Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adjuvant therapy can reduce the risk of disease recurrence in patients with stage II-IV colorectal cancer. Recently, 3 monoclonal antibodies have been shown to improve clinical outcome in this group of patients. Bevacizumab is an antiangiogenesis agent that has been shown in clinical and preclinical models to reverse the effects of proangiogenic molecules. Bevacizumab is active in the adjuvant setting and in the treatment of metastatic disease. Cetuximab is targeted to the epidermal growth factor receptor. Panitumumab is a fully human immunoglobulin G2 antibody that also binds to the epidermal growth factor receptor. Combination therapies of monoclonal therapies and chemotherapy have resulted in better clinical outcomes than with either modality alone.
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PMID:Targeted therapy in colorectal cancer. 1731 96

Breast cancer is the most frequent tumor of women. The development of effective adjuvant therapy based on postoperative administration of short-term chemotherapy (4-6 months) or long-term hormone therapy (5 years) or both, significantly improved survival of patients. However, therapy of adjuvant/metastatic disease is still palliative with a very low probability to induce complete remission and definitive cure of disease. The relevant efforts of basic research to identify the key and selective molecular alterations, which sustain breast cancer growth and progression allowed the possibility to develop specific molecular target treatments. Trastuzumab, a humanized monoclonal antibody to HER-2, is the first molecular targeting agent approved for therapy of metastatic breast cancer, capable to significantly improve clinical outcome in combination with cytotoxic therapy. Recent preliminary data from randomized, prospective, clinical trials suggest that trastuzumab decreases the risk of early recurrence by 50% in patients with HER-2-positive disease. Other novel targeted treatments are in clinical evaluation, including antiangiogenic compounds (Bevacizumab, sunitinib, vatalanib, and others) and bi-functional drugs such as lapatinib (anti Her-2 and EGFR agent) showing promising activity. This review provides an updated overview of the status of development of targeted therapy in breast cancer, as well as the challenges related to the rational use of molecular targeting agents.
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PMID:Targeted therapy of breast cancer. 1734 46

On June 20, 2006, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), administered in combination with FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) for the second-line treatment of metastatic carcinoma of the colon or rectum. Efficacy and safety were demonstrated in one Eastern Cooperative Oncology Group (ECOG) open-label, multicenter, randomized, three-arm, active-controlled trial enrolling 829 adult patients. Patients had received a fluoropyrimidine- and irinotecan-based regimen as initial therapy for metastatic disease; or they had received prior adjuvant irinotecan-based chemotherapy and had recurred within 6 months of completing therapy. Treatments included bevacizumab, 10 mg/kg, as a 90-minute i.v. infusion on day 1, every 2 weeks, either alone or in combination with FOLFOX4, or FOLFOX4 alone. The bevacizumab monotherapy arm was closed to accrual after an interim efficacy analysis suggested a possibly shorter survival in that arm. Overall survival (OS), the primary study endpoint, was significantly longer for patients receiving bevacizumab in combination with FOLFOX4 than for those receiving FOLFOX4 alone. The objective response rate was significantly higher in the FOLFOX4 plus bevacizumab arm than in the FOLFOX4 alone arm. The duration of response was approximately 6 months for both treatment arms. Patients treated with the bevacizumab combination were also reported, based on investigator assessment, to have significantly longer progression-free survival. There were no new bevacizumab safety signals. The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound-healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, and congestive heart failure.
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PMID:FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. 1740 1

Neo-angiogenesis appears to be a critical feature of tumor growth, migration, and metastasis. Therefore, inhibition of angiogenesis is an appealing strategy for treatment of cancer. Since angiogenesis is the result of several mechanistic processes, controlled by numerable pro- and anti-angiogenic factors and their receptors, multiple possibilities to prevent or reverse tumor-induced neo-vascularization have been proposed. Of these, currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Bevacizumab has been shown to be active in several malignancies, in particular colo-rectal cancer. Although early studies of bevacizumab in far-advanced metastatic breast cancer were disappointing, the results of a recently reported clinical trial by the Eastern Oncology Group comparing first line paclitaxel with or without bevacizumab has demonstrated statistically significant improvements in response rates and time progression. Ongoing studies are now investigating the benefits of bevacizumab with other chemotherapeutic and biologic agents in early metastatic disease as well as in the adjuvant setting. Other anti-angiogenic agents remain in early clinical trials. Small molecular inhibitors of VEGF receptor tyrosine kinase activity, such as sunitinib, appear promising. Nearly 40 years after it was first proposed, inhibition of angiogenesis appears to be gaining a role in medical oncology.
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PMID:Angiogenesis as targeted breast cancer therapy. 1770 41

