Recent advances in genetics and molecular biology lead to the identification of genes and protein products overexpressed by tumors. Such products, called tumor markers, were previously used only as diagnostic and prognostic tools, but are currently being the target of extensive research, with growing evidence that some of them may have an important role in the development of new treatment modalities, targeting the tumor cell biological cycle. In this article, the authors review the role of some of the traditionally known tumor markers (CEA, p53, NSE, K-ras), and describe the prevalence and the role of the epidermal growth factor receptor (EGFR) overexpression and its protein product, p185neu. New drugs have been developed, aiming at the blockade of the signaling process initiated by the EGFR. Among these, the authors highlight ZD1839 (Iressa), a new orally administered drug that reversibly and selectively inhibits the EGFR tyrosine-kinase activity. This drug has demonstrated good results in the treatment of non-small-cell lung cancer, as an isolated drug or in combination with other chemotherapy agents. Targeting the EGFR could represent a significant contribution to cancer therapy, mainly the non-small-cell lung cancer.

Keywords: Lung neoplasms. Tumor markers. Receptor epidermal growth factor.

Biological markers are cellular, structural and biochemical components that can define cellular as well as molecular changes in both normal and neoplastic cells. There are two types of biological markers: 1) intermediate markers that evaluate cellular and molecular alterations before malignancy occurs; and 2) diagnostic markers, present in association with malignancy. The identification and validation of biological markers for clinical use are performed in stages: initial identification in cell cultures of the tumor;
testing of the marker in tissues obtained in biopsies of patients with an established diagnosis of the tumor;
testing of biopsies of normal tissues and tissues with an inflammatory process;
sputum, blood or urine tests for validation as a non-invasive test that can be used in high-risk populations. Sorologic and histopathologic biological markers are cellular, structural and biochemical components found in both normal and neoplastic cells that can be quantitatively assessed by biochemical, immunological and molecular methods in the body fluids or tissues, respectively, and may be associated with malignancies and, possibly, with the neoplastic organ. Biological markers are studied in diverse primary neoplasms. However, few of them proved to be clinically valuable. The role of biological markers in lung cancer patients remains unclear because only a small number of markers has been properly identifiassessed. The aim of this paper is to understand the role of sorologic and histologic biological markers in the prognosis and survival of lung cancer patients based on our previous works. Furthermore, we present a future perspective of the early detection of lung cancer on the basis of the role of intermediate biological markers.

Keywords: Biologic markers. Lung cancer. Prognosis. Survival. Morphometric method.

Epidemiological studies have demonstrated a causal relationship between smoking and lung cancer. Although most lung cancer cases are linked to smoking, only a minority of heavy smokers develop lung cancer, leading to the notion that genetic factors affect individual susceptibility. The principal molecular changes in lung cancer are seen in tumor suppressor genes, proto-oncogenes, growth factors, telomerase activity, and methylation status of promoters. Well-known agents include angiogenesis-stimulating factors (such as vascular endothelial growth factor), as well as factors related to tumor cell proliferation and apoptosis (epidermal growth factor receptor, p53, K-ras, retinoblastoma and BCL-2). Several of these genetic factors have already been investigated, but no single parameter has yet presented sufficient selectivity regarding prognostic value or therapeutic efficacy. Treatment strategies to cure lung cancer should focus on these early genetic lesions in order to promote their repair or to eliminate these lung cancer cells.

Keywords: Smoking; Lung neoplasms; Genetic markers; Prognosis

The usefulness of serum tumor markers in lung cancer is not well defined. Objective: The aim of this study is to examine the correlation between serum tumor markers and tumor extension and its prognostic value. Patients and method: From February 1995 to September 1997, 103 patients with non-small cell lung carcinoma were evaluated at the Department of Thoracic Surgery. Serum levels of CEA, CYFRA21.1, CA15.3, CA19.9, CA72.4, and NSE were determined before treatment. Results: The serum level of CYFRA21.1 was the most frequent elevated tumor marker (55%). Patients with advanced tumor had higher mean serum level of CEA (90.8 ng/ml), CYFRA21.1 (20.3 ng/ml) and CA15.3 (56.5%) than those with localized carcinoma, respectively 10.2 ng/ml, 12.6 ng/ml and 22.2 ng/ml. Considering all serum tumor markers evaluated in this study, only patients with elevated CEA had greater chance (5.6) of presenting with advanced non-small lung carcinoma than patients with normal CEA. Overall survival was influenced by performance status (p = 0.001), tumor extension (p = 0.006), elevated serum level of CEA (p = 0.043), more than two elevated serum tumor markers (p < 0.001), and type of treatment (p < 0.001). The prognostic value of anatomical tumor extension reached the limit of significance (p = 0.052); however, two or more elevated serum tumor markers and type of treatment had independent prognostic value (respectively, p = 0.035 and p = 0.005). Conclusion: None of these serum tumor markers had clinical value in the management of NSCLC patients.

