Paclitaxel In Non-small Cell Lung Cancer Research Articles

FV-429 enhances the efficacy of paclitaxel in NSCLC by reprogramming HIF-1α-modulated FattyAcid metabolism

Solid tumors often exhibit hypoxia in their centers, which has been associated with a marked reduction in the sensitivity of the tumor cells to anti-tumor and chemotherapeutic interventions. Here, we found that the occurrence and progress of hypoxic insensitivity to paclitaxel in non-small cell lung cancer (NSCLC) are closely associated with the HIF-1α pathway. The HIF-1α protein upregulated the expression of adipose differentiation-related protein (ADRP), fatty acid synthase (FASN), and sterol regulatory element binding protein 1(SREBP1), while simultaneously downregulating carnitine palmitoyltransferase 1 (CPT1), thereby leading to a more pronounced uptake of lipids and reduced oxidation of fatty acids. Diminished levels of fatty acids led to reduced Wnt pathway activation and β-catenin nuclear translocation, leading to G2/M cell cycle arrest. In this study, FV-429, a derivative of the natural flavonoid wogonin, reprogrammed metabolism of cancer cells and decreased fatty acid levels. Moreover, paclitaxel-induced G2/M phase arrest in hypoxia-resistant NSCLC was hampered but FV-429 improved the sensitivity of these cancer cells to paclitaxel. FV-429 activated and modulated fatty acid metabolism in NSCLC cells, significantly reduced levels of fatty acids within cells and increased the oxidation of these fatty acids. The results of our study demonstrated that FV-429 could reshape fatty acid metabolism in hypoxia-induced paclitaxel-resistant NSCLC and enhance the sensitivity of NSCLC cells to paclitaxel through G2/M phase arrest deterioration, by inactivating the Wnt pathway, and suggested the possibility of using FV-429 as a promising candidate therapeutic agent for advanced NSCLC.

Cost-Effectiveness of the Addition of Bevacizumab to First-Line Chemotherapy With Carboplatin and Paclitaxel in Patients With Non–Small Cell Lung Cancer

ObjectivesTo evaluate the incremental cost-effectiveness ratio (ICER) of the addition of bevacizumab to first-line chemotherapy with carboplatin and paclitaxel in patients with non–small cell lung cancer (NSCLC) from the perspective of the Colombian health system. MethodsA Markov model was employed to evaluate the cost-effectiveness of bevacizumab + carboplatin + paclitaxel (BCP) compared with carboplatin + paclitaxel (CP) in the treatment of NSCLS during a 4-year period. The health outcome was the number of life-years gained (LYG) and quality-adjusted life-years (QALYs) obtained from the survival curves reported in a clinical study. Costs were estimated using national tariff and reported in US dollars at a date in 2019. Costs and effectiveness outcomes were discounted at a rate of 3.5% per year. A probabilistic sensitivity analysis was performed on important parameters with a Monte Carlo simulation. ResultsThe costs of BCP and CP were $30 341 and $11 735, respectively. The LYG for BCP and CP were 0.34 and 0.29, respectively. The QALY for BCP and CP were 0.27 and 0.23. The ICER of BCP versus CP was $ 465 150 QALY. The results of the Monte Carlo simulation showed that CP was cost-effective in 100% of the iterations compared with BCP. ConclusionThe addition of bevacizumab to the scheme carboplatin + paclitaxel compared to carboplatin + paclitaxel for NSCLC is not cost-effective from the point of view of the Colombian health system.

Circulating immune biomarkers as predictors of the response to pembrolizumab and weekly low dose carboplatin and paclitaxel in NSCLC and poor PS: An interim analysis.

