Bevacizumab and oxaliplatin-based chemotherapy in metastatic colorectal cancer

In metastatic colorectal cancer disease progression correlates with serum VEGF levels. The importance of VEGF in tumor-induced angiogenesis is well described in preclinical models. In this review we discuss the role of anti-VEGF therapy in combination with oxaliplatin-based chemotherapy for the treatment of metastatic colorectal cancer. A recent Phase III clinical trial in patients with metastatic colorectal cancer demonstrated the efficacy of FOLFOX4 in combination with bevacizumab, a recombinant humanized monoclonal antibody with high binding specificity for VEGF, to improve median overall survival when used as second-line therapy. The major adverse events associated with bevacizumab include grade III hypertension, bleeding and the risk of gastrointestinal perforation. Combining bevacizumab with oxaliplatin-based chemotherapy as first-line treatment for patients with metastatic colorectal cancer improves progression-free survival, as seen in the NO16966 and Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) studies, when compared with placebo and historical controls, respectively. Future research will need to focus on the mechanisms whereby bevacizumab enhances the benefit of chemotherapy to identify predictive markers that better define which patient populations will benefit the most from treatment.     

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy

BACKGROUND:

The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open‐label, single‐arm trial was evaluated.

METHODS:

Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml‐min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m² for patients on CYP3A enzyme‐inducing anti‐epileptics [EIAEDs] and 125 mg/m² for patients not on EIAEDs) were administered on days 1 and 14 of every 28‐day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression‐free survival at 6 months (PFS‐6), and secondary end points included safety and median overall survival (OS).

RESULTS:

All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0‐7.0 months) and PFS‐6 rate was 16% (95% CI, 5.0%‐32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment‐related deaths.

CONCLUSIONS:

Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society.     

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

Background:

We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial.

Methods:

A total of59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg⁻¹ bevacizumab biweekly and 50 mg m⁻² etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2α (HIF-2α) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome.

Results:

Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade ⩾3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism.

Conclusion:

Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).     

Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib,a small molecule angiokinase inhibitor

Colorectal cancer (CRC) is a common tumor type with a high mortality rate, in part due to intrinsic drug resistance. Although bevacizumab, a VEGF-directed neutralizing antibody, is particularly active in this pathology, some patients never respond for reasons not well understood. We here wish to clarify the role of autocrine VEGF signaling in the response of CRC cells to angiogenesis inhibition. Our results show that CRC cells with intrinsic bevacizumab-resistance displayed pronounced upregulation of autocrine HIF-VEGF-VEGFR signaling in response to prolonged bevacizumab exposure whereas the same signaling pathway was downregulated in bevacizumab-sensitive xenografts. Importantly, both bevacizumab-sensitive and -resistant CRC xenografts were sensitive to nintedanib, a small molecule angiokinase inhibitor, which was associated with inhibition of mTORC1. In vitro studies revealed that bevacizumab-resistant cells displayed intrinsically higher HIF-VEGF signaling intensity and hypoxia tolerance compared to their bevacizumab-sensitive counterparts. Interestingly, although nintedanib showed comparable activity toward bevacizumab-sensitive cells under normoxia and hypoxia, the drug was three-fold more toxic to the resistant cells under hypoxia, suggesting that nintedanib attenuated the survival signaling that usually protects these cells from hypoxia-mediated cell death. In conclusion, our findings support a role for autocrine VEGF signaling in the survival of CRC cells to hypoxia and thus to angiogenesis inhibition. We further show that nintedanib, a small molecule angiokinase inhibitor, is active toward CRC models with intrinsic bevacizumab resistance supporting clinical trials of nintedanib in patients that do not respond to bevacizumab, alone or in combination with bevacizumab to increase angiogenesis inhibition.     

Prognostic significance of AMPK activation in advanced stage colorectal cancer treated with chemotherapy plus bevacizumab

Background:

AMP-activated protein kinase (AMPK) has a central role in cellular energy sensing and is activated in preclinical tumour models following anti-vascular endothelial growth factor (VEGF) therapy. The possible predictive or prognostic role of AMPK status in cancer patients treated with anti-VEGF drugs has not been investigated so far.

