Incidental reduction in the size of liver hemangioma following use of VEGF inhibitor bevacizumab

BACKGROUND/AIMS: Hepatic cavernous hemangioma is the second most common liver tumor after metastases. Vascular endothelial growth factor (VEGF) is recognized as an essential regulator of blood vessel growth. High VEGF expression leads to increased angiogenic activity in cavernous hemangioma endothelial cells. The use of specific antibodies directed against VEGF abolishes this vascular endothelial growth-promoting activity in vitro. Bevacizumab is a recombinant humanized monoclonal antibody directed against VEGF which is used for the treatment of metastatic colorectal cancer in combination with 5-fluorouracil-based regimens. METHODS: We report a patient with invasive colorectal adenocarcinoma and suspected liver metastasis on radiological examination, who showed a significant decrease in the size of his liver lesions after bevacizumab treatment. Histology of the liver lesions revealed hemangioma with a strong staining for VEGF and anti-VEGFr2 antibody in the hemangioma endothelial cells. To date, surgical resection provides the only consistently effective method for treatment of hepatic hemangioma. CONCLUSIONS: This is the first documented case of hepatic hemangioma responsive to antiangiogenic therapy, suggesting a possible use for these agents in treating symptomatic patients without surgery. VEGF-signaling blockade including bevacizumab use poses a potential new treatment modality for vascular neoplasms in the liver and other sites.     

Anti-vascular endothelial growth factor antibody bevacizumab in conjunction with chemotherapy in metastasising melanoma

Purpose The combination of the antiangiogenic antibody bevacizumab with standard chemotherapy has improved the prognosis in patients with metastastic colorectal cancer and other advanced cancers. The role of combined anti-VEGF and chemotherapy in metastastic melanoma is just starting to be elucidated. Methods We tested this notion in three patients with advanced and therapy-refractory melanoma. Results Interestingly, two patients achieved objective regressions after three courses of therapy; the third patient, albeit progressing demonstrated a pronounced liquid necrosis in bulky lymphnode metastasis. Conclusion Further studies are warranted to scrutinise these impressive therapeutic effects on the combination of bevacizumab and chemotherapy in melanoma.     

Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab

Purpose  

The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients.     

Exploiting novel molecular targets in gastrointestinal cancers

Novel molecular targets are being discovered as we learn more about the aberrant processes underlying various cancers. Efforts to translate this knowledge are starting to impact on the care of patients with gastrointestinal cancers. The epidermal growth factor receptor （EGFR） pathway and angiogenesis have been targeted successfully in colorectal cancer with cetuximab, panitunumab and bevacizumab. Similarly, EGFR-targeting with erlotinib yielded significant survival benefit in pancreatic cancer when combined with gemcitabine. The multi-targeting approach with sorafenib has made it the first agent to achieve significant survival benefit in hepatocellular carcinoma. Efforts to exploit the dysregulated Akt/mTOR pathway in GI cancer therapy are ongoing. These molecular targets can be disrupted by various approaches, including the use of monoclonal antibody to intercept extracellular ligands and disrupt receptor-ligand binding, and small molecule inhibitors that interrupt the activation of intracellular kinases.     

Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies

VEGF-A is important in tumor angiogenesis, and a humanized anti-VEGF-A monoclonal antibody (bevacizumab) has been approved by the FDA as a treatment for metastatic colorectal and nonsquamous, non-small-cell lung cancer in combination with chemotherapy. However, contributions of both tumor- and stromal-cell derived VEGF-A to vascularization of human tumors grown in immunodeficient mice hindered direct comparison between the pharmacological effects of anti-VEGF antibodies with different abilities to block host VEGF. Therefore, by gene replacement technology, we engineered mice to express a humanized form of VEGF-A (hum-X VEGF) that is recognized by many anti-VEGF antibodies and has biochemical and biological properties comparable with WT mouse and human VEGF-A. The hum-X VEGF mouse model was then used to compare the activity and safety of a panel of VEGF Mabs with different affinities for VEGF-A. Although in vitro studies clearly showed a correlation between binding affinity and potency at blocking endothelial cell proliferation stimulated by VEGF, in vivo experiments failed to document any consistent correlation between antibody affinity and the ability to inhibit tumor growth and angiogenesis in most animal models. However, higher-affinity antibodies were more likely to result in glomerulosclerosis during long-term treatment.     

Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome

The underlying mechanism by which anti-VEGF agents prolong cancer patient survival is poorly understood. We show that in a mouse tumor model, VEGF systemically impairs functions of multiple organs including those in the hematopoietic and endocrine systems, leading to early death. Anti-VEGF antibody, bevacizumab, and anti-VEGF receptor 2 (VEGFR-2), but not anti-VEGFR-1, reversed VEGF-induced cancer-associated systemic syndrome (CASS) and prevented death in tumor-bearing mice. Surprisingly, VEGFR2 blockage improved survival by rescuing mice from CASS without significantly compromising tumor growth, suggesting that “off-tumor” VEGF targets are more sensitive than the tumor vasculature to anti-VEGF drugs. Similarly, VEGF-induced CASS occurred in a spontaneous breast cancer mouse model overexpressing neu. Clinically, VEGF expression and CASS severity positively correlated in various human cancers. These findings define novel therapeutic targets of anti-VEGF agents and provide mechanistic insights into the action of this new class of clinically available anti-VEGF cancer drugs.     

Intracranial hemorrhage in patients treated with bevacizumab: report of two cases

Treatment with bevacizumab,an antiangiogenic agent,in patients with metastatic or unresectable colorectal cancer was approved less than 4 years ago in Japan.Bevacizumab improves the survival of patients with metastatic colorectal cancer;however,it may lead to complications such as bleeding,which are sometimes fatal.Bevacizumab should be administered only after careful consideration because the potential risks of therapy outweigh its benefits.Therefore,pharma-ceutical companies do not recommend bevacizumab t...     

The multidisciplinary management of gastrointestinal cancer. The integration of cytotoxics and biologicals in the treatment of metastatic colorectal cancer

The management of patients with metastatic colorectal cancer (CRC) has changed dramatically over the last five years, with increasing chances of prolonged survival. The development of new drugs has contributed to the better outcome of patients with metastatic colorectal cancer. Until the mid-1990s the only available drug, with limited activity in metastatic CRC, was 5-fluorouracil (5-FU). The development of the cytotoxic agents irinotecan, oxaliplatin and capecitabine and of the monoclonal antibodies against the vascular endothelial growth factor (VEGF) bevacizumab and against the epidermal growth factor receptor (EGFR) cetuximab and panitumumab have clearly increased the therapeutic options and have improved the outcome for patients with metastatic colorectal cancer. However, their introduction also raises many new questions and challenges.     

New antiangiogenetic agents and non-small cell lung cancer

New blood vessel formation, known as angiogenesis is a fundamental event in the process of tumor growth and metastatic dissemination. Due to its central role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor have been a major focus of basic research and drug development in the field of oncology, including the treatment of non-small cell lung cancer (NSCLC). Approaches targeting VEGF include monoclonal antibodies and vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). Bevacizumab (Avastin) is an anti-VEGF recombinant humanized monoclonal antibody. A very recent randomized phase III trial demonstrated a statistically significant advantage in median survival favouring the combination of bevacizumab plus chemotherapy versus chemotherapy alone in the treatment of advanced non-squamous NSCLC. This study represents the first evidence of superior efficacy of targeted therapy combined with chemotherapy over chemotherapy alone in the treatment of NSCLC. ZD6474 is an orally bioavailable inhibitor of VEGFR-2 tyrosine kinase. First evidences of antitumor activity and its excellent toxicity profile make it a promising targeted agent for the treatment of NSCLC. A recent phase I/II study examined the combination of Epidermal Growth Factor Receptor (EGFR)-TKI erlotinib and bevacizumab in patients with non-squamous stage IIIB/IV NSCLC. Data on antitumor activity of this combination have to be considered very promising. Clinical trials of multiple targeted therapy may represent the second generation studies in the treatment of NSCLC.     

Late anastomotic colonic dehiscence due to antiangiogenic treatment, a specific drug-class complication requiring specific treatment: an example of pazopanib complication

Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), was the first angiogenesis inhibitor approved for the first-line treatment of metastatic colorectal cancer in combination with intravenous fluorouracil-based chemotherapy. Two major cohort studies--BRiTE and BEAT--reported a 2% incidence of bowel perforation, which remains a rare, but serious, complication of bevacizumab treatment. Late anastomotic complications, arising > 3 months after surgery, are emerging occurrences that may be associated with bowel perforation. We report here on such a case caused by pazopanib, a new antiangiogenic agent, and also include a review of the published cases in the literature (n = 23) and an analysis of their management. Proctectomy was the initial surgery in 17 patients (74%) with rectal cancer, and 13 of these patients had undergone adjuvant radiation prior to surgery. The majority (84%) of the complications occurred with antiangiogenic treatment after a mean number of four cycles. Patients' management was invariably associated with withdrawal of the antiangiogenic agent, together with conservative treatment in 14 patients (66%).     