Keywords: biological tumor markers, neoplasm staging, non-small cell lung carcinoma, prognosis

Objective: To characterize the clinical and histological profile, as well as treatment patterns, of patients with early-stage, locally advanced (LA), or advanced/metastatic (AM) lung cancer, diagnosed between 2000 and 2014, in Brazil. Methods: This was an analytical cross-sectional epidemiological study employing data obtained for the 2000-2014 period from the hospital cancer registries of two institutions in Brazil: the José Alencar Gomes da Silva National Cancer Institute, in the city of Rio de Janeiro; and the São Paulo Cancer Center Foundation, in the city of São Paulo. Results: We reviewed the data related to 73,167 patients with lung cancer. The proportions of patients with early-stage, LA, and AM lung cancer were 13.3%, 33.2%, and 53.4%, respectively. The patients with early-stage lung cancer were older and were most likely to receive a histological diagnosis of adenocarcinoma; the proportion of patients with early-stage lung cancer remained stable throughout the study period. In those with LA lung cancer, squamous cell carcinoma predominated, and the proportion of patients with LA lung cancer decreased significantly over the period analyzed. Those with AM lung cancer were younger and were most likely to have adenocarcinoma; the proportion of patients with AM lung cancer increased significantly during the study period. Small cell carcinoma accounted for 9.2% of all cases. In our patient sample, the main treatment modality was chemotherapy. Conclusions: It is noteworthy that the frequency of AM lung cancer increased significantly during the study period, whereas that of LA lung cancer decreased significantly and that of early-stage lung cancer remained stable. Cancer treatment patterns, by stage, were in accordance with international guidelines.

Keywords: Lung neoplasms/epidemiology; Lung neoplasms/therapy; Neoplasm staging; Brazil.

Objective: Adjuvant chemotherapy is recommended for most patients submitted to resection due to non-small cell lung cancer (NSCLC) staged as II or IIIA. However, although various chemotherapy regimens that include cisplatin have been used in phase III trials, the best choice remains unclear. The objective of this study was to describe the experience of the Instituto Nacional do Câncer (INCA, Brazilian National Cancer Institute), located in the city of Rio de Janeiro, Brazil, with the use of the cisplatin-etoposide combination in such patients, with a special focus on survival data. Methods: We retrospectively evaluated the medical charts of the patients receiving adjuvant therapy for NSCLC at the INCA between 2004 and 2008. Results: We included 51 patients, all of whom were treated with the cisplatin-etoposide combination. The median follow-up period was 31 months, and the median overall survival was 57 months. In the univariate analysis, median survival was lower in the patients submitted to chemotherapy plus radiotherapy than in those submitted to chemotherapy alone (19 vs. 57 months; p < 0.001), and there was a trend toward lower median survival in stage III patients than in stage I-II patients (34 vs. 57 months; p = 0.22). Overall survival was not significantly associated with gender (p = 0.70), histological pattern (p = 0.33), or cisplatin dose (p = 0.13). Conclusions: Our results support the use of adjuvant chemotherapy, and our survival data are similar to those reported in major randomized clinical trials. However, long-term follow-up is warranted in this population.

Keywords: Lung neoplasms; Chemotherapy, adjuvant; Survival analysis.