The treatment of metastatic colorectal cancer (mCRC) has evolved significantly over the past 10 years. For nearly 40 years, the fluoropyrimidine 5-fluorouracil (5-FU) was the only agent to be used for advanced metastatic disease. However, since the mid-1990s, the chemotherapy treatment options for patients with mCRC have been greatly facilitated with the introduction of several new cytotoxic and biologic agents. In particular, combination regimens that incorporate infusional schedules of 5-FU in combination with oxaliplatin (FOLFOX) and/or irinotecan (FOLFIRI) have significantly improved clinical efficacy as related to overall response rates, time to tumor progression, and median overall survival. Capecitabine, an oral fluoropyrimidine, has now been shown in several phase III studies to be as effective as infusional 5-FU when combined with oxaliplatin. During this same time frame, intense efforts have focused on integrating novel biologic agents with cytotoxic chemotherapy regimens. These biologic agents target critical signaling pathways such as the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Bevacizumab is a monoclonal antibody targeting VEGF-A, and when combined with fluoropyrimidine-based chemotherapy, which includes oxaliplatin or irinotecan, significantly improves clinical efficacy in the management of patients with mCRC. Cetuximab and panitumumab are monoclonal antibodies targeting EGFR, and each of these agents is approved to treat mCRC patients who have progressed on previous chemotherapy treatments. Recent studies have shown that cetuximab, when combined with cytotoxic chemotherapy, significantly enhances the management of patients with mCRC in the first-, second-, and disease-refractory settings. With these advances in treatment options, much attention is now focused on identifying the critical molecular biomarkers that can predict response and/or toxicity to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with mCRC.
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PMID:An update on treatment advances for the first-line therapy of metastatic colorectal cancer. 1792 24

Preoperative systemic chemotherapy is generally applied in patients who undergo hepatic resection for colorectal metastases. Although the tumour response rate has been improved recently with the development of new molecular targeted therapies the related hepatic injury is ill defined. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor. It can achieve high response rates and is accepted as a first line treatment in the metastatic colorectal disease. However, the data about its hepatotoxicity profile is still limited. We describe a case of secondary sclerosing cholangitis in a patient with liver metastases treated by Bevacizumab in the neoadjuvant setting and liver resection. It is possible that Bevacizumab may have induced a hypercoagulative condition that was further precipitated by surgery.
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PMID:Sclerosing cholangitis in the era of target chemotherapy: a possible anti-VEGF effect. 1829 38

Vascular endothelial growth factor (VEGF) produced by tumor cells plays a central role in stimulating angiogenesis required for solid tumor growth. VEGF-specific antibodies inhibit tumor cell line growth in animal models and a humanized monoclonal anti-VEGF antibody (bevacizumab [Avastin]) is approved as a treatment for metastatic cancer. We hypothesized that administration of an adenoviral (Ad) vector expressing the murine monoclonal antibody equivalent of bevacizumab would suppress human tumor growth in vivo. The Ad vector (AdalphaVEGF) encodes the light chain and heavy chain cDNAs of monoclonal antibody A.4.6.1, a murine antibody that specifically recognizes human VEGF with the same antigen-binding site as bevacizumab. AdalphaVEGF efficacy in vivo was evaluated with A-673 rhabdomyosarcoma and DU 145 prostate carcinoma cells in human tumor cell xenografts in SCID mice. For both tumor models, AdalphaVEGF directed the expression of high anti-human VEGF IgG antibody titers in vivo, the numbers of mitotic nuclei and blood vessels in the tumor were significantly decreased (p < 0.05), tumor growth was suppressed (p < 0.05), and there was increased survival (p < 0.005). Thus, AdalphaVEGF, encoding a murine monoclonal antibody that is the equivalent of bevacizumab, effectively suppresses the growth of human tumors, suggesting gene therapy as an alternative to bevacizumab monoclonal antibody therapy.
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PMID:Genetic delivery of the murine equivalent of bevacizumab (avastin), an anti-vascular endothelial growth factor monoclonal antibody, to suppress growth of human tumors in immunodeficient mice. 1832 12