The combination of standard-dose chemotherapy and immunotherapy has been shown to be beneficial for patients with non-small cell lung cancer (NSCLC) with good performance status (PS). However, treatment options for patients with poor PS are limited. In the present study, the feasibility and immunological effects of low-dose chemotherapy with carboplatin and paclitaxel combined with immunotherapy with pembrolizumab were examined in patients with metastatic NSCLC and a poor PS. Patients with advanced NSCLC and a PS of 2 were randomized to single-agent pembrolizumab at 200 mg every 3 weeks or pembrolizumab combined with weekly carboplatin area under the curve 1 and paclitaxel 25 mg/m2. Blood for circulating immune cell phenotyping, soluble program death ligand 1 (sPD-L1) and immune-modulatory microRNAs (miRNAs) was collected prior to treatment and at weeks 4 and 7. Ten patients were randomized to the combination arm and 10 to the single-agent arm. Therapy was well tolerated. Four patients discontinued carboplatin due to hypersensitivity reactions but continued pembrolizumab and paclitaxel treatments. Increases in activated CD4+ T cells and in immune-regulatory miRNA, and decreases in myeloid derived suppressor cells were observed in the blood of patients in the combination arm and not in the single-agent arm. Changes in circulating regulatory T cells and sPD-L1 were not observed. Seven patients in the combination arm manifested a partial response compared with only two in the single-agent arm. Weekly low-dose chemotherapy carboplatin and paclitaxel was well tolerated and immunologically active when combined with pembrolizumab in patients with advanced NSCLC and a PS of 2. This combination merits further study in this patient population.

Mechanisms promoting escape from mitotic stress-induced tumor cell death.

Non-small cell lung cancer (NSCLC) is notorious for its paltry responses to first-line therapeutic regimens. In contrast to acquired chemoresistance, little is known about the molecular underpinnings of the intrinsic resistance of chemo-naïve NSCLC. Here we report that intrinsic resistance to paclitaxel in NSCLC occurs at a cell-autonomous level because of the uncoupling of mitotic defects from apoptosis. To identify components that permit escape from mitotic stress-induced death, we used a genome-wide RNAi-based strategy, which combines a high-throughput toxicity screen with a live-cell imaging platform to measure mitotic fate. This strategy revealed that prolonging mitotic arrest with a small molecule inhibitor of the APC/cyclosome could sensitize otherwise paclitaxel-resistant NSCLC. We also defined novel roles for CASC1 and TRIM69 in supporting resistance to spindle poisons. CASC1, which is frequently co-amplified with KRAS in lung tumors, is essential for microtubule polymerization and satisfaction of the spindle assembly checkpoint. TRIM69, which associates with spindle poles and promotes centrosomal clustering, is essential for formation of a bipolar spindle. Notably, RNAi-mediated attenuation of CASC1 or TRIM69 was sufficient to inhibit tumor growth in vivo. On the basis of our results, we hypothesize that tumor evolution selects for a permissive mitotic checkpoint, which may promote survival despite chromosome segregation errors. Attacking this adaptation may restore the apoptotic consequences of mitotic damage to permit the therapeutic eradication of drug-resistant cancer cells.

Feasibility Study of Combined Chemotherapy for Advanced Lung Cancer with Idiopathic Interstitial Pneumonias and Proteomic Analysis to Detect Risk Factors for Their Acute Exacerbation

