Bevacizumab for the treatment of high-grade glioma

After karyotyping invasively obtained fetal material for decades, the field of prenatal genetic care has changed tremendously since the turn of the century. The introduction of novel technologies and strategies went along with concerns and debates, in which key issues were costs, the finding of variants of unknown or uncertain clinical relevance, commercialization and ethical and social issues. At present, there is an explosion of new genomic technologies, which need critical assessment prior to implementation, especially in the prenatal field. The key issues of the debates we had in the past will again play a major role in guiding us toward careful implementation of these new techniques in future.     

Antiangiogenic blockage: a new treatment for glioblastoma

Background: Angiogenesis is common in cancer and reflects the requirement for a vascular network to support continued uncontrolled growth. Two strategies of antiangiogenic therapy have emerged; one targeting VEGF (growth-factor-ligand-based antagonists) and the second targeting VEGF receptor (receptor-based antagonists, small-molecule tyrosine kinase inhibitors). Methods: The literature as reviewed by Reardon et al. regarding treatment of recurrent high-grade gliomas (HGG) with antiangiogenic therapy (predominantly ligand-based and administered in conjunction with cytotoxic chemotherapy) reports response rates of 30 – 60% and 6-month progression-free survival of 25 – 50%. Problems include new antiangiogenic-class side effects and control of administration and timing in relation to surgery. Results/conclusions: Ligand-based antiangiogenic therapy is a compelling targeted therapy for HGG and will continue to emerge as an important antiglioma therapy. Further studies are required to define the population of patients in whom this therapy is of benefit, identify the optimal dose and schedule, characterize the value of co-administered (cytotoxic and targeted) therapies and establish validated response measures.     

Bevacizumab for the treatment of high-grade glioma

INTRODUCTION: Gliomas are highly vascular and rich in vascular endothelial growth factor (VEGF) that promotes angiogenesis. Bevacizumab is a monoclonal antibody against VEGF inhibiting angiogenesis by preventing receptor activation. Phase II clinical trials using bevacizumab in both newly diagnosed and recurrent high-grade glioma (HGG) showed promising results. AREAS COVERED: This is a review of clinical trials investigating bevacizumab in newly diagnosed and recurrent HGGs with a focus on outcome results. A future perspective about the expected role of bevacizumab is given. Bevacizumab efficacy, safety and tolerability, the combination of radiation and bevacizumab as well as the use of bevacizumab to treat pseudoprogression are discussed. Further criteria of response evaluation needed to be adjusted in the age of anti-angiogenic therapy and this will be discussed. EXPERT OPINION: Bevacizumab has been shown to be safe and tolerable in HGG. In the recurrent disease setting, bevacizumab alone might be sufficient for a clinical benefit and is currently approved as a single agent for this indication. While clinical trials demonstrate a prolonged progression-free survival in bevacizumab-treated HGG, a benefit on OS has not been demonstrated yet. Bevacizumab has also been introduced into other settings in neuro-oncology including concurrent administration with re-irradiation for recurrent HGG.     

智能影像预测高级别脑胶质瘤MGMT启动子甲基化状态的研究进展

胶质瘤是颅内最常见的原发性恶性肿瘤,具有高度异质性,即使组织学分级相同,有时预后也具有显著差异,而基因分型则可以从本质上更好地阐述肿瘤的生物学行为,其中O6-甲基鸟嘌呤甲基转移酶(O6-methylguanine-DNA methyltransferase,MGMT)与高级别脑胶质瘤(high-grade glioma...     

基于T2WI纹理分析预测高级别胶质瘤术后复发

目的 观察基于T2WI纹理分析预测高级别胶质瘤(HGG)术后复发的价值。方法 回顾性分析71例术前接受MR检查的HGG患者，根据术后有无HGG复发分为复发组(n=45)和未复发组(n=26),比较组间MRI肿瘤形态参数的差异；于T2WI中提取瘤体、瘤周水肿区及瘤体+瘤周水肿区的纹理特征，分别基于形态特征和纹理特征构建支持向量机(SVM)和随机森林(RF)模型；绘制受试者工作特征曲线，以曲线下面积(AUC)评估各模型的预测效能。结果 组间肿瘤位置、有无囊变、有无子病灶、实质/瘤周DWI信号及强化程度差异均有统计学意义(P均<0.05)。分别于瘤体、瘤周水肿区和瘤体+瘤周水肿区筛选出12、13和13个最佳纹理特征，以之构建的SVM_形态模型预测HGG复发效能(AUC=0.76)高于RF_形态模型(AUC=0.68),SVM_纹理模型预测效能最佳(AUC=0.83)。结论 基于T2WI纹理分析能有效预测HGG术后复发，尤以SVM_纹理模型的预测效能最佳。     