Methods:

Expression of components of the AMPK pathway including phosphorylated AMPK (pAMPK), phosphorylated acetyl-Coa carboxylase (pACC) and liver kinase B1 (LKB1) was investigated by immunohistochemistry in 48 colorectal cancers treated with FOLFIRI plus bevacizumab. Correlation between pAMPK and pACC and associations between the AMPK pathway scores and clinico-pathological characteristics were assessed. Overall survival (OS) was estimated through Kaplan–Meier method, whereas hazard ratios were computed to identify prognostic factors.

Results:

Fourteen patients (29.2%) were included in the pAMPK-negative group (score ⩽5), whereas 34 patients (70.8%) were included in the pAMPK-positive group (score >5). The Spearman''s coefficient for the correlation between pAMPK and pACC scores in primary tumour samples was 0.514 (P=0.0002). Low pAMPK levels were associated with worse OS (P-value 0.0002) but not with PFS, whereas low pACC levels were associated both with worse OS and PFS (P-value 0.0007 and 0.01, respectively).

Conclusions:

Our findings suggest that high tissue AMPK activation is a prognostic biomarker in this cohort of metastatic colorectal cancer patients.     

VEGF在子宫内膜癌组织中的表达和意义

目的　探讨血管内皮生长因子 (VEGF)在子宫内膜癌组织中的表达及意义。方法　应用免疫组织化学S -P法对 5 0例子宫内膜腺癌、10例子宫内膜复杂型增生过长、10例正常子宫内膜组织中VEGF表达进行检测。结果　子宫内膜腺癌、子宫内膜复杂型增生过长、正常子宫内膜组织中VEGF的强阳性表达率分别为 74 .0 % (37/5 0 )、2 0 % (2 /10 )、10 % (1/10 ) ,统计学显示癌组织的强阳性表达率明显高于复杂性增生过长和正常组织 (P <0 .0 5 ) ;VEGF的表达与临床分期、组织学分级、肌层浸润程度、患者年龄均无明显相关性(P >0 .0 5 )。结论　VEGF高表达可能与子宫内膜癌的发生有关 ,但不能作为判断其转移及预后的指标。     

Anti-VEGF therapy: a new approach to colorectal cancer therapy

The purpose of this review is to discuss the inhibition of vascular endothelial growth factor as a treatment for advanced colorectal cancer. The review will begin by summarizing the theory behind vascular endothelial growth factor inhibition and how this affects tumor angiogenesis. The major clinical trials that have examined antivascular endothelial growth factor agents to treat patients with advanced colorectal cancer will then be described. Finally, there is a commentary regarding the status of targeted agents currently in development for the treatment of advanced colorectal cancer and a discussion of the potential future considerations for the use of antivascular endothelial growth factor agents in clinical practice.     

Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer

Background:

The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC).

Methods:

Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: −2578A/C, −1498C/T, −1154A/G, −634C/G and 936C/T; and VEGFR-2: −604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients.

Results:

Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found.

Conclusion:

Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies.     

Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer

Background:

Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme.

Methods:

Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA.

Results:

Samples for biomarker analysis were available from 24–54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF₁₂₁. No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry, or for any of the SNPs investigated.

Conclusion:

Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.     

Bevacizumab in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for first-line and maintenance treatment of metastatic colorectal cancer

Despite a slight decrease in mortality rates, recent advances in screening methods, diagnosis and overall improved therapeutic options, colorectal cancer (CRC) remains among the leading causes of cancer-related death worldwide. The major cause is the mortality related to metastatic status of CRC. Increasing clinical evidence derived from randomized trials strongly suggests that the efficacy of standard cytotoxic agents, including various combinations of 5-fluoouracil (5-FU)/leucovorin (LV), capecitabine, irinotecan and oxaliplatin, may be significantly augmented with concomitant administration of molecular agents targeting the vascular endothelial growth factor (VEGF) signaling pathways, such as bevacizumab. Herein, we critically discuss the current data on the efficacy and safety profile of bevacizumab in combination with fluoropyrimidine-based chemotherapy for first-line and maintenance treatment of metastatic CRC and briefly comment on existing controversies and future perspectives.     

乳腺癌抗血管生成治疗:现状与前景

Tumor angiogenesis plays an important role in the growth, invasion and metastasis of breast cancer, therefore re-cently a very active area of breast cancer research involves the addition of antiangiogenic therapy. Numerous clinical studies for several antiangiogenic agents have recently been conducted in breast cancer patients and have shown clinically significant improvement in outcomes. This review gives a brief background to breast cancer angiogenesis, also focusing on current prog-ress in the field of a...     

