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`OF OPHTHALMOLOGY®
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`Bevacizumab
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`Originalarticle
`contributed by:
`
`All contributors:
`
`Peter A.Karth,MD
`
`Brad H. Feldman, M.D., Vinay A. Shah M.D., Vinay A. Shah M.D., Leo A. Kim, MD, PhD, Koushik Tripathy, MD (AIIMS), FRCS
`(Glasgow),Jennifer | Lim MD, Peter A.Karth, MD
`
`Assigned editor:
`
`LeoA.Kim,MD, PhD
`
`Review:
`
`Assigned status Up to Date
`
`by Leo A. Kim, MD, PhD on November2, 2021.
`
`|
`
`Bevacizumab(Avastin; manufactured in the United States by Genentech/Roche)is arecombinant
`humanized monoclonal IgG11 antibodythat binds to and inhibits vascular endothelial growth factor
`(VEGF), reducing the growth of new blood vessels. VEGF is a biochemicalsignal protein that promotes
`angiogenesis throughoutthe bodyandin the eye.
`Contents
`1 Background
`D000068258(https://me
`MeSH (http://enwiki
`1.1. Mechanism of Action (proposed)
`
`4.2 Indicationsand Uses pedia.org/wiki/Medi=shb.nlm.nih.gov/record/u
`cal_Subject_Heading
`i?ui=D000068258)
`1.2.1 OffLabel Use in Ophthalmology
`s)
`1.2.2 Colorectal Cancer
`1.2.3 Lung Cancer
`1.2.4 Brain Cancer
`
`DiseasesDB (http//e
`nwikipedia.org/wiki/
`Diseases_Database)
`
`32964 (http://wwwdisea
`sesdatabase.com/ddb32
` 964.htm)
`
`1.3 Administration and Dosing
`1.4 Preparation
`1.5 Efficacy in Ophthalmic Pathology
`1.6 Adverse Affects and Safety
`1.6.1 General
`1.6.2 Ophthalmic
`1.6.3 Systemic
`1.7. Considerations and Comparison
`2 Additional Resources
`3 References
`
`Background
`VEGFisa memberoftheplatelet-derived growth factor (PDGF) family. The VEGF genefamilyis constituted of VEGF-A, VEGF-B, VEGF-C, VEGF-D and
`placenta growthfactor (PIGF), located on chromosome 6p12.'") The binding of VEGF withits receptors leads to endothelialcell proliferation and new blood
`vessel growth and thusplays a key role in angiogenesis. Physiology of newvessel growth and developmentare an extremely complex and coordinated process
`that requiresa cascade of receptoractivation. In this process, VEGF represents aninitial and critical rate-limiting step in physiological angiogenesis.!2! [3] 4] The
`critical role of VEGF in angiogenesis has been highlightedbythelossof a single VEGF allele resulting in defective vascularization.)
`
`There are nine VEGF-Aisoforms: VEGF491, VEGF145, VEGF14g, VEGF42, VEGF465, VEGF165», VEGF4g3, VEGFigo and VEGF29¢,!4] The most abundantisoform
`found in the eye is VEGF}¢5.!7! 8] VEGF445 is a secreted heparin-binding homodimeric 45-kDaglycoprotein witha significantfraction bound to the cell
`surface.9] VEGF activates endothelial cells by binding VEGFR-1 (Fit-1) and VEGFR-2 (KDR)endothelial cell receptors, whichin turn activatesintracellular
`signal transduction cascades.!*] VEGFR-2 is thoughtto be principally responsible for VEGFsignaling in angiogenesis.!7)
`
`VEGF-Alevels have been found greatly elevated in the vitreous of patients with choroidal neovascularization (CNV) in age-related macular degeneration
`(AMD), 10 among othereye diseases. Choroidal neovascularization may be instigated by several events, such as accumulation of lipid metabolic byproducts,
`oxidative stress, reductionin choriocapillaris blood flow, andalterations in Bruch’s membrane.!19 [11] [12] Hypoxia has been shown to be a majorinducer of
`VEGFgene transcription. As aresponse to metabolic distress, the retinal pigment epithelium (RPE) and the retina produce various factors, particularly VEGF,
`which induce CNV proliferation. VEGF has been shownto be achemo-attractantfor endothelialcell precursors, causing CNV in mouse models.'14) VEGF also
`prevents endothelialcell apoptosis.!14) Additionally, VEGF promotes metalloproteinases production by endothelialcells, causing tissue degradation that
`facilitates invasion by new vessels.!15] [16] VEGFis a powerful agonist of vascular permeability, which causes vascular leakage and macular edema.!17] VEGFis
`thoughtto cause increased vascular permeability by formation of fenestrations in microvascular endothelium.!18118119) Furthermore, VEGF was shownto up-
`regulate leukocyte adhesion to |CAM-1 in mice, thereby promoting vascular permeability and capillary non-perfusion.!2° Onthisbasis, inhibition ofVEGF
`activity is key to treatment of macular edema and prevention of progressive capillary non-perfusion,especially in diabetic retinopathy and retinal vein
`occlusions.