Bevacizumab for the treatment of cervical cancer

ABSTRACT

Introduction: Cervical cancer is still a major cause of morbidity and mortality in women. Early stages and locally advanced cervical cancer are currently treated respectively with surgery and chemoradiation with good prognosis. Persistent, recurrent and metastatic cervical cancers have a poor prognosis. Angiogenesis has been identified as a crucial factor for cervical cancer growth. Recently, research has increasingly focused on the development of targeted therapies, such as anti-angiogenic drugs. Amongst such drugs, bevacizumab, a recombinant humanized monoclonal antibody has been the subject of extensive investigation, including its use in cervical cancer. This was recently approved for the treatment of patients with metastatic, recurrent, or persistent cervical cancer.

Areas covered: The aim of this review is to discuss the role of bevacizumab in both locally advanced and metastatic or recurrent cervical cancer and to analyze the studies that have led to the approval of bevacizumab in cervical cancer.

Expert opinion: The use of bevacizumab in combination with other chemotherapies in cervical cancer has been proven safe and effective, with a significant improvement in overall survival of patients with advanced cervical cancer. Combination therapy using bevacizumab has been demonstrated to increase toxicity rates but it does not impair patient’s quality of life.     

Bevacizumab in the treatment of colorectal cancer

Bevacizumab is a humanised monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), the key mediator of tumour angiogenesis, and has been shown to improve survival when given with chemotherapy to patients with metastatic colorectal cancer. In a pivotal Phase III clinical trial, 813 subjects were treated with irinotecan, 5-fluorouracil (5-FU) and leucovorin and randomised to receive placebo or bevacizumab. Median survival for the group receiving bevacizumab was increased by 30%, from 15.6 to 20.3 months (p ≤ 001). Other Phase II and III studies in colorectal cancer have demonstrated a benefit when bevacizumab is added to regimens of 5-FU and leucovorin, and 5-FU, leucovorin and oxaliplatin. The toxicity associated with bevacizumab is generally mild, consisting of manageable hypertension, clinically insignificant proteinuria and mild mucosal bleeding. Infrequent severe toxicities have been reported, consisting of arterial thrombosis and gastrointestinal perforations (1.5%). Bevacizumab represents the first angiogenesis modulator that has a proven benefit in cancer therapy.     

弥散加权成像直方图参数模型预测高级别胶质瘤复发时间

目的 评估弥散加权成像(DWI)直方图参数预测模型对预测高级别胶质瘤(HGG)复发时间(TTR)的价值.方法 收集39例经手术病理确诊并术后复发HGG患者,根据TTR分为短期组(TTR≤6个月,n=17)及长期组(TTR＞6个月,n=22);回顾分析术前头部DWI,提取病灶的直方图参数,包括均值(mean)、方差(va...     

Convection-enhanced delivery of 131I-chTNT-1/B mAB for treatment of high-grade adult gliomas

Introduction: Despite treatment advances for malignant gliomas in adults, prognosis remains poor, largely due to the infiltrative and heterogeneous biology of these tumors. Response to adjuvant therapy is not always uniform and the blood–brain barrier prevents the majority of chemotherapeutics from adequately reaching primary tumor sites. These obstacles necessitate development of novel delivery methods and agents.

Areas covered: ¹³¹I-chTNT-1/B mAB (Cotara) is a genetically engineered chimeric monoclonal antibody that binds to the DNA–histone H1 complex. It carries ¹³¹I, which delivers sufficient energy to kill adjacent tumor cells. Through convection-enhanced delivery (CED) it provides radioimmunotherapy directly to the resection cavity. We review the pharmacology and clinical experience with ¹³¹I-chTNT-1/B mAB, detailing results of completed Phase I and II trials.

Expert opinion: Novel agents and therapeutic modalities, such as ¹³¹I-chTNT-1/B mAB, are of interest for treatment of malignant glioma, for which the prognosis continues to be dismal. ¹³¹I-chTNT-1/B mAB targets tumor cells and radioisotope labeling allows radiation delivery to the tumor with sharp fall-off. Data from Phase I and II trials of CED delivery of ¹³¹I-chTNT-1/B mAB shows it is well tolerated. Phase II trial data suggests it could be promising therapeutically, though conclusions about efficacy require further trials and clinical experience. The compound is currently in a Phase II trial for dose confirmation in patients with malignant gliomas.     

Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer

Angiogenesis is the process by which new blood vessels are created from pre-existing vessels. It is essential for the growth and development of normal cells and tissues during embryonic and neonatal development and of tumour cells. Solid tumours rely on having an extensive network of blood vessels for growth and survival. The key mediator of angiogenesis, vascular endothelial growth factor-A (VEGF-A), is critical for the growth of tumours and their subsequent metastasis and is known to initiate angiogenesis. Bevacizumab is a humanized immunoglobulin G monoclonal antibody that binds to VEGF with high specificity, thereby blocking VEGF-mediated signalling pathways and thus angiogenesis. Clinical trials have shown that bevacizumab is effective in prolonging survival in patients with metastatic colorectal cancer (CRC) when combined with standard chemotherapy. Consequently, bevacizumab has been approved in combination with 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic CRC. Bevacizumab is generally well tolerated in most patients and does not exacerbate the adverse events associated with conventional chemotherapy. Bevacizumab-related side effects are generally manageable; however, monitoring for hypertension, gastrointestinal perforation, bleeding, proteinuria and thromboembolism is advised, especially in patients with predisposing factors. In addition to demonstrated survival benefits, the convenient dosing schedule and lack of interactions should ensure the successful integration of this novel agent into clinical practice.     

Bevacizumab: current indications and future development for management of solid tumors

Background: Angiogenesis is essential for cancer growth and metastasis. VEGF is a key modulator of angiogenesis and its overexpression is correlated with advanced disease and poor prognosis. Bevacizumab, a recombinant humanized anti-VEGF mAb, is the most clinically advanced anti-angiogenic agent. Although bevacizumab has received most attention for first-line treatment of advanced colorectal and non-small-cell lung cancer, there is a rapidly growing body of evidence for its efficacy in treatment of a number of other solid tumors. Objective/methods: We present the background, current status, and important ongoing trials involving the use of bevacizumab therapy. Results/conclusions: Bevacizumab has an established role in the treatment of metastatic colon, breast, and lung cancer. Yet many questions remain on its use in other disease types and demographic groups.     

Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III,Randomized, Double-blind,Noninferiority Clinical Trial

PurposeThe purpose of this study was to compare the efficacy and safety of a proposed bevacizumab biosimilar to those of the reference product in patients with metastatic colorectal cancer (mCRC).MethodsThis Phase III, multicenter, randomized, double-blind (patient- and assessor-blind), active-controlled, 2-armed, parallel-group, noninferiority trial was conducted in patients with histologically verified colorectal cancer with evidence of at least 1 metastasis. Patients with mCRC were randomized 2:1 to receive 5 mg/kg IV of either study drug plus FOLFIRI-3 (with repeated irinotecan 100 mg/m² 60-min infusion on day 3) or the reference drug plus FOLFIRI-3 every 2 weeks for 1 year. Progression-free survival (PFS) was the primary end point, and overall survival, objective response rate, and time to treatment failure as well as safety and immunogenicity were secondary end points. The population assessable for PFS was per protocol, and the intention-to-treat population was used for sensitivity analysis. Safety was assessed based on reports of adverse events, laboratory test results, and vital sign measurements.FindingsA total of 126 patients were enrolled; PFS values in the biosimilar and reference arms were 232 days (7.7 months) and 210 days (7 months), respectively (P = 0.47). The hazard ratio of the biosimilar arm versus the reference arm was 0.79 in the per-protocol population (90% CI, 0.46–1.35; P = 0.47). The upper limit for the 2-sided 90% CI was lower than the margin of 1.44, indicating that the biosimilar drug was noninferior to the reference drug. The hazard ratio for overall survival in the intent-to-treat population was 0.99 (95% CI, 0.55–1.80; P = 0.99). The difference between other efficacy end points among the groups was not statistically significant. No significant difference was observed in the comparison of the two arms for safety. The antidrug antibody was positive in 1 patient in each arm.ImplicationsThe proposed biosimilar BE1040V was noninferior to the reference product in terms of efficacy in the treatment of mCRC, and tolerability was comparable between the 2 drugs. ClinicalTrials.gov identifier: NCT03288987.     

Antithrombotic pharmacotherapy after transcatheter aortic valve implantation: an update

Introduction: Transcatheter aortic valve implantation (TAVI) is the treatment of choice for a large proportion of patients with severe aortic stenosis. Despite numerous technological and clinical advances, TAVI remains associated with thrombotic complications requiring antithrombotic pharmacotherapy, which exposes to the risk of bleeding, especially in elderly individuals. The optimal antithrombotic regimen following TAVI is uncertain and several investigations are ongoing.