Failure of treatment with anti-VEGF monoclonal antibody for long-standing POEMS syndrome

We present the case of a 71-year-old woman with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome. Overproduction of vascular endothelial growth factor (VEGF), secreted by plasmacytoma, is considered responsible for the characteristic symptoms, and therefore anti-VEGF monoclonal antibody (bevacizumab) could be a therapeutic option. The patient was treated with bevacizumab 7 years after onset. Despite a dramatic decrease in serum VEGF levels, there was no clinical improvement, possibly because aberrant angiogenesis had already developed systemically. We suggest that careful consideration should be taken for indication of bevacizumab therapy, and this agent may be used in selected patients with a short duration POEMS syndrome.     

A case of severe bevacizumab-induced ischemic pancolitis, treated with conservative management

Bevacizumab (Avastin(?)) is a monoclonal antibody against the vascular endothelial growth factor (VEGF) receptor that increases the overall survival rate when added to standard chemotherapy regimens in patients with metastatic colorectal cancer. The known toxicities of bevacizumab are hypertension, proteinuria, wound healing complications, arterial thrombosis, bleeding, and gastrointestinal complications. Especially ischemic colitis can rapidly develop into bowel perforation, so an emergency operation often is needed. Recently, a 65-year-old male patient developed ischemic pancolitis after FOLFOX (85 mg/m(2) Oxaliplatin, d1; 200 mg/m(2) Leucovorin, d1; 400 mg/m(2) 5-FU iv bolus, d1-2; and 600 mg/m(2) 5-FU, d1-2, every two wk) and Bevacizumab combination chemotherapy was administered. However, he recovered after early conservative care without surgery. We report this case with a review of literature.     

Anti-angiogenic therapy for colorectal cancer: on the way to getting better!

Based on the theory that tumor growth and metastasis depend on vessels to provide oxygen and nutrients, antiangiogenic therapy was thought as a promising approach to cure cancer. Bevacizumab is the first validated angiogenesis inhibitor, when combined with conventional treatments, which can enhance antitumor effects and prolong survival for patients with colorectal cancer. However, recent years, bevacizumab and other angiogenesis inhibitors are more discussed with drug resistance and the diverse test results. Fortunately, antiangiogenic strategy is more than bevacizumab and more than anti-vascular endothelial growth factor. Dozens of compounds that potently inhibit neoplastic blood vessels formation with different mechanisms have been developed, and many of them are being tested clinically for colorectal cancer. This review will numerate the principal antiangiogenic drugs with various mechanisms, recapitulate the information of studying these drugs for colorectal cancer treatment and try to clue better usage of antiangiogenic therapy for patients with colorectal cancer in the future.     

Biological activity of bevacizumab,a humanized anti-VEGF antibody <Emphasis Type="Italic">in vitro</Emphasis>

Bevacizumab (Avastin, Genentech) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), a critical angiogenic factor involved in both physiological and pathological conditions. It has been recently approved by the US FDA as a first-line therapy for widespread metastatic colorectal cancer. This report is a detailed biological characterization of bevacizumab in a variety of in vitro models. It is shown that bevacizumab potently neutralizes VEGF and blocks its signal transduction through both the VEGFR-1 and VEGFR-2 receptors, as demonstrated by the inhibition of VEGF-induced cell proliferation, survival, permeability, nitric oxide production, as well as migration and tissue factor production. Although bevacizumab retains the ability to bind to human Fc receptors and complement protein C1q, it does not demonstrate cell or complement-mediated cytotoxicity in either VEGF producing or targeting cells. Thus the mechanism of anti-tumor activity of bevacizumab is most likely due to its anti-angiogenesis effect through binding and neutralization of secreted VEGF.     

Angiogenesis in human cancer: implications in cancer therapy

Angiogenesis represents an essential step in tumor proliferation, expansion, and metastasis. Tumor cells may express both proangiogenic and/or antiangiogenic factors. Under normal circumstances, angiogenesis is controlled through the equilibrium of these factors. This balance is disrupted in malignancy, resulting in promotion of angiogenesis. Among angiogenic molecules, VEGF appears to have a central role in the angiogenic process: it is the target of many proangiogenic factors, but it also regulates molecules that are implicated in endothelial proliferation. It has been suggested that VEGF may be a proximate angiogenic factor through which others act. The degree of angiogenesis and the expression of angiogenic factors have been associated with prognosis in several human neoplasms. In addition, angiogenesis offers a theoretically selective target for anticancer therapy, since it is only required for wound healing, endometrial proliferation, and pregnancy in healthy individuals. Antiangiogenic cancer treatment is still largely experimental and its clinical potential is currently being studied in clinical trials. Thalidomide, a drug with antiangiogenic properties, has shown significant efficacy in patients with relapsed or refractory multiple myeloma. In addition, an anti-VEGF monoclonal antibody prolonged survival in patients with advanced colorectal and renal cell carcinoma. Although these results are encouraging, selection of patients is essential in order to target populations most likely to benefit from antiangiogenic therapy.     

