taxane and Carcinoma--Non-Small-Cell-Lung

Taxane chemotherapy represents the standard of care in the second-line setting for non-small cell lung cancer (NSCLC) patients, but immunotherapy agents pose great challenges. Whether immunotherapy/chemotherapy alone or combination therapy has more benefits remains controversial. In this study, we provided comparisons to integrate the efficacy of immunotherapy and taxane chemotherapy as second- or later-line treatments in advanced NSCLC.. PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to September 1, 2020. Randomized controlled trials comparing immunotherapy and taxane chemotherapy were enrolled in the Bayesian network analysis. Overall survival (OS) and progression-free survival (PFS) with hazard ratios (HRs) were investigated.. Eight trials in 13 studies with 4398 patients comparing seven treatments were identified. Pembrolizumab 10 mg/kg was associated with the best improved OS, with significant differences versus docetaxel (HR 0.81, 95% credible interval [CrI] 0.74-0.88), avelumab (HR 0.84, 95% CrI 0.75-0.95), and pembrolizumab 200 mg plus docetaxel (HR 0.75, 95% CrI 0.56-1.00). Although pembrolizumab 200 mg plus docetaxel ranked the last in terms of OS, the combination therapy showed the most favorable PFS. Additionally, the anti-programmed death-ligand 1 (PD-L1) agent, avelumab, was associated with the least improvement in PFS.. As second- or later-line therapeutic strategies, pembrolizumab 10 mg/kg provided the largest OS benefits and pembrolizumab 200 mg plus docetaxel improved PFS to the greatest extent. Considering that immunotherapy has been recommended to the first-line setting of NSCLC, advanced patients who have not received immunotherapy previously might be the suitable population for our findings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Carcinoma, Non-Small-Cell Lung; Docetaxel; Humans; Immunotherapy; Lung Neoplasms

Chemotherapy is one of the most frequently employed and reliable treatment options for the management of a variety of cancers. Taxanes (paclitaxel, docetaxel and cabazitaxel) are frequently prescribed to treat breast cancer, hormone refractory prostate cancer, non-small cell lung cancer and ovarian cancer. Most of the commercial products of taxanes are available as injectables, which are not patient compliant and are associated with frequent side effects like ototoxicity, baldness and neurotoxicity. Most of these concerns are ascribable to the presence of toxic solvents in these commercial formulations, which are used to solubilize these drug(s). However, there have been several attempts to develop toxic solvent free taxane formulations, especially employing novel drug delivery systems (NDDS). These systems have been reported to result in the advancement of anticancer activity, therapeutic index, stability, biocompatibility, tissue or organ targeting, encapsulation capacity, tissue permeability, oral bioavailability, reduced toxicity and reduced incidences of abnormal reactions, sustained and controlled release in comparison to the conventional solvent-based formulations. The review is an attempt to analyze the potential of NDDS-mediated taxane delivery for safer and effective cancer chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Colloids; Drug Carriers; Drug Delivery Systems; Female; Humans; Lung Neoplasms; Male; Ovarian Neoplasms; Prostatic Neoplasms; Taxoids

A number of studies have examined the relationship between the expression of the class III β-tubulin (TUBB3) and the treatment responses to the taxane/vinorebine-based chemotherapy in patients with non-small cell lung cancer (NSCLC). However, the results of these studies were inconsistent and inconclusive. Therefore, we conducted an up-to-date meta-analysis to evaluate the prognostic role of TUBB3 in the taxane/vinorebine-based chemotherapy.. A literature search for relevant studies was conducted in PubMed, Embase, and CNKI. The inclusion criteria were the taxane/vinorebine-based chemotherapy in patients with NSCLC and the evaluation of the clinical outcomes in relation to the expression of TUBB3. The clinical outcomes analyzed in this study included the overall response rate (ORR), overall survival (OS), and event-free survival (EFS). Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were calculated to assess the risk associated with the TUBB3 expression in the taxane/vinorebine-based chemotherapy.. A total of 28 studies with 2401 NSCLC patients were qualified for this meta-analysis. We found that the positive or high level of TUBB3 expression was associated with a poorer ORR (OR = 0.24, 95% CI = 0.16-0.36, p<0.001), an unfavorable OS (HR = 1.52, 95% CI = 1.27-1.82, p<0.001), and a worse EFS (HR = 1.47, 95% CI = 1.24-1.74, p<0.001) compared to the negative or low level of TUBB3 expression. The statistically significant associations between TUBB3 and chemotherapy responses were also observed in the stratified subgroup analysis, which included the analysis by ethnic subgroup (Asian and Caucasian), chemotherapy regimen (taxane-based and vinorebine-based), TUBB3 detection method (IHC and PCR), and treatment strategy (surgery plus adjuvant chemotherapy and palliative chemotherapy).. The expression level of TUBB3 may be a useful biomarker to predict the clinical outcomes of the taxane/vinorebine-based chemotherapy in patients with NSCLC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Odds Ratio; Prognosis; Publication Bias; Taxoids; Treatment Outcome; Tubulin; Vinblastine; Vinorelbine

In this review, we discuss the plight of Alice, a patient with advanced nonsmall cell lung cancer (NSCLC) who struggles with taxane-related peripheral neuropathy (PN). Using this unique point of view helps us to appreciate the implications of PN on daily activities as well as the difficulty in decision-making regarding continuation of treatment. In addition, published reports of phase 3 trials are reviewed to identify the incidence and severity of chemotherapy-induced PN as well as the assessment tools used in these studies.. A literature review spanning the years 1998-2012 was performed. Phase 3 studies and a meta-analysis of taxane-based therapy in advanced NSCLC were selected for review for their findings regarding the incidence and severity of chemotherapy-induced PN.. In total, 16 phase 3 studies and 1 meta-analysis were reviewed. Use of grading scales and PN assessment tools was inconsistent across the studies, and some studies did not report PN at all.. The true incidence and severity of chemotherapy-induced PN in clinical trials may be masked by nonstandardized reporting; thus, a more standardized approach to grading, assessing, and reporting PN in clinical trials is greatly needed to allow for appropriate comparisons across studies. Understanding chemotherapy-induced PN from the patient's perspective as well as the development of PN at the clinical trial level will help health care providers anticipate the development of PN and improve their ability to manage it.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Neuralgia; Peripheral Nervous System Diseases; Restless Legs Syndrome; Taxoids

Outcome of patients with locally advanced non-small-cell lung cancer (NCSLC) is generally poor, with five-year survival rate of only 23%, when patients are treated with surgery only. The presentation of positive adjuvant therapy trials in NSCLC has changed clinical practice, doubling the number of patients with completely resected NSCLC referred for adjuvant chemotherapy since 2004. Furthermore, few large studies described a large number of stage III patients in non-Asiatic patients and they showed controversial results about survival in completely resected stage IIIA NSCLC. The objective of this study was to evaluate the impact of adjuvant chemotherapy in completely resected stage IIIA NCSLC, administered on a routine basis, outside clinical trials.. This is a retrospective study of patients with stage IIIA NCSLC treated between 1990 and 2008, and included in a continuous, consecutive database. Inclusion criteria were: age >18 years, complete surgical resection, and pathologically confirmed as stage IIIA. The following clinical data were obtained: age, gender, performance status, histological type, chemotherapy regimens, status at last follow-up and hospital where the treatment occurred. Kaplan-Meier's method was used to determine actuarial survival. Differences in survival were determined by Breslow and log rank analyses.. According to these inclusion criteria, 415 patients were considered for the present study. The median follow-up time of all patients was 38.2 months. The adjuvant chemotherapeutic treatment affected survival significantly (P <0.001). Also the type of chemotherapeutic treatment affected survival (P ≤0.001).. Cisplatin-based adjuvant chemotherapy was beneficial in patients who had a completed resected stage IIIA carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Deoxycytidine; Drug Evaluation; Etoposide; Female; Follow-Up Studies; Gemcitabine; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Pneumonectomy; Randomized Controlled Trials as Topic; Retrospective Studies; Taxoids; Vinblastine; Vinorelbine

Progress in the treatment of non-small-cell lung cancer (NSCLC) will require the introduction of new agents as well as better use of existing therapies. Targeted therapies are likely to have a profound effect on the treatment of NSCLC after identification of patients who are most likely to benefit. The epothilones are novel anti-tubulin agents derived from Sorangium cellulosum. β III tubulin overexpression has been implicated as a mechanism of anti-tubulin resistance that can be overcome by epothilones. Several epothilones have advanced to clinical trials; ixabepilone (BMS247550, aza-epothilone B, Bristol-Myers Squibb, New York, NY), patupilone (EPO906, Novartis, Basel, Switzerland) and sagopilone (ZK-EPO, ZK-219477, Schering AG, Berlin-Wedding, Germany) are currently in active development. Several of the epothilones, most notably ixabepilone, have demonstrated activity in lung cancer in phase I and II trials, including taxane-resistant patients. Although a phase II study failed to show superior outcome in patients with β III tubulin overexpression, other aspects of the epothilones argue for their continued development.

Topics: Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Drug Discovery; Drug Resistance, Neoplasm; Epothilones; Humans; Lung Neoplasms; Taxoids; Tubulin Modulators

Non-platinum regimens have been proposed as an alternative to the platinum-based combinations for treatment of advanced non-small cell lung cancer. However, conflicting results were reported.. Meta-analysis of phase III trials randomizing platinum-based versus non-platinum combinations as first-line chemotherapy with 1-year survival rate as a primary endpoint. Fourteen trials have been identified. Experimental arms were gemcitabine/vinorelbine (n=4), gemcitabine/taxane (n=7), gemcitabine/epirubicin (n=1), paclitaxel/vinorelbine (n=1), and gemcitabine/ifosfamide (n=1). The comparator was a doublet of a platinum compound plus a third generation agent for all but two studies (triplets). Updated data were available for 13 studies. The Peto and Yusuf method was used to generate odds ratios (OR). All tests are two-sided.. A statistical heterogeneity was detected when the 13 studies were analyzed. Considering that current guidelines recommend platinum-based doublets as standard therapy we therefore limited the meta-analysis to the set of 11 phase III studies which used a platinum-based doublet (2298 and 2304 patients in platinum-based and non-platinum arms, respectively). No significant heterogeneity was detected in this consistent group of studies. Patients treated with a platinum-based regimen benefited from a statically significant reduction in the risk of death at 1 year (OR: 0.88, 95% CI 0.78-0.99; p=0.044) and a lower risk of being refractory to chemotherapy (OR: 0.87, 0.73-0.99; p=0.049). Forty-four (1.9%) and 29 (1.3%) toxic-related deaths were reported for platinum-based and non-platinum regimens, respectively (OR: 1.53; 0.96-2.49, p=0.08). An increased risk of grade 3-4 gastro-intestinal and hematological toxicity for patients receiving platinum-based chemotherapy was statistically demonstrated. There was no statically significant increase in risk of febrile neutropenia, OR=1.23 (0.94-1.60, p=0.063).. A platinum-based doublet induced a statically significant reduction in the risk of death when compared with non-platinum chemotherapy without inducing an unacceptable increase in toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials, Phase III as Topic; Deoxycytidine; Epirubicin; Gemcitabine; Humans; Ifosfamide; Lung Neoplasms; Paclitaxel; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Vinblastine; Vinorelbine

