Use Of Vascular Endothelial Growth Factor Inhibitors Research Articles

Abstract 4591: Mechanisms of tumor-mediated endothelial cell proliferation independent of VEGF

Abstract A hallmark of cancer is dysregulated angiogenesis and blood vessel co-option, which are often driven by vascular endothelial growth factor (VEGF). Despite the key role of VEGF signaling in promoting endothelial cell (EC) proliferation, survival, and migration, the clinical use of VEGF inhibitors has modest success and faces many challenges. In particular, patients demonstrate variable initial responses to anti-VEGF therapy, and many of those who respond to treatment subsequently develop resistance. These challenges suggest that there may be VEGF-independent mechanisms driving EC proliferation in the tumor microenvironment. To study these mechanisms, we established an in vitro model using a dual-reporter system in a co-culture model of ECs and tumor cells. Specifically, we used an immortalized endothelial cell line (SVEC4-10) expressing GFP and Renilla luciferase and a mouse renal carcinoma cell line (RENCA) expressing Tomato and Firefly luciferase. This model allowed us to independently evaluate the growth rates and cell viabilities of both ECs and tumor cells in direct co-culture. Our preliminary data revealed that ECs exhibit increased growth rates when directly co-cultured with tumor cells. Interestingly, this EC proliferation is VEGF-independent and not impacted by VEGF-A knockout in tumor cells or with treatment of a pan-VEGFR small molecule inhibitor (axitinib). To further characterize if our phenotype was due to other tumor secreted factors, we used a transwell setup to eliminate direct contact between ECs and tumor cells and found that EC growth rates were substantially mitigated. These results revealed that tumor cells induced EC proliferation through a physical cell-to-cell interaction that is independent of VEGF. Further characterizing this unknown mechanism may inform therapeutic interventions to overcome the clinical challenges of anti-VEGF therapies for cancer. To expand our understanding of this VEGF-independent EC proliferation, we aim to characterize the cell surface proteome from tumor-conditioned ECs using cell surface mass spectrometry. We will validate hits from this study using our in vitro model and translate these findings to in vivo mouse models. We expect that our current and future research will reveal new insights into tumor co-option of the vascular system and identify novel targets for developing therapies to effectively treat cancer. Citation Format: Kevin L. Sheng, Jude Raj, Kris C. Wood. Mechanisms of tumor-mediated endothelial cell proliferation independent of VEGF. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4591.

Receipt of Targeted Therapy and Survival Outcomes in Patients With Metastatic Colorectal Cancer

