Xianghui Du

Concomitant chemoradiotherapy using pemetrexed and carboplatin for unresectable stage III non-small cell lung cancer (NSCLC): Preliminary results of a phase II study

BACKGROUND Concomitant chemoradiotherapy is the standard treatment of unresectable stage III non-small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is still controversial. We have conducted a phase II clinical trial in a Chinese population to evaluate concomitant treatment using pemetrexed/carboplatin chemotherapy and thoracic radiotherapy followed by pemetrexed/carboplatin consolidation chemotherapy in these patients. The purpose of this study is to evaluate the feasibility and activity, and also assess its impact on progression-free survival (PFS). PATIENTS AND METHODS A total of 21 patients were enrolled between January 2008 and October 2009. Patients received concomitant pemetrexed 500 mg/m(2), carboplatin area under the curve (AUC) 5 chemotherapy on day 1 repeated every 3 weeks for 2 cycles and thoracic radiotherapy, followed by pemetrexed/carboplatin for 3 cycles as consolidation therapy. Objective response rate according to the RECIST criteria was recorded and toxicity was evaluated using the NCI Common Toxicity Criteria. The Kaplan-Meier method was used to evaluate patient survival. Univariate analysis of patient characteristics and tumor responses was conducted using the Chi-square and Fishers exact test. RESULTS Five (23.8%) and 13 patients (61.9%) had a complete or partial response, respectively, while 2 patients disease remained stable and 1 patient had progression of the disease. The overall response rate (85.7%, 95% confidence interval (CI): 61-97%) exceeded the goal per study design. The median PFS was 12.0 months (95% CI: 10.6-13.4 months). The statistical analysis of predictive factors of efficacy revealed that the response rate and PFS seemed to a trend favoring adenocarcinoma histology. Main toxicity (grade 3 or greater, %): neutropenia 6 (28.5%); thrombocytopenia 4 (19%); anaemia 5 (23.8%); nausea/vomiting 1 (4.8%); anorexia 1 (4.8%), dysphagia 2 (9.5%), radiation pneumonitis 1 (4.8%) and fatigue 2 (9.5%). CONCLUSION This data suggests that concomitant treatment with pemetrexed/carboplatin at full systemic doses and thoracic radiotherapy was well tolerated, with promising activity in a Chinese population with unresectable stage III NSCLC. Better outcomes were observed in patients with adenocarcinoma in this study. Although the data presented herewith appears promising, this study is relatively small, and more data from randomized trials are needed to further validate this regimen.

Plasma fibrinogen levels are correlated with postoperative distant metastasis and prognosis in esophageal squamous cell carcinoma

This study investigated the correlation of preoperative plasma fibrinogen level with distant metastasis and prognosis in esophageal squamous cell carcinoma (ESCC). A total of 255 patients with ESCC who underwent surgery in Zhejiang cancer hospital (Hangzhou, China), between October 2006 and December 2009, were evaluated in this retrospective study. Population controls were selected from a pool of cancer-free subjects in the same region. Each patient and cancer-free people provided 3-mL pretreatment blood. Plasma fibrinogen level was measured by the Clauss method. The effects of hyperfibrinogenemia on locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), relapse-free survival (RFS), and overall survival (OS) were assessed using Kaplan-Meier analysis. Independent prognostic factors were identified in the multivariate Cox analysis. The proportion of hyperfibrinogenemia was higher in ESCC patients than those in controls (40.4% vs 13.6%). Subjects with hyperfibrinogenemia had a significantly higher risk of ESCC than those with normal plasma fibrinogen level (adjust OR = 4.61; 95% CI = 3.02–7.01, P < 0.001) after adjusted for age, sex and smoking status. The Kaplan-Meier curves showed that patients with hyperfibrinogenemia had worse DMFS, RFS and OS (P < 0.001). Tumor length, lymph node metastasis and plasma fibrinogen level were independent prognostic factors of ESCC (P < 0.05). Increased plasma fibrinogen level was significantly associated with elevated risk of ESCC. Preoperative plasma fibrinogen level was a predictor of distant metastasis and independently associated with prognosis of patients with ESCC.