Vinorelbine, a novel vinca alkaloid derivative developed in France, has been widely used for the treatment of breast cancer and non-small cell lung cancer since the 1990s in many foreign countries. In Japan, it has been available for the treatment of non-small cell lung cancer since 1999, and the additional indication of breast cancer was approved in May 2005. Japanese phase I clinical trials started in 1988. A total of six trials have been conducted in patients with advanced or recurrent breast cancer, and have provided evidence of efficacy in all groups of patients, including those receiving vinorelbine as first-line monotherapy and those previously treated with both anthracyclines and taxanes. This report reviews the data from these studies and also presents the results of combination therapy evaluated outside Japan. In addition,we explain why it took 17 years for vinorelbine to be approved despite the fact that as early as the beginning of development, it was scientifically proven to be very useful in patients with breast cancer, and that the new drug application was submitted in 1993. The relationship between healthcare professionals, patients and the regulatory agency is also discussed to point out related issues.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Drug Approval; Female; Fluorouracil; Humans; Japan; Lung Neoplasms; Male; Paclitaxel; Taxoids; Vinblastine; Vinorelbine

Lung cancer remains the primary cause of cancer-related death in both men and women in the United States. Chemotherapy has been shown to provide a survival benefit in patients with advanced non-small-cell lung cancer (NSCLC), and current regimens have produced median survivals of approximately 8 months and 1-year survival rates of 30% to 35% in patients with stage IIIB and IVdisease. Nevertheless, there remains room for improvement. Irinotecan (CPT-II, Camptosar) has demonstrated efficacy in the treatment of small-cell lung cancer (SCLC). It also appears to have promising activity in advanced NSCLC, producing overall response rates of up to 32%. Combinations of irinotecan and cisplatin or carboplatin (Paraplatin) have resulted in overall response rates of 25% to 56% in phase II and III studies in patients with advanced disease, with median survivals ranging from 9 to 13 months and 1-year survival rates of 33% to 58%. Current irinotecan-based doublet and triplet regimens appear to produce promising response rates with manageable toxicities. In addition, irinotecan has demonstrated potential as a radiosensitizing agent and is currently being evaluated in several trials of combined-modality therapy in patients with locally advanced NSCLC. Early trials of irinotecan in combination with cisplatin or carboplatin along with radiation therapy have reported overall response rates of 60% to 67%. The approach appears to have potential and warrants further study.

Topics: Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Irinotecan; Lung Neoplasms; Organoplatinum Compounds; Taxoids

Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy-toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. QUALY methods based on time without symptoms and toxicity allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing non-platinum-based doublets with either single-drug chemotherapy or standard cisplatin-based doublets.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Gemcitabine; Humans; Lung Neoplasms; Quality of Life; Survival Rate; Taxoids; Vinblastine; Vinorelbine

Cisplatin (Platinol)-based chemotherapy has been the standard systemic therapy for both non-small-cell and small-cell lung cancer for the past 2 decades, though the efficacy and benefit remain modest. Recently, several novel agents have been introduced that have single-agent activity comparable to cisplatin and offer the possibility of improved therapy for lung cancer. Camptothecin and taxane derivatives are associated with both different mechanisms of action and nonhematologic toxicities, and have demonstrated additive or synergistic activity when used in combination in preclinical studies. We review pertinent clinical studies of these agents in lung cancer and present our experience in combining irinotecan (Camptosar, CPT-11) with taxanes on a weekly schedule in dose-finding and efficacy studies. When chemotherapy is delivered for 4 consecutive weeks followed by a 2-week rest, hematologic toxicity is dose limiting and most prominent during weeks 3 and 4. Dose intensification is feasible if the schedule is modified so the chemotherapy is given on days 1 and 8, with cycles repeated every 3 weeks. The most common nonhematologic toxicities remain asthenia, neuropathy, and diarrhea. Future studies will explore and better define the role of these drug combinations in the treatment of lung cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Prognosis; Survival Rate; Taxoids

The plant-derived taxanes have a unique mechanism of cytotoxic action and have shown interesting response and survival data in metastatic non-small cell lung cancer (NSCLC). Based on these results, taxane-based regimens have been investigated in combination with radiotherapy in unresectable NSCLC. Trials with paclitaxel-based concurrent chemoradiotherapy have shown 50-100% tumour response rates, 12-26 month median survivals and 32-52% 2-year survival rates. Trials with concurrent chemoradiotherapy with docetaxel have shown 35-92% tumour response rates, 12-23 month median survivals, and 41-43% 2 year survival rates. Taxane-based concurrent chemoradiotherapy for stage III NSCLC appears promising. Large ongoing randomised trials will define the role of these agents in the treatment of locally advanced NSCLC.

Topics: Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Combined Modality Therapy; Docetaxel; Guidelines as Topic; Lung Neoplasms; Multicenter Studies as Topic; Neoplasm Staging; Paclitaxel; Taxoids; Treatment Outcome

Gemcitabine (Gemzar) was originally approved for use in combination with cisplatin (Platinol) for the treatment of advanced non-small-cell lung cancer (NSCLC). Research began to focus on combining gemcitabine with newer drugs, such as carboplatin (Paraplatin), vinorelbine (Navelbine), the taxanes, and the camptothecins, when it became clear that these agents had potentially increased efficacy and fewer side effects than the standard treatment. This article will briefly review the original experience with the gemcitabine/cisplatin doublet and then examine the experience to date with non-cisplatin-based gemcitabine doublet combinations in the treatment of advanced NSCLC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Disease-Free Survival; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Gemcitabine; Humans; Lung Neoplasms; Paclitaxel; Randomized Controlled Trials as Topic; Remission Induction; Taxoids; Vinblastine; Vinorelbine

Over the past 5 to 7 years, new and promising systemic agents have entered the therapeutic armamentarium in the treatment of advanced non-small-cell lung cancer. In particular, the taxanes, irinotecan, vinorelbine, and gemcitabine, have each been shown to perturb the natural history of this disease. In combination with cisplatin, these agents have yielded improvements in response rates and in survival, compared with either cisplatin alone or with older platinum combinations, with consistent 1-year survival rates of 30% to 40% or more and response rates exceeding 25%. Other factors may also be responsible for improved survival rates, including patient selection, improved supportive care, and more extensive screening procedures, such as CT and positron emission tomography, which have resulted in stage migration. Future directions will focus on the role of nonplatinum combinations, particularly in the elderly and in patients with compromised performance status; salvage therapy in patients with intact performance status; quality of life and quality adjusted survival; and the role of new biologic agents, which alter the tumor milieu and may be readily integrated into standard cytotoxic regimens. Except for unfit or unwilling patients, there is no room for therapeutic nihilism.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Gemcitabine; Humans; Immunologic Factors; Irinotecan; Lung Neoplasms; Magnetic Resonance Imaging; Middle Aged; Neoplasm Staging; Prognosis; Quality of Life; Survival Analysis; Taxoids; Tomography, X-Ray Computed; Vinblastine; Vinorelbine

Cancer management in the older patient is a growing concern, particularly with the increasing geriatric population and the high incidence of cancer among these individuals. Incidence of lung cancer in particular is known to rise with age. This article reviews prognosis, treatment options, and decision-making issues for both clinician and patient with respect to both non-small-cell and small-cell lung cancer in this population. Research findings dealing with response rates, survival rates, and symptom control in this age group are reviewed for radiotherapy, surgery, and for various chemotherapy agents, including gemcitabine, the taxanes, vinorelbine, and the topoisomerase 1 inhibitors. Quality- of-life issues are also addressed.

Topics: Age Factors; Aged; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Combined Modality Therapy; Decision Making; Deoxycytidine; Gemcitabine; Geriatrics; Humans; Lung Neoplasms; Prognosis; Quality of Life; Survival Analysis; Taxoids; Vinblastine; Vinorelbine

The TORG0503 study was undertaken to select a preferred platinum-based third-generation regimen for patients with completely resected non-small cell lung cancer (NSCLC). This study aimed to describe the quality of life (QOL) analysis of that study.. Patients with completely resected NSCLC were randomized to receive three cycles of docetaxel plus cisplatin (DC) or paclitaxel plus carboplatin (PC) on day 1 every 3 weeks. QOL was assessed at three time points (baseline, after two cycles, and after three cycles) using the Functional Assessment of Cancer Therapy-taxane (FACT-Taxane). The adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression analysis that was adjusted for the baseline score in the FACT-Taxane total score and each subscale to evaluate treatment (PC vs. DC) effectiveness.. QOL data from 104 patients (DC, n = 56 patients; PC, n = 48) were analyzed. In the FACT-Taxane total score, the baseline-adjusted OR (95% CI) of not worse QOL for the DC group was 3.3 (1.4-8.3) compared with the PC group. In the taxane subscale, the baseline-adjusted OR (95% CI) was 6.2 (2.6-16.0).. Total QOL was maintained better in the DC group than in the PC group, especially the taxane subscale that consists of neurotoxicity and taxane components in spite of no treatment-related death in both arms between DC and PC. We might recommend DC as the control regimen for the next clinical trial from the viewpoint of QOL, similar to the primary outcomes in TORG0503.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Docetaxel; Humans; Lung Neoplasms; Paclitaxel; Quality of Life; Taxoids

Chemo-radiotherapy is standard of care in the treatment of unresectable stage III NSCLC. We aimed at assessing whether the addition of concurrent taxane-chemotherapy to thoracic irradiation following chemotherapy was able to improve treatment outcome.. In PITCAP trial, patients with unresectable stage III NSCLC were randomized to receive 2 cycles of platinum-paclitaxel followed by 60-61.2Gy thoracic irradiation (control arm) or by same radiotherapy with concomitant weekly paclitaxel (experimental arm). A literature-based meta-analysis including all studies with same design was also performed.. At the time of the second interim analysis, when 151 patients were randomized, accrual was terminated. With a median follow-up of 6.1 years, median survival was 13.2 vs 15.1 months, with a 3-year survival rate of 19.5 vs 21.2% in the control and experimental arm, respectively (HR: 0.97; 95% CI 0.69-1.36; p=0.845). Treatment toxicity was manageable in both arms. The meta-analysis of 5 trials (n=866) confirmed the lack of a meaningful effect on 1-year overall survival of a taxane added concurrently to radiotherapy.. These results do not support a meaningful survival benefit with the addition of single agent taxane given concurrently to radiotherapy after platinum-based induction in locally advanced NSCLC.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Female; Humans; Induction Chemotherapy; Male; Meta-Analysis as Topic; Middle Aged; Neoplasm Staging; Paclitaxel; Survival Rate; Taxoids; Treatment Outcome

nab-Paclitaxel (nab-P) is approved, in the United States, in combination with carboplatin for the first-line treatment of advanced non-small-cell lung cancer, based on a randomized phase 3 trial of nab-P plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C). This trial revealed a higher overall response rate (33% versus 25%; p = 0.005) and longer, but not statistically significant, overall and progression-free survival for nab-P/C versus sb-P/C. In addition, nab-P/C demonstrated lower rates of grade 3 or higher peripheral neuropathy, myalgia, arthralgia, and neutropenia but higher rates of anemia and thrombocytopenia. This report analyzes patient and physician assessment of symptoms within this trial.. Patients completed the taxane subscale of the Functional Assessment of Cancer Therapy questionnaire, which focuses on taxane toxicity, including peripheral neuropathy and neurotoxicity. Mean baseline scores and changes from baseline are reported. Physicians also graded the severity of neuropathy at each patient visit using National Cancer Institute Common Toxicity Criteria.. Patients receiving nab-P/C reported significantly less worsening of peripheral neuropathy (p < 0.001), pain (p < 0.001), and hearing loss (p = 0.002). Patient-reported edema was similar between the two treatment arms. In agreement with patient-reported symptoms, the results of a per-treatment cycle physician assessment of peripheral neuropathy also favored nab-P/C over sb-P/C (p < 0.001).. In this trial of patients receiving first-line treatment for advanced non-small-cell lung cancer, nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C.

