Anti-vascular Endothelial Growth Factor Inhibitors Research Articles

Retraction of cystoid macular edema from the fovea after intravitreal anti-VEGF therapy for birdshot chorioretinopathy.

To report the effect of anti-vascular endothelial growth factor inhibitor (anti-VEGF) on fovea-involving cystoid macular edema in a patient with Birdshot chorioretinopathy. A 42-year-old male patient presented to our hospital with bilateral posterior uveitis with retinal vasculitis, cystoid macular edema and optic disc edem a. He was diagnosed with birdshot chorioretinopathy based on clinical appearance and tissue type HLA-A29. The patient underwent vitrectomy in the right eye without any change in visual acuity. Retinal leakage was reduced by oral prednisolone, which could not be tapered below 50 mg per day without relapse. Oral prednisolone, topical dexamethasone and subtenonal kenalog were associated with intraocular pressure rise in both eyes. Hence, his uveitis responded to steroids, but there was no detectable effect of any steroid-sparing immunomodulatory drugs. The patient had been on oral prednisolone 50 mg for five years when it was decided to attempt intravitreal VEGF inhibitor injection therapy. The anti-VEGF therapy diminished cystoid macular edema in the fovea and improved the visual acuity. Here we report for the first time the long-term outcomes of anti-VEGF injections on fovea-involving cystoid macular edema in Birdshot chorioretinopathy to keep steroid at the minimal possible doses and preserve a satisfying visual acuity level.

Therapeutic Management and New Upcoming Approaches for Age Related Macular Degeneration.

Age-related Macular Degeneration (AMD) is a severe eye illness that is going to lead in the race for incurable blindness globally among the elderly population. AMD is the third common reason responsible for affecting the quality of life globally. The macula and the retinal layers are adversely affected during AMD and are responsible for the loss of vision eventually. Numerous genetic variables, lipid metabolism, ageing and oxidative damage are the causative factors in the genesis of AMD. Lack of antioxidants, smoking and excessive alcohol intake contribute to increasing the risk of AMD. Management of dry AMD involves the use of nutritional supplements like zinc and antioxidants, along with conventional treatment, however, the use of nutritional supplements can only give minor benefits on the progression of dry AMD. Later stages of AMD need to be managed by cell-based interventions where the damaged or lost cells are replaced with fresh donor cells. A plethora of treatment methods are used in the management of AMD, such as nutrition, antibody-based treatments, stem cell management and nanotherapeutics. The available expensive treatments come with a number of adverse effects and future developments require the involvement of risk factor modification approaches, personalized therapy, targeting the disease specific pathways, exploring better anti-vascular endothelial growth factor (VEGF) inhibitors and many other regenerative approaches, that will broaden techniques to diagnose, control and treat AMD. This review provides an overview of the progression of AMD and the causative factors, with considerable emphasises on the current and potential prospects.

Brolucizumab for recalcitrant macular neovascularization in age-related macular degeneration with pigment epithelial detachment.

To analyze anatomic and functional response to intravitreal brolucizumab in age-related macular degeneration recalcitrant to previous intravitreal anti-VEGF therapies. In this monocentric, one arm, retrospective study, eyes affected by neovascular age-related macular degeneration (nAMD) resistant to other intravitreally injected anti-vascular endothelial growth factor inhibitors were switched to intravitreal brolucizumab. All patients underwent ophthalmological examinations at baseline and in regular follow-up intervals. Best registered visual acuity (BRVA), Goldmann tonometry, intraocular pressure (IOP), central retinal thickness (CRT) and pigment epithelial detachment (PED) characteristics were analyzed at initiation of anti-VEGF treatment, at treatment switch, and at the end of brolucizumab loading phase. The study included 20 eyes of 18 consecutively treated patients (age: 77 ± 6 years). All eyes had macular neovascularization with PED. Previous treatments included intravitreal aflibercept, bevacizumab, and ranibizumab and had not resulted in a significant improvement in BRVA (0.5 ± 0.5 logMAR vs 0.5 ± 0.6 logMAR) or mean CRT (320 ± 60 µm vs 313 ± 83 µm) up to treatment switch to brolucizumab. At the end of the brolucizumab loading phase, there was significant improvement for both BRVA (0.3 ± 0.2 logMAR, P < 0.05) and CRT (264 ± 55 µm, P < 0.05). Under previous anti-VEGF therapy, there was a significant increase/deterioration in both PED area (2.68 mm2 to 5.18 mm2, P < 0.05) and PED volume (0.39 mm3 to 1.07 mm3, P < 0.05); however, both parameters improved after switching to brolucizumab (3.81 mm2 and 0.37 mm3, P < 0.05). Our results suggest a favourable anatomical and visual response after treatment switch to brolucizumab in patients with nAMD refractory to previous anti-VEGF agents.

