Tumor neovascularization is the basis of tumor growth, progression and metastasis, involving various cell-mediated signal transduction pathways, and many factors that promote / inhibit angiogenesis. Among them, the strongest growth factor that stimulates angiogenesis is vascular endothelial growth factor(VEGF), which acts by binding to the vascular endothelial growth factor receptor (VEGFR). VEGF / VEGFR pathway inhibitors are now widely used in clinical treatment, a new generation of anti-tumor angiogenesis drug research and development has also made some breakthrough. This article reviews the mechanism of tumor angiogenesis, different molecules pathways of anti-tumor angiogenesis drugs and drug resistance mechanisms in the treatment of non-small cell lung cancer.
MIHAJLOVICJ,PECHLIVANOGLOUP,MILADINOV-MIKOVM,et al.Cancer incidence and mortality in Serbia 1999-2009[J/OL].,2013,13(1):18-28..doi:10.1186/1471-2407-13-18.
CARMELIETP,JAIN RK.Molecular mechanisms and clinical applications of angiogenesis[J].,2011,473(7347):298-307.
Abstract Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
DE PALMAM,BIZIATOD,PETROVA TV.Microenviron-mental regulation of tumour angiogenesis[J].,2017,17(8):457-474.
Abstract Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.
HUANGG,CHENL.Tumor vasculature and microenviron-ment normalization:a possible mechanism of antian-giogenesis therapy[J].,2008,23(5):661-667.
Tumor antiangiogenesis therapy has been in application for more than 30 years; however, its mechanism remains obscure. An intriguing hypothesis, which has recently gained acceptance, explores the possibility that antiangiogenesis therapy may transiently normalize tumor vasculature and its microenvironment, thus enhancing chemoradiotherapy efficacy. As the equilibrium between proangiogenesis and antiangiogenesis factors is perturbed in the tumor and tips to the former, tumor vasculature tends to exhibit abnormal structure and function. Abnormal vasculature is tightly associated with an uncharacteristic microenvironment, including uneven perfusion, hypoxia, and increased interstitial fluid pressure: This malignant microenvironment hinders the delivery of chemotherapeutics to tumor cells and desensitizes the malignant cells to radiation. Antiangiogenesis therapy can reverse the imbalance and transiently normalize this microenvironment and gives a new perspective for combining antiangiogenesis therapy and traditional chemoradiotherapy. Key words: tumor angiogenesis, antiangiogenesis therapy, vasculature normalization, tumor microenvironment
RUSSO AE,PRIOLOD,ANTONELLIG,et al.Bevacizu-mab in the treatment of NSCLC:patient selection and perspectives[J].,2017,8(14):259-269.
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SANDLERA,GRAYR, PERRY MC, et al.Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer[J]., 2006,355(24):2542-2550.
Abstract BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers. METHODS: Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival. RESULTS: The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. CONCLUSIONS: The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060 .) 2006 Massachusetts Medical Society
ZHOUC, WU YL, CHENG,et al.BEYOND: a randomi-zed, double-blind,placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer[J]. ,2015,33(19):2197-2204.
The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. Patients age 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non-small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m(2)) intravenously (CP) on day 1 of each 3-week cycle, for six cycles, plus placebo (Pl+CP) or bevacizumab (B+CP) 15 mg/kg intravenously, on day 1 of each cycle, until progression, unacceptable toxicity, or death. The primary end point was progression-free survival (PFS); secondary end points were objective response rate, overall survival, exploratory biomarkers, safety. A total of 276 patients were randomly assigned, 138 to each arm. PFS was prolonged with B+CP versus Pl+CP (median, 9.2 v 6.5 months, respectively; hazard ratio [HR], 0.40; 95% CI, 0.29 to 0.54; P < .001). Objective response rate was improved with B+CP compared with Pl+CP (54% v 26%, respectively). Overall survival was also prolonged with B+CP compared with Pl+CP (median, 24.3 v 17.7 months, respectively; HR, 0.68; 95% CI, 0.50 to 0.93; P = .0154). Median PFS was 12.4 months with B+CP and 7.9 months with Pl+CP (HR, 0.27; 95% CI, 0.12 to 0.63) in EGFR mutation-positive tumors and 8.3 and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21 to 0.53), in wild-type tumors. Safety was similar to previous studies of B+CP in NSCLC; no new safety signals were observed. The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC.
