taxane and Small-Cell-Lung-Carcinoma

Median survival of small-cell lung cancer (SCLC) patients is usually around 1 year. The advent of new drugs may have slightly improved their prognosis. We aimed to assess whether SCLC response to chemotherapy and survival had changed over time.. Consecutive SCLC patients were included at Grenoble University Hospital, France. We compared the patients' characteristics, response to chemotherapy and survival between 1997-2009 (period 1) and 2010-2017 (period 2).. A total of 529 patients were identified, of whom 498 received a first line of chemotherapy and 279 a second line. The majority (n = 290, 58%) had extensive disease. The objective response rate (ORR) to first-line chemotherapy in metastatic patients was 63% in period 1 and 62% in period 2; the ORRs to second-line chemotherapy were 39% and 29%, respectively. Median overall survival from first-line chemotherapy was 13.2 months (interquartile range [IQR] 7.4-24.4) in period 1 and 11.2 months (IQR 7.1-21.2) in period 2. Mortality in these two periods did not differ significantly even after adjustment for prognostic factors (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.66-1.00). The factors independently associated with death were cardiovascular comorbidities (HR = 1.28 [95%CI 1.05-1.55]), liver comorbidities (HR = 1.31 [95%CI 1.03-1.65]), poor ECOG performance status (3-4vs. 0-1, HR = 2.45 [95%CI 1.83-3.30]) and extensive disease (HR = 2.69 [95%CI 2.18-3.33]).. Since 1997, there has been no improvement in the survival or response rate to chemotherapy of SCLC patients. There is a desperate need for new approaches in this setting.

Topics: Aged; Bridged-Ring Compounds; Cardiovascular Diseases; Etoposide; Female; France; Humans; Liver Diseases; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Platinum Compounds; Prognosis; Small Cell Lung Carcinoma; Survival Analysis; Taxoids

Providing epidemiological data and treatment of anemia in lung cancer patients undergoing first-line chemotherapy.. Epidemiological, observational, retrospective and multicenter study carried out at 30 sites throughout Spain.. The prevalence of anemia (hemoglobin [Hb] level <12 g/dl) was 18.3% and the incidence 80.7%. Mean Hb levels were 13.4 g/dl (95% Cl: 13.2-13.6) and 11.5 g/dl (95% Cl: 11.3-11.7) at starting and at the end of chemotherapy, respectively. Of the 294 patients with anemia, 174 (59.2%) were treated. Erythropoiesis-stimulating agents were given to 90.2% patients, alone in 31.6% and combined iron in 39.7%, transfusion in 9.2% and iron and transfusion in 9.8%.. These results suggest an appropriate and rational use of erythropoiesis-stimulating agents in the treatment of chemotherapy-associated anemia in lung cancer patients. [corrected].

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blood Transfusion; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Etoposide; Female; Gemcitabine; Hematinics; Hemoglobins; Humans; Incidence; Iron; Lung Neoplasms; Male; Middle Aged; Observational Studies as Topic; Prevalence; Retrospective Studies; Small Cell Lung Carcinoma; Spain; Taxoids; Vinblastine; Vinorelbine; Young Adult

Taxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs) that might contribute to taxane response, we performed a genome-wide association study (GWAS) for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs), followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel.. GWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC) patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196) and NSCLC (A549) cell lines.. 147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values <10-4 in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value < 0.05) associated with either SCLC or NSCLC patient overall survival. Knockdown of PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667), significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA) hsa-miR-584 or hsa-miR-1468.. GWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Lung Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Small Cell Lung Carcinoma; Survival Analysis; Taxoids

Lung cancer is the second most common cancer in both men (after prostate cancer) and women (after breast cancer). The microtubule-stabilizing taxane such as docetaxel is the only agent currently approved for both first- and second-line treatment of advanced non-small cell lung cancer. Although docetaxel has made significant progress in the treatment of lung cancers either using alone or in combination with various novel targeted agents, its use often results in various undesired side-effects. These limitations have led to the search for new taxane derivatives with fewer side-effects, superior pharmacological properties, and improved anticancer activity to maximize the induced benefits for lung cancer patients. Herein, four series of taxane derivatives were used to correlate their inhibitory activities against lung cancer cells with hydrophobic and steric descriptors to gain a better understanding of their chemical-biological interactions. A parabolic correlation with MR(Y) is the most encouraging example, in which the optimum value of this parameter is well defined. On the basis of this quantitative structure-activity relationship model, six compounds (3-23 to 3-28) are suggested as potential synthetic targets. Internal (cross-validation (q(2)), quality factor (Q), Fischer statistics (F ) and Y-randomization) and external validation tests have validated all the quantitative structure-activity relationship models.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Humans; Lung Neoplasms; Male; Quantitative Structure-Activity Relationship; Small Cell Lung Carcinoma; Taxoids