Survival Rate Of Non-small Cell Lung Cancer Patients Research Articles

Autophagy facilitates the EGFR-TKI acquired resistance of non-small-cell lung cancer cells

Lung cancer is the leading cause of cancer-related mortality worldwide, with approximately 1.6 million new cases and 1.4 million deaths each year. Non-small-cell lung cancer (NSCLC) accounts for nearly 85% of all cases of lung cancer. Once diagnosed, the 5-year survival rate of NSCLC patients hardly reaches 15% despite many different treatments including surgery, radiotherapy, and chemotherapy being widely used. However, the therapeutic effect of chemotherapy is still not satisfactory in patients with advanced NSCLC and the response rate is only 20e35% with a median survival of 10e12 months. Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumors including NSCLC, and the overexpression of EGFR can affect the pathogenesis of cancer, such as cell proliferation, invasion, and metastasis. Activated EGFR can recruit a number of downstream signaling molecules such as phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) and Ras-Raf-MAPK-ERK kinase (MEK). Thus, EGFR has been the focus of molecular-targeted therapies. Drugs that inhibit the tyrosine kinase activity of EGFR, such as the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, have been developed for the treatment of NSCLC. Although both

Expression and significance of Snail and Claudin-3 in non-small cell lung cancer

背景与目的上皮-间质转化（epithelial mesenchymal transition, EMT）是肿瘤浸润和转移的关键步骤，上皮细胞极性丧失是其主要标志，表现为Claudin等上皮标记丢失。锌指转录因子Snail是调控EMT的重要转录因子，近年来对肿瘤侵袭转移机制研究发现Snail能提高多种肿瘤的侵袭能力。本研究旨在利用组织芯片技术探讨转录因子Snail和紧密连接蛋白（Claudin-3）在非小细胞肺癌（non-small cell lung cancer, NSCLC）及其淋巴结转移灶中的表达和意义。方法分别采用免疫组织化学MaxVision法和EnVision法检测59例癌旁正常肺组织、302例NSCLC原发灶以及57例淋巴结转移灶中Snail和Claudin-3的表达。结果Snail在癌旁正常肺组织、NSCLC原发灶以及淋巴结转移灶中的表达逐渐增强，差异具有统计学意义（P < 0.05）；Claudin-3在癌旁正常肺组织、NSCLC原发灶以及淋巴结转移灶中的表达逐渐减弱，差异具有统计学意义（P < 0.05）。在NSCLC原发灶中，Snail和Claudin-3的表达与肿瘤组织学类型有关（P < 0.05）。Spearman等级相关分析显示Snail与Claudin-3的表达呈负相关（r=-0.178, P=0.002)。Kaplan-Meier生存分析显示肿瘤大小、组织学类型、病理分级、有无癌转移、TNM分期、Snail的表达以及Snail与Claudin-3的差异性表达影响NSCLC患者的术后生存时间（P < 0.05）。Cox回归分析提示肿瘤大小、组织学类型、病理分级、有无癌转移和TNM分期是影响NSCLC患者预后的独立危险因素（P < 0.05）。结论Snail和Claudin-3在NSCLC的浸润、转移中具有重要意义，有助于对NSCLC患者预后的评价。

Prognostic impact of Raf‐1 and p‐Raf‐1 expressions for poor survival rate in non‐small cell lung cancer

Overexpression of Raf-1 has commonly been observed in solid tumors including non-small cell lung cancer (NSCLC). The objective of this study was to investigate whether overexpression of Raf-1, phosphorylated-Raf-1 (p-Raf-1) or both correlates with poor survival rate in NSCLC patients and to explore associations between expression of these proteins and NSCLC cell fate both in vitro and in vivo. Expression of Raf-1 and p-Raf-1 were detected by immunohistochemistry in tumor specimens from 152 NSCLC patients and associations between their expression and the clinicopathological characteristics were assessed. Five-year median survival rate of patients were analyzed by Kaplan-Meier method, log-rank test and Cox regression. Cell fate was compared between normal tumor cells and those with Raf-1 silencing, in both the adenocarcinoma cell line A549 and xenografted mice that were infected with the A549 cell line. The incidence of overexpression of both Raf-1 and p-Raf-1 in NSCLC was much higher than normal control (P < 0.05), and the survival rate of patients with positive expression of Raf-1, p-Raf-1 or both was found to be significantly lower than the negative group (P < 0.05). Both univariate and multivariate analyses showed Raf-1 (P = 0.000, P = 0.010), p-Raf-1 (P = 0.004, P = 0.046), or both (P = 0.001, P = 0.016) was good prognostic markers for poor survival rate in NSCLC patients. Suppression of Raf-1 inhibited tumorigenesis by inducing apoptosis both in vitro and in vivo. These findings demonstrate that overexpression of Raf-1, p-Raf-1 or both could be considered as a new independent prognostic biomarker for poor survival rates for NSCLC patients.

