Keneng Chen

Management of Thymic Tumors - Consensus Based on the Chinese Alliance for Research in Thymomas Multi-institutional Retrospective Studies

Thymic tumors are relatively rare malignancies comparing to other solid tumors in the chest (1). Its incidence is estimated to be at 3.93 per 1,000,000, which is about 1/00 of lung cancer and 1/25 of esophageal cancer in China. And it appears to be higher than that reported from North America, which is only 2.14 per 1,000,000 according to the SEER database. However, in the SEER database, the incidence rate was much higher in Asians (3.74 per 1,000,000) than in Caucasians (1.89 per 1,000,000) and close to the data from China. This implicates that there might be some ethnical and generic difference in thymic tumors. In the meantime, both these two registrations record only ‘malignant tumors’ that are clinically advanced diseases. A large part of early stage, low grade lesions are considered ‘benign tumors’ and thus, not registered. Therefore, the actual incidence of thymic tumors is much under-estimated. With the increasing use of screening for other malignancies such as lung cancer, it can be expected that more early stage thymic tumors would be discovered.

Comparison of the Masaoka-Koga staging and the International Association for the Study of Lung Cancer/the International Thymic Malignancies Interest Group proposal for the TNM staging systems based on the Chinese Alliance for Research in Thymomas retrospective database.

BACKGROUND To compare the predictive effect of the Masaoka-Koga staging system and the International Association for the Study of Lung Cancer (IASLC)/the International Thymic Malignancies Interest Group (ITMIG) proposal for the new TNM staging on prognosis of thymic malignancies using the Chinese Alliance for Research in Thymomas (ChART) retrospective database. METHODS From 1992 to 2012, 2,370 patients in ChART database were retrospectively reviewed. Of these, 1,198 patients with complete information on TNM stage, Masaoka-Koga stage, and survival were used for analysis. Cumulative incidence of recurrence (CIR) was assessed in R0 patients. Overall survival (OS) was evaluated both in an R0 resected cohort, as well as in all patients (any R status). CIR and OS were first analyzed according to the Masaoka-Koga staging system. Then, they were compared using the new TNM staging proposal. RESULTS Based on Masaoka-Koga staging system, significant difference was detected in CIR among all stages. However, no survival difference was revealed between stage I and II, or between stage II and III. Stage IV carried the highest risk of recurrence and worst survival. According to the new TNM staging proposal, CIR in T1a was significantly lower comparing to all other T categories (P<0.05) and there is a significant difference in OS between T1a and T1b (P=0.004). T4 had the worst OS comparing to all other T categories. CIR and OS were significantly worse in N (+) than in N0 patients. Significant difference in CIR and OS was detected between M0 and M1b, but not between M0 and M1a. OS was almost always statistically different when comparison was made between stages I-IIIa and stages IIIb-IVb. However, no statistical difference could be detected among stages IIIb to IVb. CONCLUSIONS Compared with Masaoka-Koga staging, the IASLC/ITMIG TNM staging proposal not only describes the extent of tumor invasion but also provides information on lymphatic involvement and tumor dissemination. Further study using prospectively recorded information on the proposed TNM categories would be helpful to better grouping thymic tumors for predicting prognosis and guiding clinical management.

The equivalent efficacy of multiple operations for multiple primary lung cancer and a single operation for single primary lung cancer.