PILKINGTONG, BOLANDA, BROWNT, et al.A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer[J]. ,2015,70(4):359-367.
Our aim was to evaluate the clinical effectiveness of chemotherapy treatments currently licensed in Europe and recommended by the National Institute for Health and Care Excellence (NICE) for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). A systematic search of MEDLINE, EMBASE and the Cochrane Library for randomised controlled trials (RCTs) published from 2001 to 2010 was carried out. Relative treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using standard meta-analysis and mixed treatment comparison methodology. A total of 23 RCTs were included: 18 trials compared platinum-based chemotherapy, two compared pemetrexed and three compared gefitinib. There are no statistically significant differences in OS between any of the four third-generation chemotherapy regimens. There is statistically significant evidence that pemetrexed+platinum increases OS compared with gemcitabine+platinum. There are no statistically significant differences in OS between gefitinib and docetaxel+platinum or between gefitinib and paclitaxel+platinum. There is a statistically significant improvement in PFS with gefitinib compared with docetaxel+platinum and gefitinib compared with paclitaxel+platinum. Due to reduced generic pricing, third-generation chemotherapy regimens (except vinorelbine) are still competitive options for most patients. This research provides a comprehensive evidence base, which clinicians and decision-makers can use when deciding on the optimal first-line chemotherapy treatment regimen for patients diagnosed with locally advanced or metastatic NSCLC.
AKAZAH.What is the Asian consensus statement on NCCN clinical practice guidelines in oncology (NCCN-ACS)?[J].,2016,46(4):299-302.
Abstract Cancer treatment guidelines are compiled on the basis of established evidence. Such evidence is obtained from epidemiological, pathological and pharmacological study and, most importantly of all, the information gained from clinical trials. However, very little of the kind of evidence that is required for the compilation of treatment guidelines is actually obtained from Asian countries. When one considers the ethnic differences and disparities in medical care, coupled with the tremendous cultural diversity that characterize the Asian region, it would be difficult to conclude that there is currently sufficient evidence that could form the basis for the formulation of guidelines that would be relevant and applicable to all Asian countries. An urgent issue that needs to be addressed in order to achieve a breakthrough in this difficult situation is to build up a body of evidence at an advanced level that is specific to the Asian region and Asian ethnicities. For the interim, however, it is also necessary to efficiently incorporate evidence that has been obtained in Western countries. Furthermore, an effective method of utilizing guidelines that have already been compiled in Western countries is considered to be not by simply translating them into local languages, but rather to engage in a process of adaptation, whereby the guidelines are adjusted or modified to match the circumstances of a particular country or region. The NCCN Clinical Practice Guidelines-Asian Consensus Statement (NCCN-ACS) documents have been compiled with this intention in mind, utilizing the NCCN guidelines that are widely used internationally. The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
HERBST RS, O'NEILL V J, FEHRENBACHER L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung cancer[J]. ,2007,25(30):4743-4750.
WELSH JW,KOMAKIR,AMINIA,et al.Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer[J].,2013,31(7):895-902.
Brain metastasis (BM) is a leading cause of death from non-small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety.Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility.Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations.Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.
TOWNSLEY CA,MAJORP,SIU LL,et al.Phase II study of erlotimib (OSI-774) in patients with metastatic colorectal cancer[J].,2006,94(8):1136-1143.
Abstract Erlotinib (Tarceva, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108-329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.
QUINTELA-FANDINOM,LE TOURNEAUC,DURANI,et al.Phase I combination of sorafenib and erlotinib therapy in solid tumors: safety, pharmacokinetic, and pharmacodynamic evaluation from an expansion cohort[J].,2010,9(3):751-760.
The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic and pharmacodynamic markers with clinical outcome. In addition, a novel pharmacodynamic marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. Epidermal growth factor receptor (EGFR) expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pretreatment, prior to erlotinib dosing, and during the administration of both drugs. In addition, positron emission tomography-computed tomography scans and pharmacokinetic assessments were done. Eleven patients received a total of 57 cycles (median, 5; range, 1-10). Only four patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of >or=4 cycles. Pharmacokinetic analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in seven patients. Other pharmacodynamic markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib.
KATOT,SETOT,NISHIOM,et al.Erlotinib plus bevaci-zumab phase ll study in patients with advanced non-small-cell lung cancer (JO25567):updated safety results[J].,2018,41(2):229-237.