Efficacy and safety of first-line treatments for patients with advanced hepatocellular carcinoma: A systematic review and network meta-analysis.

4094 Background: In recent years, the first-line treatment options for advanced HCC has been increasingly abundant, including transarterial therapies, combination of the immune checkpoint inhibitors (ICIs) and the anti-vascular endothelial growth factor (VEGF) inhibitor, ICIs combined with ICIs, and tyrosine kinase inhibitors. However, it remains to be confusing which treatment pattern would benefit people most, especially for different subgroups. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings for III phase randomized clinical trials (RCTs) investigating first-line treatments for HCC compared with sorafenib. The survival outcomes and toxic effects of RCTs should be reported, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher. This systematic review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The random-effects model was used to calculate the summary hazard ratios (HRs) of OS and PFS. The likelihood of ORR, and AEs of grade 3 or higher was performed by odds ratios (ORs) using a random-effects model. Results: A total of 13 phase III RCTs involving 8505 patients were included in this study. Hepatic arterial infusion of oxaliplatin combined with fluorouracil (FOHAIC-1) showed OS, PFS, and ORR benefit over all other first-line therapies, except for the regimen of sorafenib plus HAIC of FOLFOX (OS: HR, 0.88; 95% CI, 0.37-2.09; ORR: OR, 1.53; 95% CI, 0.29-8.13). More importantly, we found that sorafenib combined with FOLFOX was superior to other regimens in patients with HBV infection regarding OS except FOHAIC-1 (HR, 0.57; 95%CI, 0.21-1.52) and tremelimumab-durvalumab (HR, 0.42; 95%CI, 0.16-1.11). While in HCV-infected subgroup, ICIs combined with anti-VEGF inhibitor improved OS benefit compared with tremelimumab-durvalumab (HR, 0.31; 95% CI, 0.11-0.84) and sorafenib (HR, 0.38; 95% CI, 0.16-0.88). HAIC-FO also showed significant OS benefits to other therapies in patients with portal invasion or extrahepatic metastasis. The probability of adverse events of grade 3 or higher was significantly lower with HAIC-FO than with others except for nivolumab (RR, 0.96; 95%CI, 0.51-1.82) and tislelizumab (RR, 0.57; 95%CI, 0.30-1.08). Conclusions: This network meta-analysis supports arterial infusion as the first-line treatment for patients with HCC. In portal invasion and extrahepatic metastasis subgroups, HAIC-FO may be a preferred option, with sorafenib combined with FOLFOX as an additional option in those with HBV infection. Besides, novel combination therapy should be focused on in patients with certain subgroups.

NSCLC Patients Achieving Long-term Progression-free Survival With Docetaxel Plus Ramucirumab: A Retrospective Study.

