Untreated Non-small Cell Lung Carcinoma Research Articles

Comparison of Sputum and Oropharyngeal Microbiome Compositions in Patients with Non-Small Cell Lung Cancer

Recent findings indicate that the microbiota is involved in the development of lung cancer by inducing inflammatory responses and generating genome damage. This study aimed to compare sputum microbiomes from the mouth and oropharynx in non-small cell lung carcinoma (NSCLC) patients. A second goal was to search for bacterial taxonomic units that behave differently in the microbiome of NSCLC patients and healthy subjects. In the study, the taxonomic composition of the sputum and oropharyngeal microbiomes of 23 male patients with untreated NSCLC and 20 healthy subjects were compared. Next-generation sequencing of bacterial 16S rRNA genes was used to determine the taxonomic composition of the respiratory microbiome. Using the Kruskal-Wallis test, increased alpha diversity was observed in the sputum microbiome compared to that of the oropharynx, but this was evident only in NSCLC patients and not in healthy subjects. Using the Robust Aitchison PCA test, differences in beta diversity were found between sputum and oropharynx samples, and these differences were significant both for NSCLC patients (p = 0.045) and healthy controls (p = 0.009). However, no significant statistical differences were detected using the Robust Aitchison PCA when only comparing oropharyngeal samples from NSCLC patients and controls, nor when comparing sputum samples alone. Analysis of differences in the relative percentage of individual bacterial taxa using the Mann-Whitney U-test, and taking into account the FDR correction, showed an increase in the genus <em>Rothia</em> in oropharyngeal samples of NSCLC patients, as compared to control subjects (4.98 ± 6.33 vs 2.21 ± 6.28; p = 0.0008). However, linear discriminant analysis using LefSe did not show <em>Rothia</em> as a differentially regulated feature between NSCLC and controls in the oropharynx. Thus, more research is needed to identify possible bacterial NSCLC biomarkers in the oropharynx.

A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: Updated results from a PD-L1 unselected population.

9003 Background: Eftilagimod alpha (E) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen presenting cell (APC)/CD8 T-cell activation. Stimulation of the APCs and subsequent T cell recruitment with E may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We hereby report results of the extended first-line non-small cell lung carcinoma (NSCLC) cohort of the TACTI-002 (“Two ACTive Immunotherapies”) phase II trial. Methods: Pts with untreated metastatic NSCLC, unselected for PD-L1 expression were recruited. Objective response rate (ORR) by iRECIST was the primary endpoint (EP) and secondary EPs include ORR by RECIST 1.1, tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS) and exploratory biomarker. Pts received 30 mg E SC q2w for 8 cycles (1 cycle= 3 weeks) and then q3w for up to 1 year with P (200 mg IV q3w for up to 2 years). Imaging was done every 8 weeks. PD-L1 was assessed centrally. This has been approved by relevant CAs, ECs, and IRBs. Results: From Mar 2019 to Nov 2021 114 pts were enrolled. Median age was 67 years (44-85) and 74% were male. ECOG PS was 0 and 1 in 37% and 63% of pts, respectively. Pts presented squamous (35%) or non-squamous (62%) NSCLC with 88% of pts at stage IV at the time of study entry. All PD-L1 subgroups were represented (Table). Pts received median 6.0 (range 1–35) P and 7.0 (1-22) E administrations. 19 (17%) pts discontinued treatment due to adverse events (AEs). The most common (≥15%) AEs were dyspnea (33%), asthenia (30%), decreased appetite (22%), cough (20%), anemia (20%), fatigue (19%), pruritus (18%), constipation (17%) and diarrhea (15%). At data cut-off (Jan 2022), 75 pts with a minimum follow-up of 6 months were evaluated for efficacy. ORR (iRECIST) was 37.3% in the ITT and 41.8%% in the evaluable pts assessed by local read. DCR 73.3% was reported. Response rate for squamous and non-squamous pathology were 33.3 % and 40.3 %, respectively. Results according to RECIST 1.1 were comparable. Responses were observed in all PD-L1 subgroups (Table). 24/28 (86%) responses were already confirmed while median duration of response was not yet reached (5 events). Conclusions: E + P is safe and shows encouraging antitumor activity in first-line metastatic NSCLC patients unselected for PD-L1, warranting further investigation. Clinical trial information: NCT03625323. [Table: see text]

Clinical outcome and side effects of concomitant chemoradiotherapy in the treatment of locally advanced inoperable non-small cell lung cancer: Our experiences