Abstract INTRODUCTION: The phase II JO25567 study compared the efficacy and safety of erlotinib plus bevacizumab vs. erlotinib alone as first-line therapy for advanced epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). OBJECTIVE: Our objective is to provide updated analyses of safety and the assessment of manageability of specific adverse events. METHODS: Patients with stage IIIB/IV or recurrent, non-squamous, EGFR mutation-positive NSCLC were randomized to receive erlotinib plus bevacizumab or erlotinib. The primary endpoint was progression-free survival. Adverse event frequency rates, predictability and manageability, reasons for discontinuation, time to onset, and outcomes of specific adverse events were analyzed. RESULTS: The safety analysis population comprised 152 randomized patients (75 erlotinib plus bevacizumab; 77 erlotinib) who received at least one dose of study drug between February 2011 and March 2012. There was no difference in overall incidence of serious adverse events between arms, but more grade 3 or higher adverse events were reported with erlotinib plus bevacizumab (90.7%) than with erlotinib (53.2%), primarily due to grade 3 hypertension. Hypertension was controllable with antihypertensive medications in most cases. Proteinuria and bleeding were also more frequently reported with erlotinib plus bevacizumab than with erlotinib but were manageable and did not lead to early discontinuations. CONCLUSIONS: The addition of bevacizumab to erlotinib prolonged progression-free survival in EGFR mutation-positive NSCLC. Follow-up safety data were consistent with the known safety profiles of both erlotinib and bevacizumab in NSCLC; this combination appeared to be manageable, and treatment was well tolerated. JapicCTI-111390.
PASTINAP,NARDONEV,BOTTAC,et al.Radiotherapy prolongs the survival of advanced non-smallcell lung cancer patients undergone to an immune-modulating treatment with dose-fractioned cisplatin and metronomic etoposide and bevacizumab (mPEBev)[J].,2017,8(44):75904-75913.
Radiotherapy (RT), together with a direct cytolytic effect on tumor tissue, also elicits systemic immunological events, which sometimes result in the regression of distant metastases (abscopal effect). We have shown the safety and anti-tumor activity of a novel metronomic chemotherapy (mCH) regimen with dose-fractioned cisplatin, oral etoposide and bevacizumab, a mAb against the vasculo-endothelial-growth-factor (mPEBev regimen), in metastatic non-small-cell-lung cancer (mNSCLC). This regimen, designed on the results of translational studies, showed immune-modulating effects that could trigger and empower the immunological effects associated with tumor irradiation. In order to assess this, we carried out a retrospective analysis in a subset of 69 consecutive patients who received the mPEBev regimen within the BEVA2007 trial. Forty-five of these patients, also received palliative RT of one or more metastatic sites. Statistical analysis (a Log-rank test) revealed a much longer median survival in the group of patients who received RT [mCHvsmCH + RT: 12.1 +/-2.5 (95%CI 3.35-8.6)vs22.12 +/-4.3 (95%CI 11.9-26.087) months;P=0.015] with no difference in progression-free survival. In particular, their survival correlated with the mPEBev regimen ability to induce the percentage of activated dendritic cells (DCs) (CD3-CD11b+CD15-CD83+CD80+) [Fold to baseline value (FBV) 1vs>1: 4+/-5.389 (95%CI,0- 14.56)vs56+/-23.05 (95%CI,10.8-101.2) months;P:0.049)] and central-memory- T-cells (CD3+CD8+CD45RA-CCR7+) [FBV 1vs>1: 8+/-5.96 (95%CI,0-19.68)vs31+/-12.3 (95%CI,6.94-55.1) months;P:0.045]. These results suggest that tumor irradiation may prolong the survival of NSCLC patients undergone mPEBev regimen presumably by eliciting an immune-mediated effect and provide the rationale for further perspective clinical studies.
GARON EB,CIULEANU TE,ARRIETAO,et al.Ramu-cirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial[J].,2014,384(9944):665-673.
PARKK,KIM JH,CHO EK,et al.East Asian subgroup analysis of a randomized,double-blind,phase 3 study of docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV non-small cell lung cancer following disease progression after one prior platinum-based therapy (REVEL)[J].,2016,48(4):1177-1186.
PAZ-ARES LG,PéROLM,CIULEANUT,et al.Treatment outcomes by histology in REVEL:a randomized phase III trial of ramucirumab plus docetaxel for advanced non-small cell lung cancer[J].,2017,112(1):126-133.
