLUSIONS This study shows that the selection of the surgical approach and the extent of resection for Stage I and II thymic tumours differ by geographic region. However, these differences seem to have little impact on outcomes.

Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database

Introduction: Thymic epithelial tumors (TETs) are associated with paraneoplastic/autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs. Methods: The International Thymic Malignancy Interest Group retrospective database was examined to determine (1) baseline and treatment characteristics associated with PN/AI syndromes and (2) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan‐Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis. Results: A total of 6670 patients with known PN/AI syndrome status from 1951 to 2012 were identified. PN/AI syndromes were associated with younger age, female sex, thymoma histologic type, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the group with a PN/AI syndrome than in the group without a PN/AI syndrome (10‐year CIR 17.3% versus 21.2%, respectively [p = 0.0003]). The OS was improved in the group with a PN/AI syndrome compared to the group without a PN/AI syndrome (median OS 21.6 years versus 17.0 years, respectively [hazard ratio = 0.63, 95% confidence interval: 0.54–0.74, p < 0.0001]). However, in the multivariate model for recurrence‐free survival and OS, PN/AI syndrome was not an independent prognostic factor. Discussion: Previously, there have been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest data set in the world for TETs, PN/AI syndromes were associated with favorable features (i.e., earlier stage and complete resection status) but were not an independent prognostic factor for patients with TETs.

What's new in thymic neoplasms.

Purpose of review The past 5 years have been marked with major developments in the field of thymic malignancies. Recent findings A lack of progress over decades has been transformed into dramatic advancements over the past 5 years through the creation of the International Thymic Malignancy Interest Group (ITMIG). ITMIG has brought together an engaged worldwide community interested in this field. An unprecedented global database has been developed and is being actively analyzed. Standard definitions have been established to allow collaboration; the histologic classification has been revised and the first formal stage classification system developed. Clinical trials and innovative research approaches are being implemented. The creation of the ITMIG infrastructure has yielded many successes and provides a solid foundation for future progress. Summary Clinicians and researchers should be aware of the knowledge, structure and tools that have been established. ITMIG provides an engaged community for collaboration and progress.