Objective: Assess the relationship between adherence to long-term oxygen therapy (LTOT) with mortality in patients with chronic obstructive pulmonary disease (COPD) and chronic respiratory failure and their clinical features. Methods: Longitudinal retrospective analysis of 254 patients with COPD and chronic respiratory failure from 2008 to 2016. At baseline, we evaluated the diagnosis, spirometry values, arterial blood gas analysis, blood count, pulse oximetry, body composition and health questionnaires (dyspnea, quality of life, anxiety and depression). For referred adherence analysis to LTOT we included 199 patients, divided according to prescription of oxygen: 12h/day (G1), 15h/day (G2) and 24h/day (G3). The cause of death and dates were studied over the five-year period. Results: In five years we identified 124 deaths (62.3%). No significant difference was found in mortality between the adherence groups (p=0.75) nor did we find differences in the clinical parameters evaluated. LTOT prescription was not associated with mortality (p=0.07). In Cox regression analysis, there was no association between mortality and non-adherence to LTOT (HR: 0.75; IC95%: 0.21-2.70). The risk of mortality was increased in G3 compared with G1 (HR: 7.16; IC 95%: 1.44-35.38) and in those with a higher depression score (HR: 1.35; IC: 1.14-1.59). Conclusion: No association was found between LTOT adherence and mortality in patients with COPD and respiratory failure. There were no clinical differences between the adherence groups.

Keywords: Chronic obstructive pulmonary disease; Oxygen therapy; Cooperation and treatment adherence; Morbidity and mortality indicators.

Silica is one of the main occupational agents associated with lung cancer. It is classified by the International Agency for Research on Cancer (IARC) as a Group 1 substance, i.e., carcinogenic for humans, since 1996. The objective of this paper is to report two cases of workers previously exposed to silica who developed lung cancer, seen in an out-patient clinic, focusing on important points of the current literature on the subject.

Objective: To establish the accuracy of frozen section examination in identifying tumor spread through air spaces (STAS), as well as to propose a reproducible technical methodology for frozen section analysis. We also aim to propose a method to be incorporated into the decision making about the need for conversion to lobectomy during sublobar resection. Methods: This was a nonrandomized prospective study of 38 patients with lung cancer who underwent surgical resection. The findings regarding STAS in the frozen section were compared with the definitive histopathological study of paraffin-embedded sections. We calculated a confusion matrix to obtain the positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and accuracy. Results: The intraoperative frozen section analysis identified 7 STAS-positive cases that were also positive in the histopathological examination, as well as 3 STAS-negative cases that were positive in the in the histopathological examination. Therefore, frozen section analysis was determined to have a sensitivity of 70%, specificity of 100%, PPV of 100%, NPV of 90.3%, and accuracy of 92% for identifying STAS. Conclusions: Frozen section analysis is capable of identifying STAS during resection in patients with lung cancer. The PPV, NPV, sensitivity, and specificity showed that the technique proposed could be incorporated at other centers and would allow advances directly linked to prognosis. In addition, given the high accuracy of the technique, it could inform intraoperative decisions regarding sublobar versus lobar resection.

Keywords: Neoplasm invasiveness; Frozen sections; Lung neoplasms/pathology; Lung neoplasms/surgery.

Objective: To determine the levels of the tumor markers carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1) and carbohydrate antigen 15-3 (CA 15-3) in the blood and pleural fluid of patients with benign or malignant pleural effusion, evaluating the sensitivity of each marker in these fluids. Methods: We prospectively evaluated 85 patients with pleural effusion. The study of the pleural fluid observed the criteria established in the literature. Levels of the markers were determined using electrochemiluminescence. The sensitivity was determined on the condition that the specificity was ≥ 90%. Results: Of the 85 cases, 36 (42.4%) were malignant, 30 (35.3%) were benign, and the results were inconclusive in 19 (22.3%). In the malignant cases, the CEA and CYFRA21-1 levels were higher in the pleural fluid than in the blood, which was not observed for CA 15-3. In the benign cases, the CYFRA21-1 levels were higher in the pleural fluid than in the blood, whereas the opposite was found for CEA and CA 15-3. There were significant differences between malignant and benign cases for all markers, in pleural fluid and blood. In the pleural fluid, the sensitivity of CEA, CYFRA21-1 and CA 15-3 was 69.4, 69.4 and 66.7%, respectively, and the combined sensitivity was 80.6%. In the blood, the sensitivity was 57.1%, 71.4% and 48.6% for CEA, CYFRA21-1 and CA 15-3, respectively, and the combined sensitivity was 77%. Conclusion: The results suggest that these markers might be useful in the differentiation between malignant and benign pleural effusion.