Abstract OBJECTIVES: Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody inhibiting vascular endothelial growth factor receptor-2, increased overall survival (OS) combined with docetaxel versus docetaxel alone in non-small cell lung cancer (NSCLC) in the REVEL trial. Pre-specified exploratory analysis examined efficacy and safety by histology. MATERIALS AND METHODS: 1253 patients with NSCLC were randomized to receive ramucirumab (10mg/kg; n=628) plus docetaxel (75mg/m 2 ) or placebo plus docetaxel (n=625) after disease progression on or after platinum-based therapy, with or without bevacizumab or maintenance therapy. OS was analyzed using Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Primary quality-of-life analysis was time to deterioration (TtD) of the Lung Cancer Symptom Scale (LCSS) scores using the Kaplan-Meier method and Cox regression. RESULTS: Median OS for adenocarcinoma was 11.2 months for ramucirumab-docetaxel (n = 377) and 9.8 months for placebo-docetaxel (n=348); HR=0.83 (95% CI: 0.69-0.99). In squamous disease, median OS was 9.5 months for ramucirumab-docetaxel (n=157) versus 8.2 months for placebo-docetaxel (n=171); HR 0.88 (95% CI: 0.69-1.13). Median OS for other nonsquamous was 10.8 months for ramucirumab-docetaxel (n=74) and 9.3 months for placebo-docetaxel (n=78); HR=0.86 (95% CI: 0.59-1.26). Treatment-emergent adverse events were comparable between treatment arms across histologic subgroups. TtD for LCSS scores was similar between treatment arms in the nonsquamous and squamous subgroups. CONCLUSION: REVEL demonstrated similar favorable efficacy and manageable safety for ramucirumab-docetaxel across histologic subgroups of NSCLC. Copyright 2017. Published by Elsevier B.V.
RECKM,KAISERR,MELLEMGAARDA,et al.Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1):a phase 3,double-blind,randomised controlled trial[J].,2014,15(2):143-155.
Abstract BACKGROUND: The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). METHODS: Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m(2) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194 . FINDINGS: Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 700·1 months (IQR 300·8-1100·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 300·4 months [95% CI 200·9-300·9] vs 200·7 months [200·6-200·8]; hazard ratio [HR] 000·79 [95% CI 000·68-000·92], p=000·0019). After a median follow-up of 3100·7 months (IQR 2700·8-3600·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 1000·9 months [95% CI 800·5-1200·6] vs 700·9 months [600·7-900·1]; HR 000·75 [95% CI 000·60-000·92], p=000·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 1200·6 months [95% CI 1000·6-1500·1] vs 1000·3 months [95% CI 800·6-1200·2]; HR 000·83 [95% CI 000·70-000·99], p=000·0359), but not in the total study population (median 1000·1 months [95% CI 800·8-1100·2] vs 900·1 months [800·4-1000·4]; HR 000·94, 95% CI 000·83-100·05, p=000·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [600·6%] of 652 vs 17 [200·6%] of 655), reversible increases in alanine aminotransferase (51 [700·8%] vs six [000·9%]), and reversible increases in aspartate aminotransferase (22 [300·4%] vs three [000·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). INTERPRETATION: Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. FUNDING: Boehringer Ingelheim. Copyright 0008 2014 Elsevier Ltd. All rights reserved.
TANAKAS,SAKAMORIY,NIMIM,et al.Design paper: a phase II study of bevacizumab and erlotinib in patients with non-squamous non-small cell lung cancer that is refractory or relapsed after 1-2 previous treatment (BEST)[J].,2011,12:120.
Background Combination of erlotinib and bevacizumab is a promising regimen in advanced non-squamous non-small-cell lung cancer (NSCLC). We are conducting a single arm phase II trial which aims to evaluate the efficacy and safety of this regime as a second- or third-line chemotherapy. Methods Key eligibility criteria were histologically or cytologically confirmed non-squamous NSCLC, stage III/IV or recurrent NSCLC not indicated radical chemoradiation, prior one or two regimen of chemotherapy, age 20 years or more, and performance status of two or less. The primary endpoint is objective response rate. The secondary endpoints include overall survival, progression-free survival, disease control rate and incidence of adverse events. This trial plans to accrue 80 patients based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35% and a null hypothesis threshold response rate of 20%. A subset analysis according to EGFR mutation status is planned. Discussion We have presented the design of a single arm phase II trial to evaluate the efficacy and safety of combination of bevacizumab and erlotinib in advanced non-squamous NSCLC patients. In particular we are interested in determining the merit of further development of this regimen and whether prospective patient selection using EGFR gene is necessary in future trials. Trial registration This trial was registered at the UMIN Clinical Trials Registry as UMIN000004255 (http://www.umin.ac.jp/ctr/index.htm webcite).