The antineoplastic drug docetaxel (DOC) and the antivascular endothelial growth factor inhibitor ramucirumab (RAM) are widely used in combination for second or later-line regimens for advanced non-small cell lung cancer (NSCLC). While the median progression-free survival (PFS) of DOC+RAM has been reported to be less than six months in both clinical trials and clinical practice, there appear to be some patients with long-term PFS. This study aimed to clarify the existence and characteristics of these patients. We conducted a retrospective review of patients with advanced NSCLC treated with DOC+RAM between April 2009 and June 2022 at our three hospitals. There was no established definition of long-term PFS, thus in this study, a PFS of 12 months or longer was defined as long-term PFS. During the study period, 91 patients received DOC+RAM treatment. Of these, 14 (15.4%) achieved long-term PFS. There were no significant differences in patient characteristics between patients with PFS ≥12 months and those with PFS <12 months, except for 'clinical stage IIIA-C' at DOC+RAM initiation and 'post-surgical recurrence'. In uni- and multivariate analyses, favorable factors for PFS were 'Stage III at the start of DOC+RAM' in driver gene-negative patients, and 'under 70 years old' in driver gene-positive patients. Many patients in this study achieved long-term PFS with DOC+RAM treatment. In the future, it is expected that long-term PFS will be defined, and the background of patients who achieve such PFS will become clearer.

Advanced development of biomarkers for immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Mono-immunotherapy and combination therapy with immune checkpoint inhibitors (ICIs) and multitargeted tyrosine kinase inhibitors (TKIs) or anti-vascular endothelial growth factor (anti-VEGF) inhibitors have become new standard therapies in advanced HCC (aHCC). However, the clinical benefit of these treatments is still limited. Thus, proper biomarkers which can predict treatment response to immunotherapy to maximize clinical benefit while sparing unnecessary toxicity are urgently needed. Contrary to other malignancies, up until now, no acknowledged biomarkers are available to predict resistance or response to immunotherapy for HCC patients. Furthermore, biomarkers, which are established in other cancer types, such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB), have no stable predictive effect in HCC. Thus, plenty of research focusing on biomarkers for HCC is under exploration. In this review, we summarize the predictive and prognostic biomarkers as well as the potential predictive mechanism in order to guide future research direction for biomarker exploration and clinical treatment options in HCC.

A Linkage between Angiogenesis and Inflammation in Neovascular Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD (nAMD). Dry AMD is the most prevalent form (80-90%) of AMD cases. Neovascular AMD (10-20% of AMD cases) is treated with monthly or more sparsely given intravitreal anti-vascular endothelial growth factor inhibitors, but unfortunately, not all patients respond to the current treatments. A clinical hallmark of nAMD is choroidal neovascularization. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Cellular damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to advanced geographic atrophy and/or choroidal neovascularization and fibrosis. Currently, it is not fully known why different AMD phenotypes develop. In this review, we connect angiogenesis and inflammatory regulators in the development of nAMD and discuss therapy challenges and hopes.

Safety and efficacy of anti-VEGF antibodies in the treatment of advanced gastric carcinomas.

e16005 Background: The prognosis of gastric cancer remains poor despite advances in diagnostic techniques, neoadjuvant chemo radiotherapy and surgery. This led to the development of Anti-Vascular Endothelial Growth Factor inhibitors (Anti-VEGF), which inhibit angiogenesis, inducing a state of dormancy in the tumors. In this review, we studied the safety and efficacy of Ramucirumab (RAM) and Bevacizumab (BVZ). Methods: Following the PRISMA guidelines, we searched the literature on PubMed, Cochrane, Embase &amp; clinicaltrials.gov. A total of 311 articles were screened, and 4 studies were included. Results: When compared to placebo, in the two Phase III trials enrolling 1020 participants,RAM enhanced overall survival (OS) and progression-free survival (PFS). RAM treatment was associated with fewer hematological adverse effects, such as anemia. In addition, when administered in conjunction with CTx, bevacizumab (BVZ) improved OS (12.1m Vs 10.1m in one trial), but more clinical studies are needed to consolidate these findings. In both phase III studies with BVZ, anemia and neutropenia were shown to be less common, as shown in the table. Conclusions: Anti-VEGF inhibitors have shown to be effective in treating advanced or relapsed GC or GE CAs with minimal adverse effects. However, high-quality large prospective randomized clinical studies are still needed.[Table: see text]