Professional society guidelines recommend treating patients with metastatic colorectal cancer with targeted therapies, including epithelial growth factor receptor (EGFR) inhibitors and vascular endothelial growth factor (VEGF) inhibitors, depending on the presence or absence of certain mutations. Since most studies of first-line targeted therapies have been limited by sample size, there is a need for larger studies using data from routine clinical care. To identify factors associated with receipt of first-line targeted therapies among patients with metastatic colorectal cancer for whom RAS or BRAF mutation data in the tumor were available and investigate whether targeted therapy is associated with survival. This cohort study used deidentified data from an electronic health record-derived database to include patients from 800 sites of patient care across the US who were diagnosed with de novo metastatic colorectal cancer between January 1, 2013, and March 31, 2020 (n = 9134). Receipt of first-line targeted therapy, categorized as ever having received EGFR inhibitors, VEGF inhibitors, or neither. The secondary outcome was overall survival. The study population included 9134 patients. The median age at diagnosis was 62 years (IQR, 53-71 years), 5019 (54.9%) were male, and 5692 (62.3%) were White. The median follow-up period was 15 months. Overall, 713 patients (7.8%) received EGFR inhibitors and 5081 patients (55.6%) received VEGF inhibitors as part of their first-line treatment. Among patients with RAS wild-type (RAS-WT) tumors, 625 patients (15.5%) received EGFR inhibitors and 2053 patients (50.9%) received VEGF inhibitors. In patients with RAS mutant (RAS-Mut) tumors, 50 patients (1.1%) received EGFR inhibitors and 2682 patients (59.7%) received VEGF inhibitors; among those with BRAF-mutant (BRAF-Mut) tumors, 38 patients (6.3%) received EGFR inhibitors and 346 patients (57.2%) received VEGF inhibitors. More than one-third of the patients (36.6%) received neither EGFR inhibitors nor VEGF inhibitors. Compared with patients younger than age 40 years, those aged 80 years or older had significantly lower odds to receive targeted therapies (EGFR or VEGF inhibitors in patients with RAS-WT tumors: adjusted odds ratio [aOR], 0.53; 95% CI, 0.36-0.79; and VEGF inhibitors in patients with RAS-Mut tumors: aOR, 0.62; 95% CI, 0.42-0.90). Improved survival was associated with EGFR inhibitor therapy in patients with RAS-WT tumors (adjusted hazard ratio [aHR], 0.85; 95% CI, 0.74-0.98). Unlike in clinical trials, however, no survival benefit was noted with use of VEGF inhibitors among patients with RAS-WT (aHR, 1.00; 95% CI, 0.91-1.11) or RAS-Mut (aHR, 1.01; 95% CI, 0.93-1.10) tumors. The findings of this study showed mixed results on survival benefits associated with targeted therapy. In addition, given that some of the results differed from those of randomized clinical trials, this study highlights the importance of using data originating from routine clinical care.

The role of vascular endothelial growth factor inhibitors in the treatment of epithelial ovarian cancer.

Advanced epithelial ovarian, fallopian tube and primary peritoneal cancers (EOC) are a leading cause of gynaecological cancer-associated mortality and angiogenesis plays a key role in their growth. Vascular endothelial growth factor inhibitors (VEGFi) disrupt angiogenesis and improve the response rate, progression-free survival and in some cases, overall survival, when administered with and following cytotoxic chemotherapy, irrespective of the platinum sensitivity of EOC. Recent data have identified new indications for VEGFi in EOC: repeated exposure to VEGFi in the first- and then second-line treatment has sustained clinical efficacy; combinations of VEGFi with poly (ADP-ribose) polymerase inhibitors (PARPi) have proven effective as first-line or second-line maintenance regimens. However, recent trial data have not shown improved outcomes with combinations of VEGFi and immune checkpoint inhibitors. There remains a critical need to optimise patient selection for these effective yet somewhat toxic and expensive treatments. The search continues for validated biomarkers to optimise the use of VEGFi, of which the most promising at present is plasma Tie2. Based upon these studies, we propose a model of care incorporating VEGFi into the treatment of EOC, highlighting the need to change from the prescription of single courses of VEGFi, to allow use and re-use as clinically indicated.

Vascular toxicity associated with anti-angiogenic drugs.

Over the past two decades, the treatment of cancer has been revolutionised by the highly successful introduction of novel molecular targeted therapies and immunotherapies, including small-molecule kinase inhibitors and monoclonal antibodies that target angiogenesis by inhibiting vascular endothelial growth factor (VEGF) signaling pathways. Despite their anti-angiogenic and anti-cancer benefits, the use of VEGF inhibitors (VEGFi) and other tyrosine kinase inhibitors (TKIs) has been hampered by potent vascular toxicities especially hypertension and thromboembolism. Molecular processes underlying VEGFi-induced vascular toxicities still remain unclear but inhibition of endothelial NO synthase (eNOS), reduced nitric oxide (NO) production, oxidative stress, activation of the endothelin system, and rarefaction have been implicated. However, the pathophysiological mechanisms still remain elusive and there is an urgent need to better understand exactly how anti-angiogenic drugs cause hypertension and other cardiovascular diseases (CVDs). This is especially important because VEGFi are increasingly being used in combination with other anti-cancer dugs, such as immunotherapies (immune checkpoint inhibitors (ICIs)), other TKIs, drugs that inhibit epigenetic processes (histone deacetylase (HDAC) inhibitor) and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, which may themselves induce cardiovascular injury. Here, we discuss vascular toxicities associated with TKIs, especially VEGFi, and provide an up-to-date overview on molecular mechanisms underlying VEGFi-induced vascular toxicity and cardiovascular sequelae. We also review the vascular effects of VEGFi when used in combination with other modern anti-cancer drugs.

