Jianlin Xu

Prophylactic Cranial Irradiation for Patients with Surgically Resected Small Cell Lung Cancer

Introduction: Data on prophylactic cranial irradiation (PCI) after complete resection of SCLC are limited. The purpose of this study was to investigate the impact of PCI in this population. Methods: We retrospectively identified completely resected SCLC at the Shanghai Chest Hospital between January 2006 and January 2014. Results: A total of 349 patients (115 patients who received PCI [the PCI‐treated cohort] and 234 patients who did not [the non–PCI‐treated cohort]) were included in the study. The results demonstrated that the PCI‐treated cohort had longer overall survival than the non–PCI‐treated cohort among patients with pathologic stage (p‐stage) II (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.30–0.99, p = 0.047) and p‐stage III (HR = 0.54, 95% CI: 0.34–0.86, p = 0.009) disease. Among patients with p‐stage III disease, there was a significantly higher risk for cerebral recurrence from the time of diagnosis in the non–PCI‐treated cohort (p = 0.018). With regard to patients with p‐stage I disease, neither overall survival benefit (HR = 1.61, 95% CI: 0.68–3.83, p = 0.282) nor risk for cerebral recurrence (p = 0.389) was significant between the PCI‐treated and non–PCI‐treated cohorts. Conclusions: The data presented in the current study support using PCI in patients with p‐stage II/III disease but not in patients with p‐stage I disease. A relatively lower risk for brain metastases in p‐stage I patients might explain the inferior efficacy of PCI in this population.

EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: A real-world study in China

INTRODUCTION There are a number of uncommon EGFR mutations whose associations with TKIs are not well clarified. Here, we summarize the clinical data of patients with multiple uncommon EGFR mutations and their sensitivity to EGFR TKIs. METHODS Between January 2009 and September 2014, we retrospectively examined stage IIIB/IV NSCLC patients harboring uncommon mutations in EGFR at the Shanghai Chest Hospital. RESULTS A total of 123 NSCLC patients harboring uncommon EGFR mutations with treatment and survival details were included in this analysis. 95 Patients who received therapy that consisted of EGFR TKIs experienced a significantly improved overall survival (OS) compared with those who did not receive EGFR TKIs (18.96 months, 95% CI, 16.65-21.26 vs 12.22, 95% CI, 9.17-15.27, p=0.017). The median progression-free survival (PFS) for patients who harbored the L861Q, G719X, 20ins, Del-19+L858R, Del-19 or L858R+T790M, and the Del-19 or L858R+other mutations were 8.90 months (95% CI, 4.47-13.34), 5.98 months (95% CI, 1.53-10.42), 2.00 months (95% CI, 0.00-5.41), 9.53 months (95% CI, 0.00-19.41), 1.94 months (95% CI, 0.00-4.43), and 9.79 months (95% CI, 0.73-18.85), respectively. The best objective response rates (ORRs) for patients who harbored L861Q, G719X, 20ins, Del-19+L858R, Del-19 or L858R+T790M, Del-19 or L858R+others were 46.7%, 42.9%, 8.3%, 71.4%, 22.2%, and 55.6%, respectively. CONCLUSIONS These results suggest that EGFR TKI therapy is effective in patients with L861Q/G719X/Del-19+L858R/Del-19 or L858R+other mutations; less effective in patients with 20ins/Del-19 or L858R+T790M.

Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non-small-cell lung cancer patients with EGFR mutations

This study was designed to examine the prediction of pretreatment circulating bilirubin and cholesterol for overall survival in 459 advanced non‐small‐cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Circulating total bilirubin, direct bilirubin (DB), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) levels were measured at baseline. The mean age (standard deviation) of all study patients was 58.7 (10.5) years, and 42.9% of them was males. Ever smokers accounted for 27.0% and lung adenocarcinoma for 90.4%. The median follow‐up time and survival time were 29.5 and 34.9 months, respectively. Patients with higher DB had a 1.68‐fold increased risk of death compared with patients with lower DB (hazard ratio [HR] = 1.68, 95% confidence interval [CI]: 1.22–2.30, p = 0.001), while patients with higher TC were at a 63% reduced risk of death compared with patients with lower TC (HR = 0.37, 95% CI: 0.20–0.67, p = 0.001). As for HDL‐C, patients with higher levels had the risk of death reduced by 46% (HR = 0.54, 95% CI: 0.29–1.00, p = 0.049) compared with patients with lower levels. After the Bonferroni correction, only DB and TC were significantly associated with NSCLC survival. Our findings demonstrate for the first time that pretreatment DB was identified as a significant risk factor, yet TC as a protective factor, for overall survival in NSCLC patients with EGFR mutations.

Prognostic significance and adjuvant chemotherapy survival benefits of a solid or micropapillary pattern in patients with resected stage IB lung adenocarcinoma

Objective: To evaluate the prognostic significance and beneficiaries of adjuvant chemotherapy (ACT) in various histological patterns of stage IB lung adenocarcinoma according to the 8th tumor‐node‐metastasis (TNM) classification. Methods: A total of 1131 patients with pathological stage IB lung adenocarcinoma according to the 8th TNM classification who underwent lobectomy or segmentectomy were enrolled in this study. Based on the proportion of solid/micropapillary components, the patients were classified into 3 groups: solid/micropapillary‐negative (SMPN) (n = 719; median survival, 49.7 months; interquartile range [IQR]. 35.1‐67.0 months), solid/micropapillary‐minor (SMPM; >5% but not predominant) (n = 272; median survival, 38.8 months; IQR, 26.6‐51.5 months) and solid/micropapillary‐predominant (SMPP; >5% and the most dominant) (n = 140; median survival, 39.6 months; IQR, 26.8‐52.5 months). The predictors of disease‐specific survival and recurrence‐free survival were investigated. To reduce selection bias, propensity score‐matching analysis was implemented before survival data were compared. Results: Our data show significant differences in survival rates based on the proportion of solid/micropapillary patterns. The SMPM group had significantly higher cumulative incidences of lung cancer–specific death (P = .000) and recurrence (P = .000) compared with the SMPN group, so did the SMPP group when compared with SMPM patients (P = .000 for both). Multivariate analysis showed that the SMPM and SMPP patterns were poor prognostic factors for disease‐specific survival (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.12‐3.09 and HR, 4.56; 95% CI, 2.69‐7.71, respectively) and recurrence‐free survival (HR, 1.64; 95% CI, 1.20‐2.24 and HR, 2.43; 95% CI, 1.64‐3.60, respectively), as were older age, male sex, smoking history, larger tumor size, necrosis, and abnormal pulmonary function. Survival analysis stratified by histological pattern showed that patients with the SMPP pattern who received ACT had obviously lower cumulative incidences of lung cancer–specific death (HR, 0.46; 95% CI, 0.22‐0.93; P = .031) and recurrence (HR, 0.48; 95% CI, 0.26‐0.88; P = .017). Conclusions: Solid/micropapillary patterns were associated with poor prognosis, even if they were not predominant. ACT contributed to survival benefits in the SMPP subgroup of patients with stage IB lung adenocarcinoma.

Clinical outcomes of patients with metachronous second primary lung adenocarcinomas