Decision making for anti-VEGF inhibitor continuation: dip stick? or urine protein/creatinine ratio? (VERSiON UP study)

BackgroundMonitoring proteinuria is important for the management of patients with cancer treated with anti-vascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR) inhibitors (VEGF/Ri). Here we investigated the difference between the urine protein/creatinine ratio (UPCR) and a qualitative value test (QV) on the decision making of treatment continuation and the usefulness of UPCR testing in patients with gastrointestinal cancer treated with anti-VEGF/Ri.MethodsFrom January 2017 to December 2018, a survey was conducted based on the medical records of patients with gastrointestinal cancer with a QV of ≥2+ during the use of anti-VEGF/Ri at seven Japanese institutions participating in the Onco-nephrology Consortium. The primary endpoint was the ratio of the worst UPCR < 2.0 (low UPCR) in cases with a QV2+ at the point of the first proteinuria onset. The secondary endpoints were a comparison of low UPCR and worst UPCR ≥2.0 (high UPCR), the concordance rate between UPCR and QV in the Common Terminology Criteria for Adverse Events (CTCAE) grading, and the differences in the decision making for anti-VEGF/Ri continuation.ResultsAmong the 71 patients enrolled, the proportion of low UPCR in onset QV2+ (n = 53) was 66% (n = 35). In a comparison between low (n = 36) and high UPCR cases (n = 24), body weight (P = 0.036), onset QV status (P = 0.0134), and worst QV status (P < 0.0001) were significantly associated with UPCR levels. The concordance rate for CTCAE Grade 2 of both the QV and UPCR was 83%. Regarding the judgment of anti-VEGF/Ri continuation, treatment was continued in 42.4% of cases when the QV became 3+, whereas only 25% continued treatment when the UPCR value became high.ConclusionUrine dipstick test results may overestimate proteinuria, and the UPCR result tended to be more critical than the QV when deciding the treatment policy.Trial registrationThis study is a multiple institutional retrospectively registered observational trial. Clinical Trial number: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (protocol ID UMIN000042545).

Optical Coherence Tomography Angiography (OCTA) Analysis of Perifoveal Capillary Arcade in Patients with Retinal Vein Occlusion Treated with Anti-VEGF

Objective: To evaluate the changes in perifoveal capillary arcade in patients with retinal vein occlusion treated with intravitreal injections of anti-vascular endothelial growth factor for macular edema resulting from retinal vein occlusion with OCTA.&#x0D; Study Design: Quasi-experimental study.Place and Duration of Study: Armed Forces Institute of Ophthalmology, Rawalpindi Pakistan, from Jul 2018 to Jul 2019.&#x0D; Methodology: Patients diagnosed as case of retinal vein occlusion underwent complete eye examination. Optical coherence tomography angiography (OCTA) was done in all the patients. Patients having macular edema were prescribed intravitreal anti-vascular endothelial growth factor inhibitors on monthly basis. OCTA was repeated at the third month.&#x0D; Results: In this study, 50 eyes were evaluated. After treatment patients having perifoveal capillary arcade of less than two quadrants increased from 47.7-68.8% (p&lt;0.002) in the superficial capillary plexus and in deep capillary plexus this number increased from 50% to 88.6% (p&lt;0.05). There was also a significant decrease in the number of macular cysts in the superficial and deep capillary plexus post treatment (p&lt;0.05). Mean En face vascular density in superficial capillary plexus decreased in all the quadrants specially the foveal zone.&#x0D; Conclusion: Optical coherence tomography angiography (OCTA) showed a qualitative improvement in perifoveal arcade disruption and decrease in the number of cystic spaces. Quantitative analysis revealed a significant reduction in vessel density in all quadrants. It enables us to follow up patients with retinal vein occlusion and study the vascular arcade changes with time and treatment.

Efficacy and Safety of Antivascular Endothelial Growth Factor (Anti-VEGF) in Treating Neovascular Age-Related Macular Degeneration (AMD): A Systematic Review and Meta-analysis.

