SEARCHNARRATIVE_REVIEWophthalmology, oncology

narrative_review·ophthalmology, oncology, cardiology, endocrinology, clinical trial·PMC10813960

Exploring the Spectrum of VEGF Inhibitors’ Toxicities from Systemic to Intra-Vitreal Usage in Medical Practice

Cancers · 13 authors, 7 centres

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FIDELITY 76%

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TL;DR

This review comprehensively examines the toxicities of VEGF inhibitors (VEGFi), including both systemic (e.g., hypertension, proteinuria, thromboembolism) and intra-vitreal (e.g., ocular hypertension, intraocular inflammation) adverse effects. The main finding is that toxicity profiles differ between antibody/chimeric protein and small-molecule RTKi classes, with management strategies tailored to severity and route of administration. Clinically, early recognition and multidisciplinary management are essential to optimize patient outcomes in oncology and ophthalmology.

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**Background:** Vascular Endothelial Growth Factor inhibitors (VEGFi) are widely used for advanced neoplasms (e.g., colorectal, lung, renal, ovarian cancers) and ocular diseases (e.g., diabetic macular edema, age-related macular degeneration). However, their use is associated with a spectrum of toxicities due to disruption of the VEGF/VEGFR pathway. This review aims to delineate the causes, recognition, management, and prevention of VEGFi toxicities to assist clinicians.

**Methods:** This is a narrative review summarizing the pharmacokinetics, pharmacodynamics, etiology, pathophysiology, clinical identification, assessment, management, and preventive strategies for VEGFi toxicities. The authors categorize VEGFi into two groups: antibodies/chimeric proteins (bevacizumab, ramucirumab, aflibercept, ranibizumab, brolucizumab) and small-molecule receptor tyrosine kinase inhibitors (RTKi; e.g., sunitinib, sorafenib, cabozantinib, lenvatinib, regorafenib). Toxicity assessment is based on the Common Terminology Criteria for Adverse Events (CTCAE).

**Key Results:** The primary toxicity is vascular, including hypertension (most prevalent), proteinuria, thromboembolic events, cardiac toxicity (including QT prolongation with RTKi), hemorrhage, bowel and nasal septum perforation, skin toxicity (e.g., hand-foot syndrome), reversible posterior leukoencephalopathy syndrome (RPLS), infusion-related hypersensitivity, hypothyroidism, asthenia/fatigue, gastrointestinal toxicity, anorexia, and myelotoxicity. For intra-vitreal administration, ocular toxicities include conjunctival hemorrhage (20–40%), vitreous floaters (5–15%), rhegmatogenous retinal detachments (0.013%), retinal hemorrhage (1–10%), ocular hypertension (IOP >25 mm Hg), intraocular inflammation, brolucizumab-associated retinal vasculitis (BARV), and infectious endophthalmitis. The incidence of grade >2 myelotoxicity with RTKi includes anemia (8%), neutropenia (18%), thrombocytopenia (9%), and lymphopenia (18%). Management strategies include antihypertensives (ACE inhibitors/ARBs) for hypertension, temporary suspension for proteinuria >2 g/24h, anticoagulation for thromboembolism, and topical corticosteroids for intraocular inflammation. For severe toxicities (e.g., hypertensive emergency, life-threatening thromboembolism, RPLS), permanent discontinuation is recommended.

**Clinical Implications:** Close monitoring and proactive management of VEGFi toxicities are crucial to optimize the risk-benefit profile. Multidisciplinary collaboration (oncologists, cardiologists, ophthalmologists, endocrinologists, neurologists) is essential. Patient education on lifestyle modifications (e.g., smoking cessation, weight management) and early symptom reporting can mitigate adverse events. For intra-vitreal injections, meticulous technique and monitoring for ocular complications are vital. The review provides pragmatic intervention thresholds (e.g., blood pressure >140/90 mm Hg, 24h urine protein >2 g, left ventricular ejection fraction <50%) to guide clinical decision-making.

STUDY TYPE

narrative_review

SPECIALTY

ophthalmology

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AI pipeline

FIDELITY CHECK

76% · B

ORIGINAL PAPER

PMC10813960

Exploring the Spectrum of VEGF Inhibitors’ Toxicities from Systemic to Intra-Vitreal Usage in Medical Practice

Cancers

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ABSTRACT

Simple Summary Vascular Endothelial Growth Factor inhibitors (VEGFi), commonly employed for diverse medical conditions such as advanced neoplasms and ocular diseases, pose potential adverse effects. This review delineates the principal VEGFi utilized in clinical practice and investigates the causes, recognition, management, and prevention of VEGFi toxicities. Its aim is to assist oncologists in both clinical practice and the design of clinical trials. Abstract The use of Vascular Endothelial Growth Factor inhibitors (VEGFi) has become prevalent in the field of medicine, given the high incidence of various pathological conditions necessitating VEGF inhibition within the general population. These conditions encompass a range of advanced neoplasms, such as colorectal cancer, non-small cell lung cancer, renal cancer, ovarian cancer, and others, along with ocular diseases. The utilization of VEGFi is not without potential risks and adverse effects, requiring healthcare providers to be well-prepared for identification and management. VEGFi can be broadly categorized into two groups: antibodies or chimeric proteins that specifically target VEGF (bevacizumab, ramucirumab, aflibercept, ranibizumab, and brolucizumab) and non-selective and selective small molecules (sunitinib, sorafenib, cabozantinib, lenvatinib, regorafenib, etc.) designed to impede intracellular signaling of the VEGF receptor (RTKi, receptor tyrosine kinase inhibitors). The presentation and mechanisms of adverse effects resulting from VEGFi depend primarily on this distinction and the route of drug administration (systemic or intra-vitreal). This review provides a thorough examination of the causes, recognition, management, and preventive strategies for VEGFi toxicities with the goal of offering support to oncologists in both clinical practice and the design of clinical trials.

CITATION EXPORT

Mariachiara Santorsola, Maurizio Capuozzo, Guglielmo Nasti et al.. Exploring the Spectrum of VEGF Inhibitors’ Toxicities from Systemic to Intra-Vitreal Usage in Medical Practice. Cancers. (2024). https://doi.org/10.3390/cancers16020350

AUTHORS

13 · 7 CENTRES

Mariachiara Santorsola, Maurizio Capuozzo, Guglielmo Nasti, Francesco Sabbatino, Annabella Di Mauro, Giordana Di Mauro, Gianluca Vanni, Piera Maiolino, Marco Correra, Vincenza Granata, Oreste Gualillo, Massimiliano Berretta, Alessandro Ottaiano

1Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; [email protected] (M.S.); [email protected] (G.N.); [email protected] (A.D.M.); [email protected] (P.M.); [email protected] (M.C.); [email protected] (V.G.)
2Coordinamento Farmaceutico, ASL-Naples-3, 80056 Ercolano, Italy; [email protected]
3Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Salerno, Italy; [email protected]
4Department of Human Pathology “G. Barresi”, University of Messina, 98125 Messina, Italy; [email protected]
5Breast Unit, Department of Surgical Science, PTV Policlinico Tor Vergata University, 00133 Rome, Italy; [email protected]
6SERGAS (Servizo Galego de Saude), NEIRID Laboratory (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), IDIS (Instituto de Investigación Sanitaria de Santiago), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; [email protected]
7Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy

EDITOR / REVIEWER

David Wong