Topics: Adult; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Paraneoplastic Polyneuropathy; Quality of Life; Taxoids

DISRUPT evaluated whether adding the vascular-disrupting agent ombrabulin to a taxane-platinum doublet in the first-line setting improved progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC).. Patients were randomised to ombrabulin 35 mg/m(2) or placebo followed by a taxane-platinum regimen every 3 weeks.. Overall, 176 patients were randomised. After 124 events, median PFS was not significantly improved with ombrabulin vs placebo (5.65 vs 5.45 months; HR 0.948; 60% CI 0.813-1.106; one-sided P=0.39). The two groups showed similar overall survival (median 11.0 months in both groups), objective response rate (32% ombrabulin; 31% placebo) and safety profiles.. This study did not meet its primary endpoint of improving PFS by adding ombrabulin to a taxane-platinum regimen for first-line treatment of metastatic NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Platinum; Serine; Taxoids; Treatment Outcome

Eribulin mesylate (E7389) is an analog of halichondrin B with a unique mechanism of microtubule binding. The activity and toxicity of eribulin were assessed in patients with advanced non-small cell lung cancer (NSCLC) previously treated with a taxane.. An open-label phase II study included patients with NSCLC previously treated with platinum and taxane-based therapy, with up to two prior cytotoxic regimens, given for metastatic disease or as adjuvant therapy. Patients were stratified by taxane-sensitivity: taxane-sensitive (TS, progression >90 days after taxane) or taxane-resistant (TR, progression ≤90 days after taxane). Patients received an intravenous infusion of eribulin at 1.4 mg/m on days 1 and 8 every 21 days. The primary end point was objective response rate and secondary end points included progression-free survival and overall survival.. Sixty-six patients were accrued. The objective response rate was 5% with a median duration of response of 7.8 months. In the TS arm, 3 of 45 patients (7%) achieved a partial response and another 11 of 45 (24%) achieved stable disease for at least 3 months, whereas in the TR arm, no patients achieved a partial response and 4 of 21 (19%) achieved stable disease for at least 3 months. Median progression-free survival was 2.9 months in the TS subgroup and 1.2 months in the TR subgroup. The median overall survival was 12.6 months in the TS subgroup and 8.9 months in the TR subgroup. Toxicities were primarily hematologic; only two patients developed grade 3 neuropathy.. Eribulin mesylate is well tolerated and demonstrates activity in pretreated, TS NSCLC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Ethers, Cyclic; Female; Follow-Up Studies; Furans; Humans; Ketones; Lung Neoplasms; Macrolides; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Platinum; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

To evaluate the activity and tolerance of gemcitabine (GEM) in combination with vinorelbine (VRL) in pretreated patients with advanced non-small cell lung cancer (NSCLC).. Fifteen patients with advanced NSCLC who had disease progression after a cisplatin- or taxane-based front-line regimen were enrolled into a 2-stage design trial and were treated with VRL 30 mg/m² i.v. for 10 min followed by GEM 1,200 mg/m² i.v. for 30 min on days 1 and 15 of each 28-day cycle. Chemotherapy was given for 6 cycles unless disease progression or unacceptable toxicity was seen. The patients' median age was 64 years and the performance status (WHO) was 0 (n = 7), 1 (n = 5), and 2 (n = 3). The treatment was second line for 10 (67%) and third line or more for 5 (33%) patients.. No complete or partial responses were observed. Stable disease was seen in 4 (27%) patients and progressive disease in 11 (73%). The median time to tumor progression was 3 months (range 1-12) and the median survival was 4 months (range 2-31). Severe myelotoxicity was infrequent. Grade 2 neutropenia was observed in 2 (13%) patients, grade 2 thrombocytopenia in 1 (7%), and grade 2 anemia in 3 (20%). Nonhematologic toxicities were very mild and easily manageable.. The GEM plus VRL combination at the present doses and schedule is a safe but ineffective regimen; therefore, it is not recommended as second-line treatment in patients with advanced NSCLC.

Topics: Aged; Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Drug Administration Schedule; Female; Gemcitabine; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Taxoids; Vinblastine; Vinorelbine

Treatment options in patients with recurrent non-small cell lung cancer (NSCLC) remain limited as a result of poor activity of most agents after failure of platinum-based therapy. In the present phase I-II study, we evaluated the feasibility and efficacy of bi-weekly gemcitabine (GEM) + irinotecan (CPT-11) in patients with relapsed NSCLC.. Patients with advanced NSCLC, WHO-performance status (PS)

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Diarrhea; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Patient Compliance; Quality of Life; Survival Analysis; Taxoids

To improve the prognosis of cN2, N3 non-small cell lung cancer, we performed induction chemoradiotherapy (carboplatin-taxane chemotherapy and concurrent 50-Gy radiation) followed by surgery.. Patients with pathologically proven non-small cell lung cancer with bulky cN2, N3 disease were enrolled. Forty-one patients underwent an operation after chemoradiotherapy from January 2000 to April 2006. Either carboplatin-paclitaxel (n = 19) or carboplatin-docetaxel (n = 22) chemotherapy was randomly used. Two cycles of chemotherapy were performed with concurrent radiation (50 Gy). In all cases, conventional radiological reevaluations were performed; in the latest 21 cases, reevaluations with positron-emission tomography with fludeoxyglucose F 18 were also performed.. In all 41 cases, complete resections were performed, with no operative mortality. The histologically complete response rate, major response rate, and minor response rate were 17.1% (7/41), 56.1% (23/41), and 26.8% (11/41), respectively. The 5-year overall survival was 52.7%. There were no differences in survival between taxane groups. Both the complete response and the major response groups revealed a significantly better 5-year survivals than the minor response group (85.7%, P = .044, 52.4%, P = .01). Even with persistent N2 disease, the 5-year survival in the major response group (66%) was promising. With the combination of conventional computed tomography and positron-emission tomography with fludeoxyglucose F 18 for reevaluation, eligible patients could be selected for this protocol.. Surgery after chemoradiotherapy (carboplatin-taxane and 50-Gy radiation) for bulky cN2, N3 non-small cell lung cancer can be safely performed with promising results. Even with persistent N2 disease, the survival in the major response group was promising.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Radiotherapy Dosage; Survival Rate; Taxoids

To assess the efficacy and tolerance of the vinorelbine/cisplatin combination in non-small cell lung cancer patients pre-treated with a taxane-based regimen.. Among the 32 enrolled patients, 28 (87.5%) had a PS (WHO) of 0-1 and 13 (40.6%) have previously received both platinum compounds and taxanes. Vinorelbine (25 mg/m2 on days 1 and 8) was given by a rapid i.v. infusion and cisplatin (80 mg/m2 on day 8) after appropriate hydration. The treatment was repeated every 3 weeks.. A partial response was achieved in six patients (ORR=18.8%; 95% confidence interval: 5.23-32.27); 13 (44.8%) and 10 (34.5%) patients had stable and progressive disease, respectively (intention-to-treat analysis). Four partial responses were observed in patients who were previously treated with taxanes/platinum-containing regimens. The median time to tumor progression was 4.7 months (range, 1.3-15.4). After a median follow-up period of 6.3 months (range, 1.3-15.4) the median overall survival was 7.6 months and the 1-year survival rate 17.7%. Grade 3 and 4 granulocytopenia was observed in 11 (34.4%) patients and grade 4 thrombocytopenia in one (3.1%). Eleven (34.4%) patients presented grade 2 and 3 anemia. Febrile neutropenia occurred in one (3.1%) patient. Grade 3 and 4 nausea/vomiting was reported in one (9.3%) patient each and grade 2 fatigue in four (12.5%).. The combination of vinorelbine and cisplatin is an active and well tolerated salvage regimen in NSCLC patients pre-treated with taxane-based chemotherapy.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Survival Rate; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

To evaluate the activity and tolerance of gemcitabine in combination with oxaliplatin (GEMOX regimen) in pretreated patients with advanced non-small cell lung cancer (NSCLC).. Thirty-two patients with advanced NSCLC who had disease progression after a cisplatin- and taxane-based front-line regimen were treated with gemcitabine (1500 mg/m(2) on days 1 and 8) and oxaliplatin (130 mg/m(2) on day 8) every 3 weeks. The patients' median age was 62 years and the performance status (WHO) was 0 for 11, 1 for 17 and 2 for 4 patients. The treatment was second line for 22 (69%) and >or=third line for 10 (31%) patients.. Partial response was achieved in 5 (16%) patients, stable disease in 8 (25%) and progressive disease in 19 (59%). Two patients with stable disease and one patient with progressive disease while on previous chemotherapy experienced a partial response with GEMOX regimen. The median duration of response was 2.5 months (range, 1-11.5), the median time to tumor progression 3 months (range, 1-18) and the median survival 5.6 months (range, 1-31). Grade III neutropenia occurred in five (16%) patients, grade III thrombocytopenia in two (6%) and grade III anemia in three (9%); moreover, grades II-III asthenia was reported in eight (25%) patients and grades II-III neurotoxicity in three (9%).. The GEMOX combination is a relatively active and well tolerated second-line regimen in NSCLC patients pretreated with a taxane- and/or platinum-based chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Female; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Taxoids; Treatment Outcome

The authors evaluated the safety, tolerability, and efficacy of treatment using lonafarnib, a novel farnesyltransferase inhibitor (FTI), in combination with paclitaxel in patients with metastatic (Stage IIIB/V), taxane-refractory/resistant nonsmall cell lung carcinoma (NSCLC).. Patients with NSCLC who experienced disease progression while receiving previous taxane therapy or who had disease recurrence within 3 months after taxane therapy cessation were treated with continuous lonafarnib 100 mg orally twice per day beginning on Day 1 and paclitaxel 175 mg/m(2) intravenously over 3 hours on Day 8 of each 21-day cycle.. A total of 33 patients were enrolled, 29 of whom were evaluable for response. Partial responses (PR) and stable disease (SD) were observed in 3 (10%) and 11 patients (38%), respectively. Thus, 48% (14 of 29) experienced clinical benefit (PR or SD). The updated and final median overall survival time was 39 weeks and the median disease progression-free survival time was 16 weeks. The combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Grade 3 toxicities included fatigue (9%), diarrhea (6%), and dyspnea (6%). Grade 3 neutropenia occurred in only 1 patient (3%). Grade 4 adverse events included respiratory insufficiency in 2 patients (6%) and acute respiratory failure in 1 patient (3%).. Lonafarnib plus paclitaxel demonstrated clinical activity in patients with taxane-refractory/resistant metastatic NSCLC. In addition, the combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Evaluation of this combination therapy in additional clinical trials is warranted.