Areas covered: Clinical guidelines are mostly driven by observational trials and experts’ opinions, thus resulting into low-grade level of evidence. The aim of the current review is to critically explore the epidemiology, pathophysiology and prognostic value of thrombotic and bleeding events after TAVI, and to review the current literature on antithrombotic strategies following the procedure.

Expert opinion: Thrombotic and bleeding events remain major complications occurring in the frail population that is currently offered TAVI. Waiting for upcoming evidence from ongoing randomized clinical trials, tailoring antithrombotic therapies based on patients’ characteristics, values and circumstances is a preferable approach.     

Biological therapies for the treatment of cutaneous wounds: Phase III and launched therapies

Introduction: Normal wound healing mechanisms can be overwhelmed in the setting of complex acute and chronic tissue injury. Biological therapies are designed to augment and/or restore the body's natural wound healing abilities. There are a variety of available and emerging technologies utilizing this approach that have demonstrated the ability to augment wound healing.

Areas covered: In this review, the clinical data on launched and emerging biological therapies for wound healing applications are summarized. The methodologies discussed include biological skin equivalents, growth factors/small molecules and stem cell-based therapies.

Expert opinion: While many products possess convincing clinical data demonstrating their efficacy in comparison to standard treatment options, more robust, controlled studies are needed to determine the relative value among established and emerging biological therapies. Future bioengineering and stem cell-based approaches are of particular interest due to the simultaneous correction of multiple deficiencies present in the nonhealing wound.     

Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies

BACKGROUND: Bevacizumab is a recombinant humanized monoclonal antibody that was approved by the US Food and Drug Administration (FDA) in February 2004 for use as part of combination therapy with fluorouracil-based regimens for metastatic colorectal cancer (mCRC). OBJECTIVES: This article reviews the mechanism of action, clinical pharmacology, and pharmacodynamic and pharmacokinetic properties of bevacizumab. It summarizes data on the clinical efficacy and tolerability of bevacizumab from Phase II/III trials in mCRC, breast cancer, non-small-cell lung cancer, and renal cell carcinoma and preliminary data from investigational studies in pancreatic cancer and soft-tissue sarcomas. The dosing and administration of bevacizumab also are discussed. METHODS: A comprehensive search of the English-language literature indexed on MEDLINE (1966-April 2006) was performed using the terms Avastin, bevacizumab, vascular endothelial growth factor, angiogenesis, and bevacizumab plus colorectal cancer, breast cancer, non-small-cell lung cancer, pancreatic cancer, and renal cell carcinoma. Published abstracts from American Society of Clinical Oncology annual meetings from 2002 to 2006, FDA submission documents, and the product information for bevacizumab also were reviewed. Pertinent review articles, preclinical studies, and editorials and all published Phase II/III clinical trials were selected for review. The reference lists of identified articles were examined for additional publications. RESULTS: Bevacizumab exhibits linear pharmacokinetics in the dose range between 0.3 and 10 mg/kg q2-3wk and steady state, which is reached in approximately 100 days. The estimated t(1/2) of bevacizumab is approximately 20 days. After correction for body weight, clearance and V(d) are reported to be a respective 26% and 22% higher in men than in women. Statistical analyses have not been performed, however, and the clinical impact of these gender differences has not been assessed. No dose adjustment is currently recommended based on age, sex, or renal function. Bevacizumab has been reported to result in changes in exposure to concomitant chemotherapy, although formal drug-interaction studies have not been performed. Surrogate markers of disease progression or treatment response to bevacizumab have been studied, but no significant correlations with any outcome measure have been found. When combined with standard chemotherapy regimens, bevacizumab has been associated with significant improvements compared with chemotherapy alone in the efficacy end points of overall survival, progression-free survival, and response rates in patients with mCRC (all, P < 0.05). Based on these findings, bevacizumab is considered a first-line option for this disease. Combination bevacizumab regimens have been associated with clinical activity in breast cancer, non-small-cell lung cancer, renal cell carcinoma, pancreatic cancer, and soft-tissue sarcoma. The observed toxicities of bevacizumab include hypertension, proteinuria, mild to moderate hemorrhage, wound healing complications, and thromboembolic events. A bevacizumab dose of 5 mg/kg q2wk has been established as effective and well tolerated in the setting of mCRC. A variety of dosing schemes have been investigated in other solid neoplasms, but no consensus has been reached on the optimal bevacizumab regimen. CONCLUSIONS: Bevacizumab is effective and generally well tolerated as first-line therapy for mCRC. The results from clinical studies of bevacizumab as a single agent or as part of combination regimens for breast cancer, non-small-cell lung cancer, renal cell carcinoma, and other solid malignancies have been promising. The most effective regimens for various malignancies and predictive markers of treatment response have not been fully determined. Combining bevacizumab with chemotherapy or other novel targeted agents appears to be a rational approach that may enhance efficacy while limiting the traditional nonselective toxicities.     

