Si Yu Wang

Risk of cerebral metastases for postoperative locally advanced non-small-cell lung cancer

BACKGROUND Cerebral metastases are the main determining factor in the failure of locally advanced non-small-cell lung cancer (NSCLC) management. Our study assessed the risk factors of brain metastases in patients with postoperative, locally advanced NSCLC. Implications for PCI treatment are discussed. METHODS Two hundred twenty-three patients treated with surgical resection for stage III-N2 NSCLC were retrospective analyzed to elucidate risk factors for development of brain metastases, and to establish a mathematical model. RESULTS Median survival time for this patient population was 29.5 months. Frequency of brain metastases in the entire patient population was 38.1% (85/223). Frequency of brain metastases in patients with single mediastinal lymph-node region with metastases at 1, 2, and 3 years was 5.6%, 14.0%, and 19.0%, respectively. The frequency of brain metastases in patients with multiple mediastinal lymph-node regions with metastases was 31.8%, 60.3%, 68.0%, respectively (P<0.001). The frequency of brain metastases among patients with mediastinal metastasis number less than 4, 4-6, and more than 6 was significantly different (P<0.001). There were also significant differences in brain metastases frequency between patients with complete versus incomplete resection (P=0.001), and patients with non-squmous versus squamous (P=0.029), and patients administered adjuvant chemotherapy versus none (P=0.032). CONCLUSION A mathematical model to predict brain metastases risk was developed. It can aid in selection of patients with locally advanced NSCLC for PCI in clinical trails.

A randomized phase 2 trial of erlotinib versus pemetrexed as second-line therapy in the treatment of patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma

The current study was undertaken to investigate the efficacy and safety of erlotinib versus pemetrexed as second‐line therapy for patients with advanced epidermal growth factor receptor (EGFR) wild‐type and EGFR fluorescence in situ hybridization (FISH)‐positive lung adenocarcinoma.

Meta-analysis of EGFR tyrosine kinase inhibitors compared with chemotherapy as second-line treatment in pretreated advanced non-small cell lung cancer

Background Since efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy in the treatment of patients with pretreated advanced non-small cell lung cancer (NSCLC) remain controversial, we performed a meta-analysis to compare them. Methods An internet search of several databases was performed, including PubMed, Embase, and the Cochrane database. Randomized trials that compared an EGFR-TKI with chemotherapy in the second-line setting were included. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3–4 toxicities. The PFS, OS for the EGFR mutation-positive (EGFR M+) and EGFR mutation-negative (EGFR M−) subgroups were pooled. The pooled hazard ratios (HRs) and odds ratios (ORs) with their corresponding confidence intervals (CIs) were calculated on the STATA software. Results Our meta-analysis combined 3,825 patients from 10 randomized trials. Overall, EGFR-TKIs and second-line chemotherapy have equivalent efficacy in terms of PFS (HR, 1.03; 95%CI, 0.87–1.21; P = 0.73; I2 = 78.7%, Pheterogeneity<0.001), OS (HR, 1.00; 95%CI, 0.92–1.08; P = 0.90; I2 = 0.0%, Pheterogeneity = 0.88), and ORR (OR, 1.34; 95%CI, 0.86–2.08; P = 0.20; I2 = 73.1%, Pheterogeneity<0.001). However, subgroup analysis based on EGFR mutation status showed that second-line chemotherapy significantly improved PFS (HR, 1.35; 95%CI, 1.09–1.66; P = 0.01; I2 = 55.7%, Pheterogeneity = 0.046) for EGFR M− patients, whereas OS was equal (HR, 0.96; 95%CI, 0.77–1.19; P = 0.69; I2 = 0.0%, Pheterogeneity = 0.43); EGFR-TKIs significantly improved PFS (HR, 0.28; 95%CI, 0.15–0.53; P<0.001; I2 = 4.1%, Pheterogeneity = 0.35) for EGFR M+ patients, whereas OS was equal (HR, 0.86; 95%CI, 0.44–1.68; P = 0.65; I2 = 0.0%, Pheterogeneity = 0.77). Compared with chemotherapy, EGFR-TKIs led to more grade 3–4 rash, but less fatigue/asthenia disorder, leukopenia and thrombocytopenia. Conclusions Our analysis suggests that chemotherapy in the second-line setting can prolong PFS in EGFR M− patients, whereas it has no impact on OS. EGFR-TKIs seem superior over chemotherapy as second-line therapy for EGFR M+ patients. Our findings support obtaining information on EGFR mutational status before initiation of second-line treatment.