Topics: Adult; Aged; Alkyl and Aryl Transferases; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Drug Therapy, Combination; Enzyme Inhibitors; Farnesyltranstransferase; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Paclitaxel; Piperidines; Pyridines; Remission Induction; Survival Rate; Taxoids; Treatment Outcome

Pegylated filgrastim is a new formulation of a neutrophil colony-stimulating factor that has a long circulating half-life, permitting a single dose of filgrastim per cycle of chemotherapy. The pegylated filgrastim is recommended to be administered not less than 24 hours following chemotherapy and not less than 14 days prior to chemotherapy based on the theoretic concern that marrow suppression would be accentuated. This schedule of usage for pegylated filgrastim may compromise its application for weekly chemotherapy schedules. We have treated 80 patients with pegylated filgrastim administered on the same day as chemotherapy; the latter delivered on a weekly schedule. Twenty-four patients had non-small cell lung cancer (NSCLC) and were treated with one of two weekly chemotherapy regimens alternating triplets [AT] taxane, cisplatin, irinotecan alternating with gemcitabine, cisplatin, vinorelbine or alternating doublets [AD] taxane, cisplatin alternating with gemcitabine, vinorelbine; four of these patients also received weekly taxane and carboplatin with concomitant thoracic radiation. A consistent pattern emerged in which leukocytosis was observed at Day 8; median WBC 15,800/uL (range 7,200 to 35,000/uL); at Day 14, the median WBC was 9,300/uL (range 1,100 to 17,400/uL). Pegylated filgrastim can be given safely simultaneously with chemotherapy in weekly chemotherapy schedules. The pegfilgrastim can be administered on an every two week (fortnightly) schedule to maintain a weekly chemotherapy schedule.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Drug Administration Schedule; Filgrastim; Gemcitabine; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Lung Neoplasms; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Taxoids; Vinblastine; Vinorelbine

Second-line chemotherapy for patients with nonsmall cell lung carcinoma has been ineffective due to the lack of activity of older agents following platinum-based therapy. This Phase II trial evaluated the feasibility, toxicity, and efficacy of two active new agents, gemcitabine and vinorelbine, used in combination as second-line therapy for patients with nonsmall cell lung carcinoma.. Patients with advanced nonsmall cell lung carcinoma who had progressive disease after previous chemotherapy or combined-modality therapy were eligible for this trial. All patients received vinorelbine 20 mg/m(2) followed by gemcitabine 1000 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle. Patients were reevaluated for a response after two treatment courses: responding patients and those with stable disease received a maximum of six courses. Fifty-five patients were treated between January 1998 and November 1998; 47 patients (85%) had previously received both a taxane and a platinum agent.. Objective responses were seen in 9 of 50 evaluable patients (18%), including 8 partial responses and 1 complete response. Twenty-four additional patients (48%) had either minor response or stable disease. The median time to progression for patients with objective response or stable disease was 5 months. The median survival was 6.5 months with an actuarial 1-year survival of 20%. The treatment was well tolerated with uncommon nonhematologic toxicity and no alopecia. Grade 3 neutropenia and thrombocytopenia occurred in 27% and 22% of patients, respectively, but Grade 4 neutropenia was uncommon (occurring in 9% of patients) and only 4 patients required hospitalization for treatment of neutropenia and fever.. The combination of vinorelbine and gemcitabine is active and well tolerated as second-line therapy for patients with advanced nonsmall cell lung carcinoma. This regimen merits further evaluation as a first-line therapy for patients with this disease.

Topics: Actuarial Analysis; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Disease Progression; Feasibility Studies; Female; Fever; Gemcitabine; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Platinum Compounds; Remission Induction; Survival Rate; Taxoids; Thrombocytopenia; Vinblastine; Vinorelbine

Dose-limiting toxicities significantly impact the benefit/risk profile of many drugs. Whole genome sequencing (WGS) in patients receiving drugs with dose-limiting toxicities can identify therapeutic hypotheses to prevent these toxicities. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting neurological toxicity of chemotherapies with no effective approach for prevention.. We conducted a genetic study of time-to-first peripheral neuropathy event using 30× germline WGS data from whole blood samples from 4900 European-ancestry cancer patients in 14 randomized controlled trials. A substantial number of patients in these trials received taxane and platinum-based chemotherapies as part of their treatment regimen, either standard of care or in combination with the PD-L1 inhibitor atezolizumab. The trials spanned several cancers including renal cell carcinoma, triple negative breast cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, and melanoma.. We identified a locus consisting of low-frequency variants in intron 13 of GRID2 associated with time-to-onset of first peripheral neuropathy (PN) indexed by rs17020773 (p = 2.03 × 10. Our genetic study provides insight into the impact of low-frequency and rare coding genetic variation on PN risk and suggests that further study of GPR68 in sensory neurons may yield a therapeutic hypothesis for prevention of CIPN.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Paclitaxel; Peripheral Nervous System Diseases; Randomized Controlled Trials as Topic; Receptors, G-Protein-Coupled; Taxoids

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Docetaxel; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Lung Neoplasms; Paclitaxel; Taxoids

Immunotherapy is now a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC), but its uptake and effectiveness among older patients outside clinical trials remain poorly understood.. To understand treatment patterns and evaluate the overall survival associated with checkpoint inhibitor immunotherapy, cytotoxic chemotherapy, and combined chemoimmunotherapy for older patients who have advanced NSCLC and Medicare coverage.. This retrospective cohort study included Medicare-insured patients in the US aged 66 to 89 years who initiated first palliative-intent systemic therapy for lung cancer between January 1, 2016, and December 31, 2018. Survival follow-up continued through March 31, 2020. A total of 19 529 patients who had advanced lung cancer and were insured by a Medicare fee-for-service plan were included in the analysis.. Regimens included pembrolizumab monotherapy (n = 3079), combined platinum-based drug (ie, cisplatin or carboplatin [hereinafter, platinum]) and pemetrexed disodium (n = 5159), combined platinum and a taxane (ie, paclitaxel, nab-paclitaxel, or docetaxel) (n = 9866), and combined platinum, pemetrexed, and pembrolizumab (n = 1425), as ascertained using Medicare claims from the Centers for Medicare & Medicaid Services.. The primary outcome was overall survival, which was measured using the restricted mean survival time (RMST) with propensity score adjustment for clinical and sociodemographic characteristics. Median survival was also reported for comparison with outcomes from registrational trials.. A total of 19 529 patients (54% male, 46% female; median age, 73.8 [interquartile range, 69.9-78.4] years) were identified for analysis. The uptake of pembrolizumab-containing regimens in the Medicare population was rapid, increasing from 0.7% of first-line treatments in the second quarter of 2016 to 42.4% in the third quarter of 2018. Patients who were older (≥70 years, 2484 [81%]), were female (1577 [51%]), and/or had higher Risk Stratification Index scores (highest quintile, 922 [30%]) were more likely to receive single-agent pembrolizumab than chemotherapy. After propensity score adjustment, pembrolizumab was associated with survival similar to platinum/pemetrexed (RMST difference, -0.2 [95% CI, -0.5 to 0.2] months) or platinum/taxane (RMST difference, -0.7 [95% CI, -1.0 to -0.4] months). Patients receiving platinum/pemetrexed/pembrolizumab chemoimmunotherapy also had adjusted survival similar to those receiving platinum/pemetrexed chemotherapy (RMST difference, 0.5 [95% CI, 0.1-0.9] months). The unadjusted median survival was 11.4 (95% CI, 10.5-12.3) months among patients receiving single-agent pembrolizumab, approximately 15 months shorter than observed among pembrolizumab-treated participants in the KEYNOTE-024 trial. The unadjusted median survival was 12.9 (95% CI, 11.8-14.0) months among patients receiving platinum/pemetrexed/pembrolizumab chemoimmunotherapy, approximately 10 months shorter than observed among platinum/pemetrexed/pembrolizumab-treated participants in the KEYNOTE-189 trial.. Immunotherapy has been incorporated rapidly into treatment for patients with advanced NSCLC. However, survival estimates in the Medicare population are much shorter than those reported in registrational trials. These results provide contemporary estimates of survival for older patients with advanced NSCLC treated in routine practice, facilitating patient-centered decision-making.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Cohort Studies; Female; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Male; Medicare; Pemetrexed; Retrospective Studies; Survival Analysis; Taxoids; United States

The CDK4/6 inhibitor palbociclib reduces tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Palbociclib in combination with anti-hormonal therapy brings significant benefit to breast cancer patients. In this study, novel combination approaches and underlying molecular/cellular mechanisms for palbociclib were explored in squamous cell lung cancer (SqCLC), the second most common subtype of non-small cell lung cancer. While approximate 20% lung patients benefit from immunotherapy, most SqCLC patients who receive platinum-doublet chemotherapy as first-line treatment, which often includes a taxane, are still in need of more effective combination therapies. Our results demonstrated enhanced cytotoxicity and anti-tumor effect with palbociclib plus taxanes at clinically achievable doses in multiple SqCLC models with diverse cancer genetic backgrounds. Comprehensive gene expression analysis revealed a sustained disruption of pRB-E2F signaling by combination that was accompanied with enhanced regulation of pleiotropic biological effects. These included several novel mechanisms such as abrogation of G2/M and mitotic spindle assembly checkpoints, as well as impaired induction of hypoxia-inducible factor 1 alpha (HIF-1α). The decrease in HIF-1α modulated a couple key angiogenic and anti-angiogenic factors, resulting in an enhanced anti-angiogenic effect. This preclinical work suggests a new therapeutic opportunity for palbociclib in lung and other cancers currently treated with taxane based chemotherapy as standard of care.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; E2F Transcription Factors; Female; G2 Phase Cell Cycle Checkpoints; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Piperazines; Pyridines; Retinoblastoma Protein; Signal Transduction; Taxoids

Topics: Animals; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Disease Models, Animal; Hyperalgesia; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Nicotine; Paclitaxel; Peripheral Nervous System Diseases; Receptors, Cholinergic; Taxoids

Chemotherapy is one of the methods to treat patients with non-small cell lung cancer (NSCLC) developing resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib. Previous studies revealed that the sensitivity to chemotherapy may depend on different cellular mechanisms of acquired EGFR-TKIs resistance. Thus, the present study aimed to investigate the sensitivity of distinct gefitinib-resistant NSCLC cell lines to chemotherapy in order to help select effective treatment regimens for patients with EGFR-TKI resistance. In the present study, we established two gefitinib-resistant cell lines (PC-9/ZD and PC-9/GR) with the human lung adenocarcinoma cell line PC-9 (carrying the delE746-A750 mutation in the EGFR gene). PC-9/ZD cell line expressed the T790M mutation, while PC-9/GR presented the phenotypes of epithelial to mesenchymal transition (EMT). PC-9/ZD cells were more sensitive to paclitaxel and docetaxel than PC-9 cells and knockdown of T790M decreased this sensitivity. In addition, PC-9/GR cells were less sensitive to chemotherapeutic drugs tested, including cisplatin, gemcitabine, pemetrexed, paclitaxel and docetaxel, compared to PC-9 and PC-9/ZD cells. CDH1 transfection reversed the EMT and restored the sensitivity to chemotherapy in PC-9/GR cells. Furthermore, PC-9 cells became resistant to chemotherapy after TGF-β1-induced EMT. The EMT in NSCLC cells significantly increased cancer stem cell (CSC) properties and tumorgenicity. Collectively, the present study revealed that gefitinib-resistant NSCLC cells carrying the T790M mutation were sensitive to taxane chemotherapy, indicating that T790M is a useful biomarker for the selection of chemotherapy. EMT in NSCLC cells confers resistance to chemotherapy, which may be associated with enhanced CSC properties.

