Progress in the Treatment and Outcomes for Early-Stage Non-Small Cell Lung Cancer

Purpose

The purpose of this study is to assess temporal trends in population-based treatment and survival rates in patients with early-stage non-small cell lung cancer (NSCLC).

Methods

Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Chi-square test, Kaplan–Meier method, and Cox regression models were employed in SPSS 23.0.

Results

Fifty-seven thousand and eighty-eight NSCLC patients with early-stage disease from 1988 to 2014 were identified. 6409 (11.2%) were diagnosed in 1988–1994, 5800 (10.2%) 1995–1999, 13,031 (22.8%) 2000–2004, 15,786 (27.7%) 2005–2009, and 16,062 (28.1%) 2010–2014. We observed a significant increase in the proportion of older patients, adenocarcinoma histology, and rate of wedge resection over the study period. The five-year overall survival (OS) for the entire cohort was 63.3%. Those undergoing resection without adjuvant therapy had the highest outcomes. Lobectomy was associated with better outcomes compared to wedge resection or pneumonectomy. A significant difference in five-year OS by year of diagnosis (1988–1994: 58.8% vs. 1995–1999: 60.6% vs. 2000–2004: 63.2% vs. 2005–2009: 66.1%; p?<?0.001) was observed. This significant OS difference was also observed regardless of age, surgery type, and T stage, but also only in those with adenocarcinoma. On multivariable analysis, year of diagnosis, age, gender, race, treatment and surgery type, histology, T stage, and tumor grade remained independent prognostic factors for OS.

Conclusions

Overall survival for early-stage NSCLC has significantly improved over the recent decades despite an increasing proportion of older patients and those undergoing sublobar resection or SBRT. This finding may be limited to those with adenocarcinoma.

     

外科治疗ⅢA期N2非小细胞肺癌的预后分析及临床意义

目的探讨经手术治疗的ⅢA期N2非小细胞肺癌不同亚组病人的生存率差异，分析影响ⅢA期N2非小细胞肺癌预后因素。方法对1991年1月～2000年1月我院146例手术治疗的ⅢA期N2 NSCLC患者进行分析。对一些可能影响预后的因素：病理类型、肿瘤位置、肿瘤大小（T）、手术方式、临床N2情况、N2转移组数及个数、术后辅助治疗等，用Kaplan—Meier曲线及Log rank检验生存率差异，Cox单因素，多因素分析各因素对生存率的影响。结果146例手术治疗的ⅢA期N2 NSCLC的3年5年生存率分别为19．86％和14．56％。单因素分析示肿瘤位置，临床N2情况，N2转移组数及个数是影响生存率的因素，多因素分析示肿瘤大小，临床N2情况，N2转移组数和肿瘤位置影响预后。右肺下叶肿瘤单组或单个N2转移，预后最好。结论纵膈是否有微转移淋巴结，转移淋巴结个数和组数是影响术后生存率主要因素。纵膈淋巴结微转移（mN2）．单组N2转移（N2L1），N2转移数少于4个的病人术后预后好，宜手术治疗。右肺下叶肿瘤发生单组N2淋巴结转移预后好。     

Taxanes in the Treatment of Non-Small Cell Lung Cancer

Paclitaxel and docetaxel, drugs that bind tightly to beta-tubulin and disrupt microtubule dynamics, are widely used in the treatment of non-small cell lung cancer (NSCLC), the most common cause of cancer death in men and women living in the US. These well tolerated drugs, alone or in combination with another cytotoxic agent, have been shown to increase the survival of patients with metastatic disease or malignant effusions. Both paclitaxel and docetaxel can be combined with concurrent chest irradiation for patients with locally advanced NSCLC. The combination of carboplatin and paclitaxel, when given postoperatively to patients with stage IB NSCLC, improved survival compared with surgery alone, with little toxicity. Taxane combinations are undergoing study as adjuvant therapy for patients with other stages of operable disease. Except for a recent trial with bevacizumab, efforts to improve the efficacy of taxane/platinum combinations in patients with advanced disease by adding a third 'targeted' drug have thus far been unsuccessful.     