Prognostic impact of postoperative radiation in patients undergoing radical esophagectomy for pathologic lymph node positive esophageal cancer

PurposeThough postoperative radiation for esophageal squamous cell carcinoma is offered in selected cases, there is conflicting evidence as to whether it improves overall survival (OS). A retrospective investigation was performed to analyze the prognostic impact of postoperative radiation therapy (PORT) in a large cohort of patients.MethodsFrom 2001 to 2009, 725 patients underwent radical esophagectomy (R0) with or without PORT were eligible for retrospective analysis. Patients were grouped into surgery alone (n = 467) and surgery plus PORT (n = 258). Median irradiation doses were 50 Gy (range: 40-56 Gy). Radiation fields encompassed the bilateral supraclavicular fossa, mediastinum, subcarinal area, and the tumor bed for the upper/middle-third disease; the bilateral supraclavicular fossa, mediastinum, the tumor bed, subcarinal area, and lower thoracic paraesophageal area for the lower-third disease. Kaplan-Meier and Cox regression analysis were used to compare OS.ResultsAfter median follow-up of 53 months, the median OS was 29 months in the PORT group and 23 months in the surgery alone group. The addition of PORT improved OS at 3 years from 36.6 to 43.6% compared with surgery alone. The use of PORT was associated with significantly improved OS (p = 0.018). For American Joint Committee on Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0), there was significant improvement in OS (p = 0.002) in the PORT group, not only for lymph-node metastatic ratio (LNMR) ≥0.25 (p = 0.001), but also for LNMR <0.25 (p = 0.043). However, for stage IIB disease (T1-2N1M0) there was no significant differences. The addition of POCT didn’t prolong the OS significantly (Surgery alone group, p = 0.079; PORT group, p = 0.111).ConclusionsThis large retrospective analysis supports the use of PORT for pathologic lymph node positive stage III esophageal squamous cell carcinoma. Given the retrospective nature of this study, the results should be confirmed by appropriately powered randomized trials. Further development of adjuvant therapy in EC is warranted.

Elevated platelet count is a strong predictor of poor prognosis in stage I non-small cell lung cancer patients

Abstract Stage I non-small cell lung cancer (NSCLC) show a highly variable biological behavior which cannot be accurately predicted by the current available prognostic markers. Platelet plays a significant role in cancer cell growth, progression and metastasis. This study aimed to investigate whether preoperative platelet count correlate with clinical prognosis in localized NSCLC. A retrospective clinical analysis was designed for a total of 234 stage I NSCLC patients in our hospital between October 2006 and December 2009. Pre-operative platelet count was measured. The association of platelet count with clinical pathological factors and patient outcome was evaluated. A significant correlation was detected between platelet count and tumor cell differentiation and T stage. Patients with elevated platelet count had an elevated risk of disease progression and death compared to patients with normal platelet count. The hazard ratio was 5.314 (95% confidence interval [CI] 2.750–10.269) for disease progression and 3.139 (95% CI 1.227–8.034) for death. The trend linking increasing platelet count with risk was also statistically significant for both the outcomes (p < 0.05). These finding demonstrate that preoperative platelet count is a useful predictor of high risk progression and poor prognosis in stage I NSCLC patients.

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer

BACKGROUND Concurrent chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) are often associated with significant incidence of toxic effects in elderly patients with esophageal cancer. This phase I trial was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S-1, an oral 5-FU derivative, when given with radiotherapy in elderly patients. METHODS Patients who were age of 70 years or older with histologically confirmed esophageal cancer, and had an Eastern Cooperative Oncology Group (ECOG) score of 0-2 were eligible for this study. Radiotherapy was administered in 1.8 Gy fractions 5 times weekly to a total dose of 54 Gy. S-1 was administered on days 1-14 and 29-42 at the following dosages: 60, 70, and 80 mg/m(2)/day. TRIAL REGISTRATION NCT01175447 (ClinicalTrials.gov). RESULTS Twelve previously untreated patients were enrolled in this study. No grade 3 or 4 toxicity was observed in six patients treated at the 60 and 70 mg/m(2) dose levels. DLT was observed in four of six patients treated at the 80 mg/m(2) dose level. Two patients developed grade 3 esophagitis, one patient developed grade 3 esophagitis and pneumonitis, and one patient developed grade 3 thrombocytopaenia. Endoscopic complete response (CR) was observed in eight patients (66.7%). The median progression free survival (PFS) was 20 months and median overall survival was 29 months. CONCLUSIONS The MTD of S-1 was 80 mg/m(2), and the recommended dose (RD) for phase II studies was 70 mg/m(2). This regimen was well tolerated and active in elderly patients with esophageal cancer, meriting further investigation in phase II studies.

