Yongyu Liu

Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II–IIIA (N1–N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study

BACKGROUND Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II-IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with EGFR-mutant stage IB-IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II-IIIA (N1-N2) NSCLC. METHODS We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18-75 years with completely resected (R0), stage II-IIIA (N1-N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079. FINDINGS Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8-44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months [95% CI 24·9-32·5]) than with vinorelbine plus cisplatin (18·0 months [13·6-22·3]; hazard ratio [HR] 0·60, 95% CI 0·42-0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two [2%] patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 [34%] patients vs none with gefitinib), leucopenia (14 [16%] vs none), and vomiting (eight [9%] vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related. INTERPRETATION Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature. FUNDING Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of Peoples Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.

The role of postoperative radiotherapy for stage I/II/III thymic tumor—results of the ChART retrospective database

BACKGROUND Postoperative radiotherapy (PORT) for thymic tumor is still controversial. The object of the study is to evaluate the role of PORT for stage I to III thymic tumors. METHODS The Chinese Alliance for Research in Thymomas (ChART) was searched for patients with stage I to III thymic tumors who underwent surgical resection without neoajuvant therapy between 1994 and 2012. Univariate and multivariate survival analyses were performed. Cox proportional hazard model was used to determine the hazard ratio for death. RESULT From the ChART database, 1,546 stage I to III patients were identified. Among these patients, 649 (41.98%) received PORT. PORT was associated with gender, histological type (World Health Organization, WHO), thymectomy extent, resection status, Masaoka-Koga stage and adjuvant chemotherapy. The 5-year and 10-year overall survival (OS) rates and disease-free survival (DFS) rates for patients underwent surgery followed by PORT were 90% and 80%, 81% and 63%, comparing with 96% and 95%, 92% and 90% for patients underwent surgery alone (P=0.001, P<0.001) respectively. In univariate analysis, age, histological type (WHO), Masaoka-Koga stage, completeness of resection, and PORT were associated with OS. Multivariable analysis showed that histological type (WHO) (P=0.001), Masaoka-Koga stage (P=0.029) and completeness of resection (P=0.003) were independently prognostic factors of OS. In univariate analysis, gender, myasthenia gravis, histological subtype, Masaoka-Koga stage, surgical approach, PORT and completeness of resection were associated with DFS. Multivariate analysis showed that histological subtype (P<0.001), Masaoka-Koga stage (P=0.005) and completeness of resection (P=0.006) were independent prognostic factors for DFS. Subgroup analysis showed that patients with incomplete resection underwent PORT achieved better OS and DFS (P=0.010, 0.017, respectively). However, patients with complete resection underwent PORT had the worse OS and DFS (P<0.001, P<0.001, respectively). CONCLUSIONS The current retrospective study indicates that PORT after incomplete resection could improve OS and DFS for patients with stage I to III thymic tumors. However for those after complete resection, PORT does not seem to have any survival benefit on the whole.

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.

Thymectomy versus tumor resection for early-stage thymic malignancies: a Chinese Alliance for Research in Thymomas (ChART) retrospective database analysis

BACKGROUND To evaluate the surgical outcomes of tumor resection with or without total thymectomy for thymic epithelial tumors (TETs) using the Chinese Alliance for Research in Thymomas (ChART) retrospective database. METHODS Patients without preoperative therapy, who underwent surgery for early-stage (Masaoka-Koga stage I and II) tumors, were enrolled for the study. They were divided into thymectomy and thymomectomy groups according to the resection extent of the thymus. Demographic and surgical outcomes were compared between the two patients groups. RESULTS A total of 1,047 patients were enrolled, with 796 cases in the thymectomy group and 251 cases in the thymomectomy group. Improvement rate of myasthenia gravis (MG) was higher after thymectomy than after thymomectomy (91.6% vs. 50.0%, P<0.001). Ten-year overall survival was similar between the two groups (90.9% after thymectomy and 89.4% after thymomectomy, P=0.732). Overall, recurrence rate was 3.1% after thymectomy and 5.4% after thymomectomy, with no significant difference between the two groups (P=0.149). Stratified analysis revealed no significant difference in recurrence rates in Masaoka-Koga stage I tumors (3.2% vs. 1.4%, P=0.259). However in patients with Masaoka-Koga stage II tumors, recurrence was significantly less after thymectomy group than after thymomectomy (2.9% vs. 14.5%, P=0.001). CONCLUSIONS Thymectomy, instead of tumor resection alone, should still be recommended as the surgical standard for thymic malignancies, especially for stage II tumors and those with concomitant MG.