Background/Aim. About 1.8 million new lung cancer cases are diagnosed worldwide every year, and about 1.6 million cases have a fatal outcome. Despite improvements in treatment in the previous decades, the survival of patients with lung cancer is still poor. The five-year survival rate is about 50% for patients with localized disease, 20% for patients with regionally advanced disease, 2% for patients with metastatic disease, and about 14% for all stages. The median survival of patients with untreated non-small cell lung carcinoma (NSCLC) in the advanced stage is four to five months, and the annual survival rate is only 10%. The aim of the study was to determine the results of treatment with concomitant chemoradiotherapy (CHRT) in terms of efficacy and toxicity in selected patients with advanced inoperable NSCLC. Methods. The study included data analysis of 31 patients of both sexes who were diagnosed and histopathologically verified with NSCLC in inoperable stage III and were referred by the Council for Malignant Lung Diseases to the Radiotherapy Department of the Military Medical Academy in Belgrade, Serbia for concomitant CHRT treatment. Upon expiry of the three months from the performed radiation treatment (RT), the tumor resonance was assessed based on multislice computed tomography (MSCT) examination of the chest and upper abdomen according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. According to the same criteria, progression-free survival (PFS), as well as overall survival (OS), was assessed every three months during the first two years, then every 6 months or until the onset of disease symptoms. Results. The median PFS was 13 months, and the median OS was 20 months. During and immediately after RT, 9 (29%) patients had a grade 2 or higher adverse events. Conclusion. The use of concomitant CHRT in patients in the third stage of locally advanced inoperable NSCLC provides a good opportunity for a favorable therapeutic outcome with an acceptable degree of acute and late toxicity and represents the standard therapeutic approach for selected patients in this stage of the disease.

Expression of Caspase-3 and c-myc in Non-Small Cell Lung Cancer

Caspase-3 is a cysteine protease that plays an important role in the process of apoptotic cell death, but little has been studied clinically on caspase-3 in lung cancer. Increased c-myc expression can result in mitosis or apoptosis, and its contribution to the pathogenesis and prognosis of lung cancer has gained interest. In the present study, the expressions of caspase-3 and c-myc, along with their possible correlations with prognostic variables, were analyzed in resected non-small cell lung carcinomas (NSCLC). Archival tumor tissues from 147 previously untreated NSCLC patients were examined by immunohistochemistry for the expressions of caspase-3 and c-myc proteins. Clinical information was obtained through the computerized retrospective database from the tumor registry. The expressions of caspase-3 and c-myc were detected in 60 (88/147) and 16% (24/147) of tumors, respectively. No association was found between caspase-3 and c-myc expressions. A multivariate analysis demonstrated the N status and pathologic stage to be significantly correlated with poor survival (p-value=.018 and .002, respectively), but positive expression of caspase-3 was associated with a good prognosis (p=.03). Our data suggest the involvement of caspase-3 in the tumorigenesis of NSCLC. It is also noteworthy that caspase-3 expression might be a favorable prognostic indicator in these tumors.

Treatment of Inoperable Non-small Cell Lung Carcinoma Stage IIIB and IV with Cisplatin, Epidoxorubicin, Vindesine and Lonidamine: A Phase II Study

The polychemotherapeutic regimen PEV (cisplatin, epidoxorubicin and vindesine) + lonidamine proved to be valid in terms of activity and efficacy in the treatment of patients with advanced, previously untreated non-small cell lung carcinoma. The goal of the study was to verify whether a different dose of lonidamine, together with an increase in cisplatin and epidoxorubicin compared to the standard regimen, is able to improve the activity and efficacy of PEV without increasing toxicity. Thirty-one patients were treated with cisplatin (80 mg/m2/i.v.), epidoxorubicin (70 mg/m2/i.v.) and vindesine (3 mg/m2/i.v.) every 28 days for 6 courses in combination with lonidamine (600 mg/day on days 1 and 2 of each course followed by 450 mg/day until progression of disease or intolerance). All the patients were monitored for clinical response, median duration of response and survival and for toxicity. The clinical response in the 29 assessable patients was: 41.4% partial remission, 48.3% stable disease, and 10.3% progression of disease. The median duration of response was 8.5 months (range, 4-26+) and median survival was 12 months (range, 4-26+). Survival was above the median in 15 stage IIIb patients, and 2 patients were long survivors at 26+ months. The toxicity of PEV + lonidamine was mild; there were no toxic deaths nor acute toxicity of grade 4 according to the WHO scoring system. Our polychemotherapeutic regimen proved to be valid in terms of activity and efficacy, and a further dose increase in single chemotherapeutic agents as well as lonidamine could therefore be justified.