Clinicopathological variables predicting HER-2 gene status in immunohistochemistry-equivocal (2+) invasive breast cancer

BACKGROUND AND OBJECTIVE Human epidermal growth factor receptor-2 (HER-2) gene status is crucial to guide treatment decisions regarding the use of HER-2-targeted therapies in breast cancer. An invasive breast cancer with HER-2 2+ score is regarded as HER-2 status equivocal and should further determine by fluorescent in situ hybridization (FISH), which is considered the standard test for HER-2 status. Here, we aimed to establish a risk score to allow for prediction of the presence of HER-2 gene status. METHODS A total of 182 HER-2 2+ by immunohistochemistry (IHC) invasive breast cancer cases were enrolled in this study. The association between clinicopathological variables like age, sex, tumor grade, hormone receptor (HR) status, P53 and proliferation index (Ki67), and FISH result using US Food and Drug Administration (FDA) criteria was evaluated. Also, we compared the HER-2 FISH results using FDA criteria and 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline. RESULTS The study population had a median age of 48 years (range, 29-78 years). Estrogen receptor (ER) was expressed in 131 (72.0%) patients. 73.1% of patients (133/182) were progesterone receptor (PR) positive. The median Ki67 value was 20% (range, 3-90%). There was good agreement between the FDA and 2013 ASCO/CAP guideline. Sixty-three of all patients were HER-2 FISH amplified (positive) based on FDA criteria. Tumors with HER-2 amplified were more likely to harbor ER negative (58.8% vs. 25.2%, P<0.001) or PR negative (57.1% vs. 26.3%, P<0.001) or P53 negative (44.8% vs. 29.8%, P=0.048). A significant high level of Ki67 was detected in HER-2 amplified groups (P=0.006). We created a risk score that comprised HR, P53 and Ki67. A significant association between risk score and HER-2 FISH amplification was observed (χ(2)=30.41, P<0.001). CONCLUSIONS This novel immunohistochemical risk score could be highly useful to predict the presence of HER-2 gene status in invasive breast cancer.

Prophylactic cranial irradiation in resected small cell lung cancer: A systematic review with meta-analysis

Background: The use of PCI in early operable patients with small cell lung cancer (SCLC) is still controversial. Therefore, we conducted a systematic review with meta-analysis to investigate the effects of PCI in resected SCLC patients. Methods: Relevant studies were identified from PubMed and EMBASE databases, the pooled hazard risks were obtained by the random-effects model. We also analyzed the brain metastasis (BM) risk in p-stage I patients without PCI. Results: Five retrospective studies were identified and a total of 1691 patients were included in our analysis, 315 of them received PCI. For all the resected patients, PCI was associated with improved overall survival (HR: 0.52, 95% CI: 0.33-0.82), and reduced brain metastasis risk (RR: 0.50, 95%CI: 0.32-0.78). However, with regard to p-stage I patients, no survival benefit was brought by PCI (HR: 0.87, 95% CI: 0.34-2.24). Moreover, the pooled analysis of 7 studies found that the 5-year brain metastasis risk was relatively low (12%, 95% CI: 8%-17%) for p-stage I patients without PCI. Conclusions: PCI might be associated with a favorable survival advantage and reduced BM risk in complete resected SCLC patients, except for p-stage I patients.