Idiopathic interstitial pneumonias (IIPs) are among the most common complications in patients with lung cancer. In such patients, the most serious expression of the toxicity of anticancer treatment in Japan is the acute exacerbation of IIPs. However, there has been no consensus and no evidence presented regarding the optimal treatment for advanced lung cancer with IIP. The results of our retrospective study of lung cancer with IIPs suggest that combined chemotherapy with carboplatin plus etoposide or carboplatin plus paclitaxel might be used for patients with small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) with IIPs. We, therefore, performed a prospective study of carboplatin plus etoposide and of carboplatin plus paclitaxel to assess their safety and potential efficacy for the treatment of advanced lung cancer with IIP. From July 2002 through October 2008, 35 Japanese patients (28 men and 7 women), including 14 with idiopathic pulmonary fibrosis, were enrolled and treated with carboplatin plus etoposide for SCLC and with carboplatin plus paclitaxel for NSCLC. Two patients with idiopathic pulmonary fibrosis (5.7%), 1 receiving each treatment, had treatment-associated acute exacerbations of IIPs. The overall response rate, median progressionfree survival, median survival time, and 1-year survival rate of patients with SCLC were 88%, 5.5 months, 8.7 months, and 29%, respectively. The overall response rate, median progression-free survival, median survival time, and 1-year survival rate of patients with NSCLC were 61%, 5.3 months, 10.6 months, and 22%, respectively. The antitumor efficacy was comparable to that in a randomized phase III study of Japanese patients without IIPs. We observed an incidence of treatment-related acute exacerbation of 5.7%. In previous studies in Japan, the incidence of chemotherapy-related acute exacerbation has ranged from 8.7% to 21%. The regimens carboplatin plus etoposide and carboplatin plus paclitaxel were effective for patients with advanced lung cancer with IIPs and appeared to be safer than suggested by previous reports. In 2009, a national questionnaire survey for first-line chemotherapy for patients with lung cancer and IIPs was supported by a grant to the Diffuse Lung Diseases Research Group from the Ministry of Health, Labour and Welfare of Japan [The 2009 annual report of the Diffuse Lung Diseases Research Group]. The incidence of acute exacerbation associated with first-line chemotherapy was 13.1%. The main regimens were carboplatin plus paclitaxel and a platinum agent plus etoposide and were used for 100 cases (25%) and 80 cases (15%), respectively. The incidence of treatment-related acute exacerbation was 5% and 6%, respectively. These rates were lower than the mean incidence in this survey and that in previous reports. The results of this survey support our prospective studies. To further confirm the usefulness of carboplatin plus etoposide and paclitaxel for treating advanced lung

Effect of age on chemotherapy-induced hematologic toxicity

20634 Background: About 20% of older patients with advanced non-small cell lung cancer (NSCLC) receive chemotherapy. One reason for this is the increased incidence of cytopenias. Limited data exist regarding the effect of age on severity of chemotherapy induced cytopenia. This study was conducted to address this question. Methods: A review was conducted to identify chemotherapy-naïve patients who received standard doses of carboplatin and paclitaxel for NSCLC. Age, gender, smoking and alcohol history and stage at diagnosis were recorded. Values for hemoglobin (Hgb), total white blood cell count (WBC) and platelet (Plt) counts before, and nadir counts following each chemotherapy cycle were obtained. Patients were dichotomized based on age to <60 years old or ≥ 60 years old. Comparisons according to age were performed using Wilcoxon test and Chi-square test (for patient characteristics) while unpaired T-test was used to assess hematological parameters. Multivariate comparisons of change over time of hematological parameters between age groups were performed using mixed models with autoregressive covariance assumption to account for correlated data. Gender, disease stage, smoking and alcohol intake were the co-variates studied. Results: Of the 90 patients identified, 37 (41%) were <60 and 53 (59%) were ≥60 years old. No differences in patient and hematological parameters were noted between age groups. There was no effect of age on either pre-chemotherapy, or nadir values of Hgb, WBC or Plt. Nadir values for Hgb, WBC and Plt correlated with the corresponding pre-chemotherapy values. In the multivariate analysis, pre-chemotherapy and nadir values of the hematological parameters showed a statistically significant decrease over time (chemotherapy cycles) but the decrease was independent of age. Conclusions: Pre-chemotherapy values and number of chemotherapy cycles administered, rather than age affected the nadir counts of Hgb, WBC and plt. Age alone may not be a valid criterion for determining eligibility for chemotherapy in this patient population. Pre-chemotherapy and nadir WBC counts based on age Cycle Pre-chemotherapy Mean (SD) Nadir Mean (SD) WBC count (× 103/μL) Age < 60 yrs Age ≥ 60 yrs Age < 60 yrs Age ≥ 60 yrs 1 9.9 (4.04) 9.40 (3.56) 3.47 (1.57) 3.04 (1.87) 2 7.3 (5.00) 7.00 (2.62) 2.93 (1.69) 2.48 (1.41) 3 5.34 (2.00) 5.73 (2.20) 2.44 (1.54) 2.26 (1.35) 4 5.46 (1.96) 6.04 (2.43) 2.43 (1.00) 2.56 (1.37) 5 4.48 (0.71) 6.61 (3.98) 1.99 (0.72) 2.39 (1.24) No significant financial relationships to disclose.