MicroRNAs as tumor inhibitors, oncogenes, biomarkers for drug efficacy and outcome predictors in lung cancer (Review)

Lung cancer remains the leading cause of cancer-related death worldwide for both men and women, and non-small cell lung cancer (NSCLC) accounts for approximately 80% of all cases. Despite improvements in early diagnosis and newly developed therapies, the 5-year survival rate for NSCLC patients remains low (15%). Therapy in NSCLC has reached a plateau. Understanding genomic medicine may provide insight into the oncogenesis of lung cancer and open the door to molecular diagnosis, new biomarkers and a more accurate prognosis of lung cancer. It is well known that almost half of the genes regulated by microRNAs (miRNAs) are located in cancer-associated genomic regions. In the present study, we discuss the potential of miRNAs to function as suppressors and biomarkers for chemoresistance and prognosis of lung cancer.

Recursive partitioning analysis classification and graded prognostic assessment for non-small cell lung cancer patients with brain metastasis: A retrospective cohort study

To assess prognostic factors and validate the effectiveness of recursive partitioning analysis (RPA) classes and graded prognostic assessment (GPA) in 290 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). From Jan 2008 to Dec 2009, the clinical data of 290 NSCLC cases with BM treated with multiple modalities including brain irradiation, systemic chemotherapy and tyrosine kinase inhibitors (TKIs) in two institutes were analyzed. Survival was estimated by Kaplan-Meier method. The differences of survival rates in subgroups were assayed using log-rank test. Multivariate Cox's regression method was used to analyze the impact of prognostic factors on survival. Two prognostic indexes models (RPA and GPA) were validated respectively. All patients were followed up for 1-44 months, the median survival time after brain irradiation and its corresponding 95% confidence interval (95% CI) was 14 (12.3-15.8) months. 1-, 2- and 3-year survival rates in the whole group were 56.0%, 28.3%, and 12.0%, respectively. The survival curves of subgroups, stratified by both RPA and GPA, were significantly different (P<0.001). In the multivariate analysis as RPA and GPA entered Cox's regression model, Karnofsky performance status (KPS) ≥ 70, adenocarcinoma subtype, longer administration of TKIs remained their prognostic significance, RPA classes and GPA also appeared in the prognostic model. KPS ≥70, adenocarcinoma subtype, longer treatment of molecular targeted drug, and RPA classes and GPA are the independent prognostic factors affecting the survival rates of NSCLC patients with BM.

Prognostic significance of serum miRNA‐21 expression in human non‐small cell lung cancer

Deregulation of microRNAs (miRNAs) plays important roles in tumor progression. The aim of this study was to investigate miR-21 expression in serum of non-small cell lung cancer (NSCLC) and its correlation with prognosis of NSCLC patients. Dysregulated miRNAs in NSCLC serum were identified by microarray. MiR-21 expression in NSCLC and control serum was detected by TaqMan RT-PCR assay. The correlation of serum miR-21 with clinicopathological factors of NSCLC patients was analyzed. Furthermore, the prognostic significance of serum miR-21 was analyzed by using Kaplan-Meier curves with log-rank tests and a Cox proportional hazard model. The level of miR-21 expression was higher in NSCLC serum samples than in control serum samples (P < 0.01). High serum miR-21 was significantly correlated with tumor-node metastases stage and lymph node metastasis of NSCLC patients (P = 0.016 and 0.026, respectively). The 3-year actuarial overall survival rates in NSCLC patients with high serum miR-21 expression (39.8%) was significantly shorter than those with low serum miR-21 expression (58.2%; P < 0.001). Furthermore, univariate and multivariate analyses for overall survival showed that serum miR-21 expression was an independent prognostic factor for NSCLC patients (P = 0.015, RR = 2.01, 95% CI: 1.78-3.26). Serum miR-21 expression might be useful as a prognostic marker for NSCLC patients.

Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines

Non-small-cell lung cancer (NSCLC) is the most deadly type of cancer in the United States and worldwide. Although new therapy is available, the survival rate of NSCLC patients remains low. One hallmark of cancer cells is defects in the apoptotic cell death program. In this study, we investigate the role of B-cell lymphoma 2 (Bcl-2) family members Bcl-2, Bcl-x(L) and Mcl-1, known to regulate cell survival and death, in a panel of fourteen NSCLC cell lines. NSCLC cell lines express high levels of Mcl-1 and Bcl-x(L), but not Bcl-2. Silencing the expression of Mcl-1 with small interfering RNA (siRNA) oligonucleotides potently killed a subgroup of NSCLC cell lines. In contrast, Bcl-x(L) siRNA had no effect in these lines unless Mcl-1 siRNA was also introduced. Interestingly, high MCL1 to BCL-xl messenger RNA determines whether the cells depend on Mcl-1 for survival. We further investigated the role of Mcl-1 in NSCLC cells using a Mcl-1-dependent cell line, H23. The expression of a complementary DNA containing only the coding region of MCL1 rescued H23 cells from the toxicity of a 3' untranslated region (UTR) targeting Mcl-1 siRNA but not a siRNA targeting the coding region of MCL1. Furthermore, we show that Mcl-1 sequesters the BH3-only protein Noxa and Bim and the apoptotic effector Bak. Not surprisingly, Noxa, Bim, or Bak knockdown partially rescued H23 cells from toxicity mediated by Mcl-1 siRNA to different degrees. Collectively, our results indicate that targeting Mcl-1 may improve therapy for a subset of NSCLC patients.

P53R2 expression as a prognostic biomarker in early stage non-small cell lung cancer

p53R2 is a small subunit of ribonucleotide reductase (RR) which has 80% homology to hRRM2 and metastasis-suppressing potential. Previous reports suggested that the expression of p53R2 is used as a prognostic factor and chemotherapy response indicator in several types of cancer. This study aimed to elucidate the association of p53R2 expression and the clinicopathological characteristics of early stage non-small cell lung cancer (NSCLC). Immunohistochemistry was conducted on a tissue array including 92 early stage NSCLC samples. Correlations between p53R2 and clinicopathological factors, recurrence/metastasis and outcomes were analyzed. The analyses showed that there was no correlation between p53R2 expression and the clinicopathological factors. Among disease-free patients during follow-up, patients with p53R2(+) had a better outcome than those with p53R2(-) (P=0.022). By using Cox multivariate regression analysis, p53R2 (risk factor 3.801; 95% CI 1.004-9.454; P=0.044) served as a prognostic biomarker in the prediction of the survival rate for NSCLC patients. Detection of the RR subunit p53R2 may therefore be a useful prognostic marker in early stage NSCLC.

Surgical Results of Metastatic Spinal Cord Compression Secondary to Non-Small Cell Lung Cancer

The results for 37 surgical interventions in 31 consecutive patients with non-small cell lung cancer (NSCLC) with symptomatic spinal cord compression were reviewed retrospectively. To evaluate postoperative outcomes and survival rates of NSCLC patients surgically treated for symptomatic spinal metastasis. For patients with spinal cord compression secondary to lung cancer, the prognosis is usually poor. However, with the development of new chemotherapeutic drugs and targeted therapeutic agents, the survival rate may be better. From November 2000 to March 2005, 31 patients with symptomatic metastatic spinal cord compression secondary to NSCLC underwent palliative surgery using a posterolateral transpedicular approach (PTA) or combined posterior and anterior procedures. The indication for surgery was neurologic progression due to spinal cord compression. The patients ranged in age from 20 to 81 years (mean, 61.4 years). Twenty-eight patients (90%) underwent PTA, and 3 patients had combined posterior and anterior procedures. Neurologic improvement by at least one Frankel grade was noted in 25 of 31 cases (80%). Overall, 74% of patients (23 of 31) were able to walk after surgery. There was no case of intraoperative mortality, but two deaths occurred in the postoperative period. Median survival time was 8.8 months. Even though lung cancer is considered an aggressive tumor, it is justifiable to aggressively treat patients with symptomatic spinal cord compression. Surgery by PTA can lead to good results in these patients.