Background The incidence of adenocarcinomas as multiple primary lung cancers (MPLCs) is increasing. How to determine the treatment strategies of MPLCs, especially second primary lung adenocarcinomas (SPLACs), and the prognostic factors associated with it are unclear. Methods The clinical records of patients undergoing surgery for second adenocarcinomas based on Martini–Melamed criteria between 2001 and 2014 were retrospectively reviewed. Survival rates were calculated by the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis was conducted using the Cox proportional hazards model. Results A total of 115 patients with SPLACs were identified based on Martini–Melamed criteria. With respect to the second resections, three subgroups with low- (adenocarcinoma in situ, n=6; minimally invasive adenocarcinoma, n=19), intermediate- (lepidic, n=9; acinar, n=40; papillary, n=23), and high-grades (solid, n=9; micropapillary, n=2; invasive mucinous, n=7) were assigned. The 5-year overall survival (OS) rates from the time of the first and the second resections were 86.5% and 69.5%, respectively. Cox multivariate analysis identified computed tomography (CT) morphology of SPLACs (ground glass opacity predominant versus solid predominant; hazard ratio [HR]=0.42; P=0.036), histologic classification (same/similar vs different; HR=0.06; P<0.001), pathologic stage of the primary (stage I vs II; HR=0.20; P=0.015) and second tumors (stage I vs IIIa; HR=0.21; P=0.002), and histologic grade of SPLACs (low- vs high-grade, HR=0.05, P=0.016; intermediate- vs high-grade, HR=0.37, P=0.027) as significantly favorable prognostic factors for OS. Conclusion In addition to pathologic stage of the initial tumors and histologic classification, pathologic stage and CT morphology of SPLACs were identified as predictors of survival. The histologic grade of SPLACs based on the new adenocarcinoma classification could provide additional prognostic information.

Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head‐to‐head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first‐line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression‐free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3–19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2–6.3) or gefitinib (11.9 months, 95% CI, 9.1–14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09–0.29, p < 0.001) and 0.48 (95% CI, 0.29–0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations.

Adjuvant chemotherapy may improve prognosis after resection of stage I lung cancer with lymphovascular invasion

Objectives This study explored the prognostic significance and adjuvant chemotherapy benefits in resected patients with stage I non–small cell lung cancer with lymphovascular invasion. Methods A total of 2633 patients who received complete resection with pathologic stage I non–small cell lung cancer in the Shanghai Chest Hospital (2008‐2012) were enrolled in the study, of whom 222 were diagnosed with lymphovascular invasion. By using the Kaplan–Meier method and Cox proportional hazard regression model, we explored the impact of lymphovascular invasion on prognosis and determined if the use of adjuvant chemotherapy is associated with improved outcomes in patients with lymphovascular invasion. A propensity score–matched analysis was implemented to reduce the selection bias. Results Patients with lymphovascular invasion had an unfavorable overall survival and recurrence‐free survival in stage I non–small cell lung cancer. Multivariate Cox analysis indicated that lymphovascular invasion was an independent poor prognostic factor for recurrence‐free survival (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.58‐2.71; P < .001) and overall survival (HR, 2.04; 95% CI, 1.45‐2.87; P < .001) in patients with stage I. After using propensity score–matched pairs, analysis of 65 pairs of patients with lymphovascular invasion indicated a beneficial recurrence‐free survival (HR, 0.33; 95% CI, 0.16‐0.67; P = .002) and overall survival (HR, 0.30; 95% CI, 0.12‐0.74; P = .009) from adjuvant chemotherapy. Conclusions Lymphovascular invasion was correlated with poor prognosis in patients with stage I non–small cell lung cancer. For such patients, adjuvant chemotherapy was associated with improved survival. Our study suggests that adjuvant chemotherapy might be an appropriate option for patients with stage I non–small cell lung cancer with lymphovascular invasion.

EGFR tyrosine kinase inhibitors versus chemotherapy as first-line therapy for non-small cell lung cancer patients with the L858R point mutation

