Clinical outcome for EML4-ALK-positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy

BackgroundThe EML4-ALK fusion oncogene represents a recently identified molecular target in a subset of patients with non-small-cell lung cancer (NSCLC). Limited data have been available, however, on the outcome of first-line platinum-based chemotherapy in patients with EML4-ALK-positive advanced NSCLC who have not been treated with an ALK kinase inhibitor.Patients and methodsThe efficacy of platinum-based chemotherapy was compared between patients with advanced nonsquamous NSCLC who harbor EML4-ALK and those who harbor EGFR mutations and those with neither molecular abnormality.ResultsAmong 200 patients with advanced nonsquamous NSCLC, 18 (9.0%) were positive for EML4-ALK, 31 (15.5%) harbored EGFR mutations, and 151 (75.5%) were wild type for both abnormalities. Platinum-based combination chemotherapy showed similar efficacies in the EML4-ALK, EGFR mutation, and wild-type cohorts in terms of response rate and progression-free survival, and overall survival in the EML4-ALK cohort closely resembled that in the wild-type cohort. Within the EML4-ALK cohort, patients with variants 1 or 3 of the fusion gene were predominant and did not appear to differ in their sensitivity to the platinum-based regimens.ConclusionPatients with EML4-ALK-positive advanced NSCLC manifest an aggressive clinical course similar to that of those with wild-type tumors if the effective targeted therapy is not instituted.     

Second-line docetaxel and gemcitabine combination chemotherapy in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy

Docetaxel has been the only single active agent against chemotherapy-pretreated non-small-cell lung cancer (NSCLC). The purpose of this phase II study was to evaluate the efficacy and safety of docetaxel combined with gemcitabine, another effective drug, in patients with NSCLC previously treated with platinum-based chemotherapy. Thirty-three patients were enrolled. Prior chemotherapy was cisplatin combined with etoposide in 24 patients and vinorelbine in 9 patients. Tumors were sensitive (n=15), resistant (n=9), and refractory (n=9) to front-line chemotherapy. Treatment was docetaxel 85 mg/m² on d 1, and gemcitabine 1200 mg/m² on d 1 and 8, with cycles repeated every three weeks. Ten patients (30.3%, 95% CI: 15.6–48.7) achieved a partial response and 15 (45.5%) stable disease. Responses were similar frequencies in platinum-sensitive and platinum-resistant/refractory tumors. With a median follow-up period of 5.7 mo (range 1.6–20.0), the median and 6-mo event-free survival were 5.5 mo, 40.6%, respectively. Median and 6-mo over-all survival were 7.3 mo and 52.7%. Patients with progressive disease to chemotherapy (p=0.0008), higher LDH (p=0.005), and NSE levels (p=0.03) survived shorter than other patients. In patients refractory to prior chemotherapy, survival was poor as borderline significantly (p=0.06). The major hematological toxicity was neutropenia. Grade III–IV neutropenia was noted in 14 (42%) patients, with three episodes of febrile neutropenia in 111 cycles. Docetaxel combined with gemcitabine is an active and safe second-line therapy for patients with NSCLC.     

FANCD2 expression in advanced non-small-cell lung cancer and response to platinum-based chemotherapy

Fanconi's anemia (FA) is a genetically heterogeneous disease characterized by cancer susceptibility and hypersensitivity to cross-linking agents such as cisplatin. Recently, inactivation of the FA pathway has been proposed to contribute to genomic instability and an increased sensitivity to cisplatin-based therapy in a subset of ovarian tumors. Platinum-based chemotherapy constitutes standard systemic therapy for advanced non-small-cell lung cancer (NSCLC), but resistance to platinum chemotherapy is common. In this study, we evaluated the status of the FA pathway in tumor samples derived from patients with NSCLC in relation to their response to platinum-based chemotherapy. For this purpose, we assessed the expression of FANCD2 protein (a marker for FA pathway functioning) by immunohistochemistry in tumor specimens from 47 patients treated with platinum-based chemotherapy. FANCD2 expression could be detected in 32% of the cases (15 of 47). Expression of FANCD2 was not correlated with any patient or tumor characteristics, and FANCD2 expression was not a predictor of response to chemotherapy or patient survival. In conclusion, the activation status of the FA pathway had no value in predicting sensitivity to platinum-based chemotherapy in patients with advanced NSCLC.     