A Phase III, randomized, double-blind, placebo-controlled, multicenter study of fruquintinib in Chinese patients with advanced nonsquamous non-small-cell lung cancer – The FALUCA study

ObjectivesFruquintinib is an orally active kinase inhibitor that selectively targets the vascular endothelial growth factor (VEGF) receptor. A Phase II trial has demonstrated a significant benefit in progression-free survival (PFS) for fruquintinib-treated patients with locally advanced/metastatic nonsquamous non-small-cell lung cancer (NSCLC) who have progressed after second-line chemotherapy. This Phase III trial is a randomized, double-blind, multicenter trial to confirm fruquintinib’s efficacy in the same patient population. Materials and methodsFrom December 2015 to February 2018, 730 patients were screened, of whom 527 were enrolled into the study. Participants were randomized 2:1 to receive fruquintinib (n = 354) or placebo (n = 173) once daily for 3 weeks on-treatment, and 1 week off-treatment. Patients were stratified according to epidermal growth factor receptor mutation status and prior use of VEGF inhibitors. Primary endpoint was overall survival (OS). ResultsMedian OS was 8.9 months for the fruquintinib group and 10.4 months for placebo group (hazard ratio [HR] 1.02; 95 % confidence interval [CI], 0.82–1.28; P = 0.841), with median PFS of 3.7 months and 1.0 months, respectively (HR 0.34; 95 % CI, 0.28–0.43; P < 0.001). Objective response rate and disease control rate were 13.8 % and 66.7 % for fruquintinib, and 0.6 % and 24.9 % for placebo, respectively (P < 0.001). Hypertension was the most frequent treatment-emergent adverse event (≥grade 3) observed in fruquintinib-treated patients (21.0 %). Post hoc analysis revealed that fruquintinib prolonged the median OS for patients who did not receive subsequent antitumor therapy: 7.0 months versus 5.1 months for placebo (HR 0.65; 95 % CI, 0.46–0.91; P = 0.012). Patients receiving fruquintinib also reported improvements in quality of life for most functional scales measured by EORTC QLQ-C30 and LC13 questionnaires. ConclusionAlthough the study did not meet its primary endpoint, fruquintinib could be effective in combination with other agents for the treatment of patients with NSCLC who have failed second-line chemotherapy.

An observational study of vascular endothelial growth factor inhibitors as second-line treatment for metastatic colorectal cancer treated with bevacizumab plus FOLFIRI beyond progression: the association with RAS mutation and tumor sidedness

Background: The BRiTE and ARIES studies suggested that the continued use of bevacizumab beyond progression (BBP) was beneficial. This study investigated the efficacy and safety of the vascular endothelial growth factor inhibitors (VEGFis) bevacizumab and aflibercept as second-line treatments for patients with metastatic colorectal cancer (mCRC) that progressed following the application of bevacizumab-containing chemotherapy as a first-line treatment. Methods: This observational cohort study (OCS) analyzed the medical records of 73 patients with mCRC divided into a no-VEGFi group (n=48) and a VEGFi group (n=25). Progression-free survival (PFS) was the primary endpoint, and the overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were secondary endpoints. Results: The results revealed that the PFS, ORR, and DCR of the VEGFi group were significantly superior to those of the no-VEGFi group, even in those with wild-type and mutant-type RAS or left-sided mCRC (all P 0.05). Patients with primary left-sided lesions and continued use of VEGFi exhibited the most marked effect on PFS (P=0.001). No significant differences were observed in the incidence of grade 3 or 4 adverse events (AEs) between the two groups (P=0.133). Conclusions: These results support the use of VEGFi as a second-line treatment after bevacizumab beyond the initial progression in this OCS. Bevacizumab or aflibercept combined with second-line chemotherapy in mCRC has an acceptable safety profile and is relatively active. Regardless of the RAS gene type, VEGFi plus FOLOFX6 exhibited superior PFS to that of FLFOX6 as a second-line treatment, and a greater improvement in PFS was obtained for the left-sided lesions than for the right-sided lesions.