Patterns of metastasis, response to treatment and survival in young patients with advanced non small cell lung cancer (NSCLC)

7343 Background: We analysed our cancer registry to determine the clinicopathologic characteristics, response to treatment and survival rates of NSCLC patients under 50 years of age at diagnosis. Methods:From 1997 to 2003 in our oncological centre we treated 47 patients under 50 years of age at diagnosis. Pts characteristics: male/female, 29/18; 9 pts were <40 years old; stage IIIA, IIIB, IV in 7/5/35; histological type: adenocarcinoma 18 pts (38%), NSCLC not specified 19 (40%). Radical treatment were applied only to 7 patients: chemoradiotherapy in 4 and chemosurgery in 3 pts. In pts with stage IV disease 46% had brain mts at the diagnosis, 34% bone mts, 29% liver mts, 23% adrenal mts and 50% presented multiple mts sites at diagnosis. In three pts the diagnosis was an incidental finding, the symptoms-diagnosis delay was < 1 month in 17 patients, 1–3 months in 9 pts and > 4 months in 18 pts. All patients were treated with first line chemotherapy: at the beginning of treatment ECOG-PS was 0/1/2 in 8/35/4; platinum-based doublets were administered in 90% of the patients. Results: in 40 pts evaluable for response we obtained 1 RC and 15 RP with ORR 40%; SD and PD were observed in 23% and 37%, respectively; (ORR intention-to-treat analysis 34%). Five pts progressed with brain metastasis and 2 with leptomeningeal carcinomatosis (49% of pts presented brain involvement during the clinical course). Median time to progression and survival were 2.8 and 10 months, respectively. Second-line chemotherapy was administered to 23 pts (49%): 14 pts were treated with taxanes. Fifteen pts were evaluable for response after second-line CT: we observed 3 PR (20%), 1 SD and 11 PD. Conclusions: Patients younger than 50 years with advanced/metastatic disease present data of response to chemotherapy, time to progression and survival comparable to older patients. In these patients brain and bone involvement was more frequent than expected. No significant financial relationships to disclose.

Patterns of metastasis, response to treatment and survival in young patients with advanced non small cell lung cancer (NSCLC)

7343 Background: We analysed our cancer registry to determine the clinicopathologic characteristics, response to treatment and survival rates of NSCLC patients under 50 years of age at diagnosis. Methods:From 1997 to 2003 in our oncological centre we treated 47 patients under 50 years of age at diagnosis. Pts characteristics: male/female, 29/18; 9 pts were <40 years old; stage IIIA, IIIB, IV in 7/5/35; histological type: adenocarcinoma 18 pts (38%), NSCLC not specified 19 (40%). Radical treatment were applied only to 7 patients: chemoradiotherapy in 4 and chemosurgery in 3 pts. In pts with stage IV disease 46% had brain mts at the diagnosis, 34% bone mts, 29% liver mts, 23% adrenal mts and 50% presented multiple mts sites at diagnosis. In three pts the diagnosis was an incidental finding, the symptoms-diagnosis delay was < 1 month in 17 patients, 1–3 months in 9 pts and > 4 months in 18 pts. All patients were treated with first line chemotherapy: at the beginning of treatment ECOG-PS was 0/1/2 in 8/35/4; platinum-based doublets were administered in 90% of the patients. Results: in 40 pts evaluable for response we obtained 1 RC and 15 RP with ORR 40%; SD and PD were observed in 23% and 37%, respectively; (ORR intention-to-treat analysis 34%). Five pts progressed with brain metastasis and 2 with leptomeningeal carcinomatosis (49% of pts presented brain involvement during the clinical course). Median time to progression and survival were 2.8 and 10 months, respectively. Second-line chemotherapy was administered to 23 pts (49%): 14 pts were treated with taxanes. Fifteen pts were evaluable for response after second-line CT: we observed 3 PR (20%), 1 SD and 11 PD. Conclusions: Patients younger than 50 years with advanced/metastatic disease present data of response to chemotherapy, time to progression and survival comparable to older patients. In these patients brain and bone involvement was more frequent than expected. No significant financial relationships to disclose.