Clinical Usefulness of D2-40 in Non-Small Cell Lung Cancer

D2-40 is a recently developed monoclonal antibody that reacts with a 40 kDa O-linked sialoglycoprotein and has been used for the assessment of lymphatic invasion in tumor specimens. We have evaluated the diagnostic usefulness of D2-40 and association of its immunopositivity with clinicopathological parameters in adenocarcinoma and squamous cell carcinoma of the lung. We investigated 97 cases of surgically resected adenocarcinoma or squamous cell carcinoma of the lung for the determination of D2-40 positivity in tumor cells and peritumoral lymphatic vessel density (LVD) using an immunostaining method. D2-40 immunoreactivity in tumor cells was invariably negative in adenocarcinoma but 47% of squamous cell carcinomas were positive. D2-40 positivity in the tumor was significantly associated with high LVD in squamous cell carcinoma (P < 0.006). There was no significant association between peritumoral LVD and clinicopathologic parameters, including lymphatic vessel invasion, lymph node metastasis, and survival in adenocarcinoma and squamous cell carcinoma. These results suggest that D2-40 immunoreactivity in tumor cells can be used for distinguishing between adenocarcinoma and squamous cell carcinoma and that the reactivity of tumor cells with D2-40 is positively correlated with LVD in squamous cell carcinoma but not with lymph node metastasis in adenocarcinoma and squamous cell carcinoma.     

Clusterin Immunoexpression and its Clinical Significance in Patients with Non-Small Cell Lung Cancer

Clusterin is an enigmatic glycoprotein with a nearly ubiquitous tissue distribution. It plays important roles in various pathophysiological processes, including tissue remodeling, reproduction, lipid transport, complement regulation, and apoptosis. Clusterin appears to have two main isoforms that result from alternative splicing. The secreted and nuclear forms of clusterin have been reported to play different roles in human malignancies. The purpose of this study was to examine clusterin immunoexpression and its clinical significance in a group of Chinese patients with non-small cell lung cancer (NSCLC). Tissue samples from the primary tumors of 121 patients with completely resected NSCLC were obtained. Clusterin protein expression was evaluated by immunohistochemical staining with an antibody against all clusterin isoforms. Staining patterns were observed and graded based on intensity and density and were correlated with clinical and pathological data. Both cytoplasmic and nuclear clusterin immunostaining patterns were observed. Clusterin staining was observed only in the cytoplasm in 70 patients (57.9%), only in the nucleus in 27 patients (22.3%), and in both the cytoplasm and nucleus in 16 patients (13.2%). A significant association was observed between positive cytoplasmic clusterin expression and histologic type as indicated by adenocarcinomas that were more likely to have clusterin staining only in the cytoplasm. Clusterin immunostaining was neither associated with recurrence-free survival (RFS) nor overall survival of patients by univariate or multivariate analysis. For patients undergoing chemotherapy, those with only cytoplasmic clusterin staining had worse survival than other patients. In conclusion, both cytoplasmic and nuclear immunostaining patterns of clusterin were detected in the tumors of patients with NSCLC. Adenocarcinomas were more likely to have only cytoplasmic staining. The immunoexpression of clusterin was not associated with prognosis, and cytoplasm-only immunostaining of clusterin was inversely correlated with chemosensitivity in this group of patients.     