This study is aimed at assessing the efficacy and safety of antivascular endothelial growth factor (anti-VEGF) inhibitors in treating age-related macular degeneration (AMD). PubMed, Embase, and Cochrane library were searched. Weighted mean difference (WMD) and relative risk (RR) with 95% confidence interval (CI) were applied to assess outcomes. Eighteen randomized controlled trials involved 8,847 neovascular AMD patients were selected for the meta-analysis. Pegaptanib (WMD: 6.70; P < 0.001) and ranibizumab (WMD: 17.80; P < 0.001) were associated with greater BCVA changes than control after 1 year. Bevacizumab was linked with less changes in central macular thickness after 1 year compared to control (WMD: -38.50; P < 0.001), but more changes compared to ranibizumab (WMD: 10.69; P = 0.024). The incidence of gain of 15 or more letter visual acuity after 1 year was increased when compared with bevacizumab versus control (RR: 7.80; P = 0.001), pegaptanib versus control (RR: 2.83; P = 0.015), and ranibizumab versus control (RR: 3.92; P = 0.003). Moreover, ranibizumab was associated with more BCVA changes and an increased incidence of gain of 15 or more letter visual acuity after 2 years compared with control (RR: 5.77; P < 0.001). This study found that most anti-VEGF inhibitors provided better efficacy than non-anti-VEGF intervention, and the treatment effectiveness among various anti-VEGF agents was equally effective.

Combination intravitreal anti-vascular endothelial growth factor inhibitors and macular laser photocoagulation relative to intravitreal injection monotherapy in macular oedema secondary to retinal vein occlusion: a meta-analysis of randomized controlled trials.

This meta-analysis investigates the efficacy and safety of intravitreal anti-VEGF injections (IVI) compared to combination laser photocoagulation and IVI (LPC-IVI) in treating macular oedema secondary to retinal vein occlusion (RVO). A literature search of MEDLINE, EMBASE and Cochrane CENTRAL was conducted from inception until March 2021. Randomized controlled trials that reported relevant efficacy and/or safety parameters following LPC-IVI relative to IVI were included. Meta-analysis was conducted with a random effects model. The primary outcome was best-corrected visual acuity (BCVA), while secondary outcomes were central macular thickness (CMT), central retinal thickness (CRT), central subfield thickness (CST), number of IVIs received, and incidence of adverse events. A total of 10 studies were included, for which 362 eyes were randomized to LPC-IVI and 365 to IVI. In comparing macular laser photocoagulation with IVI (MLP-IVI) in BRVO patients, no significant differences were seen in final BCVA (p = 0.78) or change in BCVA (p = 0.09) after treatment. Similarly, no significant differences were seen in final CMT (p = 0.54), change in CMT (p = 0.33), final CRT (p = 0.90), change in CRT (p = 0.97), or number of injections required (p = 0.78). The same results were seen in subgroup analyses for macular laser without peripheral laser in BRVO and CRVO patients. Consistent results were observed when considering peripheral LPC-IVI to IVI in BRVO and CRVO. No significant differences were seen between combination MLP-IVI or peripheral LPC-IVI relative to IVI monotherapy for final BCVA or OCT parameters in macular oedema secondary to RVO.

Trends in Endophthalmitis Associated With Intravitreal Injection of Anti-VEGF Agentsat a Tertiary Referral Center.