Angiogenesis and cancer: A cross-talk between basic science and clinical trials (the "do ut des" paradigm)

Angiogenesis plays a crucial role in facilitating tumor growth and the metastatic process, and it is the result of a dynamic balance between pro-angiogenic factors, like vascular endothelial growth factor (VEGF) and platelet-derived growth factor, and antiangiogenic factors, like thrombospondin-1 and angiostatin. Many drugs that target human tumors, like bevacizumab and some VEGF-receptor tyrosine-kinase inhibitors (e.g., BAY 43-9006, SU11248 and PTK787/ZK222584) have been studied in clinical trials, with favorable toxicity reports and encouraging results in advanced colorectal cancer, renal cell cancer, breast cancer and non-squamous non-small cell lung cancer, either combined with chemotherapy, or in monotherapy. Another potential approach to inhibiting angiogenesis is through metronomic chemotherapy (low doses of chemotherapy for long periods of time). This review describes the mechanisms of the angiogenic process and evaluates the recent data about antiangiogenic therapies in clinical trials.     

Thrombo-embolic risks and bevacizumab: data from the literature and recommendations for the use of anticoagulants and antiaggregants

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor. The use of bevacizumab has shown survival benefit in variety of cancers. However, a specific toxicity profile has been observed with bevacizumab such as hypertension, proteinuria, gastrointestinal perforation and arterial thrombosis. Non-small-cell lung cancer is often associated with thrombotic event therefore guidelines are expected to prescribe bevacizumab in this population. This article presents data from literature about the thrombotic risk and provides recommendations for the use of anticoagulant and antiaggregant treatments.     

Anti-VEGF– and anti-VEGF receptor–induced vascular alteration in mouse healthy tissues

Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti–VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1–specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF–specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF–specific drugs.     

Monoclonal Antibodies as Therapeutic Agents: Advances and Challenges

Despite the major advances in conventional forms of treatment (i.e. surgical techniques, radiotherapy and chemotherapy) and improved survival rates, cancer is still the second leading cause of death in developing countries. One major limitation of cytotoxic drugs and radiation in the treatment of cancer patients is their inability to discriminate between malignant and normal tissues. This in turn prevents the delivery of the optimal (therapeutic) dose of such agents to malignant tissues for their eradication. With the advent of hybridoma technology in 1975, it has been possible for the first time to produce large amounts of an antibody (i.e. monoclonal antibody) against any antigens of interest. Since each antibody is highly specific for a particular antigen, this typical feature of the antibodies has resulted in their widespread use in diagnostic kits, medical research (e.g. to unravel the function of the antigen in physiological and pathological conditions), and more recently, for the management of a wide range of human diseases such as autoimmune disease and human cancers. Thanks to recent advances in genetic engineering, the immunogenicity of rodent antibodies was reduced by producing the chimeric or humanized version of such antibodies or by developing the fully human antibodies. In other instances, as intact antibodies are too large for rapid penetration into solid tumours, it has been possible to develop a smaller fragment of such antibodies (e.g. Fab, scFv, VHH) with greater potential for use in cancer imaging and therapy. Depending on the target antigens and the antibody format, monoclonal antibodies can induce their anti-tumour activities by several mechanisms including activation of the host effector cells. To date, several mAbs have been approved for management of human cancers including: anti-EGFR antibody cetuximab and anti-VEGF antibody bevacizumab for treatment of metastatic colorectal cancer, anti-HER-2 antibody trastuzumab for metastatic breast cancer, anti-CD20 antibodies rituximab and ibritumomab tituxetan for non-Hodgkin lymphoma, anti- CD52 antibody alemeutumab for chronic lymphocytic leukaemia, and anti-CD33 antibody gemutuzumab ozogamicin for the treatment of acute myeloid leukaemia patients. Monoclonal antibodies currently account for about 30% of all new drugs in development, with more than 500 antibodies at different stages of clinical trials worldwide. In this review, the characteristic features of some of the therapeutic antibodies and the antigens recognised by such antibodies will be discussed as well as several challenges that need to be addressed in order to facilitate their widespread use as “magic bullets” in the management of human diseases and in particular human cancers.