BACKGROUND The incidence of synchronous and metachronous multiple primary lung cancers (MPLCs) has been increasing recently. The new multidisciplinary classification of lung adenocarcinoma and TNM Classification of Lung Cancer (7(th) edition, 2009), have improved the understanding of MPLC. Most researchers recommend that surgical therapy should be actively pursued if the patients physical condition and lung function permit it and if a complete cure can be achieved. However, few studies have reported the long-term efficacy of surgical treatment for MPLC, which we explored in this study. METHODS A total of 1,290 Lung cancer patients from a prospectively maintained database, treated by a single surgeon group between January 2000 and July 2013, at Beijing Cancer Hospital, Peking University, were reviewed. We retrospectively analyzed the clinical data of 31 patients diagnosed with MPLC out of 1290 lung cancer patients, focusing on long-term survival. RESULTS MPLC patients accounted for 2.4% (31/1,290) of the patient cohort: 27 had synchronous MPLC (87.1%) and 4 had metachronous MPLC (12.9%). The 1-, 3- and 5-year postoperative survival rates were 100%, 75.8% and 75.8%. On stratification according to TNM stage, the 1-, 3- and 5-year of patients with stage I cancer (20 patients) were 100%, 77.2% and 77.2%, not statistically significant with those for the entire cohort (1,290 patients; 95.4%, 80.5% and 66.2%, P=0.455). CONCLUSIONS When the patients physical condition and tumor-related factors permit it, surgery should be the first choice of treatment for MPLC; it is associated with an equivalent efficacy to that of surgery for single primary lung cancer.

Lymph node metastases in thymic malignancies: a Chinese Alliance for Research in Thymomas retrospective database analysis

OBJECTIVES Lymphatic involvement is believed to be relatively rare in thymic epithelial tumours. The incidence and prognostic significance of nodal metastases are still unclear. The goal of this study was to define the incidence and prognostic relevance of nodal metastasis in patients with thymic epithelial tumours, using a nationwide retrospective database of the Chinese Alliance for Research in Thymomas. METHODS Patients who underwent upfront surgical resection without preoperative therapy were enrolled for the study. The International Thymic Malignancies Interest Group proposal of a new staging system for thymic epithelial tumours was used to redefine the pathological stage. The incidence of nodal metastasis and its relationship with clinicopathological characteristics and its impact on survival were examined accordingly. RESULTS A total of 1617 patients were enrolled in this study. Lymph node metastasis was identified in 35 patients (2.2%). No nodal involvement was found in type A, AB or B1 thymomas. The incidence of nodal metastasis in thymoma (B2/B3) and thymic carcinoma was 1.3% and 7.9%, respectively, and it was most commonly seen in patients with neuroendocrine thymic tumours (16.7%, P < 0.001). According to the primary tumour invasion stage, incidences of nodal metastasis were 0.2% in T1, 6.9% in T2, 8.5% in T3 and 7.4% in T4 tumours (P < 0.001). Gender, pleural or distant metastasis and resection status were also correlated with nodal metastasis (P < 0.05) in univariable analysis. Multivariable analysis revealed that patients with non-thymoma histological characteristics (P < 0.001) and tumours in non-T1 stage (P < 0.001) had significantly greater risk of developing nodal metastasis. The overall survival of patients without nodal metastasis was significantly higher than that of patients with nodal involvement (P < 0.001). Disease-free survival of patients after R0 resection without nodal metastasis was also significantly higher than those with nodal metastasis (P < 0.001). On multivariable analysis, overall survival was significantly associated with histology of the tumour (P = 0.019) and complete resection (P = 0.047), and there was a trend towards significance (P = 0.052) in the association between overall survival and nodal involvement. CONCLUSIONS Lymph node metastasis in low-grade, early stage thymic tumours is a rare phenomenon. However, it is not uncommon in tumours with a higher stage or a higher histological grade, especially in neuroendocrine thymic tumours. Nodal involvement as well as tumour invasion and histological grade may denote worse prognosis. Lymph node dissection may be warranted in selected high-risk patients.