VASUDEV NS,REYNOLDS AR.Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions[J].,2014,17(3):471-494.
Erratum to: Angiogenesis DOI 10.1007/s10456-014-9420-y The author wishes to correct the errors in Table02 1 of the original publication. The content in Table02 1 , under the section entitled ‘Colorectal cancer’ has three errors. For the AVF2107 trial, in the treatment column, “ FOLFIRI ” should be replaced with “IFL” For the NO16966 trial, in the outcome column “Improvement in OS and PFS” should be replaced with “Improvement in PFS” and Definitions of the abbreviations IFL and XELOX were omitted and have been added to the foot of the table. The correct Table02 1 is provided in this Erratum.
RAMLAUR,GORBUNOVAV,CIULEANU TE,et al.Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer:a randomized,controlled phase III trial[J].,2012,30(29):3640-3647.
To compare the efficacy of aflibercept (ziv-aflibercept), a recombinant human fusion protein targeting the vascular endothelial growth factor (VEGF) pathway, with or without docetaxel in platinum-pretreated patients with advanced or metastatic nonsquamous non-small-cell lung cancer.In this international, double-blind, placebo-controlled phase III trial, 913 patients were randomly assigned to (ziv-)aflibercept 6 mg/kg intravenous (IV; n = 456) or IV placebo (n = 457), both administered every 3 weeks and in combination with docetaxel 75 mg/m(2). The primary end point was overall survival (OS). Other efficacy outcomes, safety, and immunogenicity were also assessed.Patient characteristics were balanced between arms; 12.3% of patients had received prior bevacizumab. (Ziv-)Aflibercept did not improve OS (hazard ratio [HR], 1.01; 95% CI, 0.87 to 1.17; stratified log-rank P = .90). The median OS was 10.1 months (95% CI, 9.2 to 11.6 months) for (ziv-)aflibercept and 10.4 months (95% CI, 9.2 to 11.9 months) for placebo. In exploratory analyses, median progression-free survival was 5.2 months (95% CI, 4.4 to 5.6 months) for (ziv-)aflibercept versus 4.1 months (95% CI, 3.5 to 4.3 months) for placebo (HR, 0.82; 95% CI, 0.72 to 0.94; P = .0035); overall response rate was 23.3% of evaluable patients (95% CI, 19.1% to 27.4%) in the (ziv-)aflibercept arm versus 8.9% (95% CI, 6.1% to 11.6%; P < .001) in the placebo arm. Grade 3 adverse events occurring more frequently in the (ziv-)aflibercept arm versus the placebo arm were neutropenia (28.0% v 21.1%, respectively), fatigue (11.1% v 4.2%, respectively), stomatitis (8.8% v 0.7%, respectively), and hypertension (7.3% v 0.9%, respectively).The addition of (ziv-)aflibercept to standard docetaxel therapy did not improve OS. In exploratory analyses, secondary efficacy end points did seem to be improved in the (ziv-)aflibercept arm. The study regimen was associated with increased toxicities, consistent with known anti-VEGF and chemotherapy-induced events.
PAZ-ARES LG,BIESMAB,HEIGENERD,et al.Phase III,randomized,double-blind,placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced,nonsquamous non-small-cell lung cancer[J].,2012,30(25):3084-3092.
DOWLATIA,GRAYR,SANDLER AB,et al.Cell adhesion molecules,vascular endothelial growth factor,and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab--an eastern cooperative oncology group study[J].,2008,14(5):1407-1412.
HERBST RS,SUNY,EBERHARDT WE,et al.Vande-tanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC):a double-blind,randomised,phase 3 trial[J].,2010,11(7):619-626.