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.

Postoperative survival for patients with thymoma complicating myasthenia gravis-preliminary retrospective results of the ChART database.

BACKGROUND It is so far not clear that how myasthenia gravis (MG) affected the prognosis of thymoma patients. The aim of this assay is to compare the postoperative survival between patients with thymoma only and those with both thymoma and MG. METHODS The Chinese Alliance for Research in Thymomas (ChART) registry recruited patients with thymoma from 18 centers over the country on an intention to treat basis from 1992 to 2012. Two groups were formed according to whether the patient complicated MG. Demographic and clinical data were reviewed, patients were followed and their survival status were analyzed. RESULTS There were 1,850 patients included in this study, including 421 with and 1,429 without MG. Complete thymectomy were done in 91.2% patients in MG group and 71.0% in non-MG group (P<0.05). There were more percentage of patients with the histology of thymoma AB, B1, or B2 (P<0.05) in MG group, and more percentage of patients with MG were in Masaoka stage I and II. The 5- and 10-year overall survival (OS) rates were both higher in MG group (93% vs. 88%; 83% vs. 81%, P=0.034) respectively. The survival rate was significantly higher in patients with MG when the Masaoka staging was 3/4 (P=0.003). Among patients with advanced stage thymoma (stage 3, 4a, 4b), the constituent ratios of 3, 4a, 4b were similar between MG and non-MG group. Histologically, however, there were significantly more proportion of AB/B1/B2/B3 in the MG group while there were more C in the non-MG group (P=0.000). Univariate analyses for all patients showed that MG, WHO classification, Masaoka stage, surgical approach, chemotherapy and radiotherapy and resectability were significant factors, and multivariate analysis showed WHO classification, Masaoka stage, and resectability were strong independent prognostic indicators. CONCLUSIONS Although MG is not an independent prognostic factor, the survival of patients with thymoma was superior when MG was present, especially in late Masaoka stage patients. Possible reasons included early diagnosis of the tumor, better histologic types, an overall higher R0 resection and less recurrence.

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.

Perioperative outcomes and long-term survival in clinically early-stage thymic malignancies: video-assisted thoracoscopic thymectomy versus open approaches

BACKGROUND Video-assisted thoracoscopic surgery (VATS) theoretically offers advantages over open thymectomy for clinically early-stage (Masaoka-Koga stage I and II) thymic malignancies. However, long-term outcomes have not been well studied. We compared the postoperative outcomes and survival from a cohort study based on the database of the Chinese Alliance for Research in Thymomas (ChART). METHODS Between 1994 and 2012, data of 1,117 patients having surgery for clinically early-stage (Masaoka-Koga stage I and II) tumors were enrolled for the study. Among them, 241 cases underwent VATS thymectomy (VATS group), while 876 cases underwent open thymectomy (Open group). Univariate analyses were used to compare the clinical character and perioperative outcomes between the two groups. And multivariate analysis was performed to determine the independent predictive factors for long-term survival. RESULTS Compared with the Open group, the VATS group had higher percentage of total thymectomy (80.5% vs. 73.9%, P=0.028), resection rate (98.8% vs. 88.7%, P=0.000) and less recurrence (2.9% vs. 16.0%, P=0.000). Five-year overall survival was 92% after VATS and 92% after open thymectomy, with no significant difference between the two groups (P=0.15). However, 5-year disease free survival were 92% in VATS group and 83% in Open group (P=0.011). Cox proportional hazards model revealed that WHO classification, Masaoka-Koga stage and adjuvant therapy were independent predictive factors for overall survival, while surgical approach had no significant impact on long-term outcome. CONCLUSIONS This study suggests that VATS thymectomy is an effective approach for clinically early-stage thymic malignancies. And it may offer better perioperative outcomes, as well as equal oncological survival.

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.