Lymph node metastasis in thymic malignancies: A Chinese multicenter prospective observational study

Objectives To study the incidence and pattern of lymph node metastases in thymic malignancies. Methods This multicenter prospective observational trial with intentional lymph node dissection was carried out by the Chinese Alliance for Research in Thymomas (ChART). Data on patients with thymic tumors without pretreatment were collected prospectively. Results from this prospective study were then compared with those from a previously reported ChART retrospective study. Results Among 275 patients, metastasis was detected in 41 nodes (3.04%) in 15 patients (5.5%). The rate of lymph node metastasis was 2.1% (5/238) in patients with thymomas, 25% (6/24) in those with thymic carcinomas, and 50% (4/8) in those with neuroendocrine tumors (P < .001). The rate of lymph node metastasis in category T1 to T4 tumors was 2.7% (6/222) in T1, 7.7% (1/13) in T2, 18.4% (7/38) in T3, and 50% (1/2) in T4 (P < .001). Nodal involvement was significantly higher compared with the ChART retrospective study (5.5% vs 2.2%; P = .002), although the 2 groups were comparable in terms of tumor stage and histology. Metastasis was found in N1 nodes in 13 patients (86.7%) and in N2 nodes in 8 patients (53.3%); 6 patients (40%) had simultaneous N1/N2 diseases and 6 (40%) had multistation involvement. Based on World Health Organization histological classification and Union for International Cancer Control T category, patients were divided into a low‐risk group (1/192; 0.5%) with T1‐2 and type A‐B2 diseases and a high‐risk group (14/83; 16.9%) of category T3 and above or histology B3 and above tumors for nodal metastasis (P < .001). On multivariate analysis, type B3/thymic carcinoma/neuroendocrine tumors, category T3 or above, and N2 dissection predicted a greater likelihood of finding nodal metastasis. Conclusions Lymph node involvement in thymic malignancies is more common than previously recognized, especially in tumors with aggressive histology and advanced T category. Intentional lymph node dissection increases the detection of nodal involvement and improves accuracy of staging. In selected high‐risk patients, systemic dissection of both N1and N2 nodes should be considered for accurate tumor staging.

The application of postoperative chemotherapy in thymic tumors and its prognostic effect

BACKGROUND To study the role of postoperative chemotherapy and its prognostic effect in Masaoka-Koga stage III and IV thymic tumors. METHODS Between 1994 and 2012, 1,700 patients with thymic tumors who underwent surgery without neoadjuvant therapy were enrolled for the study. Among them, 665 patients in Masaoka-Koga stage III and IV were further analyzed to evaluate the clinical value of postoperative chemotherapy. The Kaplan-Meier method was used to obtain the survival curve of the patients divided into different subgroups, and the Cox regression analysis was used to make multivariate analysis on the factors affecting prognosis. A Propensity-Matched Study was used to evaluate the clinical value of chemotherapy. RESULTS Two-hundred and twenty-one patients were treated with postoperative chemotherapy, while the rest 444 cases were not. The two groups showed significant differences (P<0.05) regarding the incidence of myasthenia gravis, World Health Organization (WHO) histological subtypes, pathological staging, resection status and the use of postoperative radiotherapy. WHO type C tumors, incomplete resection, and postoperative radiotherapy were significantly related to increased recurrence and worse survival (P<0.05). Five-year and 10-year disease free survivals (DFS) and recurrence rates in patients who underwent surgery followed by postoperative chemotherapy were 51% and 30%, 46% and 68%, comparing with 73% and 58%, 26% and 40% in patients who had no adjuvant chemotherapy after surgery (P=0.001, P=0.001, respectively). In propensity-matched study, 158 pairs of patients with or without postoperative chemotherapy (316 patients in total) were selected and compared accordingly. Similar 5-year survival rates were detected between the two groups (P=0.332). CONCLUSIONS Pathologically higher grade histology, incomplete resection, and postoperative radiotherapy were found to be associated with worse outcomes in advanced stage thymic tumors. At present, there is no evidence to show that postoperative chemotherapy may help improve prognosis in patients with Masaoka-Koga stage III and IV thymic tumors.

A multi-center evaluation of a powered surgical stapler in video-assisted thoracoscopic lung resection procedures in China.