To report the incidence and clinical features of infectious endophthalmitis after intravitreal (IV) injection of anti-vascular endothelial growth factor inhibitors (VEGF) between 2018 and 2020 and to compare to prior rates. Retrospective analysis of patients with endophthalmitis after anti-VEGF IV injections treated at Bascom Palmer Eye Institute between January 1, 2018, and December 31, 2020. Between 2018 and 2020, the rate of clinically diagnosed endophthalmitis was 0.014% (10/71,858) and of culture-positive was 0.008% (6/71,858). Clinically diagnosed endophthalmitis rates per injection were: aflibercept (0.022%); ranibizumab (0.019%); bevacizumab (0%); and brolucizumab (0%). Clinically diagnosed endophthalmitis rates were similar in the present study compared to those from 2005 to 2017 (P = .84). Fifteen eyes were diagnosed with endophthalmitis (10 in-house, five external referrals). Of culture-positive eyes, the organisms were coagulase-negative Staphylococcus (8/11), Streptococcus species (2/11), and Abiotrophia defectiva (1/11). A universal face-masking policy in 2020 did not lower infection rates (P = .73). Endophthalmitis rates after IV anti-VEGF remain low and are similar to prior reports. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:319-326.].

89-OR: Cardiovascular and Mortality Risk with Intravitreal Anti-Vascular Endothelial Growth Factor (VEGF) Inhibitors in Patients with Diabetic Retinopathy (DR)

While intravenous anti-VEGF agents are known to contribute to arterial thromboembolic events, the cardiovascular (CV) safety of intravitreal anti-VEGF inhibitors remain unclear. Using Medicare and 2 U.S. commercial claims datasets (1/2009-12/2017), we identified 1:1 propensity score matched patients aged ≥18 years with DR initiating treatment with (1) intravitreal anti-VEGF injections or (2) laser procedure or intravitreal steroid injections (30,681 matched pairs). We assessed a composite CV outcome [myocardial infarction (MI) or stroke], its individual components, and mortality, using an intention-to-treat (ITT) scheme censoring at 180 days and 365 days of follow-up. We estimated pooled HRs and 95% CIs adjusting for 85 baseline covariates. Compared to laser or steroid treatment, intravitreal anti-VEGF injections were associated with a similar risk of the composite CV outcome [HR:0.91 (95% CI:078, 1.06)], MI [0.91 (0.74, 1.11)], stroke [0.92 (0.74, 1.15)], or risk of mortality [1.14 (0.87, 1.51)] at 6 months of follow up. Results were consistent in an ITT analysis censoring at 365 days (Table). Intravitreal anti-VEGF injections, compared to laser or steroid treatment, had similar risk of CV events and mortality in patients with DR. Disclosure M. Roh: None. H. Tesfaye: None. L. P. Aiello: Consultant; Self; KalVista Pharmaceuticals, Novo Nordisk, Regeneron Pharmaceuticals Inc., Stock/Shareholder; Self; KalVista Pharmaceuticals. S. C. Kim: Research Support; Self; AbbVie Inc., Bristol-Myers Squibb Company, Pfizer Inc., Roche Pharma. E. Patorno: Research Support; Self; Boehringer Ingelheim International GmbH, National Institutes of Health.

Outcomes with novel combinations in non-clear cell renal cell carcinoma(nccRCC): ORACLE study.

4580 Background: Despite advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of new combination therapies (including immunotherapy (IO), anti-vascular endothelial growth factor inhibitors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors) in metastatic nccRCC is not known. Methods: In this multicenter retrospective analysis, we explored the efficacy of combination systemic therapies in patients with nccRCC. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints include progression- free survival (PFS), disease control rate (DCR), median duration of response (DOR), overall survival (OS), and biomarker correlates. Results: Among 66 included patients, median age was 59 yr; 60% were male and 62% white. Histologies included papillary (38%), chromophobe (17%), unclassified (24%), translocation (12%), and other (9 %). Sarcomatoid and/or rhabdoid differentiation was present in 18%, 70% had prior nephrectomy, 86% were IMDC intermediate/poor risk, 29% and 32% had liver and bone metastasis respectively. 67% received combination treatment in the first line. Comparison of outcomes based on treatment regimen is shown in the table. Conclusions: Antitumor activity was observed with novel combinations in nccRCC which warrants further prospective studies. Response rates and survival with combination therapy in this dataset remain inferior to rates seen in clear cell RCC.[Table: see text]

Current Status of Biologics in Perioperative Treatment for Resectable or Borderline Resectable Liver Metastases