Expression of lung resistance-related protein (LRP) in non-small cell lung carcinomas of smokers and non-smokers and its predictive value for doxorubicin resistance.

Immunohistochemical methods were used to determine the expression of the lung resistance-related protein (LRP) in 87 cases of untreated non-small cell lung carcinoma. LRP expression was detected in 39 patients (45%). A significant correlation between LRP expression and tumor resistance to doxorubicin was found (p=0.03, Fisher's exact test). An inter-relationship between LRP expression and gender, age, stage, lymph node status and survival times was not observed. Furthermore, a relationship between LRP expression and proliferation (cell cycle phases, take rate of lung tumors in nude mice and cyclin A expression) was not detectable. However, a correlation of borderline significance was noticed between LRP expression and the patients' smoking habits. Carcinomas in heavy smokers (more than 30 cigarettes daily) were more frequently LRP-positive than carcinomas found in non-smokers (p=0.09, Fisher's exact test).

Prognostic value of basic fibroblast growth factor and its receptor (FGFR-1) in patients with non-small cell lung carcinomas.

Tumour specimens of 206 patients with untreated non-small cell lung carcinomas (NSCLC) were analysed immunohistochemically for the expression of the basic fibroblast growth factor (bFGF) and for its receptor (FGFR-1, Flg). Seventy of the tumours showed weak expression, 109 moderate and 27 high expression of bFGF. Thirty-eight tumours had low expression of FGFR-1, 116 had moderate and 52 cases high expression. Patients with high FGFR-1 expression had significantly shorter survival times than patients with weak or moderate expressions (P < 0.05), but there was no significant correlation between bFGF expression and patient survival. The results of the multivariate analysis demonstrated that FGFR-1 in the presence of stage is not an independent prognostic factor.

Consolidation biochemotherapy for patients with advanced nonsmall cell lung carcinoma responding to induction PVM (cisplatin, vinblastine, mitomycin-C) regimen: A phase II study

The authors investigated a consolidation biochemotherapy program with subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN alpha) biologic response modifiers (BRM) in patients with advanced nonsmall cell lung carcinoma (NSCLC) with responsive or stable disease to induction chemotherapy. Patients with proven, advanced, previously untreated NSCLC were entered into the study. Induction chemotherapy consisted of cisplatin, 120 mg/m2 intravenously (i.v.), on Day 1; vinblastine, 6 mg/m2 i.v., on Day 1; and mitomycin-C, 6 mg/m2 i.v., on Day 1 (PVM), every 3 weeks. Subsequently, patients with complete response (CR), partial response (PR), and stable disease (SD) received consolidation biochemotherapy with subcutaneous rIL-2, 3 MU/m2 twice/day, and rIFN alpha, 3 MU once/day, 5 days a week, starting 2 weeks after the second PVM course. After 3 and 6 weeks of BRM treatment, patients had a 14-day rest period to intercalate consolidating PVM courses. Seventy-seven patients were enrolled in the trial. After 2 PVM induction courses, 16 patients progressed and went off the study, whereas 61 patients were eligible for consolidation biochemotherapy. Among the 61 patients, 9 were not treated with BRM for several reasons, whereas 52 patients began biochemotherapy and were evaluable for toxicity. Furthermore, a few days after starting BRM, 9 patients discontinued therapy due to side effects; the remaining 43 patients received adequate treatment and were fully evaluable. In the 52 evaluable patients, the following BRM related toxicities were observed: World Health Organization (WHO) grade 2-3 fever in 85% of patients, asthenia in 71%, anorexia in 63%, and flu-like syndrome in 18.5%. PVM-related vomiting was present in 19% of patients. WHO Grade 3-4 myelosuppression, from both BRM and PVM (overlapping toxicity), was anemia in 16% of patients, leukopenia in 12%, and thrombocytopenia in 19%. There were three toxic deaths: two due to BRM-induced hypotension and one from pneumonia. In the 43 fully evaluable patients (23 PR and 20 SD after induction chemotherapy), after a median of 6 weeks of biochemotherapy (range, 3-16 weeks), we observed 5 of 20 patients achieving PR from SD, and 6 of 23 with confirmed PR. In these 11 patients, the median duration of response was 21 weeks (range, 7-80 weeks). Overall response improvement was 11.6% in the 43 patients and 6.4% in the 77 total enrolled patients. Median survival was 41 weeks (range, 15-173 weeks) in the 43 patients and 38 weeks (range, 1.4-173 weeks) in the 77 patients. In this study, biochemotherapy, when administered by this dose and schedule, did not offer substantial benefit although it caused significant toxicity.