Topics: Biomarkers, Tumor; Bridged-Ring Compounds; Carcinogenesis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Docetaxel; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; ErbB Receptors; Gefitinib; Gene Knockdown Techniques; Humans; Mutation; Neoplastic Stem Cells; Paclitaxel; Protein Kinase Inhibitors; Quinazolines; Taxoids

Emerging data highlight different clinical behaviors according to KRAS amino acid substitutions (AASs) in patients with non-small-cell lung cancer (NSCLC). We aimed to evaluate whether different KRAS AASs were associated with different responses to chemotherapy.. We retrospectively reviewed data from 1190 patients with KRAS mutations who underwent first-line platinum-based chemotherapy for stage IV NSCLC. The response to different chemotherapy regimens was evaluated using the Response Evaluation Criteria In Solid Tumors criteria (v 1.1). Overall survival and time to progression (TTP) were secondary endpoints.. Taxane was associated with the best response in the entire cohort (odds ratio, 2.52; 95% confidence interval [CI], 1.82-3.48; P < .001), especially in G12V patients (odds ratio, 2.15; 95% CI, 1.05-4.41; P = .036). Taxane was associated with improved TTP in the entire cohort (hazard ratio [HR], 0.31; 95% CI, 0.26-0.38; P < .001), especially in G13D patients (HR, 0.47; 95% CI, 0.22-1.01; P = .054). Pemetrexed was associated with the worst TTP in the entire cohort, particularly in G12V patients, who had the worst response rates (HR, 0.55; 95% CI, 0.30-0.99; P = .049). No impact on overall survival was observed according to different chemotherapy regimens and AASs.. KRAS-specific AAS appears to induce different responses to chemotherapy regimens after first-line platinum-based chemotherapy in advanced NSCLC.

Topics: Aged; Antineoplastic Agents; Biomarkers, Pharmacological; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cohort Studies; DNA Mutational Analysis; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Pemetrexed; Proto-Oncogene Proteins p21(ras); Retrospective Studies; Survival Analysis; Taxoids

Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin-chemoresistant NSCLCs.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzazepines; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease-Free Survival; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histones; Humans; Hydrazones; Jumonji Domain-Containing Histone Demethylases; Lung Neoplasms; Methylation; Mice; Neoadjuvant Therapy; Pyrimidines; Taxoids; Transcription, Genetic

Weekly (qw) nanoparticle albumin-bound (nab)-paclitaxel was approved for advanced non-small-cell lung cancer based on the results from a phase III trial in which nab-paclitaxel/carboplatin demonstrated a significantly greater response rate compared with paclitaxel/carboplatin every 3 weeks (q3w). Little information exists on relative real-world results.. The present retrospective study used data from a national electronic medical record database. Patients receiving first-line nab-paclitaxel qw, paclitaxel qw, or paclitaxel q3w for stage IV non-small-cell lung cancer (NSCLC) were identified. The total cumulative dose, time to treatment discontinuation (TTD), and database persistence (a proxy measure for survival) were analyzed for all patients and for the squamous and elderly subgroups.. A total of 114, 208, and 153 patients received nab-paclitaxel qw, paclitaxel qw, and paclitaxel q3w, respectively. In the corresponding treatment arms, the median age was 72, 69, and 67 years; 56%, 48%, and 37% were aged ≥ 70 years; and 75%, 43%, and 23% had squamous cell NSCLC. The total cumulative dose was significantly greater with nab-paclitaxel qw. The TTD was longer with nab-paclitaxel qw than with paclitaxel qw (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.40-0.72; P < .001) or with paclitaxel q3w (HR, 0.53; 95% CI, 0.38-0.73; P < .001). Database persistence was longer with nab-paclitaxel qw than with paclitaxel qw (HR, 0.56; 95% CI, 0.39-0.79; P = .001) or with paclitaxel q3w (HR, 0.52; 95% CI, 0.34-0.78; P = .002). The TTD after experiencing any hematologic adverse event was longer with nab-paclitaxel qw. The findings were consistent across the subgroup analyses.. In a real-world setting, nab-paclitaxel qw was associated with a significantly greater cumulative dose and significantly longer TTD and database persistence compared with paclitaxel qw and paclitaxel q3w.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Community Networks; Female; Humans; Lung Neoplasms; Male; Nanoparticles; Neoplasm Staging; Paclitaxel; Retrospective Studies; Survival Analysis; Taxoids; United States; Withholding Treatment

A variety of regimens are used as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC), which may include combination regimens and single agents, depending on histology, molecular profile, and performance status.. To describe the types of first-line therapies and compare overall survival between therapies used for patients with advanced NSCLC in an integrated health care system.. This retrospective cohort study included patients aged 18 years or older from Kaiser Permanente California with a diagnosis of stage IIIB/IV NSCLC. First systemic treatment date occurred from January 1, 2008, through September 30, 2013. Overall survival was measured as the number of months from initial treatment until death, end of enrollment, or September 30, 2014. Treatment regimens were categorized into 6 mutually exclusive groups: platinum doublets; pemetrexed-based, bevacizumab-based, and pemetrexed + bevacizumab-based combinations; singlets; and tyrosine-kinase inhibitors (TKIs). Survival was compared using Kaplan-Meier curves and adjusted Cox proportional hazard models. Subgroup analyses were performed by age group and by nonsquamous histology.. Of 2,081 patients, approximately half (52.3%) received platinum doublets, followed by TKIs (19.0%), pemetrexed-based regimens (13.4%), bevacizumab-regimens (8.0%), singlets (5.5%), and pemetrexed + bevacizumab-based combinations (1.8%). Median survival was longest for pemetrexed + bevacizumab-based combinations (18.5 months), followed by bevacizumab-based regimens (14.5), TKIs (12.7), pemetrexed-based regimens (10.4), doublets (9.2), and singlets (5.3). There was a significantly reduced risk of mortality for pemetrexed + bevacizumab-based combinations (HR = 0.64; 95% CI = 0.42-0.94) and TKIs (HR = 0.83; 95% CI = 0.73-0.94) compared with doublets. Singlets were associated with an increased risk of mortality (HR = 1.50; 95% CI = 1.22-1.84). Subgroup analysis among patients aged 65 years and over found no significant differences among treatment groups, with the exception of singlets, which were associated with an increased risk of mortality compared with doublets (HR = 1.51; 95% CI = 1.20-1.90). Among patients under aged 65 years, pemetrexed + bevacizumab-based combinations (HR = 0.36; 95% CI = 0.21-0.64) and TKIs (HR = 0.76; 95% CI = 0.59-0.97) were associated with a reduced risk of mortality, and singlets were associated with an increased risk (HR = 1.85; 95% CI = 1.17-2.92).. In this cohort of patients with advanced NSCLC, patients received a platinum agent with or without bevacizumab or pemetrexed, a TKI, or a single agent. Younger patients (aged < 65 years) receiving bevacizumab + pemetrexed-based combinations had a survival advantage over those receiving platinum doublets, and this finding merits further investigation. Younger patients receiving TKIs also had longer survival. Compared with platinum doublets, we found no survival advantage for older patients receiving bevacizumab or pemetrexed, which suggests that combination therapy of a platinum agent and taxane, such as carboplatin and paclitaxel, could be a reasonable option for older patients who are not candidates for targeted therapy.. No outside funding supported this study. Rashid has received past funding from Bristol-Myers Squibb, Astellas, Novartis, and Pfizer. No other authors report any potential financial conflicts of interest. Study concept and design were primarily contributed by Spence and Hui, with input from the other authors. Hui, Spence, and Rashid took the lead in data collection, and data interpretation was performed by Schottinger, Millares, and Spence, assisted by the other authors. The manuscript was written primarily by Spence, along with Chang, and revised by Spence, with input from the other authors.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Pemetrexed; Proportional Hazards Models; Retrospective Studies; Taxoids

The study was conducted to evaluate the efficacy and safety of weekly intravenous nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) treatment in patients with advanced non-small-cell lung cancer (NSCLC) who have undergone multi-line therapy, and to investigate the association of secreted protein acidic and rich in cysteine (SPARC) expression status with clinical outcome.. Sixty-four patients who received NAB-paclitaxel treatment (130 mg/m. Sixty-two patients had response evaluation and complete survival follow-up data; 83.9% received the weekly NAB-paclitaxel as fourth-line treatment or beyond. The objective response and disease control rates (n = 62) were 16.1% (10/62) and 64.5% (40/62), respectively. The median progression-free and overall survival rates were 3.7 (95% confidence interval 2.6-4.8) and 9.8 months (95% confidence interval 6.9-12.8), respectively. Previous treatment with taxane did not affect the response to NAB-paclitaxel. The main grade 3-4 toxicities experienced were neutropenia (9.4%) and leukopenia (7.8%). Patients with SPARC expression in tumor stroma but not in cancer cells had poorer progression-free survival compared with those with negative SPARC expression in tumor stroma cells (3.3 vs. 5.0 months, P = 0.036).. Weekly NAB-paclitaxel might be effective for heavily pretreated NSCLC patients. SPARC expression in tumor stroma cells might be a potential negative predictor of NAB-paclitaxel.