The efficacy of EGFR tyrosine kinase inhibitors (TKIs) varies among different EGFR mutations. Here, we directly compared the efficacy of first-line TKIs to chemotherapy for non-small cell lung cancer (NSCLC) patients with the L858R mutation. The progression-free survival (PFS) for patients receiving TKIs as first-line therapy was longer than those who received chemotherapy (hazard ratio [HR]: 0.44, P < 0.001). Subgroup analyses showed that first-line TKI therapy resulted in longer PFS among non-smokers (HR: 0.41, P < 0.001), male (HR: 0.49, P = 0.002), female (HR: 0.39, P < 0.001), and patients with adenocarcinoma histology (HR: 0.41, P < 0.001). However, among patients with non-adenocarcinoma histology (HR: 1.11, P = 0.824) and those who used to smoke (HR: 0.55, P = 0.093), first-line TKI therapy failed to demonstrate statistically longer PFS compared to chemotherapy. Our results demonstrated that for patients with L858R mutation, first-line TKI therapy provided better survival benefits. However, among non-adenocarcinoma patients and those who used to smoke, the PFS in cohorts receiving first-line chemotherapy or TKI were not significantly different. The results of the current study will be helpful for decision-making in the treatment of patients with L858R mutation.

Survival prognostic factors for patients with synchronous brain oligometastatic non-small-cell lung carcinoma receiving local therapy.

Introduction Clinical evidence for patients with synchronous brain oligometastatic non-small-cell lung carcinoma is limited. We aimed to summarize the clinical data of these patients to explore the survival prognostic factors for this population. Methods From September 1995 to July 2011, patients with 1–3 synchronous brain oligometastases, who were treated with stereotactic radiosurgery (SRS) or surgical resection as the primary treatment, were identified at Shanghai Chest Hospital. Results A total of 76 patients (22 patients underwent brain surgery as primary treatment and 54 patients received SRS) were available for survival analysis. The overall survival (OS) for patients treated with SRS and brain surgery as the primary treatment were 12.6 months (95% confidence interval [CI] 10.3–14.9) and 16.4 months (95% CI 8.8–24.1), respectively (adjusted hazard ratio =0.59, 95% CI 0.33–1.07, P=0.08). Among 76 patients treated with SRS or brain surgery, 21 patients who underwent primary tumor resection did not experience a significantly improved OS (16.4 months, 95% CI 9.6–23.2), compared with those who did not undergo resection (11.9 months, 95% CI 9.7–14.0; adjusted hazard ratio =0.81, 95% CI 0.46–1.44, P=0.46). Factors associated with survival benefits included stage I–II of primary lung tumor and solitary brain metastasis. Conclusion There was no significant difference in OS for patients with synchronous brain oligometastasis receiving SRS or surgical resection. Among this population, the number of brain metastases and stage of primary lung disease were the factors associated with a survival benefit.

The EGFR tyrosine kinase inhibitors as second-line therapy for EGFR wild-type non-small-cell lung cancer: a real-world study in People's Republic of China

Introduction Clinical evidence comparing chemotherapy and tyrosine kinase inhibitors (TKIs) as second-line therapy for epidermal growth factor receptor (EGFR) wild-type non-small-cell lung cancer (NSCLC) are conflicting. Methods We retrospectively reviewed stage IV EGFR wild-type NSCLC patients who relapsed on first-line chemotherapy at the Shanghai Chest Hospital to compare the efficacy of TKIs and chemotherapy as second-line therapy among different clinical subgroups. Results The progression-free survival (PFS) and overall survival for patients receiving chemotherapy as second-line therapy for NSCLC were longer than patients who received TKIs. The hazard ratios (HRs) were 0.40 (P<0.001) and 0.50 (P<0.001), respectively. Subgroup analyses showed that second-line TKI therapy resulted in inferior PFS among smokers (HR =0.24, P<0.001), males (HR =0.33, P<0.001), females (HR =0.54, P=0.004), and patients with adenocarcinoma (HR =0.48, P<0.001) and nonadenocarcinoma histology (HR =0.20, P<0.001). Among never-smokers, the PFS in cohorts receiving second-line chemotherapy or TKIs was not significantly different (HR =0.70, P=0.08). Conclusion These results suggest that EGFR TKI therapy was inferior compared to chemotherapy in EGFR wild-type NSCLC patients who relapsed from first-line chemotherapy; however, among never-smokers, these two treatment strategies were comparable.