Keywords: Biological tumor marker; Cyfra 21.1; CEA; CA 15.3; Pleural effusion.

A review of the role of radiotherapy in lung cancer is presented, with the most recent innovations. Indications for postoperative irradiation and chemo-radiotherapy in non-small cell lung cancer are discussed. Recommendations are made for prophylactic cranium irradiation and perspectives of thoracic radiotherapy for small cell lung cancer. Recent techniques and results of the "Brazilian Consensus on Lung Cancer - Radiotherapy" are also presented.

Lung cancer is one of the most incident types of cancer and a leading cause of cancer mortality in Brazil. We reviewed the current status of lung cancer by searching relevant data on prevention, diagnosis, and treatment in the country. This review highlights several issues that need to be addressed, including smoking control, patient lack of awareness, late diagnosis, and disparities in the access to cancer health care facilities in Brazil. We propose strategies to help overcome these limitations and challenge health care providers, as well as the society and governmental representatives, to work together and to take a step forward in fighting lung cancer.

Keywords: Lung neoplasms/epidemiology; Lung neoplasms/therapy; Lung neoplasms/diagnosis; Biomarkers; Brazil.

Our objective was to determine the levels of lactate dehydrogenase, IL-6, IL-8, and VEGF, as well as the total and differential cell counts, in the pleural fluid of lung transplant recipients, correlating those levels with the occurrence and severity of rejection. We analyzed pleural fluid samples collected from 18 patients at various time points (up to postoperative day 4). The levels of IL-6, IL-8, and VEGF tended to elevate in parallel with increases in the severity of rejection. Our results suggest that these levels are markers of acute graft rejection in lung transplant recipients.

Keywords: Lung transplantation; Pleural effusion; Cytokines; Graft rejection.

Objective: To estimate and compare the frequency of CYP1A1*2A gene polymorphisms in a Brazilian population and determine the possible contribution of these genetic variations to lung cancer risk. Methods: The study population included 200 patients with lung cancer, and the control group consisted of 264 blood donors. Genomic DNA was obtained from peripheral blood samples. The PCR-RFLP method was used for analysis of the CYP1A1*2A gene. Results: There was no statistically significant difference between the lung cancer patients and the controls in terms of the distribution of CYP1A1*2A polymorphisms (p = 0.49). A multivariate logistic regression model analysis by ethnic group revealed that, within the lung cancer group, the CYP1A1*2A genotype CC plus TC was more common among the African-Brazilian patients than among the White patients (adjusted OR = 3.19; 95% CI: 1.53‑6.65). Conclusions: The CYP1A1*2A gene cannot be linked with lung cancer risk in Brazilian patients at this time. Larger epidemiologic studies are needed in order to establish whether the CC plus TC polymorphism increases the risk of lung cancer in African-Brazilians.

Keywords: Lung neoplasms; Polymorphism, genetic; Metabolism.

Several advances have been made in the treatment of advanced non-small cell lung cancer in the last few years. Combined therapies using chemotherapy have improved survival of patients with locally advanced disease (stage III) when compared to either radiation or surgery. New chemotherapeutic agents, used alone or combined, have also made a strong impact with metastatic disease (stage IV). Ongoing randomized trials will certainly define new treatment standards and hopefully improve the outcome of patients with non-small cell lung cancer.

Keywords: Locally advanced. Non-small cell lung cancer.

For patients with stage III (A or B) non-small cell lung cancer, radiation is still the standard treatment. However, long-term survival remains poor and new alternatives and therapeutic associations are being studied. Recently, chemotherapy has been in focus, with several combinations with radiation therapy and/or surgery. An update of the recently published data about the controversies on whether or not one should combine chemotherapy with radiation in locally advanced lung tumors was done. Cisplatin-based chemotherapy regimens combined with radiation are favorable, with a possible increase in survival of 3% in 2 years and 2% in 5 years. Neither the best drug combination nor the ideal association regimen have been defined yet. The indication of a combined treatment must be based on patient's clinical conditions and on a balance between quality of life, toxicity, and cost of chemotherapy.

Keywords: Lung neoplasms. Radiation therapy. Chemotherapy.