Inhibition of epidermoid carcinoma A431 cell growth and angiogenesis in nude mice by early and late treatment with a novel dextran derivative

We investigated the effect of a new dextran derivative, phenylacetate carboxymethyl benzylamide dextran (NaPaC), on epidermoid carcinoma A431 cells secreting a large quantity of angiogenic factor, vascular endothelial growth factor (VEGF). In vitro, NaPaC inhibited the proliferation of A431 cells (IC(50)=5 micro M). Also, NaPaC decreased the binding of radiolabelled VEGF(165) to endothelial cells (IC(50)=0.2 micro M). In vivo, we explored the effects of NaPaC (15 mg kg(-1)) on A431 xenograft growth starting the drug administration at the time of tumour cell inoculation (early treatment) and 1 week later, when tumours were well established (late treatment). Early treatment was more efficient on tumour inhibition (70% vs control) than late treatment (50% vs control). Early and late NaPaC-treatment increased the aponecrosis in tumour by 70 and 30%, respectively. Whatever treatment, NaPaC inhibited the intratumour endothelial cell density in the same manner. In contrast, vessel area was decreased only when NaPaC was injected early (35%). These results show that NaPaC has a potent inhibitory effect, dependent on treatment outset, on epidermoid carcinoma growth associated with an intratumour microvascular network diminution and an aponecrosis increase. As this drug is nontoxic at efficient dose, it offers interesting perspectives for the therapy of malignant lesions.     

Carboxymethyl benzylamide dextran inhibits angiogenesis and growth of VEGF-overexpressing human epidermoid carcinoma xenograft in nude mice

Vascular endothelial growth factor (VEGF) expression is elevated in a wide variety of solid tumours. Inhibition of VEGF activities is able to reduce angiogenesis and tumour growth. We have recently shown in vitro that carboxymethyl dextran benzylamide (CMDB7) prevents the binding of VEGF(165) to its cell surface receptors and thus inhibits VEGF activities on endothelial cells. In the present study, we explored the effects of CMDB7 on highly aggressive human epidermoid carcinoma A431 cells known to overexpress epidermal growth factor receptors (EGFRs) and produce a high amount of VEGF and a minor quantity of bFGF. In vitro, CMDB7 blocked the mitogenic activity of A431-conditioned medium on endothelial cells. Concerning A431 cells, CMDB7 inhibited their proliferation and the VEGF(165) binding to them. In vivo, administration of CMDB7 (10 mg kg(-1)) three times per week for 2 weeks inhibited the growth of A431 xenografts in nude mice by 73% as compared to the control group. Immunostaining of endothelial cells with mouse-specific GSL-1 lectin in tumour sections revealed that CMDB7 also inhibited the density of intratumour endothelial cells by 66%. These findings demonstrate that CMDB7 has an efficient antiangiogenic and antitumour action in vivo even when tumour cells produce a high level of VEGF and EGFRs.     

结直肠癌组织Survivin和VEGF表达与临床病理特征相关性的研究

目的:探讨结直肠癌组织中凋亡抑制基因Survivin和血管内皮生长因子(vascular endothelial growth factor,VEGF)表达与结直肠癌临床病理特征的相关性,及其在结直肠癌发生发展中的作用。方法:应用免疫组织化学方法检测61例结直肠癌及肿瘤切端非癌组织中VEGF及Survivin的表达。结果:Survivin在正常结直肠组织不表达,结直肠癌组织中45例(73.77%)阳性表达,VEGF在非癌结直肠组织不表达,癌组织中42例(68.85%)阳性表达。结直肠癌组织中Survivin及VEGF表达与肿瘤浸润深度、Duke分期及有无淋巴结转移关系密切,P<0.05。结论:Survivin和VEGF参与结直肠癌血管新生的调节,与肿瘤的发生发展及预后有密切关系。     

Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer

BACKGROUND:

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC).

METHODS:

Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2‐stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point.

RESULTS:

Twenty‐seven patients with advanced HCC (median age, 60 years) were enrolled in this multi‐institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8‐7.1). Median survival time was 9.5 months (95% CI, 7.1‐17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea.

CONCLUSIONS:

In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression‐free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. Cancer 2012. © 2011 American Cancer Society.     