Identification of Key circRNAs in Non-Small Cell Lung Cancer

BackgroundOur work aimed to identify the key differentially expressed circular RNAs (circRNAs) (DECs) in non-small cell lung cancer (NSCLC).Materials and MethodsAn integrated analysis based on public NSCLC datasets obtained from Gene Expression Omnibus was performed. DECs in NSCLC were subsequently identified. Bioinformatics analyses were utilized for describing the predictable functions of DECs including circRNA-miRNA network construction and pathway enrichment. The diagnostic value of candidate DECs among NSCLC and healthy individuals were preliminarily evaluated in GSE101586, GSEE101684, GSE112214 datasets.ResultsA total of 43 up-regulated and 78 down-regulated DECs in NSCLC were identified. The mTOR signaling pathway, ErbB signaling pathway and cell cycle were significantly enriched from the originated genes of DECs in NSCLC. In the circRNA-miRNA network, hsa-circ-0002702, hsa-circ-0049271, hsa-circ-0009150 and hsa-circ-0053958 had high connectivity with miRNAs, which respectively interacted with 122, 42, 41, and 39 miRNAs. hsa_circ_0003028, hsa_circ_0015278, hsa_circ_0043256, hsa_circ_0049657 and hsa_circ_0074930 could distinguish NSCLC patients from healthy individuals in GSE101586, GSEE101684, GSE112214 datasets.ConclusionsDECs including hsa_circ_0003028, hsa_circ_0015278, hsa_circ_0043256, hsa_circ_0049657 and hsa_circ_0074930 had diagnostic value in NSCLC. These DECs might play key roles in NSCLC pathogenesis through the mTOR signaling pathway, ErbB signaling pathway and cell cycle.     

PTEN基因在非小细胞肺癌中表达的临床研究

目的研究PTEN基因在人非小细胞肺癌中表达情况，探讨PTEN基因在人肺癌发生、发展过程中的可能作用。方法采用免疫组化方法检测143例非小细胞肺癌、20例正常肺组织及良性病变中PTEN蛋白表达情况。结果在正常肺组织及肺良性病变组织中无失表达：肺癌组织中失表达率57．34％（82／143），两者比较有显著性差异（P〈0．001）；肺癌组织中PTEN基因表达水平与肿瘤细胞分化程度、TNM分期、淋巴结转移程度存在相关性（P〈0．001）；PTEN蛋白失表达组．肺癌患者的术后五年生存率显著低于表达组（P〈0．001）；吸烟组患者PTEN基因失表达率显著高于无吸烟组（P〈0．001）。结论PTEN蛋白失表达与肺癌的发生、发展及预后有关；多因素分析PTEN基因失表达是影响非小细胞肺癌预后的独立因素。     

PTEN蛋白表达在非小细胞肺癌的临床意义研究

目的探讨PTEN蛋白在非小细胞肺癌（NSCLC）中的表达及生物学和临床意义。方法应用免疫组织化学法检测60例NSCLC组织中PTEN基因蛋白的表达,20例肺良性病变组织中PTEN基因蛋白的表达。结果PTEN蛋白在NSCLC中的总阳性表达率高于肺良性病变组织,两者比较差异有统计学意义（P〈0．01）;PTEN蛋白表达随NSCLC临床分期增加呈下降趋势,但三组之间比较差异无统计学意义（P〉0．05）;PTEN蛋白阳性表达率在NSCLC高中分化组高于低分化组,两者之间比较差异有统计学意义（P〈0．01）,NSCLC无淋巴结转移组PTEN蛋白阳性表达率有淋巴结转移组,两者差异有统计学意义（P〈0．01）,PTEN和nm23-H1蛋白表达与NSCLC患者年龄、性别、组织学分型、肿瘤部位及肿瘤大小均无关（P〉0．05）。结论PTEN蛋白表达与NSCLC的组织分化程度及淋巴结转移有关,NSCLC中PTEN蛋白低表达易发生淋巴结转移,检测PTEN蛋白可在一定程度上评估NSCLC的预后。     