The role of docetaxel in N2 locally advanced non-small-cell lung cancer

Patients with locally advanced non-small-cell lung cancer (NSCLC) are a heterogeneous group often treated with multimodality therapy. Docetaxel has an established role in the treatment of advanced-stage NSCLC and has demonstrated promising activity in the locally advanced setting. Herein, we review the available data on the role of docetaxel in locally advanced NSCLC. The phase I/II data regarding the use of docetaxel concomitantly with radiation as a single agent or combined with platinum compounds are reviewed. In addition, we discuss the role of docetaxel induction therapy before surgery or definitive radiation therapy. Additionally, we address the role of docetaxel in consolidation therapy in patients with locally advanced NSCLC.     

铂类化疗药物治疗肺癌患者症状簇的调查研究

目的探讨采用铂类药物化疗治疗肺癌患者的症状簇情况。方法选取2017年2月至2017年7月间某三级甲等肿瘤专科医院收治的630例采用铂类药物化疗的肺癌患者,采用中文版安德森症状评估量表,对化疗第1周期和第2周期化疗症状簇进行问卷调查。结果第1周期和第2周期患者症状发生频率前3位均为疲劳、胃口差及恶心,第1周期严重程度前3位症状为睡眠不安、胃口差及呕吐,第2周期严重程度前3位症状为睡眠不安、疲劳和胃口差。第1周期、第2周期化疗的肺癌患者KMO检验和Bartlett球形检验分别为:KMO=0. 839和KMO=0. 772,Bartlett球形检验P <0. 01。患者两个化疗周期均存在3个特征值> 1的因子,分别为消化道症状簇、心理症状簇和病感症状簇。结论护理人员需根据肺癌患者症状簇的变化情况,采取有针对性的干预措施,改善症状,提高生活质量。     

Prognostic indicators in locally advanced gastric cancer (LAGC) treated with preoperative chemotherapy and D2-gastrectomy

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy is increasingly considered an effective treatment option for patients with gastric carcinoma. Aim of the study is to evaluate the prognostic significance of the pathological response and of known prognostic factors in a group of accurately staged locally advanced gastric cancer (LAGC) patients. METHODS: Thirty-three patients with LAGC, staged by laparoscopy, underwent D2-gastrectomy after preoperative chemotherapy. Survival was calculated by Kaplan-Meier method and differences were assessed by the Log-rank and Breslow test. Multivariate analysis was performed using the Cox proportional hazard model in backward stepwise regression. RESULTS: Curative resection (R0) was achieved in 81.8% of patients. A complete or subtotal pathological response was documented in 3 and 6%, respectively. Nineteen out of thirty-three (57.6%) patients were alive and 16 of them were free of relapse at last follow-up. Survival rates were 81, 67, and 59% at 12, 24, and 36 months, respectively. At univariate and multivariate analysis, only R0 resection was found to be an independent prognostic factor. CONCLUSIONS: In the current study, R0 resection is the most important prognostic factor for resectable LAGC; according to our results we feel encouraged to consider neoadjuvant chemotherapy a promising modality for increasing the R0-percentage of gastric carcinoma patients who could benefit from a curative surgery.     

Docetaxel and granulocyte colony-stimulating factor in patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapy: a multicenter phase II trial