大肠癌血管内皮生长因子及其受体的表达和临床意义

目的　探讨血管内皮生长因子 (VEGF)及其受体 (KDR)在大肠癌组织中的表达及其与临床特征之间的关系 ,为通过阻断VEGF及其受体KDR的作用治疗大肠癌提供依据。方法　应用免疫组织化学SABC法检测 6 8例大肠癌组织和癌旁组织VEGF及KDR蛋白的表达 ,2 0例正常组织作对照。结果　 2 0例正常组织中未发现VEGF及KDR的表达 ,6 8例大肠癌组织中VEGF表达阳性率为 5 5 .9%( 38/6 8) ,KDR表达阳性率为 45 .6 %( 31/6 8) ,均明显高于癌旁组织 ( 11.8%,8/6 8;8.8%,6 /6 8) (P <0 .0 1)。大肠癌组织VEGF及KDR的表达与肿瘤浸润深度、淋巴结转移、远处转移、血管侵犯、Dukes′分期密切相关 ,而与组织学分型无关。VEGF和KDR的表达密切相关。结论　VEGF及其受体KDR在大肠癌的生长、进展和转移中起了重要作用。     

白桦脂酸对人类大肠癌细胞裸鼠体内生长及血管生成的抑制作用(英文)

Objective:Angiogenesis plays a major role in the pathogenesis of many disorders.Vascular endothelial growth factor(VEGF) has been shown to be the key regulator of normal and pathological angiogenesis.Many studies showed that decreased expression of VEGF has been inhibited growth and migration of cancer cells.The aim of this study was to explore the effects of Betulinic acid on the VEGF expression and the growth of colorectal cell SW480 xenografts in nude mice.Methods:The xenografts derived from colorectal c...     

Emerging clinical principles on the use of bevacizumab for the treatment of malignant gliomas

Despite advances in adjuvant therapy, the prognosis for most patients with high‐grade glioma (HGG) is poor, and almost all HGGs have a likelihood of disease recurrence. HGGs are highly vascularized tumors with elevated expression levels of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. A compelling biologic rationale, a pressing need for improved therapeutics and positive results from studies of bevacizumab in other tumor types, led to the evaluation of bevacizumab in the treatment of HGG. It was demonstrated previously that bevacizumab, which is a humanized monoclonal antibody that targets VEGF, improved outcomes when combined with chemotherapy (most commonly irinotecan) in patients with recurrent HGG; and, on the basis of an improved objective response rate in 2 prospective phase 2 studies, bevacizumab was granted accelerated approval by the US Food and Drug Administration as a single agent in patients with previously treated glioblastoma (GB). Bevacizumab‐containing therapy has been associated with manageable, class‐specific toxicity; however, severe treatment‐related adverse events are observed in a minority of patients. Preliminary data on bevacizumab‐based therapy in recurrent anaplastic gliomas, in the frontline treatment of GB, and in additional patient populations are also encouraging. With the goal of addressing unanswered questions regarding the optimal use of bevacizumab, the objective of the current review was to provide a summary of the clinical efficacy and safety data on bevacizumab in patients with HGG, the practical issues surrounding the administration of bevacizumab, and ongoing investigations of bevacizumab in additional brain tumor treatment settings. Cancer 2010. © 2010 American Cancer Society.     

Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix

The aim of the study was to evaluate VEGF expression in tumour biopsies as a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. A retrospective study was carried out on 100 patients. Pre-treatment tumour VEGF expression was examined immunohistochemically in formalin-fixed, paraffin-embedded biopsies using a widely available commercial antibody. A semi-quantitative analysis was made using a scoring system of 0, 1, 2, and 3, for increasing intensity of staining. High VEGF expression was associated with a poor prognosis. A univariate log rank analysis found a significant relationship with overall survival (P = 0.0008) and metastasis-free survival (P = 0.0062), but not local control (P = 0.23). There was no correlation between VEGF expression and disease stage, tumour differentiation, patient age, or tumour radiosensitivity (SF2). In a Cox multivariate analysis of survival VEGF expression was the most significant independent prognostic factor (P = 0.001). After allowing for VEGF only SF2 was a significant prognostic factor (P = 0.003). In conclusion, immunohistochemical analysis of VEGF expression is a highly significant and independent prognostic indicator of overall and metastasis-free survival for patients treated with radiotherapy for advanced carcinoma of the cervix. It is also a rapid and easy method that could be used in the clinical setting, to identify patients at high risk of failure with conventional radiotherapy who may benefit from novel approaches or chemoradiotherapy.