The Patterns of Care Study and Regional Cancer Registry for non–small-cell lung cancer in Japan

Purpose We examined whether the data registered in the Japanese Patterns of Care Study (PCS) for patients with non–small-cell lung cancer (NSCLC) represent the actual situation of radiotherapy in Japan. The Osaka Cancer Registry (OCR) data, forming the largest database of a regional cancer registry in Japan, were adopted for use as a benchmark against the national condition. Patients and methods We examined 906 patients of the PCS treated between 1995 and 1997 and 845 patients of the OCR registered between 1988 and 1992. The investigation was made by descriptive statistical methods to measure age, stage, combined treatments, type of treated hospitals, and prognosis. Furthermore, the national averages (NAs) of the PCS process (PCS NA) were also calculated to compensate for the imbalance in the PCS data sampling. Results The mean age was 67.3 ± 10.1 in PCS and 64.4 ± 11.0 in OCR ( p < 0.001), 67.2 in PCS NA. The male ratio was 84.2% in PCS and 84.0% in OCR ( p = 0.411), 84.1% in PCS NA. The ratio of the patients at the localized stage was 24.2% in PCS and 15.6% in OCR ( p = 0.001), 21.1% in PCS NA. The ratio of surgery combined was 24.2% in PCS and 28.9% in OCR ( p = 0.026), 25.3% in PCS NA. The ratio of chemotherapy combined was 50.1% in PCS and 67.5% in OCR ( p = 0.001), 47.4% in PCS NA. Because the definitions of institution classification and period of prognostic inquiry were different between the two databases, the 3-year survival rates were calculated for reference. In the nonsurgery group, it was 20.3% in PCS and 11.3% in OCR ( p = 0.001), and in the surgery group it was 52.5% in PCS and 42.2% in OCR ( p = 0.057). Conclusions Ages in the two databases were inconsistent. Sex distributions were consistent. Surgery and chemotherapy were more frequently performed for the OCR patients, and more patients at more advanced stages were also observed in OCR. The PCS NAs of sex, stage, and ratio of surgery combined were at the midpoints between those of PCS and OCR. The survival rate of NSCLC patients in the OCR was significantly inferior to that in the PCS. The follow-up rate of the PCS was lower than that of the OCR. The general features of PCS data showed similarity to OCR data, and the results of the PCS NAs suggested the effectiveness of this method to adjust the sampling imbalance in PCS.

Co-deletion of both p15/p16 genes correlates with poor prognosis non-small cell lung cnacer

Objective: To investigate the relationship between co-deletion of p15/p16 genes and the prognostic significance in patients with non-small cell lung cancer (NSCLC). Methods: By using polymerase chain reaction (PCR), the loss of p15/p16 genes was examined in DNA samples from 140 NSCLC patients. Results: The rate of co-deletion in adenocarcinoma was significantly higher than that in squamous cell carcinoma (P 0.05). By a five years’ follow-up survey, the survival rate of NSCLC patients with co-deletion of p15/p16 genes was obviously lower than that of patients without co-deletion (P<0.01). In the multivariate analysis, co-deletion of p15/p16 genes and TNM stages were identified as independent predictors for overall survival (P<0.01). Conclusion: Since the co-deletion of p15/p16 genes is significantly related to the prognosis of NSCLC patients, detecting co-deletion of both genes might be used as a potential marker for NSCLC prognosis.