High Incidence of EGFR Mutations in Pneumonic-Type Non-Small Cell Lung Cancer

To retrospectively identify computed tomography (CT) features that correlate with epidermal growth factor receptor (EGFR) mutation in surgically resected pneumonic-type lung cancer (P-LC).A total of 953 consecutive patients with surgically resected lung cancer in the First Affiliated Hospital of Guangzhou Medical University from August 2011 to August 2013 were studied. The CT manifestations were reevaluated independently by 2 radiologists. The presence of pneumonic-type consolidation with pathological confirmed non-small lung cancer (NSCLC) was defined as P-LC. EGFR mutation was determined by direct DNA sequencing or amplification refractory mutation system-PCR. EGFR mutation rates as well as clinical and pathological manifestations between P-LC and control lung cancer patients were compared.P-LC was diagnosed in 85 patients. Among these patients, 82 were adenocarcinoma (including 78 cases of invasive adenocarcinoma and 4 cases of microinvasive adenocarcinoma), 2 were squamous carcinoma and 1 was other type. P-LC occurred more frequently in female (58.8% vs 37.1%, P < 0.01), nonsmoking (76.5% vs 56.5%, P = 0.001) and adenocarcinoma (58.8% vs 37.1%, P < 0.01) patients. Moreover, EGFR mutations were found in 39 of 52 P-LC patients (75%) and 263 of 542 non-P-LC NSCLC patients (48.5%). However, no difference was found on the mutation sites of EGFR. Histological type, sex, and radiological manifestations (P-LC vs non-P-LC) but not smoking or sequencing method can be served as the independent predictor of EGFR mutations.P-LC patients showed a significant higher incidence of EGFR mutations, which was independent of sex, histological type, and smoking history. The patients with imaging manifestation of pneumonic-type consolidation are highly suggested to perform EGFR mutation analysis to guide the sequential treatment.     

Survival and Racial Differences of Non-Small Cell Lung Cancer in the United States Military

BACKGROUND

Lung cancer is the leading cause of cancer-related death in the United States (US) Military and worldwide, with non-small cell lung cancer (NSCLC) accounting for 87 % of cases.

OBJECTIVES

Using a US military cohort who receives equal and open access to healthcare, we sought to examine demographic, clinical features and outcomes with NSCLC.

DESIGN AND PARTICIPANTS

We conducted a retrospective cohort analysis of 4,751 patients, aged ≥ 18 years and diagnosed with a first primary NSCLC between 1 January 2003 and 31 December 2013 in the US Department of Defense (DoD) cancer registry.

MAIN MEASURES

Differences by patient and disease characteristics were compared using Chi-square and t-test. Kaplan Meier curves and Cox proportional hazards regression assessed overall survival.

RESULTS

The mean age at diagnosis was 66 years, 64 % were male, 72 % were Caucasian, 41 % were diagnosed at early stage, 77 % received treatment and 82 % had a history of tobacco use. Mean age at diagnosis was highest among Caucasians (67 years) and lowest among African Americans (AA; 62 years). Asian/Pacific Islanders (PI) were more likely to be female (p < 0.0001), have adenocarcinoma histology (p = 0.0003) and less likely to have a history of tobacco use (p < 0.0001) compared to other racial/ethnic groups. In multivariable survival analysis, older age, male gender, increasing stage, not receiving treatment, and tobacco history were associated with higher mortality risk. Untreated patients exhibited a 39 % higher mortality risk compared to treated patients (HR = 1.39; 95%CI = 1.23–1.57). Compared to Caucasian patients, Asian/PIs demonstrated a 20 % lower risk of death (HR = 0.80; 95%CI = 0.66–0.96). There was no difference in mortality risk between AAs and Hispanics compared to Caucasians.