Purpose: To investigate the activity of docetaxel and granulocyte colony-stimulating factor support (G-CSF) in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with cisplatin. Patients and methods: A total of 60 patients with locoregional and metastatic NSCLC who had relapsed or progressed after first-line treatment with cisplatin-based regimens were enrolled into the trial. Docetaxel at 100 mg/m² was given as a 1-h infusion with G-CSF (rhG-CSF given s.c. at 150 μg/m²) support from day 2 to day 8 every 3 weeks; all patients received premedication with corticosteroids. Results: In all, 1 (1.6%) and 14 (23.3%) patients achieved a complete response (CR) and a partial response (PR), respectively, for an overall response rate of 25% (95% CI 14.0–35.9%); stable disease (SD) and progressive disease (PD) were documented in 18 (30%) and 27 (45%) patients, respectively. The median duration of response was 20 weeks and the median time to tumor progression was 28 weeks. The median overall survival was 32 weeks and the 1-year survival rate was 23%. A total of 263 courses were given at a median of 3 cycles/patient. Grade 3 and 4 neutropenia occurred in 11 (18%) and 14 (23%) patients, respectively, with 18 (30%) patients requiring hospitalization for neutropenic fever; 1 patient died of sepsis. Grade 2 peripheral neuropathy occurred in 9 patients (15%) and grade 3 asthenia, in 4 (7%). Other toxicities were mild. Conclusions: Docetaxel has considerable single-agent activity in patients with NSCLC who have relapsed or progressed after first-line chemotherapy with cisplatin-based regimens. Received: 17 June 1998 / Accepted: 17 August 1998     

Prophylactic cranial irradiation for patients with locally advanced non-small-cell lung cancer

Over the past decade, studies have shown improved survival in patients with locally advanced non-small-cell lung cancer. This can be attributed to better systemic therapy, growing experience with combined-modality therapy, technologic advances allowing for increased radiation doses, better supportive care, and better patient selection. With longer survival, we are seeing an increase in the incidence of central nervous system (CNS) metastases. Prophylactic cranial irradiation (PCI) decreases the incidence of CNS metastases in these patients and may have a favorable impact on quality of life and overall survival. This paper reviews the incidence of CNS metastases in non-small-cell lung cancer patients, past experience with PCI, and a current study evaluating the impact of PCI on survival, neuropsychological function, and quality of life.     

Comparison of outcomes for patients with unresectable, locally advanced non-small-cell lung cancer treated with induction chemotherapy followed by concurrent chemoradiation vs. concurrent chemoradiation alone

PURPOSE: To retrospectively compare outcomes for patients with unresectable locally advanced non-small-cell lung cancer (NSCLC) treated at our institution with concurrent chemoradiation with or without induction chemotherapy. METHODS AND MATERIALS: We retrospectively analyzed 265 consecutive patients who received definitive treatment with three-dimensional conformal radiation and concurrent chemotherapy. Of these, 127 patients received induction chemotherapy before concurrent chemoradiation. RESULTS: The two groups of patients (with induction vs. without induction chemotherapy) were similar in age, performance status, weight loss, histology, grade, and stage. Patients who received induction chemotherapy had better overall survival (median, 1.9 vs. 1.4 years; 5-year rate, 25% vs. 12%; p < 0.001) and distant metastasis-free survival (5-year rate, 42% vs. 23%; p = 0.021). Locoregional control was not significantly different between the two groups. Multivariate analysis showed that induction chemotherapy was the most significant factor affecting overall survival, with a hazard ratio of 0.55 (95% confidence interval 0.40-0.75; p < 0.001). A planned subgroup analysis showed that induction chemotherapy was associated with a significant overall survival benefit for patients with adenocarcinoma or large-cell carcinoma (5-year rate, 24% vs. 8%; p = 0.003) but not for those with squamous cell carcinoma. A multivariate analysis of patients with adenocarcinoma or large-cell carcinoma confirmed that induction chemotherapy was the most significant factor associated with better overall survival, with a hazard ratio of 0.47 (95% confidence interval, 0.28-0.78; p = 0.003). CONCLUSION: Our retrospective analysis suggests that in combination with concurrent chemoradiation, induction chemotherapy may provide a small but significant survival benefit for patients with unresectable locally advanced adenocarcinoma or large-cell carcinoma of the lung.     