Prognosis of Patients with Non-Small Cell Lung Cancer after Surgery

Background : Lung cancer continues to be the leading cause of cancer death in the United States and it's incidence has been rapidly increasing in Korea, too. The overall cure rate for non-small cell lung cancer(NSCLC) is approximately 10%, and the cure is generally achieved by surgery. Unfortunately, however, less than 15% of all patients and less than 25% of those who present with localized disease are candidates for curative surgical resection. So preoperative staging evaluation followed by curative resection has a major role in determining the long tenn prognosis of NSCLC patients. Therefore, we have conducted this study to compare pre-operative and post-operative staging and the long-tenn relapse-free survival rates in NSCLC patients according to its stage. Methods : We analyzed the medical records of 217 NSCLC patients who were operated on for curative resection in Seoul National University Hospital, retrospectively. Among them, 170 patients who were completely resected were selected to determine the long term relapse-free survival rates. Results : Among 217 NSCLC patients, men were 157 and women were 30. The median age was 58 and the difference between men and women was not found. The discrepancy rate between preoperative and postoperative staging was 40.1%. Its major cause was due to the difference of nodal staging. The 3-year relapse-free survival rates were 73%, 53% and 48% in stage I, II and IIIa, respectively. There was no difference of relapse-free duration in recurred patients according to the stage or histologic types. Conclusion : The postoperative pathologic staging determines the long tenn prognosis of patients with NSCLC after surgery, but current preoperative clinical staging can not predict the postoperative pathologic staging correctly. So the improved modality of staging system is required to predict the pathologic staging more correctly.

Paclitaxel and carboplatin in the treatment of advanced non-small cell lung cancer

Based on the superior response rates (21% to 24%) of patients treated with single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in Eastern Cooperative Oncology Group and M.D. Anderson Cancer Center trials in non-small cell lung cancer (NSCLC) and on the superior 1-year survival rates of NSCLC patients treated with carboplatin in a randomized study of cisplatin combination and analogues, we initiated a phase II trial of paclitaxel/carboplatin in patients with stage IV or effusion-positive stage III NSCLC. Eligibility stipulated chemotherapy-naive patients with measurable disease, good performance status, and adequate hematologic, hepatic, and renal function. Previous radiotherapy was restricted to < or = 30% of marrow-bearing bone. Paclitaxel was initially given at 135 mg/m2 over 24 hours followed by carboplatin dosed to a targeted area under the concentration versus time curve (AUC) of 7.5, with treatment repeated at 3-week intervals for six cycles. Granulocyte colony-stimulating factor was introduced during the second and subsequent cycles, with the paclitaxel dose sequentially escalated in 40 mg/m2 increments to a maximum dose of 215 mg/m2 in patients with less than grade 4 granulocytopenia and less than grade 3 thrombocytopenia. Of 54 patients enrolled, 30 currently are evaluable for response, 23 for toxicity. Myelosuppression has been the principal toxicity, with grade 3 or 4 granulocytopenia occurring in 70% of patients after the first cycle. After the introduction of granulocyte colony-stimulating factor, granulocytopenia decreased to 37% during the second cycle and then consistently to 20% or lower during subsequent cycles. Only 22% of cycles have been delayed for 1 week or more. Neutropenic fever has occurred in five (5%) of 100 evaluable cycles. Other grade 3 or 4 toxicities include thrombocytopenia (13%), anemia (9%), fatigue (9%), and hemorrhagic cystitis (1%). The paclitaxel dose was boosted to 215 mg/m2 in 12 (70%) of 17 patients by cycle 3 or 4. At an AUC of 7.5, the median first-cycle carboplatin dose was 434 mg/m2 (range, 293 to 709 mg/m2). The objective response rate is 50%, with three complete, 12 partial, and five minor responses. We conclude that the paclitaxel/carboplatin combination is active in advanced NSCLC and, with AUC-based dosing of carboplatin, can be given at 3-week intervals. Although dose limiting at a paclitaxel dose of 135 mg/m2, granulocytopenia can be reduced substantially with granulocyte colony-stimulating factor, allowing sequential dose escalation of paclitaxel to 175 mg/m2 and 215 mg/m2 in 70% of patients receiving three or more cycles.