Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

Keefe, Dorothy; Bowen, Joanne M.; Gibson, Rachel J.; Tan, Thean Hsiang; Okera, Meena; Stringer, Andrea M.

doi:10.1634/theoncologist.2010-0271

Cited by 78 publications

(49 citation statements)

References 79 publications

(102 reference statements)

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“…On the basis of cumulative adverse events observed in the expanded cohort of 1.6 mg/kg, the recommended phase II dose level of dalantercept as monotherapy is 1.2 mg/kg (75% of 1.6 mg/kg) every 3 weeks. In the present study, no clinically relevant hypertension, proteinuria, gastrointestinal perforations, or hemorrhage were observed, and thus the safety profile of dalantercept appears to be distinct from that of VEGF pathway inhibitors (32)(33)(34)(35). This result suggests that dalantercept potentially could be administered concurrently with a VEGF pathway inhibitor to achieve enhanced antiangiogenic effect.…”

Section: Discussionmentioning

confidence: 44%

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Bendell

Gordon

Hurwitz

et al. 2014

Clinical Cancer Research

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Section: Discussionmentioning

confidence: 44%

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Bendell

Gordon

Hurwitz

et al. 2014

Clinical Cancer Research

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“…Surveillance must be performed in HCC patients with high-grade oesophageal varices, RCC patients with brain metastases, patients with coagulopathies or congenital bleeding disorders [54] and particularly in patients given simultaneous treatment with anticoagulants [55].…”

Section: Bleedingmentioning

confidence: 99%

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

Gao

2015

Basic Clin Pharma Tox

126

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Sorafenib is the first multi-kinase inhibitor (TKI) approved for the treatment of advanced hepatocellular cancer (HCC) and metastatic renal cell cancer (RCC) and is increasingly being used to treat patients with well-differentiated radioiodine-resistant thyroid cancer (DTC). Sorafenib demonstrates targeted activity on several families of receptor and non-receptor tyrosine kinases that are involved in angiogenesis, tumour growth and metastatic progression of cancer. Sorafenib treatment results in longterm efficacy and low incidence of life-threatening toxicities. Although sorafenib has demonstrated many benefits in patients, the adverse effects cannot be ignored. The most common treatment-related toxicities include diarrhoea, fatigue, hand-foot skin reaction and hypertension. Most of these toxicities are considered mild to moderate and manageable to varying degrees; however, cardiovascular events might lead to death. In this MiniReview, we summarize the adverse effects of sorafenib that commonly occur in patients with advanced cancers.Over the past few years, targeted therapy utilizing multi-tyrosine kinase inhibitors (TKIs) has been widely used for treatment of cancers. TKIs are designed to block specific cancer cell processes and are usually better tolerated than most conventional chemotherapeutic drugs. Sorafenib is the first orally active TKI approved by the Food and Drug Administration (FDA). Sorafenib mainly targets vascular endothelial growth factor (VEGFR1-3) and Raf kinases. Other reported targets include K-Ras, BRAF, V599E mutant BRAF, platelet-derived growth factor receptor-b (PDGFR-b), FMS-like tyrosine kinase 3 (FLT3), c-Kit and RET, and several other receptor tyrosine kinases (RTKs) via various modes of action, such as inhibition of the Ras/Raf/MAPK and PI3K/AKT/mTOR signalling pathways [1][2][3]. The anticancer activity of sorafenib thus results from a dual inhibitory effect towards angiogenesis and tumour cell proliferation. Sorafenib also possesses the function of inducing apoptosis in cancer cells by inhibiting the phosphorylation of initiation factor eIF4E and loss of the antiapoptotic protein myeloid cell leukaemia-1(Mcl-1) [4].In 2007, sorafenib was approved by the FDA for the treatment of advanced hepatocellular cancer (HCC) [5,6] and metastatic renal cell cancer (RCC) [7,8]. Oral administration of sorafenib is associated with improved quality of life and prolonged overall survival of patients [9]. Recently, the most positive phase III results were observed in well-differentiated radioiodine-resistant thyroid cancer (DTC) [10], resulting in the increased use of sorafenib to treat patients with DTC.

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“…Angiogenesis inhibitors such as bevacizumab, sunitinib, sorafenib, and pazopanib are known to induce hypertension [15]. The mechanism involves the inhibition of VEGF on vasculatures, leading to decreases in nitric oxide and prostaglandin I2 and subsequently to increased vasoconstriction and blood pressure.…”

Section: Hepatotoxicitymentioning

confidence: 99%

The changing paradigm for supportive care in cancer patients

Chan

Lees

Keefe

2014

Support Care Cancer

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Dear Editor, With scientific advances in cancer supportive care and the incorporation of effective supportive care strategies into contemporary cancer treatment, there has been a substantial reduction in the occurrence of severe toxicities traditionally associated with cytotoxic chemotherapy over the past two decades. For example, appropriate prophylaxis with antiemetics (including a 5-HT 3 antagonist, corticosteroid, and NK-1 antagonist) has greatly reduced chemotherapy-induced nausea and vomiting, colony-stimulating factors have curbed febrile neutropenia, and the integrated use of mouth care and palifermin has decreased the severity of oral mucositis. In addition, the introduction of structured management and care pathways into clinical practice has widely promoted these supportive care strategies for patients. We may not currently have all the answers on the prevention of chemotherapyinduced toxicities, but most oncology clinicians today can capably handle toxicities which were previously considered difficult to manage.Innovations in cancer therapeutics have improved the oncologist's toolkit to cure and control many cancers previously difficult to manage. Targeted therapy agents are now commonly used in the management of cancers ranging from chronic myeloid leukemia to renal cell carcinoma, and new indications and increased lines of therapy continue to arise. Initially "targeted" drugs were thought to have unique mechanisms for targeting cancer cells and were considered to produce fewer side effects than traditional cytotoxic chemotherapy. Importantly, however, clinicians are now observing a number of emerging and highly prevalent side effects associated with the use of targeted therapies [1]. These agents, which carry with them significant financial cost, are also associated with an increase in chronic complications that can decrease a patient's quality of life [2]. We must, therefore, strive to understand and be responsive to the side effects of these novel therapeutics to enable optimal patient adherence to and participation in their treatment.In this commentary, we highlight toxicities that are commonly associated with targeted therapies, namely dermatological, gastrointestinal (diarrhea and stomatitis), hepatotoxicity, cardiotoxicity, neurotoxicity, and immunotoxicity. More importantly, we will emphasize the current impediments to understanding the mechanisms behind emerging side effects and the lack of effective strategies for managing these toxicities. Dermatological toxicitiesCommonly associated with targeted agents is a range of dermatological toxicities, which are different from the skin toxicities seen with traditional cytotoxic chemotherapy. The first of these class-related skin toxicities is observed with epidermal growth factor receptor inhibitors (EGFRI), including agents used for the treatment of lung (gefitinib, erlotinib, and afatinib), pancreatic (erlotinib), breast (lapatinib), head and neck (cetuximab), and colorectal cancers (cetuximab and panitumumab). They usually manifest as papulopu...

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Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

Cited by 78 publications

References 79 publications

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

The changing paradigm for supportive care in cancer patients

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