1095 A phase II study of CPT 11 (irinotecan 350 mg/m 2 every 3 weeks) in untreated non-small cell lung carcinomas

Patients with untreated, stage IV, non small cell lung cancers (NSCLC); aged ≤ 75; WHO PS ≤ I; normal hematologic renal and hepatic baseline value have been selected for (treatment with the new Topolsomerase I inhibitor CPT 11 delivered as a 30’ IV infusion every 3 weeks at the dose of 350 mg/m2. Nineteen patients have been so far entered (M/F: 15/4; median age 62 (41–75); PS 0: 26%, 1: 63%,2: 11%); median number of involved organs: 3 (1–6) with lung in 30%, mediastinum in 21%, bone in 8% and liver in 5% of patients. All patients but one were chemotherapy naive. Patients have received 74 cycles (96% at the planned dose) and the median Relative Dose Intensity was 0.99. Efficacy (Preliminary Results) PR: 4; NC: 5; PD: 6; not evaluable: 4. Safety The following grade 3 or 4 toxicities have been observed: (% of patients) neutropenia: 28%; delayed diarrhea:. 26%; nausea/vomiting: 26%; anemia: 22%. An early cholinergic-like syndrome, never severe, was frequently observed. The most common symptom was diffuse sweating in 16% of patients. One toxic death occurred due to the combination of diarrhea and infection. Conclusion Severe neutropenia combined to severe diarrhea is the limiting toxicity. From these preliminary results, CPT 11 could be an effective drug in NSCLC, as formerly shown in Japanese studies.

PROGNOSTIC-SIGNIFICANCE OF PROLIFERATING CELL NUCLEAR ANTIGEN (PCNA) IN ADENOCARCINOMA OF THE LUNG

The aim of the study was to investigate the prognostic value of the proliferating cell nuclear antigen (PCNA) expression in non-small cell lung carcinomas (NSCLC). Two hundred and sixteen patients with previously untreated NSCLC entered into this investigation. For assessment of PCNA expression the streptavidin-biotinylated peroxidase complex method was performed using imnuunohistochemistry and Mab PC10. The tumors were scored for the percentage of PCNA-positive cells (low proliferative activity less than or equal to 25%; high proliferative activity >25%). Univariate analyses of all patients showed a trend that those with high proliferating tumors had shorter survival times than those with lower proliferating tumors. Similar results were obtained when the analysis was restricted to squamous cell carcinomas. Patients with adenocarcinomas and with high proliferating tumors had significantly shorter survival times than those with low proliferating tumors (p=0.028). No correlation was found between extent of tumors or metastasis and expression of PCNA. The multivariate analysis including age, sex, extent of tumors and metastasis as well as PCNA revealed a highly significant influence of extent of tumors (p=0.007) and metastasis (p=0.003) whereas all other factors including PCNA were of no significant influence.

Relationship of inherent resistance to doxorubicin, proliferative activity and expression of P-glycoprotein 170, and glutathione S-transferase-pi in human lung tumors.

This study analyzed whether proliferative activity and expression of P-glycoprotein 170 (P-170) or glutathione S-transferase-pi (GST-pi) in human non-small cell lung carcinomas (NSCLC) represent independent factors in resistance to doxorubicin or whether an association exists between these factors. Thirty-six patients with previously untreated NSCLC participated in the study. The thymidine labelling index (TLI) was measured for detection of proliferative activity, and immunohistochemistry was used for detection of P-170 and GST-pi. The resistance of tumors was determined in vitro by the nucleotide incorporation assay. Negative correlations between TLI and P-170 (P = 0.0009) or GST-pi (P = 0.007) were found. Positive correlations existed between resistance to doxorubicin in vitro and P-170 (P = 0.005) or GST-pi (P less than 0.0001). Expression of P-170 and GST-pi showed highly significant (P less than 0.0001) positive correlation. The results demonstrate that a significant positive relationship between P-170 and GST-pi in NSCLC exists and that the expression is increased in resistant tumors and in tumors with a low proliferative activity.