This review provides an overview of the current role of biologics, anti-vascular endothelial growth factor (VEGF) inhibitors and anti-epidermal growth factor receptor (EGFR) inhibitors, in the perioperative treatment of colorectal liver metastases as well as a discussion of their future trends. Over the past decade, a number of clinical trials have suggested that the use of biologics with cytotoxic agents may increase median overall survival in certain subsets of patients with colorectal liver metastases. The benefit of these agents is limited to borderline resectable and unresectable hepatic metastases and is not seen in upfront resectable disease. In the RAS wild-type population, the difference in efficacy of VEGF and EGFR inhibitors in combination with chemotherapy is minimal. These agents perform differently depending on primary tumor location; bevacizumab has greater efficacy in right-sided tumors, whereas cetuximab has greater efficacy in left-sided tumors. While biologics benefit patients in the neoadjuvant setting, studies have not shown similar results in the adjuvant setting. Given the variability of patient presentations as well as the risk of treatment-related toxicity, the addition of biologics requires careful consideration of patient’s medical fitness, surgical risk, and tumor profile.

A History of Anti-VEGF Inhibitors in the Ophthalmic Literature: A Bibliographic Review.

This work aimed to analyze the 100 most-cited articles on antivascular endothelial growth factor (anti-VEGF) inhibitors. A literature search for anti-VEGF inhibitors using the Web of Science was completed using the bibliographic databases for peer-reviewed literature published in Ophthalmology, the New England Journal of Medicine, Journal of the American Medical Association, and Lancet. Primary outcomes were the most frequently cited articles and journals with the most citations as well as the specific drug and disease process studied. There were 42 696 cumulative citations among the top 100 articles. The articles were published between 2004 to 2016, with most articles published in 2006. Ophthalmology published the greatest number of articles among the top 100 at 48, whereas the New England Journal of Medicine has the most citations per publication at 1714. Ranibizumab was the medication researched in most articles at 56, followed by bevacizumab at 48, aflibercept at 10, and pegaptanib at 9. Forty-two articles investigated treatment of age-related macular degeneration, followed by 24 investigating diabetic macular edema, 10 for retinal vein occlusion, 8 for proliferative diabetic retinopathy, 2 for retinopathy of prematurity and polypoidal choroidal vasculopathy, and 1 for corneal neovascularization. As evidenced by the considerable number of citations accumulated over the past 20 years, anti-VEGF inhibitors have led to significant research in ophthalmology.

CONSEQUENCES OF LAPSES IN TREATMENT WITH VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN ROUTINE CLINICAL PRACTICE.

Evaluating outcomes in patients receiving intravitreal antivascular endothelial growth factor (VEGF) inhibitors for neovascular age-related macular degeneration whom experience a lapse in treatment. A retrospective chart review evaluating 3,304 patients ≥18 years who experienced treatment lapses ≥3 months compared with control counterparts. Demographic information, macular thickness as measured by central subfield thickness, and visual acuity were collected at baseline, the first postlapse appointment, and at 3, 6, and 12 months after the lapse for the study group. Lapse (n = 241) and control patients (n = 241) had similar baseline visual acuity and central subfield thickness (Early Treatment Diabetic Retinopathy Study: 58.9 ± 20.2 [20/63] vs. 59.2 ± 20.1 [20/63]; central subfield thickness: 252.4 ± 63.2 µm vs. 259.8 ± 66.2 µm, P = 0.21). Analysis revealed that lapse patients experienced a significant increase in central subfield thickness after lapse when compared with controls (279.4 ± 86.9 µm vs. 253.7 ± 65.9 µm, P < 0.01), which normalized on resumption of treatment (259.1 ± 79 µm vs. 246.8 ± 57.6 µm, P = 0.06). Study patients also experienced loss in the visual acuity after lapse when compared with controls (52.9 ± 23.6 Early Treatment Diabetic Retinopathy Study [20/100] vs. 59.9 ± 20.8 [20/63] Early Treatment Diabetic Retinopathy Study, P < 0.01) that did not recover through 12 months of follow-up. Patients with neovascular age-related macular degeneration who have lapses in care are at risk for poorer outcomes. Although macular thickness normalizes on resumption of treatment, their decline in the visual acuity does not recover.