An observational study of vascular endothelial growth factor inhibitors as second-line treatment for metastatic colorectal cancer treated with bevacizumab plus FOLFIRI beyond progression: the association with RAS mutation and tumor sidedness.

BackgroundThe BRiTE and ARIES studies suggested that the continued use of bevacizumab beyond progression (BBP) was beneficial. This study investigated the efficacy and safety of the vascular endothelial growth factor inhibitors (VEGFis) bevacizumab and aflibercept as second-line treatments for patients with metastatic colorectal cancer (mCRC) that progressed following the application of bevacizumab-containing chemotherapy as a first-line treatment.MethodsThis observational cohort study (OCS) analyzed the medical records of 73 patients with mCRC divided into a no-VEGFi group (n=48) and a VEGFi group (n=25). Progression-free survival (PFS) was the primary endpoint, and the overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were secondary endpoints.ResultsThe results revealed that the PFS, ORR, and DCR of the VEGFi group were significantly superior to those of the no-VEGFi group, even in those with wild-type and mutant-type RAS or left-sided mCRC (all P<0.05); however, OS did not differ significantly between the two groups (all P>0.05). Patients with primary left-sided lesions and continued use of VEGFi exhibited the most marked effect on PFS (P=0.001). No significant differences were observed in the incidence of grade 3 or 4 adverse events (AEs) between the two groups (P=0.133).ConclusionsThese results support the use of VEGFi as a second-line treatment after bevacizumab beyond the initial progression in this OCS. Bevacizumab or aflibercept combined with second-line chemotherapy in mCRC has an acceptable safety profile and is relatively active. Regardless of the RAS gene type, VEGFi plus FOLOFX6 exhibited superior PFS to that of FLFOX6 as a second-line treatment, and a greater improvement in PFS was obtained for the left-sided lesions than for the right-sided lesions.

Vascular endothelial growth factor and programmed death-1 pathway inhibitors in renal cell carcinoma.

Advanced renal cell carcinoma has historically carried a poor prognosis with very limited treatment options. However, in recent years, the treatment landscape has changed drastically, with many new therapeutic options and improved survival for patients. Novel treatments consist of molecularly targeted agents against the vascular endothelial growth factor (VEGF) pathway as well as the immune checkpoint inhibitors, which stimulate an antitumor immune response. Recent strategy has focused on the development of combination therapy with the use of VEGF inhibitors and immune checkpoint inhibitors in the first-line setting. As more treatments are approved and the options for therapy expand further, there is a growing need for predictive biomarkers to personalize treatment choices for individual patients. Prospective clinical trials comparing the sequencing of treatments are needed to help determine the best therapeutic approach.

Bevacizumab in the treatment of radiation injury for children with central nervous system tumors.