Network analysis of differentially expressed smoking‑associated mRNAs, lncRNAs and miRNAs reveals key regulators in smoking‑associated lung cancer

Lung cancer is the leading cause of cancer-associated mortality worldwide. Smoking is one of the most significant etiological contributors to lung cancer development. However, the molecular mechanisms underlying smoking-induced induction and progression of lung cancer have remained to be fully elucidated. Furthermore, long non-coding RNAs (lncRNAs) are increasingly recognized to have important roles in diverse biological processes. The present study focused on identifying differentially expressed mRNAs, lncRNAs and micro (mi)RNAs in smoking-associated lung cancer. Smoking-associated co-expression networks and protein-protein interaction (PPI) networks were constructed to identify hub lncRNAs and genes in smoking-associated lung cancer. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of differentially expressed lncRNAs were performed. A total of 314 mRNAs, 24 lncRNAs and 4 miRNAs were identified to be deregulated in smoking-associated lung cancer. PPI network analysis identified 20 hub genes in smoking-associated lung cancer, including dynein axonemal heavy chain 7, dynein cytoplasmic 2 heavy chain 1, WD repeat domain 78, collagen type III α 1 chain (COL3A1), COL1A1 and COL1A2. Furthermore, co-expression network analysis indicated that relaxin family peptide receptor 1, receptor activity modifying protein 2-antisense RNA 1, long intergenic non-protein coding RNA 312 (LINC00312) and LINC00472 were key lncRNAs in smoking-associated lung cancer. A bioinformatics analysis indicated these smoking-associated lncRNAs have a role in various processes and pathways, including cell proliferation and the cyclic guanosine monophosphate cGMP)/protein kinase cGMP-dependent 1 signaling pathway. Of note, these hub genes and lncRNAs were identified to be associated with the prognosis of lung cancer patients. In conclusion, the present study provides useful information for further exploring the diagnostic and prognostic value of the potential candidate biomarkers, as well as their utility as drug targets for smoking-associated lung cancer.

A phase II study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer

Background Concurrent chemoradiotherapy (CCRT) using conventional platinum-based doublets are often associated with significant incidence of toxic effects in elderly patients with esophageal cancer. We previously reported a phase I trial of CCRT using S-1, an oral 5-fluorouracil derivative, which yielded well safe and active outcomes. Methods Patients with histologically confirmed esophageal cancer, who were age of 70 years or older with performance status (PS) score of 0-2 or age of 66 to 69 with PS score of 2, were eligible for this Phase II trial. Radiotherapy was delivered in 1.8 Gy per fraction to a total dose of 54 Gy. Concurrently, S-1 was administered at 70 mg/m2 on days 1–14 and 29–42. The primary end point was 2-year overall survival rate. Results Thirty patients were enrolled, and 28 patients completed the full course of radiotherapy. No grade 4 toxicity or treatment-related death occurred. The grade 3 toxicities included esophagitis (16.7%), leucopoenia (13.3%), neutropenia (10%), anaemia (3.3%), pneumonitis (3.3%) and fatigue (3.3%). The median progression-free survival time and median survival time was 19 and 24 months, respectively. The 2-year overall survival rate was 45.1%, which exceeded the predefined threshold of 2-year OS 35% and met the primary end point of the study. Conclusions The results suggest that CCRT using S-1 is effective with mild toxicity in elderly patients with esophageal cancer. A phase III trial is needed to further evaluate this regimen.

Perineural invasion correlates with postoperative distant metastasis and poor overall survival in patients with PT1-3N0M0 esophageal squamous cell carcinoma.

The aim of this study was to determine the prognostic value of perineural invasion (PNI) in patients with PT1–3N0M0 esophageal squamous cell carcinoma (ESCC) who underwent curative resection. A total of 148 patients with PT1–3N0M0 ESCC, who underwent surgery in Zhejiang Cancer Hospital (Hangzhou, People’s Republic of China), between 2006 and 2009, were evaluated in this retrospective study. The effects of PNI on distant metastasis-free survival (DMFS) and overall survival (OS) were assessed using Kaplan–Meier analysis. Independent prognostic factors were identified by multivariate Cox analysis. Positive PNI was identified in 25.0% of all the cases. The depth of invasion (PT stage) was closely associated with the PNI positivity (P<0.001). The 5-year DMFS rate and OS rate of the PNI-positive patients were significantly worse than those of the PNI-negative patients (DMFS: 37.2% vs 62.3%, P=0.009; OS: 31.3% vs 74.3%, P,0.001). Multivariate analysis indicated that the positivity of PNI was an independent prognostic factor for both DMFS (hazard ratio [HR] =2.35, P=0.039) and OS (HR =3.56, P=0.002). Our results suggest that PNI was a predictor of distant metastasis and independently associated with prognosis of patients with PT1–3N0M0 ESCC.