Topics: Adult; Aged; Albumin-Bound Paclitaxel; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Nanoparticles; Osteonectin; Retrospective Studies; Taxoids; Treatment Outcome

Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development.. Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of ≥50 patients.. Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with ≥50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60)).. approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Cisplatin; Combined Modality Therapy; Docetaxel; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Risk Factors; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

The ATP-binding cassette (ABC) ABCG2, involved in multidrug resistance (MDR) in cancer cells, plays an integral role in drug resistance. Single nucleotide polymorphisms (SNPs) have been identified in many MDR-associated ABC genes that seem to influence drug sensitivity/resistance through various mechanisms. Therefore, we investigated whether ABCG2 haplotype-tagging SNPs (htSNPs) were associated with clinical outcomes in patients with unresectable non-small cell lung cancer (NSCLC) treated with front-line platinum-based chemotherapy.. We genotyped 4 ABCG2 htSNPs for 129 unresectable NSCLC cases treated with first-line platinum-based chemotherapy. Clinical characteristics, treatment outcomes, and predictive value of the htSNPs in patient response, survival, and adverse events related to platinum-based chemotherapy were analyzed according to each ABCG2 htSNP using the χ test, Kaplan-Meier method, and Cox proportional hazard model.. The rs2725264 was significantly related to overall survival (OS) (P=0.018, log-rank test). The median survival duration (in months) for patients with the rs2725264 T/T, T/C, and C/C genotypes was 35.75 (95% confidence interval [CI], 24.25-47.25), 34.25 (hazard ratio [HR] 1.27 [0.68 to 2.35]; 95% CI, 27.16-41.34), and 14.89 (HR 3.22 [1.26 to 8.24], 95% CI, 13.86-15.92), respectively. The rs2725264 was identified as an independent factor by Cox proportional hazard model analysis (P=0.028). In the taxane-based groups, OS was associated with rs2725264 (P=0.041), whereas in the gemcitabine-based groups, OS was associated with rs4148149 (P=0.014).. Our data suggest ABCG2 htSNPs rs2725264 (overall group and taxane-platinum combination group) and rs4148149 (gemcitabine-platinum combination group) were associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy. Thus, the ABCG2 htSNP rs2725264 may be independently associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Cisplatin; Deoxycytidine; Disease-Free Survival; Female; Gemcitabine; Haplotypes; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Proteins; Paclitaxel; Polymorphism, Single Nucleotide; Predictive Value of Tests; Survival Rate; Taxoids; Treatment Outcome

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

Taxanes, such as docetaxel and taxol, have been used as firstline chemotherapies in advanced lung adenocarcinoma (LAD), but limited responses to chemotherapy remain a major impediment in the clinic. Treatment with 5-azacytidine increases the sensitivity of SPC-A1/DTX cell line to taxanes. The results of DNA methylation microarray and cDNA array analysis indicate that DNA methylation contributes to the downregulation of secreted frizzled related protein 1 (SFRP1) in SPC-A1/DTX cells. Overexpression of SFRP1 reverses the chemoresistance of taxane-resistant LAD cell lines and enhances the in vivo sensitivity of taxane-resistant LAD cells to taxanes. Meanwhile, short hairpin RNA (shRNA)-mediated SFRP1 knockdown decreases the sensitivity of parental LAD cell lines to taxanes. Furthermore, FH535, a reversible Wnt signaling inhibitor, enhances the sensitivity of taxane-resistant LAD cells to taxanes. The level of SFRP1 in tumors of nonresponding patients is significantly lower than that in tumors of responders. Taken together, our results provide the direct evidence that SFRP1 is a clinically important determinant of taxanes resistance in human LAD cells, suggesting that SFRP1 might be a novel therapeutic target for the treatment of taxane-resistant LAD patients.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Azacitidine; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; DNA Methylation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Intercellular Signaling Peptides and Proteins; Lung Neoplasms; Male; Membrane Proteins; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Sulfonamides; Taxoids; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Aberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancer-associated gene loci and correlated results with clinical outcomes.. We studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates.. Cav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance  = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03-0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention.. CAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae.

Topics: Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Caveolin 1; Cell Line, Tumor; CpG Islands; DNA Methylation; Drug Combinations; Epithelial-Mesenchymal Transition; Humans; Multivariate Analysis; Platinum Compounds; Promoter Regions, Genetic; Regression Analysis; Retrospective Studies; Survival Analysis; Taxoids; Treatment Outcome

Lung carcinoma is the most common malignancy and the leading cause of cancer deaths worldwide. Although clinical factors including age, performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy, the genetic profile of individual patients may be an independent predictor of response and toxicity. The present study aimed to identify pharmacogenetic markers associated with clinical response and toxicity in patients with advanced non-small cell lung cancer (NSCLC) treated primarily with carboplatin and paclitaxel.. Genomic DNA samples from 90 adult male patients diagnosed with stage IIIB/IV NSCLC were genotyped for SNPs in candidate genes of relevance to platinating agents and paclitaxel and analyzed for association with survival and toxicities in univariate and multivariate models.. After adjusting for performance status and stage, SNPs in the drug transporters ABCB1 and ABCC1, as well as within NQO1 were associated with progression-free survival. With respect to hematological and nonhematological toxicities, SNPs in drug transporters (ABCB1 and ABCG2) were associated with thrombocytopenia, nausea and neutropenia, whereas SNPs in the DNA repair pathway genes ERCC4 and XPC were significantly associated with neutropenia and sensory neuropathy, respectively.. Our study evaluated and identified SNPs in key candidate genes in platinating agent and taxane pathways associated with outcome and toxicity in advanced NSCLC. If validated in large prospective studies, these findings might provide opportunities to personalize therapeutic strategies.

Topics: Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; DNA-Binding Proteins; Female; Genetic Association Studies; Humans; Male; Middle Aged; Multidrug Resistance-Associated Proteins; NAD(P)H Dehydrogenase (Quinone); Nausea; Neoplasm Staging; Neutropenia; Paclitaxel; Polymorphism, Single Nucleotide; Taxoids; Thrombocytopenia

Mitosis is the most conspicuous cell cycle phase and Shugoshin-like 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation during mitosis. We studied the role of SGOL1 and its splice variants in non-small cell lung cancer (NSCLC) using 82 frozen NSCLC tissue samples. SGOL1-B expression was prevalent in smokers, in cases with a wild-type (WT) EGFR status, and in cases with the focal copy number amplification of genes that are known to be important for defining the biological behaviors of NSCLC. The overexpression of SGOL1-B1 in an NSCLC cell line induced aberrant chromosome missegregation, precociously separated chromatids, and delayed mitotic progression. A higher level of SGOL1-B mRNA was related to taxane resistance, while the forced downregulation of SGOL1-B increased the sensitivity to taxane. These results suggest that the expression of SGOL1-B causes abnormal mitosis and taxane resistance in NSCLC cells.

Topics: Aged; Aged, 80 and over; Alternative Splicing; Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Amplification; Gene Dosage; Gene Expression; Gene Expression Regulation, Neoplastic; Genetic Variation; Humans; Lung Neoplasms; Male; Middle Aged; Mitosis; Neoplasm Staging; Risk Factors; Taxoids

This study's objectives were to determine whether tumor response measured by computed tomography (CT) and evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) correlated with overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy and surgical resection.. We measured primary tumor size on CT before and after neoadjuvant chemotherapy in 160 NSCLC patients who underwent surgical resection. The relationship between CT-measured response (RECIST) and histopathologic response (≤ 10% viable tumor) and OS were assessed by Kaplan-Meier survival, univariable, and multivariable Cox proportional hazards regression.. There was a statistically significant association between CT-measured response (RECIST) and OS (p = 0.03). However, histopathologic response was a stronger predictor of OS (p = 0.002), with a more pronounced separation of the survival curves when compared with CT-measured response. In multivariable Cox regression analysis, only pathologic stage and histopathologic response were significant predictors of OS. A 41% overall discordance rate was noted between CT RECIST response and histopathologic response. CT RECIST classified as nonresponders a subset of patients with histopathologic response (8 out of 30 points, 27%) who demonstrated prolonged survival after neoadjuvant chemotherapy.. We were unable to show that CT RECIST is a reliable predictor of OS in patients with NSCLC undergoing surgical resection after neoadjuvant chemotherapy. The failure of CT RECIST to predict long-term outcome may be because of the inability of CT imaging to consistently identify patients with histopathologic response. CT RECIST may have only a limited role as an efficacy endpoint after neoadjuvant chemotherapy in patients with resectable NSCLC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Platinum; Prognosis; Retrospective Studies; Survival Rate; Taxoids; Tomography, X-Ray Computed

Currently, there is no clinically validated test for the prediction of response to tubulin-targeting agents in non-small cell lung cancer (NSCLC). Here, we investigated the significance of nuclear expression of the mitotic checkpoint gene checkpoint with forkhead and ringfinger domains (CHFR) as predictor of response and overall survival with taxane-based first-line chemotherapy in advanced stage NSCLC.. We studied a cohort of 41 patients (median age 63 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. CHFR expression by immunohistochemistry (score 0-4) was correlated with clinical outcome using chi-square test and Cox proportional models. A cutoff score of "3" was determined by receiver operator characteristics analysis for "low" CHFR expression. Results were validated in an additional 20 patients who received taxane-based chemotherapy at Emory University Hospital and the Atlanta VAMC.. High expression (score = 4) of CHFR is strongly associated with adverse outcomes: the risk for progressive disease after first-line chemotherapy with carboplatin-paclitaxel was 52% in patients with CHFR-high versus only 19% in those with CHFR-low tumors (P = 0.033). Median overall survival was strongly correlated with CHFR expression status (CHFR low: 9.9 months; CHFR high: 6.2 months; P = 0.002). After multivariate adjustment, reduced CHFR expression remained a powerful predictor of improved overall survival (HR = 0.24; 95% CI, 0.1-0.58%; P = 0.002). In the validation set, low CHFR expression was associated with higher likelihood of clinical benefit (P = 0.03) and improved overall survival (P = 0.038).. CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy.

Topics: Adult; Aged; Biomarkers, Tumor; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Poly-ADP-Ribose Binding Proteins; Prognosis; Taxoids; Ubiquitin-Protein Ligases

NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI-H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC.

Topics: Antineoplastic Agents; Base Sequence; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Paclitaxel; rap1 GTP-Binding Proteins; RNA Interference; RNA, Messenger; STAT3 Transcription Factor; Taxoids

Tubulin-binding agents (TBAs) are effective in non-small cell lung cancer (NSCLC) treatment. Both βIII- and βV-tubulins are expressed by cancer cells and may lead to resistance against TBAs.. Pre-treatment samples from 65 locally advanced or oligometastatic NSCLC patients, who underwent uniform induction chemotherapy with paclitaxel and platinum followed by radiochemotherapy with vinorelbine and platinum were retrospectively analysed by immunohistochemistry. Protein expression of βIII- and βV-tubulin was morphometrically quantified.. Median pre-treatment H-score for βIII-tubulin was 110 (range: 0-290), and 160 for βV-tubulin (range: 0-290). Low βIII-tubulin expression was associated with improved overall survival (OS) (P=0.0127, hazard ratio (HR): 0.328). An association between high βV-tubulin expression and prolonged progression-free survival (PFS, median 19.2 vs 9.4 months in high vs low expressors; P=0.0315, HR: 1.899) was found. Further, high βV-tubulin expression was associated with objective response (median H-score 172.5 for CR+PR vs 120 for SD+PD patients, P=0.0104) or disease control following induction chemotherapy (170 for CR+PR+SD vs 100 for PD patients, P=0.0081), but not radiochemotherapy.. Expression of βV-tubulin was associated with treatment response and PFS following paclitaxel-based chemotherapy of locally advanced and oligometastatic NSCLC patients. Prolonged OS was associated with low levels of βIII-tubulin. Prospective evaluation of βIII/βV-tubulin expression in NSCLC is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Disease-Free Survival; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Retrospective Studies; Taxoids; Transfection; Treatment Outcome; Tubulin