BACKGROUND Lung cancer is one of the most prevalent malignancies worldwide. The number of anatomic lung cancer resections performed via video-assisted thoracoscopic surgery (VATS) is growing rapidly. Staplers are widely used in VATS procedures, but there is limited clinical data regarding how they might affect performance and postoperative outcomes, including air leak. This clinical trial assessed the use of a powered stapler in VATS lung resection, with a primary study endpoint being occurrence and duration of air leak and prolonged air leak (PAL). METHODS Data was collected from a single arm, multi-center study in Chinese patients receiving VATS wedge resection or lobectomy. Intra-operative data included surgery duration; cartridge selection for ligation/transection of bronchus, major vessels, and lung parenchyma; staple line interventions; blood loss; and device usage. Post-operative data included air leak assessments, chest tube duration, length of hospital stay, and adverse events (AEs). RESULTS A total of 94 procedures across four institutions in China were included in the final analysis: 15 wedge resections, 74 lobectomies, and five wedge resections followed by lobectomies. Post-operative air leak occurred in five (5.3%) patients who had lobectomy procedures, with PAL in one (1.1%) patient. Sites were generally consistent relative to cartridge use by tissue type. The incidence of stapler firings requiring surgical interventions was seven out of 550 (1.3%). Surgeons participating in the study were satisfied with the articulation and overall usability of the stapler. CONCLUSIONS The powered staplers make the VATS procedure easier for the surgeons and have achieved intra- and post-operative patient outcomes comparable to those previously reported.

Chinese expert consensus on mediastinal lymph node dissection in esophagectomy for esophageal cancer (2017 edition)

Esophageal cancer is an aggressive malignancy and a major cause of cancer-related deaths globally. In 2012, about 460,000 new cases of esophageal cancer were diagnosed worldwide, with 400,000 deaths attributed to the disease (1).

Preoperative Induction Therapy for Locally Advanced Thymic Tumors: A Retrospective Analysis Using the ChART Database

BACKGROUND To evaluate the role of preoperative induction therapy on prognosis of locally advanced thymic malignancies. METHODS Between 1994 and 2012, patients received preoperative induction therapies (IT group) in the Chinese Alliance for Research in Thymomas (ChART) database, were compared with those having surgery directly after preoperative evaluation (DS group). All tumors receiving induction therapies were locally advanced (clinically stage III-IV) before treatment and those turned out to be in pathological stage I and II were considered downstaged by induction. Clinical pathological characteristics were retrospectively analyzed. To more accurately study the effect of induction therapies, stage IV patients were then excluded. Only stage I-III tumors in the IT group and stage III cases in the DS group were selected for further comparison in a subgroup analysis. RESULTS Only 68 (4%) out of 1,713 patients had induction therapies, with a R0 resection of 67.6%, 5-year recurrence of 44.9%, and 5- and 10-year overall survivals (OS) of 49.7% and 19.9%. Seventeen patients (25%) were downstaged after induction. Significantly more thymomas were downstaged than thymic carcinomas (38.7% vs. 13.9%, P=0.02). Tumors downstaged after induction had significantly higher 5-year OS than those not downstaged (93.8% vs. 35.6%, P=0.013). For the subgroup analysis when stage IV patients were excluded, 5-year OS was 85.2% in the DS group and 68.1% in the IT group (P=0.000), although R0 resection were similar (76.4% vs. 73.3%, P=0.63). However, 5-year OS in tumors downstaged after induction (93.8%) was similar to those in the DS group (85.2%, P=0.438), both significantly higher than those not downstaged after induction (35.6%, P=0.000). CONCLUSIONS Preoperative neoadjuvant therapy have been used only occasionally in locally advanced thymic malignances. Effective induction therapy leading to tumor downstaging may be beneficial for potentially unresectable diseases, especially in patients with thymomas. These findings would be helpful to related studies in the future.

The Society for Translational Medicine: the assessment and prevention of venous thromboembolism after lung cancer surgery

Cancer is an independent major risk factor for venous thromboembolism (VTE), which is the second leading cause of death in medically and surgically treated patients with cancer (1-5). The association between VTE and lung cancer has been reported more than 20 years ago (6,7).