Abstract BACKGROUND: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). METHODS: Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB-IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m(2) intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377 . FINDINGS: 1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0.79, 97.58% CI 0.70-0.90; p<0.0001); median PFS was 4.0 months in the vandetanib group versus 3.2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0.79, 0.62-1.00, p=0.024); median PFS was 4.6 months in the vandetanib group versus 4.2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group). INTERPRETATION: The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy. 2010 Elsevier Ltd. All rights reserved.
PILKINGTONG,BOLANDA,BROWNT,et al.A syste-matic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer[J].,2015,70(4):359-367.
Our aim was to evaluate the clinical effectiveness of chemotherapy treatments currently licensed in Europe and recommended by the National Institute for Health and Care Excellence (NICE) for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). A systematic search of MEDLINE, EMBASE and the Cochrane Library for randomised controlled trials (RCTs) published from 2001 to 2010 was carried out. Relative treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using standard meta-analysis and mixed treatment comparison methodology. A total of 23 RCTs were included: 18 trials compared platinum-based chemotherapy, two compared pemetrexed and three compared gefitinib. There are no statistically significant differences in OS between any of the four third-generation chemotherapy regimens. There is statistically significant evidence that pemetrexed+platinum increases OS compared with gemcitabine+platinum. There are no statistically significant differences in OS between gefitinib and docetaxel+platinum or between gefitinib and paclitaxel+platinum. There is a statistically significant improvement in PFS with gefitinib compared with docetaxel+platinum and gefitinib compared with paclitaxel+platinum. Due to reduced generic pricing, third-generation chemotherapy regimens (except vinorelbine) are still competitive options for most patients. This research provides a comprehensive evidence base, which clinicians and decision-makers can use when deciding on the optimal first-line chemotherapy treatment regimen for patients diagnosed with locally advanced or metastatic NSCLC.
SANDLERA,GRAYR,PERRY ML,et al.Paclitaxel-car-boplatin alone or with bevacizumab for non-small-cell lung cancer[J].,2006,355(24):2542-2550.
Abstract BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers. METHODS: Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival. RESULTS: The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. CONCLUSIONS: The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060 .) 2006 Massachusetts Medical Society
JUBB AM,MILLER KD,RUGO HS,et al.Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer[J].,2011,17(2):372-381.
react-text: 106 Angiogenesis, an essential component of tumor growth and survival, is regulated by complex interactions between several cell types and soluble mediators. Heterogeneous tumor vasculature originates from the collective effect of the nature of carcinoma and the complexity of the angiogenic network. Although the application of angiogenesis inhibitors in some types of cancers has shown clinical... /react-text react-text: 107 /react-text [Show full abstract]
KOPETZS,HOFF PM,MORRIS JS,et al.Phase II trial of infusional fluorouracil,irinotecan,and bevacizumab for metastatic colorectal cancer:efficacy and circulating angiogenic biomarkers associated with therapeutic resistance[J].,2010,28(3):453-459.
Abstract PURPOSE: We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance. PATIENTS AND METHODS: We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD). RESULTS: Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001). CONCLUSION: Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.
BEYOND: a randomi-zed, double-blind,placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer
A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer
O'NEILL V J, FEHRENBACHER L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung cancer
Phase I combination of sorafenib and erlotinib therapy in solid tumors: safety, pharmacokinetic, and pharmacodynamic evaluation from an expansion cohort
Radiotherapy prolongs the survival of advanced non-smallcell lung cancer patients undergone to an immune-modulating treatment with dose-fractioned cisplatin and metronomic etoposide and bevacizumab (mPEBev)
Ramu-cirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial
East Asian subgroup analysis of a randomized,double-blind,phase 3 study of docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV non-small cell lung cancer following disease progression after one prior platinum-based therapy (REVEL)
Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1):a phase 3,double-blind,randomised controlled trial
Design paper: a phase II study of bevacizumab and erlotinib in patients with non-squamous non-small cell lung cancer that is refractory or relapsed after 1-2 previous treatment (BEST)
Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer:a randomized,controlled phase III trial
Phase III,randomized,double-blind,placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced,nonsquamous non-small-cell lung cancer
Cell adhesion molecules,vascular endothelial growth factor,and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab--an eastern cooperative oncology group study
Vande-tanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC):a double-blind,randomised,phase 3 trial
A syste-matic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer
Phase II trial of infusional fluorouracil,irinotecan,and bevacizumab for metastatic colorectal cancer:efficacy and circulating angiogenic biomarkers associated with therapeutic resistance