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

Polymorphisms in DNA repair genes were thought to represent important determinants of platinum drug efficacy. This study tested whether XPD Lys751Gln and XRCC1 T-77C polymorphisms were associated with survival in platinum-treated patients with advanced non-small-cell lung cancer (NSCLC). In this study, 199 advanced NSCLC patients with platinum-based chemotherapy were recruited. During the median 26.5 months of follow-up, patients with the XPD 751Lys/Lys genotype had a median survival time of 17.0 months (95% CI, 14.5-19.6 months), not much longer than those carried Lys/Gln heterozygote (12.0 months; 95% CI, 3.4-20.6 months; log-rank test, P=0.542). In Cox proportional hazards model, no significant associations were found between XPD Lys751Gln polymorphism and survival. For XRCC1 T-77C polymorphism, the median survival of patients with TC+CC genotype (18 months; 95% CI, 13.5-22.5 months) was similar to those with the TT genotype (16.0 months; 95% CI, 13.3-18.7 months; log-rank test, P=0.399). XRCC1 T-77C polymorphism was not associated with survival in Cox proportional hazards model. Additionally, the analysis for combination of these two polymorphisms also showed no prognostic significance for NSCLC. Our findings indicated that neither XPD Lys751Gln nor XRCC1 T-77C could be genetic determinant for prognosis of advanced NSCLC patients treated with platinum-based chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cisplatin; Disease-Free Survival; DNA-Binding Proteins; Female; Genetic Association Studies; Genotype; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Polymorphism, Single Nucleotide; Prognosis; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine; X-ray Repair Cross Complementing Protein 1; Xeroderma Pigmentosum Group D Protein

Variations in genes related to biological activity of anticancer drugs could influence treatment responses and lung cancer prognosis. Genetic variants in four biological pathways, that is, glutathione metabolism, DNA repair, cell cycle, and epidermal growth factor receptor (EGFR), were systematically investigated to examine their association with survival in advanced stage non-small cell lung cancer (NSCLC) treated with chemotherapy.. A total of 894 tagging single-nucleotide polymorphisms (SNP) in 70 genes from the four pathways were genotyped and analyzed in a 1,076-patient cohort. Association with overall survival was analyzed at SNP and whole-gene levels within all patients and major chemotherapy agent combination groups.. A poorer overall survival was observed in patients with genetic variations in GSS (glutathione pathway) and MAP3K1 (EGFR pathway; HR = 1.45; 95% CI = 1.20-1.77 and HR = 1.25; 95% CI = 1.05-1.50, respectively). In the stratified analysis on patients receiving platinum plus taxane treatment, we observed a hazardous effect on overall survival by the MAP3K1 variant (HR = 1.38; 95% CI = 1.11-1.72) and a protective effect by RAF1 (HR = 0.64; 95% CI = 0.50-0.82) in the EGFR pathway. In patients receiving platinum plus gemcitabine treatment, RAF1 and GPX5 (glutathione pathway) genetic variations showed protective effects on survival (HR = 0.54; 95% CI = 0.38-0.77; HR = 0.67; 95% CI = 0.52-0.85, respectively); in contrast, NRAS (EGFR pathway) and GPX7 (glutathione pathway) variations showed hazardous effects on overall survival (HR = 1.91; 95% CI = 1.30-2.80; HR = 1.83; 95% CI = 1.27-2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis.. Common genetic variations in genes of EGFR and glutathione pathways may be associated with overall survival among patients with advanced stage NSCLC treated with platinum, taxane, and/or gemicitabine combinations.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Deoxycytidine; DNA Repair; ErbB Receptors; Female; Gemcitabine; Glutathione; Glutathione Peroxidase; Humans; Lung Neoplasms; Male; Platinum; Polymorphism, Single Nucleotide; Prognosis; Proto-Oncogene Proteins c-raf; Taxoids

To determine whether genetic variations in CMPK1 or RRM1, which impact the pharmacodynamics of gemcitabine, differentially affect the outcomes of non-small cell lung cancer (NSCLC) patients treated with gemcitabine or taxane/cisplatinum.. We conducted retrospective study evaluating the associations between overall survival in 298 NSCLC patients at stages IIIA/IIIB (140) and IV (158), treated with gemcitabine (139) or taxane (159)/cisplatinum and 14 tagging single-nucleotide polymorphisms (tSNPs): 4 in CMPK1 and 10 in RRM1.. The wild-type genotypes of CMPK1 IVS1+1057 and IVS1-928 were associated with shorter overall survival in patients treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 1.97 and 1.89; Cox pBonferroni = 0.008 and 0.020), whereas this effect was not observed in patients treated with taxane/cisplatinum. No associations were observed for the other 2 CMPK1 or 10 RRM1 tSNPs. Analysis of the interaction between the CMPK1 and RRM1 genes showed that the survival of patients with CMPK1 IVS1+1057 CC and RRM1 IVS1-2374 TT, IVS7+25 AA, IVS7-425 AA, or IVS8+287 TT was significantly shorter when they were treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 3.00, 2.89, 3.14, and 3.00; Cox pBonferroni = 0.007, 0.012, 0.006, and 0.007). However, these effects were not observed in patients treated with taxane/cisplatinum.. These findings suggest that polymorphisms of CMPK1 and their combination with those of RRM1 are helpful in identifying patients who will benefit less from a gemcitabine/cisplatinum as the first-line regimen.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Cohort Studies; Deoxycytidine; DNA, Neoplasm; Female; Follow-Up Studies; Gemcitabine; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Nucleoside-Phosphate Kinase; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Retrospective Studies; Ribonucleoside Diphosphate Reductase; Survival Rate; Taxoids; Treatment Outcome; Tumor Suppressor Proteins

Multiple biologically relevant polymorphisms may have more accurate prediction of cancer prognosis compared with single polymorphism because of the modest effect. This study investigated whether the functional polymorphisms in P53 pathway genes, P53 Arg72Pro (rs1042522), P73 G4C14-to-A4T14 (rs2273953 and rs1801173), and MDM2 T309G (rs2279744), alone or in combination, affect survival in advanced non-small cell lung cancer (NSCLC) patients.. A total of 199 stage III-IV NSCLC patients with platinum-based chemotherapy were recruited between 2002 and 2004. Associations between genotypes and survival were assessed using Kaplan-Meier method. Cox proportional hazard models were performed to identify significant variables.. During the median 26.5 months of follow-up, the P53 Pro/Pro genotype was strongly associated with shorter overall survival compared with the Arg/Arg genotype (12.0 versus 20.0 months; log-rank p = 0.002; hazard ratio = 1.86; 95% confidence interval [CI], 1.15-3.02). Pairwise combination analysis showed that patients carrying the variant P53 Pro/Pro-P73 GC/GC or P53 Pro/Pro-MDM2 GG genotypes had survival time only half of that for those carrying the wild-type genotypes, with hazard ratio being 2.47 (95% CI, 1.20-5.10) and 2.00 (95% CI, 1.15-3.46), respectively. Furthermore, a combined effect was seen with survival time being gradually shorter with increasing number of unfavorable genotypes in these three genes (p(trend) = 0.039), indicating a gene-dose effect in association with survival.. These findings suggest that genetic polymorphisms in the P53 pathway may be promising biomarkers for individualized chemotherapy and prognosis of NSCLC patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; DNA-Binding Proteins; DNA, Neoplasm; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Nuclear Proteins; Organoplatinum Compounds; Oxaliplatin; Polymerase Chain Reaction; Polymorphism, Genetic; Proto-Oncogene Proteins c-mdm2; Survival Rate; Taxoids; Treatment Outcome; Tumor Protein p73; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Vinblastine; Vinorelbine

The DNA repair pathway and isotype composition of beta-tubulin are known to be associated with resistance to platinum- and taxane-based chemotherapy, respectively. The aim of this study was to identify the clinical significance of excision repair cross-complementation 1 (ERCC1), breast cancer susceptibility gene 1 (BRCA1), X-ray repair cross-complementation 1 (XRCC1) and betaIII-tubulin on the chemotherapy response and overall survival in patients with non-small cell lung cancer (NSCLC) who received neoadjuvant chemotherapy.. Protein expression profiles were evaluated by immunohistochemistry on surgical specimens of 82 NSCLC patients who underwent platinum- and taxane-based neoadjuvant chemotherapy. The expression levels of proteins were measured semi-quantitatively and the correlation with tumor responses, pathologic cell death rate and survival were evaluated.. There were 73 (89.0%) clinical stage III patients. Lobectomy, bilobectomy, and pneumonectomy were performed in 54 (65.0%), 11 (13.4%), and 17 (20.7%) patients, respectively. There was no correlation between clinical response and protein expression. The expression levels of ERCC1, BRCA1, and XRCC1 increased proportionally to the cell death rate (p<0.05); however, betaIII-tubulin expression did not correlate with cell viability. Multivariate analysis demonstrated that early pathologic stage, adjuvant chemotherapy, high ERCC1 and low betaIII-tubulin expression were good prognostic factors for overall survival (p<0.05).. The inverse correlation between DNA repair proteins and cell viability suggests that these protein expression levels can be markers for chemotherapy responsiveness. However, only ERCC1 and betaIII-tubulin were prognostic factors after platinum- and taxane-based neoadjuvant chemotherapy following surgical resection.

Topics: Adult; Aged; BRCA1 Protein; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; DNA-Binding Proteins; Drug Resistance, Neoplasm; Endonucleases; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Platinum Compounds; Pneumonectomy; Predictive Value of Tests; Prognosis; Survival Analysis; Taxoids; Tubulin; X-ray Repair Cross Complementing Protein 1

The purpose of this study was to identify total lifetime medical-care costs and costs associated with first-line chemotherapy treatment among older patients with stage IIIB/IV non-small-cell lung cancer treated with commonly used two-drug chemotherapy ("doublet") regimens in the United States.. Study patients included individuals aged 65 years and older who received a diagnosis of stage IIIB/IV non-small-cell lung cancer in a Surveillance, Epidemiology and End Results cancer registry between 1997 and 2002 and who received first-line treatment with commonly used doublet regimens. Patients were followed retrospectively in the Surveillance, Epidemiology and End Results-Medicare database to evaluate lifetime medical-care costs and costs while on first-line chemotherapy treatment. Pairwise comparisons of treatment costs were estimated by using nonparametric bootstrap methods.. Lifetime medical-care costs totaled approximately $70,000 and on-treatment costs for first-line chemotherapy totaled approximately $30,000 among study patients and were dominated by hospitalization and physician costs. Lifetime costs were significantly higher among patients treated with first-line cisplatin/carboplatin (platinum) plus a taxane compared with those who received platinum plus gemcitabine [difference: $4781 ($1558-$8039)] or other doublet therapy [difference: $5961 ($2333-$9614)]. Total on-treatment costs for first-line chemotherapy were significantly higher among patients treated with platinum plus a taxane compared with those who received platinum plus gemcitabine [difference: $5825 ($3872-$7770)], platinum plus another agent [difference: $5968 ($3995-$7975)], or another doublet therapy [difference: $3663 ($1620-$5740)].. There is a cost differential between first-line doublet regimens in terms of lifetime and on-treatment costs. Although doublet therapy with platinum and a taxane was the most frequently utilized regimen, it was associated with the highest lifetime and on-treatment costs.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Female; Gemcitabine; Health Care Costs; Humans; Lung Neoplasms; Male; Population Surveillance; Retrospective Studies; Taxoids; United States