Radiation-induced injury is a well-described toxicity in children receiving radiation therapy for tumors of the central nervous system. Standard therapy has historically consisted primarily of high-dose corticosteroids, which carry significant side effects. Preclinical models suggest that radiation necrosis may be mediated in part through vascular endothelial growth factor (VEGF) overexpression, providing the rationale for use of VEGF inhibitors in the treatment of CNS radiation necrosis. We present the first prospective experience examining the safety, feasibility, neurologic outcomes, and imaging characteristics of bevacizumab therapy for CNS radiation necrosis in children. Seven patients between 1 and 25years of age with neurologic deterioration and MRI findings consistent with radiation injury or necrosis were enrolled on an IRB-approved pilot feasibility study. Patients received bevacizumab at a dose of 10mg/kg intravenously every 2weeks for up to 6 total doses. Five patients (83%) were able to wean off corticosteroid therapy during the study period and 4 patients (57%) demonstrated improvement in serial neurologic exams. All patients demonstrated a decrease in T1-weighted post-gadolinium enhancement on MRI, while 5 (71%) showed a decrease in FLAIR signal. Four patients developed a progressive disease of their underlying tumor during bevacizumab therapy. Our experience lends support to the safety and feasibility of bevacizumab administration for the treatment of radiation necrosis for appropriately selected patients within the pediatric population.

VEGF modulation and renal effects: Case report and review of the literature

Angiogenesis has been known for decades to be an essential step in cancer growth. Inrecent years, the vascular endothelial growth factor (VEGF) family was identified as a crucialstimulus (and product by tumors) for neovascularization, nutrition, oxygen delivery, andmetastatic dissemination; VEGF inhibition currently has an important role in cancer therapy.The development and increased use of VEGF inhibitors has led to the identification of sideeffects and renal complications. Vascular endothelial growth factor is produced by renalpodocytes to maintain a healthy endothelium, mesangium, and tubular structures. With thedisruption of nutritional processes in the kidney, there can be renal injury starting at the cellularlevel and referred to by some experts as anti-VEGF nephropathy (hypertension, thromboticmicroangiopathy, proteinuria, renal failure).Here we present the case of a man with renal cell carcinoma who was treated with surgicalresection and later started on sunitinib. He developed several acute and chronic medicalproblems, including some related to anti-VEGF toxicity.

An Evidence-Based Review of Vascular Endothelial Growth Factor Inhibition in Pediatric Retinal Diseases: Part 2. Coats’ Disease, Best Disease, and Uveitis With Childhood Neovascularization

Vascular endothelial growth factor (VEGF) is an important factor in the pathogenesis of multiple retinal neovascular disorders. This report focuses on the quality and depth of new evidence for the use of VEGF inhibitors in selected pediatric ocular diseases, including Coats' disease, Best disease, and childhood uveitis. Because much of the literature comprises case reports and retrospective case series, the level of evidence supporting its use as a primary treatment option, or even as adjuvant therapy, is low. The standard of care is treatment of the underlying disorder to prevent neovascularization (retinal or subretinal), vitreous hemorrhage, or subsequent retinal detachment. However, these complications may not present until late in the disease course. It may then be useful to treat with these agents. Prospective studies are warranted to further elucidate the role of anti-VEGF therapy in these diseases.

Aflibercept: Bimonthly intravitreal injection for AMD

Aflibercept: Bimonthly intravitreal injection for AMD

Kidney complications: Why don't statins always work?

The vasculature suffers damage as a result of diabetes, often leading to conditions such as kidney failure. In bench to bedside, Christian Rask-Madsen and George King examine endogenous factors that protect against damage of the vasculature, such as vascular-endothelial growth factor (VEGF). Recent studies report that VEGF is expressed by kidneys and fends off renal failure; such findings have implications for the development of treatments that harness endogenous factors and sound a note of caution for the therapeutic use of VEGF inhibitors. People with end-stage renal disease often die of cardiovascular complications and clinical studies have shown that one popular class of drugs, statins, does not work in this population. In bedside to bench, S. Ananth Karumanchi and Ravi Thadhani show how this clinical finding is spurring research into the biological mechanisms behind cardiovascular death in people with kidney disease.