Weekly paclitaxel in advanced non-small cell lung cancer

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most commonly used agents in treating patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). It is usually given once every 3 weeks. We have evaluated paclitaxel given once per week for 3 weeks every 4 weeks for patients with recurrent or metastatic NSCLC. Two consecutive studies using weekly paclitaxel were performed. The first study was a dose-escalation study with paclitaxel beginning at 50 mg/m 2 days 1, 8, and 15 every 4 weeks. Subsequent dose escalation was performed with 10 mg/m 2 increments per week. The second phase II study used paclitaxel at 80 mg/m 2 days 1, 8, and 15 every 4 weeks. The phase I study showed that the maximum tolerated dose was 90 mg/m 2/wk for 3 weeks with 1 week off. The efficacy and side effects of both phase I and II were quite similar; therefore, the results were combined. Seventeen patients were in the phase I and 30 patients in the phase II study. The mean age was 72 years. Twenty-three patients had Eastern Cooperative Oncology Group performance status of 2 and 16 patients had received prior chemotherapy. One complete and 13 partial responses were observed with response duration ranging from 1 to 18+ months. Overall response rate was 30% (95% confidence interval, 18.5% to 42%). Overall median survival was 184 days. Grade 3 4 neutropenia was 8.5%, grade 3 4 infections was 6.4%, and grade 2 peripheral neuropathy was also 6.4%. Hyperglycemia with random blood sugar levels greater than 250 mg/dL was 6.4% and grade 3 fatigue was 4.3%. In general, treatment was well tolerated. In the best prognostic group of 16 patients without prior chemotherapy and with performance status 0 to 1, the response rate was 37.5% with a 1-year survival rate of 44% and median survival of 305 days. Prior chemotherapy, poor performance status, age higher than 70 years, and male gender carried a worse prognosis. In both phase I and II studies we observed limited myelosuppression, peripheral neuropathy, and constitutional symptoms. Weekly paclitaxel, delivered at our schedule, is an active and well-tolerated regimen. The role of weekly paclitaxel in NSCLC should be better defined in future randomized studies.