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

Patients with cancer may present with one or more circulatory markers of haemostatic activation which may be associated with tumor growth and cancer cell dissemination. In our clinical practice we observed haemostatic abnormalities with or without thrombotic episodes in cancer patients. The aim of the present study was to detect the D-dimer plasma levels in advanced-stage lung cancer patients before, during and after chemotherapy, and to determine whether there is a correlation with response rate, disease recurrence and survival, in order to estimate the possible predictive value of D-dimer plasma levels. Forty-seven/52 patients were evaluable and analysed; 38 patients had non-small-cell lung cancer (NSCLC) and 9 small-cell lung cancer (SCLC) and all were at an advanced stage or inoperable. Two (4.3%) achieved complete response (CR), 17 (36.2%) partial response (PR), and 16 (34%) had progressive disease (PD). We found that 14/19 (73.7%) patients with CR or PR showed a reduction in D-dimer plasma values and 11/16 (68.8%) with PD showed increased values; also, in patients with recurrent disease (12/13, 92.3%), D-dimer plasma levels were increased. All of the above values were statistically significant. D-Dimer plasma levels decrease or increase after response and progressive disease, respectively, and can act as a predictive factor of the evolution of the disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Deoxycytidine; Disease Progression; Docetaxel; Female; Fibrin Fibrinogen Degradation Products; Gemcitabine; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Patient Compliance; Predictive Value of Tests; Prospective Studies; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine

The global development of new anticancer treatments is desirable. However, whether results of clinical trials performed in one population can be fully extrapolated to another population remains in question. We retrospectively compared "common arms" of platinum-based doublet phase III trials among Japanese, European, and American patients with non-small cell lung cancer to develop the basis for global standardization in clinical trials. Patient demographics were very similar through all studies, indicating that extrinsic ethnic factors including socioeconomic factors, medical service background, and patient selection process for clinical trials may be consistent between geographically different oncology groups. The doses of docetaxel, gemcitabine, and vinorelbine were lower in Japanese studies. The toxicity profile was generally acceptable and similar among many studies. Thus, the dose and schedule of anticancer agents established in prior phase I and II studies conducted in each country were appropriate and applicable to large patient populations in these countries. Response rates seemed to be distributed randomly from one study to another, whereas patient survival might be better in Japanese studies. In conclusion, geographical differences in the dose of anticancer agents, response, survival and toxicity of lung cancer chemotherapy were actually observed. However, extrapolation of clinical data obtained in one country to another population and global clinical trials were considered possible with adequate dose adjustment based on dose finding studies using a carefully projected protocol.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials, Phase III as Topic; Deoxycytidine; Europe; Gemcitabine; Humans; Japan; Lung Neoplasms; Platinum; Retrospective Studies; Survival Rate; Taxoids; United States; Vinblastine; Vinorelbine

The apoptosis stimulator STA-4783 acts by inducing expression of heat shock protein (Hsp)70 on tumor cell surfaces and disrupting the cytoskeletal network. Currently in development by Synta Pharmaceuticals for the potential treatment of solid tumors, phase II clinical trials in non-small-cell lung cancer, melanoma and sarcoma have been initiated.

Topics: Animals; Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Humans; Hydrazines; Lung Neoplasms; Melanoma; RNA, Messenger; Taxoids; Tubulin Modulators

This study determined the prevalence and the prognostic value of the expression of microtubule components in tumors of 19 patients with non small cell lung cancer receiving taxane-based regimens. Patient samples were stained with antibodies directed against total beta tubulin, classes I, II and III beta tubulin isotypes, delta2 alpha tubulin, tau protein, and the P-gp protein involved in the classical multidrug resistance phenotype. All tumors were stained with pan-beta tubulin antibody and class I tubulin isotype. A majority of the tumor samples expressed class II and class III, although the percentage of positive cells varied significantly between tumors. delta2 alpha tubulin, tau protein and Pgp protein were found in only one tumor sample each. Progression-free survival was shorter (41 days) in patients whose tumors expressed high levels of class III tubulin isotype in comparison to patients with low levels (288 days, p = 0.02). There were 2 responses to chemotherapy among 9 patients (22%) with high levels of class III tubulin vs. 6 among 10 patients (60%) with low levels of expression (Fisher exact test: p = 0.11). These data suggest that high expression of class III tubulin by tumor cells is associated with poor prognosis in patients with NSCLC receiving a taxane-based regimen.

Topics: Aged; Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Microtubule-Associated Proteins; Middle Aged; Neoplasm Proteins; Taxoids; Tubulin

To determine the effect of taxane-based chemotherapy on intratumoral levels of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) in patients with non-small cell lung cancer (NSCLC).. Lung specimens obtained at the time of surgery were used to measure levels of COX-2 and PGE(2) in tumors and adjacent nontumorous tissues in three subsets of NSCLC patients who underwent: (A) surgical resection only (n = 16); (B) surgical resection after preoperative taxane-based chemotherapy (n = 13); or (C) surgical resection after preoperative chemotherapy coadministered with the selective COX-2 inhibitor, celecoxib 400 mg bid (n = 17).. Levels of intratumoral PGE(2) were nearly 3-fold higher among patients who received preoperative chemotherapy compared with those treated by surgery alone (P < 0.001). This difference was abrogated by the addition of celecoxib to preoperative chemotherapy (P < 0.001). Amounts of intratumoral COX-2 were approximately 3-fold higher in groups of patients who received preoperative chemotherapy with celecoxib (P < 0.0001) or without celecoxib (P < 0.001), compared with the group who underwent surgical resection only. Importantly, statistically significant positive correlations between COX-2 and PGE(2) were observed in the surgery only (r = 0.502, P = 0.047) and preoperative chemotherapy groups (r = 0.740, P = 0.004); this correlation was abrogated when celecoxib was given with chemotherapy (r = 0.005, P = 0.98).. Treatment with chemotherapy led to increased amounts of COX-2 and PGE(2) in NSCLC. Cotreatment with celecoxib abrogated the increase in levels of PGE(2) but not COX-2 induced by chemotherapy. Importantly, these results clearly show that levels of a pharmacologic target (i.e., COX-2) can be affected by both the intrinsic molecular properties of a tumor and therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Celecoxib; Combined Modality Therapy; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Taxoids

Cancer chemotherapy with some of the taxane class of agents can be associated with significant neurotoxicity, arthralgias, myalgias, and skin changes that may offset the therapeutic benefits of taxane use.. The authors developed and tested a set of questions to assess these important side effects of taxane therapy from the patient's perspective. The current study evaluated the taxane subscale of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system. Reliability, validity, and responsiveness to expected change were evaluated in the context of an ongoing clinical trial comparing four cycles of carboplatin plus paclitaxel with a strategy of carboplatin plus paclitaxel until disease progression in patients with advanced nonsmall cell lung carcinoma (NSCLC).. The 16-item Taxane subscale score and the 11-item peripheral neuropathy subset both demonstrated excellent internal consistency and concurrent validity, and the scores worsened as one would predict during a 12-week treatment course of taxane therapy. Results of the psychometric analyses supported the use of this subscale for measuring the unwanted adverse consequences of effective cancer therapies. Measuring the patient perception of treatment side effects also allowed a preliminary exploration of the relative quality of life (QOL) impact of symptom relief and treatment toxicity. The results indicated that toxicity and symptom improvement may make relatively equivalent contributions to total QOL as measured by the summary score from a multidimensional QOL instrument, the Functional Assessment of Cancer Therapy-General. However, symptom status and improvement appear to play a stronger role than taxane toxicity in patients' global rating of their QOL.. Future research might examine this question of competing benefits as a potential aid to decision-making regarding the administration of toxic therapies in the setting of advanced disease.

Topics: Antineoplastic Agents, Phytogenic; Attitude to Health; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Quality of Life; Randomized Controlled Trials as Topic; Surveys and Questionnaires; Taxoids

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; DNA Mutational Analysis; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Microtubules; Polymorphism, Genetic; Taxoids; Tubulin; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Combined Modality Therapy; Humans; Lung Neoplasms; Quality of Life; Taxoids; Treatment Outcome

Taxane-based chemotherapy now plays an important role in the first-line treatment on patients with advanced non-small-cell lung cancer (NSCLC). Recent attention has been focused on the treatment of patients with NSCLC who failed to respond to taxane-based chemotherapy. In the present article, we report the effect of single-agent vinorelbine (VNR) in 10 patients with NSCLC previously treated with taxanes. An antitumor effect was observed in five patients, resulting in a response rate of 50.0% (5/10). The absence of vinca alkaloid pretreatment was an important factor in the clinical response in these patients. Further study is warranted to investigate the clinical efficacy of VNR monotherapy in taxane-resistant NSCLC patients.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pilot Projects; Salvage Therapy; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

It is reported that the single-agent administration of vinorelbine (VNR) is improper in salvage therapy for non-small cell lung cancer. However, there are few reports on its use as second line in taxane-containing chemotherapy. We used single-agent VNR administration for nine cases of taxane-resistant non-small cell lung cancer, and an antitumor effect was seen in four cases. We present three of these cases. A factor for the high response rate is considered to be that vinca alkaloid is not used as a pre-treatment. Moreover, VNR may be effective even if there is a gene mutation for beta tubulin, which causes taxane resistance.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Salvage Therapy; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Gemcitabine; Humans; Lung Neoplasms; Paclitaxel; Taxoids; Vinblastine; Vinorelbine

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Gemcitabine; Humans; Lung Neoplasms; Organoplatinum Compounds; Taxoids; Vinca Alkaloids

Although the overall survival rates for patients with metastatic non-small cell lung cancer have not changed in the past two decades, meta-analytic studies have confirmed that a modest increase in mean survival time can be gained with platinum-based combination chemotherapy. With appropriate selection of patients, chemotherapy will have symptomatic benefits in more than 60% of patients, and concerns regarding the costs of chemotherapy will be lessened by the observation that in some instances chemotherapy is less costly than best supportive care. Until the end of the 1980s, apart from the few active agents and their analogues no new drugs became available, but in the past 5 years several new agents have shown promising results and are now being included in combination programs. Large-scale comparative studies, looking for the combination with the best therapeutic index, are awaited with great interest. The number of patients with non-small cell lung cancer is so great that even modest improvements in therapy will have a great impact on survival rates.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Gemcitabine; Humans; Lung Neoplasms; Randomized Controlled Trials as Topic; Taxoids; Vinblastine; Vinorelbine

Taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere) are promising agents for use against ovarian cancer and other malignancies. Recently, SB-T-1011, a semisynthetic taxane, has been prepared from 14-hydroxy-10-deacetylbaccatin III. SB-T-1011 shows similar or greater in vitro cytostatic activity than paclitaxel, depending on the tumor cell line. The administration of taxanes is problematic due to their low solubility in most pharmaceutically acceptable solvents; formulations used clinically contain Cremophor/ethanol (diluent 12) or polysorbate 80/ethanol, excipients which may cause serious adverse effects. To eliminate these vehicles, we have prepared paclitaxel liposome formulations. The objective of the present work was to evaluate the antitumor activity of paclitaxel and two semisynthetic analogs in Cremophor-based and liposomal formulations. Antitumor activity was evaluated against A121a, a taxane-sensitive human ovarian tumor, growing as subcutaneous xenografts in athymic nude mice. Free and liposomal formulations of each taxane showed similar antitumor effect. The antitumor activity of paclitaxel and SB-T-1011 was similar, and docetaxel was more potent than either paclitaxel or SB-T-1011. Overall, taxane liposomes were better tolerated and more easily administered iv than taxane formulated in Cremophor/ethanol.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Carcinoma, Non-Small-Cell Lung; Colonic Neoplasms; Docetaxel; Drug Carriers; Female; Humans; Liposomes; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Paclitaxel; Taxoids