Association Between Hormone Receptor Expression and Epidermal Growth Factor Receptor Mutation in Patients Operated on for Non-Small Cell Lung Cancer

BACKGROUND Estrogen receptor (ER) and progesterone receptor (PR) play important roles in breast cancer. Similarly, there have been several reports of ER and PR expression in lung cancers, but the results have not been consistent. The aim of this study was to investigate the association between hormone receptor expression and clinicopathologic factors and epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). METHODS We evaluated 316 resected NSCLC specimens for ER-α, PR, human epidermal growth factor receptor 2, and aromatase (n=272) expression using immunohistochemical methods. EGFR mutations were evaluated with polymerase chain reaction (PCR). RESULTS ER-α and PR were detected in 36.1% and 44.9% of all patients, respectively. The expression of ER-α was observed mostly in cytoplasm (94.7%) and the expression of PR was observed mostly in nucleus (95.8%). Aromatase was detected in the cytoplasm of 64.0% of patients. ER-α expression was significantly associated with female gender (p=0.004). The expression of PR was significantly associated with better clinicopathologic features. ER-α expression showed a positive correlation with PR (r=0.275; p<0.001) and aromatase (r=0.244; p<0.001) expression levels. EGFR mutation was independently associated with the female gender (p=0.001), negative expression of PR (p<0.001), and negative expression of aromatase (p=0.027). CONCLUSIONS The expression of ER-α and PR distinguish a subset of NSCLC that has defined clinicopathologic features. Negative expression of PR and aromatase correlate with EGFR mutation.

Epidermal Growth Factor Receptor Mutation Status and Adjuvant Chemotherapy in Resected Advanced Non–Small-Cell Lung Cancer

INTRODUCTION This study was to assess the association of epidermal growth factor receptor (EGFR) mutation status and efficacy of adjuvant chemotherapy in patients with fully resected IIIA-N2 non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Tumor samples (n = 150) from patients with IIIA-N2 NSCLC who either had or had not received paclitaxel plus carboplatin or vinorelbine plus carboplatin doublet adjuvant chemotherapy were analyzed for EGFR mutations. The association of the presence of EGFR mutations and survival was assessed. RESULTS Mutations were identified in 43 (28.7%) patients (n = 25 in the no chemotherapy [observation] arm and n = 18 in the chemotherapy arm). Patients with EGFR mutations had statistically significant improved disease-free survival (41 months [95% CI, 25.1-56.9 months] vs. 20 months [95% CI, 15.0-25.0 months]; 2P = .005) and overall survival (50 months [95% CI, 37.6-62.4 months] vs. 25 months [95% CI, 20.8-29.2 months]; 2P = .001), regardless of treatment. The patients with wild-type EGFR had greater overall survival with chemotherapy compared with no adjuvant therapy (hazard ratio [HR] 4.748 [95% CI, 2.844-7.928]; 2P < .001). In contrast, in patients with EGFR mutation in the observation group compared with the chemotherapy group had longer median disease-free survival (49 months [95% CI, 35.1-62.9 months] for the observation arm vs. 30 months [95% CI, 23.8-36.2 months] for the chemotherapy arm, 2P = .195) and overall survival (59 months [95% CI, 43.9-74.1 months] vs. 33 months [95% CI, 24.7-41.3 months]; 2P = .050). CONCLUSIONS In this exploratory study, the status of EGFR mutations was associated with different clinical outcomes in patients with resected IIIA-N2 NSCLC. Further studies are required to confirm that a patients adjuvant treatment may be customized to their EGFR mutational status.

Adjuvant carboplatin-based chemotherapy in resected stage IIIA-N2 non-small cell lung cancer

Instruction: We determined whether adjuvant vinorelbine/paclitaxel plus carboplatin prolonged overall survival among patients with completely resected stage IIIA-N2 non-small cell lung cancer (NSCLC). Methods: We randomly assigned patients with completely resected stage IIIA-N2 NSCLC to a control group or to a treatment group with vinorelbine/carboplatin or paclitaxel/carboplatin doublet adjuvant chemotherapy. The primary endpoint was overall survival; secondary endpoints were disease-free survival and the toxicity and safety of the regimen. Results: This trial was terminated before accumulation of the planned numbers for registration because of the results of bigger clinical trial. Finally, 150 patients underwent randomization to vinorelbine/paclitaxel plus carboplatin (79 patients) or observation. In the chemotherapy group, 38 patients received vinorelbine plus carboplatin and 41 patients received paclitaxel plus carboplatin. In both groups, the median age was 57 years, 73% were men, and 28% had squamous carcinoma. Chemotherapy caused neutropenia in 82% of the patients (including grade 3 and 4 neutropenia in 42%), and there were no treatment-related deaths in this trial. After a median follow-up of 29 months (range, 1–110 months), the overall survival was significantly prolonged in the chemotherapy group, when compared with the observation group (33 months [95% confidence interval {CI}, 27.4–38.6] versus 24 months [95% CI, 15.8–32.2], p = 0.037), as was disease-free survival (32 months [95% CI, 21.3–42.7] versus 20 months (95% CI, 13.1–26.9), p = 0.020). The 5-year overall survival rates were 31.1% and 19.1%, respectively. Conclusions: Although with limitations, this clinical trial showed that adjuvant vinorelbine/paclitaxel plus carboplatin has an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected stage IIIA-N2 NSCLC.

Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer

BACKGROUND Bilirubin levels have been associated with risk of several malignancies. The association between pretreatment serum bilirubin levels and survival of curatively resected non-small-cell lung cancer (NSCLC) is unclear. METHODS This analysis was performed retrospectively in a cohort of 1617 consecutive patients with bilirubin levels within the range considered normal, who received curative resection for NSCLC. The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off points. The significance of pretreatment serum total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) levels in the prognosis of patients with curatively resected NSCLC was investigated. RESULTS The cutoff points of serum TBIL, DBIL and IBIL were 9.50μmol/L, 3.45μmol/L and 6.95μmol/L, respectively. High TBIL was observed in 65.2% of entire patient population, high DBIL 50%, and high IBIL 56.8%. The high-TBIL group had significantly lengthened overall survival (OS; hazard ratio [HR], 0.73; 95% confidence interval [CI] 0.63-0.84; P<0.001), disease-free survival (DFS; HR, 0.72; 95% CI 0.64-0.82; P<0.001) and distant metastasis-free survival (DMFS; HR, 0.74; 95% CI 0.60-0.91; P=0.004). Similarly, high-DBIL and high-IBIL levels were associated with longer OS, DFS, and DMFS with significant differences. In multivariable analysis, IBIL level was identified as an independent significant prognostic factor. CONCLUSIONS Moderately elevated pretreatment bilirubin levels are associated with longer OS, DFS, and DMFS for patients with curatively resected NSCLC. IBIL is an independent prognostic factor in curative resected NSCLC.

Phase 2 trial of neoadjuvant bevacizumab plus pemetrexed and carboplatin in patients with unresectable stage III lung adenocarcinoma (GASTO 1001)

The objective of this phase 2 trial was to assess the efficacy and safety of induction bevacizumab plus chemotherapy followed by surgery in patients with unresectable stage III lung adenocarcinoma.

The feasibility of adjuvant carboplatin and docetaxel in patients with curatively resected locally advanced non-small cell lung cancer

BACKGROUND Adjuvant cisplatin-based chemotherapy benefits selected patients with stages II and III non-small cell lung cancer (NSCLC). However, carboplatin being tolerated better than cisplatin, carboplatin-based adjuvant therapy may have better chemotherapy compliance. This study aimed to investigate the feasibility and toxicity of adjuvant carboplatin and docetaxel in patients with completely resected locally advanced NSCLC. METHODS Eighty patients with completely resected locally advanced NSCLC were enrolled in this trial. Adjuvant chemotherapy was initiated between 1 and 4 weeks after surgery, and consisted of four cycles of carboplatin (AUC=5), and docetaxel (Taxotere, 75mg/m(2)) every 3 weeks, after which patients received prophylactic G-CSF supportive therapy. RESULTS Patient demographics were: Median age 55 years (range 34-73): gender ratio was 56.3% male/43.7% female: 72.5% of the patients were at stage IIIA and 27.5% were at stage IIIB. The two most common histologies were adenocarcinoma (62.5%) and squamous cell carcinoma (17.5%). Sixty-six patients (82.5%) received four cycles of therapy over a 12-week period. Fourteen patients (17.5%) did not complete therapy due to: patient refusal (n=12), severe adverse events (n=1) and bone metastases during chemotherapy (n=1). No treatment related deaths were observed and the primary adverse events were hematologic toxicity, alopecia, fatigue and gastointestinal reaction (nausea, vomiting and diarrhea). CONCLUSION Combination therapy with carboplatin and docetaxel with the use of G-CSF supportive therapy has an acceptable toxicity profile such that the majority of patients completed four cycles of therapy in 12 weeks.

Discordance of epidermal growth factor receptor mutations between primary tumors and corresponding mediastinal nodal metastases in patients operated on for stage N2 non-small cell lung cancer

The discordance of epidermal growth factor receptor (EGFR) mutations between primary lung tumors and the corresponding mediastinal nodal metastases has not yet been well elucidated. We investigate the discordance of EGFR mutations between primary tumors and the corresponding mediastinal nodal metastases, and the discordance of EGFR mutations between different mediastinal lymph node stations in patients operated on for stage N2 non‐small cell lung cancer (NSCLC). Two hundred and nineteen surgically resected primary tumors and their 553 corresponding mediastinal nodal metastases were evaluated for EGFR mutations in exon 19 or 21 by TaqMan real‐time polymerase chain reaction (PCR) analysis. EGFR mutation was detected in 26.0% (57/219) of the primary tumors and 14.8% (82/553) of the corresponding mediastinal nodal metastases. In 162 cases with EGFR wild‐type in primary tumors, none of their 402 corresponding mediastinal nodal metastases had EGFR mutation. In 57 cases with EGFR mutations in primary tumors, EGFR mutations were detected in 82 of all 151 metastatic lymph node stations (54.3%), 34 cases had EGFR mutations in mediastinal nodal metastases, and 23 cases had lost the mutations in mediastinal nodal metastases. Among the 219 cases, 196 cases had at least two metastatic lymph node stations, 9.0% (18/196) of cases with multiple metastatic nodal stations exhibited discordance in EGFR mutations between different lymph node stations. The possibility of discordance in EGFR mutations between primary tumors and corresponding mediastinal nodal metastases, and between different mediastinal lymph node stations should be considered whenever these mutations are used for the selection of patients for EGFR‐directed tyrosine kinase inhibitor therapy.