Random-effects model for meta-analysis of clinical trials: an update

The random-effects model is often used for meta-analysis of clinical studies. The method explicitly accounts for the heterogeneity of studies through a statistical parameter representing the inter-study variation. We discuss several iterative and non-iterative alternative methods for estimating the inter-study variance and hence the overall population treatment effect. We show that the leading methods for estimating the inter-study variance are special cases of a general method-of-moments estimate of the inter-study variance. The general method suggests two new two-step methods. The iterative estimate is statistically optimal and it can be easily calculated on a spreadsheet program, such as Microsoft Excel, available on the desktop of most researchers. The two-step methods approximate the optimal iterative method better than the earlier one-step non-iterative methods.     

A UK-wide survey of follow-up practices for patients with high-grade glioma treated with radical intent

Rationale and objective High‐grade glioma profoundly affects patients and their families. The best ongoing care for patients completing radical treatment is uncertain. To address this issue a UK‐wide audit surveying the follow‐up practices of multidisciplinary cancer teams was conducted. Method An online survey package was used with a paper version available. Results Of 102 clinicians approached 86 replied, a response rate of 84%. Three‐monthly outpatient department appointments led by an oncologist and a specialist nurse were the norm, but more controversially, some centres conduct joint clinics with the whole neurosurgical/oncology team present or available. Nurse‐led telephone follow‐up in place of hospital visits is uncommon. Regular scanning is conducted despite the clinical benefits being contentious. Access to a range of allied services providing supportive care is considered, but the actual levels of need and the efficiency with which they are delivered require further investigation. Conclusions The picture of UK follow‐up practices revealed by this survey demonstrates that research is now needed to determine what preferences patients and families have for follow‐up and their satisfaction with these.     

Intermittent preventive treatment against malaria: an update

Intermittent preventive treatment (IPT) against malaria is a malaria control strategy aimed at reducing the burden of malaria in certain high-risk groups, namely pregnant women and children. Three strategies – IPT in pregnancy (IPTp), infants (IPTi) and children (IPTc) – are reviewed here focusing on the mechanism of action, choice of drugs available, controversies and future research. Drugs for IPT need to be co-formulated, long acting, safe and preferably administered as a single dose. There is no obvious replacement for sulfadoxine–pyrimethamine, the most commonly utilized drug combination. All strategies face similar problems of rising drug resistance, falling malaria transmission and a policy shift from controlling disease to malaria elimination and eradication. IPT is an accepted form of malaria control, but to date only IPTp has been adopted as policy.     

磁敏感加权成像用于诊断及治疗胶质瘤研究进展

胶质瘤是常见脑原发性恶性肿瘤。根据不同组织磁化率的差异,磁敏感加权成像(SWI)可较好地显示小静脉、出血、钙化及铁沉积。本文就SWI在诊断及治疗胶质瘤中的研究进展进行综述。     

18F-FDOPA PET/CT评估放射化学治疗用于高级别脑胶质瘤效果

目的 观察以¹⁸F-L-6-氟-3,4-二羟基苯丙氨酸(¹⁸F-FDOPA)PET/CT评估放射及化学治疗(放疗及化疗)用于高级别脑胶质瘤效果的价值。方法 回顾性分析84例接受精准放疗及同步化疗的高级别脑胶质瘤患者资料,根据疗效将其分为有效组(完全缓解+部分缓解+疾病稳定,n=60)及无效组(疾病进展,n=24)。比较组间及组内治疗前后肿瘤¹⁸F-FDOPA PET/CT代谢参数,包括肿瘤代谢体积(MTV)、最大标准摄取值(SUV_max)及平均标准摄取值(SUV_mean);以Spearman相关性分析观察代谢参数与放化疗效果的相关性。结果 治疗后有效组MTV、SUV_max及SUV_mean均低于无效组(P均<0.05)。有效组治疗前、后代谢参数差异有统计学意义(P均<0.05)。高级别脑胶质瘤MTV、SUV_max、SUV_mean与放化疗效果呈负相关(r=-0.63、-0.52、-0...