CONCLUSION

The lack of significant outcome disparity between AAs and Caucasians and the earlier stage at diagnosis than usually seen in civilian populations suggest that equal access to healthcare may play a role in early detection and survival.KEY WORDS: military, lung cancer, survival outcomes     

Predictive Value of 18F-FDG PET and CT Morphologic Features for Recurrence in Pathological Stage IA Non-Small Cell Lung Cancer

Patients with pathological stage IA non-small cell lung cancer (NSCLC) may relapse despite complete surgical resection without lymphovascular invasion. A method of selecting a high-risk group for adjuvant therapy is necessary. The aim of this study was to assess the predictive value of ¹⁸F-fluorodeoxyglucose (FDG) uptake and the morphologic features of computed tomography (CT) for recurrence in pathological stage IA NSCLC.One hundred forty-five patients with pathological stage IA NSCLC who underwent pretreatment with FDG positron emission tomography and CT evaluations were retrospectively enrolled. The associations among tumor recurrence and patient characteristics, maximal standard uptake value (SUVmax) of primary tumors, and CT imaging features were investigated using univariate and multivariate analyses. A receiver operating characteristic (ROC) curve analysis was performed to quantify the predictive value of these factors.Tumor recurrence developed in 21 (14.5%) of the 145 patients, and the 5-year recurrence-free survival rate was 77%. The univariate analysis demonstrated that SUVmax, the grade of histological differentiation, tumor size, and the presence of bronchovascular bundle thickening were significant predictive factors (P < 0.05). A higher SUVmax (≥2.5) (P = 0.021), a lower ground-glass opacity ratio (≤17%) (P = 0.014), and the presence of bronchovascular bundle thickening (P = 0.003) were independent predictive factors of tumor recurrence in the multivariate analysis. The use of this predictive model yielded a greater area under the ROC curve (0.877), which suggests good discrimination.The combined evaluation of FDG uptake and CT morphologic features may be helpful in the prediction of recurrence in patients with pathological stage IA NSCLC and in the stratification of a high-risk group for postoperative adjuvant therapy or prospective clinical trials.     

吉西他滨联合顺铂治疗晚期非小细胞肺癌的临床观察

目的探讨吉西他滨联合顺铂治疗晚期非小细胞肺（NSCLC）的疗效及毒性。方法对26例晚期非小细胞肺癌患者予以顺铀80mg／m^2,VD,第1天,吉西他滨800—1000／m^2,VD,第1、8天,21d为一个周期,完成3个周期后评价疗效。结果全组总有效率为38．5％,其中鳞癌为40％,腺癌为36．4％,中位生存期12．1个月,1年生存率为41％。主要毒性反应为骨髓抑制和恶心呕吐,绝大多数患者可以耐受良好。结论吉西他滨联合顺铂治疗晚期非小细胞肺癌是安全、有效的化疗方案,可延长患者生存存期,毒性反应可以耐受。     

Improving Survival and Reducing Toxicity with Chemotherapy in Advanced Non-Small Cell Lung Cancer

The role of chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC) has been debated over three decades, but it is only relatively recently that chemotherapy has become a standard of care for this disease. In addition to prolonging survival, chemotherapy can palliate distressing symptoms. Concerns that the adverse effects of chemotherapy are likely to outweigh its benefits have largely not been confirmed by quality-of-life data reported among patients with good performance status. Platinum-based chemotherapy regimens in which cisplatin or carboplatin are partnered by a third-generation cytotoxic drug such as gemcitabine, paclitaxel or vinorelbine, have similar activity and efficacy, but differ in adverse effect profiles. Response rates of 30-40% should be expected with median and 1-year survival of 8-10 months and 30-40%, respectively. In the second-line setting chemotherapy with docetaxel has been shown to be significantly superior to best supportive care alone. In a recent trial that compared docetaxel to the novel antifolate, pemetrexed the response rates and survival rates did not differ, but the toxicity profile favored pemetrexed. Overall, these data demonstrate that progress has been made in the use of chemotherapy to improve survival in patients with NSCLC without increasing the incidence of further toxicity. In the past, the potential to survive 1 year was extremely small, whereas now many more patients reach this milestone as well as the 2-year point. However, a plateau has probably been reached with existing cytotoxic drugs and there is a general belief that the next significant advance in the treatment of NSCLC will come from the addition of drugs that target specific molecular pathways in sequence with standard chemotherapy regimens.