Atrial Natriuretic Peptide Reduces Vascular Leakage and Choroidal Neovascularization

Atrial natriuretic peptide (ANP) is a hormone with diuretic, natriuretic, and vasodilatory properties. ANP blocks vascular endothelial growth factor (VEGF) production and signaling in vitro; however, its role in vascular leakage and angiogenesis is unknown. In vitro, retinal barrier permeability (transepithelial electrical resistance (TEER)) was measured in cultured retinal endothelial (HuREC) and retinal epithelial (ARPE-19) cells with VEGF (10 ng/ml), ANP (1 pM to 1 micromol/L), and/or isatin, an ANP receptor antagonist. In vivo, blood-retinal barrier (BRB) leakage was studied using the Evans Blue dye technique in rats treated with intravitreal injections of ANP, VEGF, or vehicle. Choroidal neovascularization was generated by laser injury, and 7 days later, lesion size and leakage was quantitated. ANP significantly reversed VEGF-induced BRB TEER reduction in both HuREC and ARPE-19 cells, modeling the inner and the outer BRB, respectively. Isatin, a specific ANP receptor antagonist, reversed ANP's effect. ANP reduced the response of ARPE-19 cells to VEGF apically but not basolaterally, suggesting polarized expression of the ANP receptors in these cells. ANP's TEER response was concentration but not time dependent. In vivo, ANP significantly reduced VEGF-induced BRB leakage and the size of laser-induced choroidal neovascularization lesions. In sum, ANP is an effective inhibitor of VEGF-induced vascular leakage and angiogenesis in vivo. These results may lead to new treatments for ocular diseases where VEGF plays a central role, such as age-related macular degeneration or diabetic retinopathy.

Systemic VEGF Inhibition Induces Hepatic EPO Production and Erythrocytosis Via HIF-2a-Dependent and -Independent Mechanisms

Vascular endothelial growth factor (VEGF) exerts crucial functions during pathological angiogenesis and normal physiology. We have previously reported increased hematocrit (60–75%) and erythrocytosis after high-grade VEGF inhibition by diverse methods, including adenoviral expression of soluble VEGF receptor (VEGFR) ectodomains, recombinant VEGF Trap protein and the VEGFR2-selective antibody DC101. Erythrocytosis occurred in both mice and primate models in an erythropoietin (Epo)-dependent manner, with unexpected >40-fold induction of hepatic erythropoietin through a hypoxia- and HIF-1α-independent mechanism involving disruption of endothelial-hepatocyte cross-talk.To identify candidate transcription factors required for VEGF inhibition-dependent hepatic Epo induction, we performed hepatic gene expression profiling, revealing up-regulation of HIF-2α target genes (Loxl2 and Cited2). Systemic VEGF inhibition resulted in hepatic stabilization of the HIF-2α protein without concomitant liver hypoxia. Conversely, hepatocyte-specific deletion of the Hif2a gene in Hif2aflox/flox mice strongly diminished the hematocrit elevation and hepatic Epo synthesis after systemic VEGF inhibition, indicating an essential role for HIF-2α. These results are consistent with other reports indicating potent regulation of hepatic Epo production by HIF-2α. In addition to the previously characterized Epo-dependent erythrocytosis, RBC mass monitoring in VEGF inhibitor-treated mice reveals that an erythrocytosis-independent mechanism also contributes to elevated hematocrit. VEGF inhibition initially moderately elevates hematocrit from a baseline of 47% to approximately 50–55% without a parallel increase in RBC mass or reticulocyte index. This initial hematocrit elevation (phase 1) occurs over the first 5 days of VEGF inhibition and is associated with decreased plasma volume (PV) as measured by Evans blue dye injection. Subsequently, a persistent erythrocytosis ensues, as reflected by increased RBC mass and reticulocytosis (phase 2) and is responsible for the vast majority of the erythrocytosis observed with stringent in vivo VEGF inhibition. Together, decreased PV (phase 1) with elevated erythrocytosis (phase 2) combine to maximally elevate hematocrit (near 75%) under stringent VEGF inhibition. Notably, phase 2 but not phase 1 hematocrit elevation and Epo induction were ablated by hepatocyte Hif2a gene deletion, again suggesting that phase 1 elevation arises through distinct mechanisms.Clinical implications of our work include the use of VEGF inhibitors for the simultaneous treatment of malignancy and anemia as well as the use of hematocrit and/or Epo as surrogate markers for the efficacy of in vivo VEGF inhibition. Accordingly, we will summarize our initial attempts at prospective monitoring of these parameters in cancer patient populations treated with VEGF inhibitors.Overall, these data highlight unexpected physiologic consequences of VEGF inhibition and indicate that VEGF is a previously unsuspected negative regulator of hepatic Epo synthesis and erythrocytosis via HIF-2α-dependent and -independent mechanisms.