Paclitaxel

A number of first-line chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC) are advocated in treatment guidelines and/or by various clinical investigators. Platinum-based chemotherapy has clearly demonstrated efficacy in patients with advanced NSCLC and is generally recommended as first-line therapy, although there is increasing interest in the use of non-platinum chemotherapy regimens. Among the platinum-based combinations currently used in clinical practice are regimens such as cisplatin or carboplatin combined with paclitaxel, vinorelbine, gemcitabine, docetaxel or irinotecan. The particular combinations employed may vary between institutions and geographical regions. Several pharmacoeconomic analyses have been conducted on paclitaxel in NSCLC and most have focused on its use in combination with cisplatin. In terms of clinical efficacy, paclitaxel-cisplatin combinations achieved significantly higher response rates than teniposide plus cisplatin or etoposide plus cisplatin (previously thought to be among the more effective regimens available) in two large randomised trials. One of these studies showed a survival advantage for paclitaxel plus cisplatin [with or without a granulocyte colony-stimulating factor (G-CSF)] compared with etoposide plus cisplatin. A Canadian cost-effectiveness analysis incorporated data from one of the large randomised comparative trials and showed that the incremental cost per life-year saved for outpatient administration of paclitaxel plus cisplatin versus etoposide plus cisplatin was $US 22181 (30619 Canadian dollars; $Can) [1997 costs]. A European analysis incorporated data from the other large randomised study and showed slightly higher costs per responder for paclitaxel plus cisplatin than for teniposide plus cisplatin in The Netherlands ($US 30769 vs $US 29592) and Spain ($US 19 923 vs $US 19724) but lower costs per responder in Belgium ($US 22852 vs $US 25000) and France ($US28 080 vs $US 34747) [1995/96 costs]. In other cost-effectiveness analyses, paclitaxel plus cisplatin was associated with a cost per life-year saved relative to best supportive care of approximately $US 10000 in a US study (year of costing not reported) or $US 11200 in a Canadian analysis ($Can 15400; 1995 costs). Results were less favourable when combining paclitaxel with carboplatin instead of cisplatin and particularly when G-CSF was added to paclitaxel plus cisplatin. The Canadian study incorporated the concept of extended dominance in a threshold analysis and ranked paclitaxel plus cisplatin first among several comparator regimens (including vinorelbine plus cisplatin) when the threshold level was $Can 75000 ($US 54526) per life-year saved or per quality-adjusted life-year gained (1995 values). Current treatment guidelines for advanced NSCLC recognise paclitaxel-platinum combinations as one of the first-line chemotherapy treatment options. In two large head-to-head comparative clinical trials, paclitaxel plus cisplatin was associated with significantly greater response rates than cisplatin in combination with either teniposide or etoposide, and a survival advantage was shown for paclitaxel plus cisplatin (with or without G-CSF) over etoposide plus cisplatin. There are limitations to the currently available pharmacoeconomic data and further economic analyses of paclitaxel-carboplatin regimens are warranted, as this combination is widely used in NSCLC and appears to have some clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile. Nevertheless, results of various cost-effectiveness studies support the use of paclitaxel-platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced NSCLC.

Is cisplatin necessary for the treatment of non-small cell lung cancer (NSCLC)? — Analysis of consecutive trials of paclitaxel in NSCLC

Is cisplatin necessary for the treatment of non-small cell lung cancer (NSCLC)? — Analysis of consecutive trials of paclitaxel in NSCLC

Dose-finding and sequencing study of paclitaxel and carboplatin in non-small cell lung cancer

A dose-finding study was set up to identify the optimal dose of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin for phase II studies in patients with advanced chemotherapy-naive non-small cell lung cancer (NSCLC). The influence of drug sequence on the toxicity and pharmacokinetics of both agents was also assessed. To develop an ambulatory regimen for palliation of advanced NSCLC, paclitaxel was infused over 3 hours with standard premedication and carboplatin over 30 minutes. Cycles were repeated every 4 weeks. At each dose level, at least six patients were randomized to receive either paclitaxel followed by carboplatin or the reverse sequence. In the second and following cycles the alternate sequence was administered. The pharmacokinetics of both paclitaxel and carboplatin were compared in the first two cycles in at least two patients per dose level. Sixty-two patients have been entered in this study. Paclitaxel was increased from 100 mg/m2 in 25 mg/m2 increments up to a maximum of 225 mg/m2 combined with a fixed carboplatin dose (300 mg/m2). Thereafter, the drug doses were increased to a maximum of 400 mg/m2 carboplatin and 250 mg/m2 paclitaxel. In 243 cycles, the most frequent side effects were neutropenia, alopecia, and mild emesis. Only one patient developed a major hypersensitivity reaction to paclitaxel. Bone pain, myalgia, and peripheral neurotoxicity occurred more frequently at paclitaxel doses above 200 mg/m2. No significant differences in toxicity or in the pharmacokinetics of either drug were observed between the two drug sequences. The pharmacokinetics of paclitaxel were nonlinear and consistent with saturation. At the highest paclitaxel dose (250 mg/m2 with carboplatin 350 mg/m2) a toxic death due to severe leukopenia, thrombocytopenia, and hemorrhage occurred. Safe doses for phase II trials in untreated NSCLC are 200 mg/m2 paclitaxel with 300 mg/m2 carboplatin. Of 50 evaluable patients, five of the six major responses were observed at paclitaxel doses of 175 mg/m2 and above, which suggests a dose-response relationship for paclitaxel in NSCLC.