Recent advances in the understanding of the biology of renal cell carcinoma (RCC) have been translated into clinical treatment options in metastatic disease. The introduction of targeted therapy against the vascular endothelial growth factor (VEGF) pathway and related elements has produced robust clinical effects, exceeding those of historical treatment options. Sunitinib (Sutent) and bevacizumab (Avastin) plus interferon have established roles in the initial treatment of metastatic RCC. Sorafenib (Nexavar) is established for cytokine-refractory RCC and is being explored in other settings. Temsirolimus (Torisel) is the only agent to extend overall survival to date, although this finding has been restricted to a poor-risk population. Several clinical questions have thus emerged in regard to the optimal timing, type, and sequence of targeted therapy in metastatic RCC. Novel agents targeting the VEGF or alternative pathways have also emerged and are beginning to undergo clinical testing.
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PMID:Targeted therapy for metastatic renal cell carcinoma: a home run or a work in progress? 1847 14

Angiogenesis is an important factor for cancer development and progression in humans. Hereditary and sporadic renal cell carcinoma are characterized by inactivation of the Von-Hippel Lindau (VHL) gene, which results in hyperactivity of the hypoxia-inducible factor-a (HIFa). As a consequence, there is a production of angiogenic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The activity of these factors is associated with oncogenesis, growth, and metastatic potential of renal-cell carcinoma. These data indicate that angiogenic factors are the promising therapeutic targets in this disease. Surgery can cure the patients with renal cancer if disease is diagnosed at an early stage. On the contrary, inoperable or metastatic disease is not curable. Until recently, the only drugs approved for the treatment of advanced disease were the cytokines, interferon, and interleukin. Nevertheless, only a minority of patients (about 15%) would benefited from this treatment, while the toxicity was considerable. During the last 5 years a new era of biological agents, with considerable activity has been developed and tested in clinical trials and (some of them) have been approved in USA and Europe. These agents are: Sunitinib, Bevacizumab, Sorafenib and Temserolimus. Bevacizumab is an anti-VEGF monoclonal antibody, Sunitinib and Sorafenib are multi- tyrosine kinase inhibitors (TKIs), while Temserolimus is a mTOR inhibitor. The common these in their development is the inhibition of angiogenesis, which may explain their significant activity in renal-cell carcinoma. All the agents have been proven more effective than the interferon as first or second-line treatment. This review will focus in these recent developments and the intense continuing clinical research in this field.
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PMID:Targeting angiogenesis in renal cell carcinoma. 1869 Aug 41

As first line chemotherapy Bevacizumab, associated with a platinum based regime, improves survival in patients with metastatic, non small cell, non epidermoid bronchial carcinoma. Marketing authorization for this indication was obtained in 2007. This treatment produces specific secondary effects related to its anti-angiogenic action. Physiologically, vascular endothelial growth factor (VEGF) is important in the process of scar formation. Bevacizumab inhibits scar formation and may encourage bleeding. The aim of this article is to analyse the specific risks associated with invasive procedures and to produce practical recommendations. Unfortunately there are few data in the literature. We depend, therefore, principally on studies of neo-adjuvant chemotherapy in metastatic colo-rectal cancer prior to excision of hepatic metastases and on our own experience of excision of pulmonary metastases from solid tumours treated with bevacizumab. We recommend a delay of 2 days between implantation of an intravenous device and the initiation of bevacizumab, a delay of at least 5 weeks between the last injection of bevacizumab and invasive surgery and a delay of 4 weeks between surgery and the initiation of bevacizumab treatment. Obviously, referral to a medico-surgical team experienced in the management of these patients is strongly recommended.
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PMID:[Bevacizumab and invasive procedures: practical recommendations]. 1931 16


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