Gemcitabine in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: a phase II California cancer consortium trial

A phase II trial was designed to evaluate the efficacy and toxicity of gemcitabine in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-containing regimens and prospectively categorized for platinum response status. Treatment consisted of gemcitabine 1000 mg/m2 given intravenously on days 1 and 8 of a 21-day cycle. The status of p53 in pretreatment tumor tissue was assessed by immunohistochemistry (IHC). Sixty-one patients who progressed or recurred following platinum-based therapy were enrolled, 26 platinum-sensitive and 35 platinum-refractory. A median of 4 treatment courses (range, 2-7 courses) was delivered. Of the 55 patients assessable for response, there was 1 confirmed complete response and 3 with a confirmed partial response for an overall response proportion of 7%. Twenty-one patients had stable disease while 28 progressed and 2 patients had an unconfirmed partial response. Three of the responders (2 confirmed, 1 unconfirmed) were platinum-refractory. Median progression-free survival (PFS) and overall survival for all patients were 4.1 months and 8.6 months, respectively. Median PFS and overall survival for the platinum-sensitive and platinum-refractory cohorts were 5.4 months versus 3.1 months, and 11.9 months versus 7.1 months, respectively. Toxicity was principally hematologic with grade 3/4 neutropenia in 21% and grade 4 platelets in 8%. There were no treatment-related deaths. Twenty-four of 33 patients (73%) had p53-positive tumors. Although no significant association between platinum sensitivity and p53 status was seen, patients with platinum-sensitive disease and negative p53 by IHC had a trend toward longer survival compared to those with platinum-refractory disease and/or p53 positivity (P = 0.06). We concluded that salvage gemcitabine in this dose and schedule is safe and tolerable in previously platinum-treated patients with NSCLC.     

肺纵隔淋巴结转移的临床预测

目的：探讨肺癌临床病理生理特征与纵隔淋巴结转移的相关性。方法：对378例行肺切除加纵隔淋巴结廓清术后的肺癌患者进行回顾性研究,应用Logistic回归分析判定预测有意义的相关性因素,应用X^2检测判定不同危险因素组间纵隔淋巴结转移发生率的判别。结果全部378例患者中,纵隔淋巴结转移105列,转移率为27．8％,多因素分析显示,腺癌、CT扫描阳性（纵隔淋巴结增大）和病理分别为T3是纵隔淋巴结转移有意义的预测指标（P＜0．001）。316例胸部CT扫描阴性患者中,纵隔淋巴结转移为23．4％（74／316）。多因素分析显示,腺癌、病理分期为T2和3腺癌患者的纵隔淋巴结转移发生率为33％,显著高于鳞癌的15．3％（P＜0．01）。结论对CT扫描阳性、腺癌及病理分期为T3的患者应该考虑有纵隔淋巴结转移可能性。对CT扫描阴性的临床分期T2和T3腺癌患者亦应高度怀疑纵隔淋巴结转移存在的可能性。     

Survival rates and tolerability of platinum-based chemotherapy regimens for elderly patients with non-small-cell lung cancer (NSCLC)

BACKGROUND: The combination therapy for non-small-cell lung cancer (NSCLC) with platinum-based treatment is well known, but its utility in elderly has not been explored systematically. AIM: To examine whether aging compromises survival or exacerbates toxicity in patients with advanced lung cancer receiving platinum-based treatment. METHODS: We performed a nested case-control study in a cohort of chemotherapy na?ve patients enrolled January 1998-December 2003. Cases were consecutive patients over 70 at diagnosis with stage III or IV NSCLC. Controls were a subset of patients under 70 years matched by stage and year in which they had been treated. All patients received Cisplatin (80 mg/m2) or Carboplatin (4-6 AUC), every 4 weeks, followed by Vinorelbine (30 mg/m2) for a maximum of six courses. The medical history, physical examination and tumor imaging evaluation were performed at baseline and then monthly. Survival was calculated by Kaplan-Meier method and log-rank test was used for survival comparisons. Chi-squared test was used to compare side effects in the two groups. RESULTS: A total of 419 patients were identified for the case-control study (205 elderly/214 young) with 3.6 cycles per patient, on average. The 2- and 3-year survival rates were 20.5% and 6.8% for elderly patients and 9.8% and 2.3% for younger patients (p=0.017 and 0.014, respectively for 2 and 3 years). The proportion of patients with adverse effects, either grade 3 or 4, was the same in both groups at 2 years (43.9% versus 43.9%; p=0.99). CONCLUSIONS: Although elderly patients may self-select or be selected to be healthier, our findings suggest that elderly patients currently undergoing chemotherapy for lung cancer do as well or better than younger patients. Elderly age alone should not preclude patients from receiving platinum-based chemotherapy, since it seems well tolerated and effective in non-small-cell lung cancer among elderly patients.     