Imaging of Therapeutic Effects of Anti-Vascular Endothelial Growth Factor Inhibitors by Optical Coherence Tomography Angiography in a Rat Model.

PurposeThe aim of the study was to investigate optical coherence tomography angiography (OCTA) as a high-resolution in vivo imaging modality for monitoring therapeutic response to different vascular endothelial growth factor inhibitors in the rat model of laser-induced choroidal neovascularization (CNV). Further, OCTA findings were compared with fluorescein angiography (FA) and fluorescence microscopy.MethodsLaser treatment at day (D)0 was followed by intravitreal injection of aflibercept, AF564, and NaCl in dark agouti rats. Imaging with OCTA and FA was performed at D2, D7, D14, and D21. OCTA was compared to FA as well as confocal imaged flat mounts and analysis included quantification of CNV area, pixel intensity, vessel density, and number of vessel junctions.ResultsWithin laser lesions, neovascularization were visible especially in deeper retinal layers on OCTA, but not on FA images. Using OCTA, mean CNV area (D21) at the level of the outer nuclear layer (ONL) was 0.017 mm² following aflibercept administration, 0.016 mm² following AF564 and 0.026 mm² following NaCl injection (P = 0.04 and P = 0.03). Similar differences between treatment groups were determined by FA and histology, although the overall CNV area was always larger on FA due to dye leakage (P ≤ 0.0001, all layers).ConclusionsCompared to FA, OCTA imaging allows for a more precise and quantitative analysis of new blood vessel formation and therapeutic response to vascular endothelial growth factor (VEGF)-inhibitors, whereas it does not permit assessment of leakage.Translational RelevanceThese findings suggest that OCTA may be particularly useful for the investigation of new treatment targets in the animal model.

Results of dexamethasone intravitreal implant (Ozurdex) in diabetic macular edema patients: Early versus late switch.

To assess the functional and anatomical outcomes of intravitreal dexamethasone implant Ozurdex® in eyes with diabetic macular edema that did not adequately respond to vascular endothelial growth factor inhibitors. Multicenter, retrospective, and real-life case series study conducted on consecutive diabetic macular edema patients who underwent treatment with one or more dexamethasone implant injections and were followed up for a minimum of 12months. Subjects were divided into three groups: I-naïve patients, II-previously treated eyes that received three intravitreal antivascular endothelial growth factor inhibitors injections before the study (early switch), and III-previously treated eyes that received >3 intravitreal antivascular endothelial growth factor inhibitors injections before the study (late switch). Primary endpoints were best-corrected visual acuity and central retinal thickness at month12. A total of 129 eyes (21 naïve and 108 previously treated, Group II: 32 and Group III: 76) were included. At month12, best-corrected visual acuity significantly improved from 0.27 ± 0.23 and 0.31 ± 0.22 at baseline to 0.36 ± 0.25 and 0.37 ± 0.23 at month12 in naïve and previously treated eyes, respectively, and p = 0.0063 and 0.0060, respectively. Central retinal thickness, in naïve and previously treated eyes, was significantly reduced from 483.0 ± 143.4 and 431.3 ± 115.5 µm, at baseline, to 278.8 ± 72.1 and 269.3 ± 66.2 µm, at month12, respectively, and p < 0.0001 each, respectively. Best-corrected visual acuity improvement was significantly greater in both absolute and percentage values, p = 0.0393 and 0.0118, respectively, in Group II than in Group III. In eyes with insufficient response to antivascular endothelial growth factor inhibitors, switching to dexamethasone at the time to 3-monthly antivascular endothelial growth factor inhibitors injections provided better functional outcomes than those that received >3 antivascular endothelial growth factor inhibitors injections.