Reversible Bony Changes after Treatment with Bevacizumab in a Child with Cutaneovisceral Angiomatosis with Thrombocytopenia Syndrome: A Case Report and Review of the Literature.

Cutaneovisceral Angiomatosis with Thrombocytopenia (CAT) syndrome is a rare vascular disorder involving the skin and gastrointestinal tract. Clinical features of CAT syndrome include multiple, discrete skin lesions, gastrointestinal bleeding and thrombocytopenia. CAT syndrome is typically treated with angiogenesis inhibitors like corticosteroids and vincristine. Bevacizumab is a relatively new antiangiogenic agent that is FDA approved as a first-line agent for metastatic carcinoma of the colon or rectum in combination with a 5-FU based regimen. Bevacizumab is a humanized monoclonal antibody that binds all five isoforms of human vascular endothelial growth factor (VEGF) and prevents its interaction with the VEGF receptor. There is currently very little clinical pediatric experience with antiangiogenic agents.Case: Though subtly symptomatic from birth, our patient was diagnosed with CAT syndrome at four months of age after an episode of grossly bloody stools. After failed therapy with corticosteroids and vincristine, the patient was given bevacizumab 10mg/kg/dose every two weeks for four doses with excellent clinical response. After her fourth dose, a chest radiograph revealed incidental, asymptomatic metaphyseal lesions of the humeri. A complete bone survey revealed similar lesions in the metaphyses of nearly all of her long bones. (Figure 1) Given preclinical data suggesting these lesions could result from the use of VEGF inhibitors, bevacizumab was discontinued. All metaphyseal lesions subsequently resolved. (Figure 2) To our knowledge, this is the first report of bony toxicity in a human receiving bevacizumab. A thorough literature review on VEGF inhibitors revealed no reported cases of metaphyseal lesions or stunted growth in humans receiving VEGF inhibitors. Animal studies, however, suggest this may be possible. Growth plates consist of avascular cartilage that is eventually replaced by bone. This process requires invasion of the cartilage with metaphyseal blood vessels and has been shown to be directed by a VEGF gradient (Nature Medicine 1999; 5(6): 623–628). Preclinical studies performed using VEGF inhibitors in monkeys demonstrated reversible physeal dysplasia of the distal femur in the monkeys with open growth plates (Toxicol Pathol , 1999; 27(1): 78–86). We hypothesize that use of the VEGF inhibitor, bevacizumab, in a small child with active epiphyseal growth plates caused the radiographic lesions we observed. It appears that this side effect is reversible, at least after short-term use. We propose that close monitoring for bony toxicity is required for all children receiving bevacizumab and that this drug should be used only with caution in children with active bone growth. [Display omitted] [Display omitted]

Mechanisms of adverse effects of anti-VEGF therapy for cancer

Advances in understanding the role of vascular endothelial growth factor (VEGF) in normal physiology are giving insight into the basis of adverse effects attributed to the use of VEGF inhibitors in clinical oncology. These effects are typically downstream consequences of suppression of cellular signalling pathways important in the regulation and maintenance of the microvasculature. Downregulation of these pathways in normal organs can lead to vascular disturbances and even regression of blood vessels, which could be intensified by concurrent pathological conditions. These changes are generally manageable and pose less risk than the tumours being treated, but they highlight the properties shared by tumour vessels and the vasculature of normal organs.