Assessment of XPD Lys751Gln and XRCC1 T-77C polymorphisms in advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy

Polymorphisms in DNA repair genes were thought to represent important determinants of platinum drug efficacy. This study tested whether XPD Lys751Gln and XRCC1 T-77C polymorphisms were associated with survival in platinum-treated patients with advanced non-small-cell lung cancer (NSCLC). In this study, 199 advanced NSCLC patients with platinum-based chemotherapy were recruited. During the median 26.5 months of follow-up, patients with the XPD 751Lys/Lys genotype had a median survival time of 17.0 months (95% CI, 14.5-19.6 months), not much longer than those carried Lys/Gln heterozygote (12.0 months; 95% CI, 3.4-20.6 months; log-rank test, P = 0.542). In Cox proportional hazards model, no significant associations were found between XPD Lys751Gln polymorphism and survival. For XRCC1 T-77C polymorphism, the median survival of patients with TC + CC genotype (18 months; 95% CI, 13.5-22.5 months) was similar to those with the TT genotype (16.0 months; 95% CI, 13.3-18.7 months; log-rank test, P = 0.399). XRCC1 T-77C polymorphism was not associated with survival in Cox proportional hazards model. Additionally, the analysis for combination of these two polymorphisms also showed no prognostic significance for NSCLC. Our findings indicated that neither XPD Lys751Gln nor XRCC1 T-77C could be genetic determinant for prognosis of advanced NSCLC patients treated with platinum-based chemotherapy.     

The predictive value of 53BP1 and BRCA1 mRNA expression in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy

Platinum-based chemotherapy is the standard first-line treatment for non-oncogene-addicted non-small cell lung cancers (NSCLCs) and the analysis of multiple DNA repair genes could improve current models for predicting chemosensitivity. We investigated the potential predictive role of components of the 53BP1 pathway in conjunction with BRCA1. The mRNA expression of BRCA1, MDC1, CASPASE3, UBC13, RNF8, 53BP1, PIAS4, UBC9 and MMSET was analyzed by real-time PCR in 115 advanced NSCLC patients treated with first-line platinum-based chemotherapy. Patients expressing low levels of both BRCA1 and 53BP1 obtained a median progression-free survival of 10.3 months and overall survival of 19.3 months, while among those with low BRCA1 and high 53BP1 progression-free survival was 5.9 months (P <0.0001) and overall survival was 8.2 months (P=0.001). The expression of 53BP1 refines BRCA1-based predictive modeling to identify patients most likely to benefit from platinum-based chemotherapy.     

Clinical significance of (18)F-FDG uptake by N2 lymph nodes in patients with resected stage IIIA N2 non-small-cell lung cancer: a retrospective study

This study evaluated the potential role of (18)F-fluoro-2-deoxy-glucose (FDG) uptake by primary tumors and N2 nodes on positron emission tomography (PET) in patients with stage IIIA N2 non-small-cell lung cancer (NSCLC). We retrospectively analyzed PET scans of 57 NSCLC patients who received surgical resection and proved pathologically to have stage IIIA N2 disease between January 2000 and April 2005. On each patient's PET scan, FDG uptake by the primary tumor and N2 nodes was evaluated using the maximum standardized uptake value (SUV). The SUV of the primary tumor (SUVt) and the highest value of the N2 nodes (SUVn) in each patient were treated as continuous variables for initial analysis. The SUVn and T stage (T1-2 vs. T3) were significant prognostic factors in univariate analysis (P=0.004 and 0.017, respectively), but the SUVt was not. Adjusted for the size of the N2 node (1cm), SUVt, and T stage (T1-2 vs. T3), the SUVn was associated with survival (P=0.019). Patients were divided into those with a low and high SUVn using a cutoff value. Controlling for the size of N2 nodes and T stages, patients with a low SUVn showed a tendency for prolonged survival (P=0.053). These results suggest that FDG uptake by the N2 node may predict survival of patients with stage IIIA N2 NSCLC.