`
`Mechanism of Action (proposed)
`Bevacizumabbinds to soluble VEGFandinhibits the binding of VEGF molecules to its receptors on the surface of endothelial cells. Bevacizumabis a
`nonspecific VEGFinhibitor with two bindingsites per molecule.{512121) Bevacizumab prevents all VEGF-A isoforms from binding to endothelialcell
`receptors.!5121[22] [23] Reduction in activity of VEGF inhibits angiogenesis and vascular permeability.
`
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`Bevacizumabuse in ophthalmology is off-label, meaning it is not FDA approved forocular use. In USA more than 20% of the used drugs are off-label. It is most
`commonly used to treat CNV (in AMDand otherdiseases), diabetic macular edema (DME), and macular edema duetoretinalvein occlusions.Interest in
`bevacizumabforocular use began due to the molecularsimilarity it shares with ranibizumab (Lucentis; Genentech), which is FDA approved for AMD, DME, and
`macular edema dueto retinal vein occlusions. The debate overthe use of bevacizumab versusranibizumab will be discussed in the Considerations section.
`
`Off-label use does carry risk for both the practitioner and the patient. Off-label use mayraise the risk of lawsuit should a patient have a negative outcome from
`its use. From the patient's perspective, there may be a theoreticallack of safety data for off-label use as compared to FDA approved drugs. As part of the FDA
`approval process, sponsors submit detailed information about safety and efficacy as shown in large randomized multi-centerclinical trials done for specific
`indications. The approvalprocess involves the FDA carefully examining extensive databasesofstudies in toxicologic evaluations, animal studiesand clinical
`trials!24 Off-label drugs do not receive this structured rigorousevaluation processonanofficial basis by the FDAin particular disease states.!25)
`
`However,the off-label use of medication is extremely prevalentand is a vital part of prescribing practices across medicine. Many patients benefit when they
`receive medications under circumstances not approved by the FDA. Typically, the makers of generic drugs have little financial incentive to attemptthe costly
`process of FDA approvalfor a new indication, despite wide off-label use. In fact, off-label uses are often the standard of care for some health conditions. In
`manyareas of oncology,pediatrics, geriatrics, and obstetrics, patients could not obtain treatment withoutoff-label prescribing. When medicalandscientific
`evidencevalidate off-label uses (both safety andefficacy) and use is accepted by the medical community, physicians may consideruse of these medications in
`the bestinterest of their patients.'25) Both practitioners and patients should weigh the risks and benefits of using medication in an off-label manner and
`patients should always be informed of their treatment options.!2527] Bevacizumabis one of many such drugs witha longhistory ofsafety and efficacy, albeit
`without FDA approvalfor ocular use. Based on its affordability, the world health organization has put bevacizumab and not ranibizumabin WHO modellist of
`essential drugs. http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf
`
`Colorectal Cancer
`Bevacizumabis FDA approved in metastatic colorectal cancer, with intravenous 5-fluorouracil-based chemotherapyas first- or second-line treatment. It also is
`used with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatmentin patients who have progressed on a
`first-line bevacizumab-containing regimen.
`
`Lung Cancer
`Bevacizumabis FDA approved for use in non-squamous non-smallcell lung cancer, in conjunction with carboplatin and paclitaxelforfirst line treatment of
`unresectable, locally advanced, recurrent or metastatic disease.
`
`Brain Cancer
`Bevacizumabhas a FDAindicationforglioblastoma, as a single agent for adult patients with progressive disease following prior therapy.
`
`However, the indication of metastatic breast carcinomafor intravenous bevacizumab was removed by the FDA asit did not improvethe survival or the quality
`of life when compared to thepossible life-threatening complications if the intravenous drug.
`
`Administration and Dosing
`In ophthalmology, bevacizumabis typically given by transconjunctival intravitreal injections into the posterior segment, althoughit has been used in the form
`of topical drops or sub-conjunctivalinjection. Intravitreal injections for retinal pathologies are typically administered at4-6 week intervals, althoughthis varies
`widely based ondisease and response. The typical dose is 1.25mgin0.05mlin adults,and halfthat dose in babies. While other doses (2.5mg) have been
`evaluated inlargetrials, nosignificantbenefit has been shown overthe 1.25mg standard dose,!28) although some advocate“super-doses” in certain
`situations:
`
`Preparation
`Bevacizumabisa clear to slightly opalescent, colorless to pale brown,sterile solution for intravenous infusion.Its pH is 6.2. It is supplied in 100 mg and 400 mg
`preservative-free, single-use vials with a volumeof 4 mL or 16 mLof bevacizumab (25 mg/mL) !22)
`
`Bevacizumabis only commercially available inthe 4ml and 16mlintravenousformulation.Intravitreal aliquots are typically compounded from these largevials.
`The American Academy of Ophthalmology risk management guidelines recommend preparing individual syringes. Typically compounding pharmacies provide
`this service.
`
`Several studies have shownnobacterial growth and minimal degradation at three monthsof refrigerated bevazicumab compounded into syringes.{0191132)
`Althoughrare, there have been reported casesof bacterial endophthalmitis associated with contaminated batches of compounded bevacizumabandthis
`continues to be an issue of concern.!341 [34][35]
`
`Anotherissueis counterfeit or spurious batches of Avastin which have been notedto cause cluster endopthImitis.
`
`Efficacy in Ophthalmic Pathology
`Bevacizumabis considered efficacious for treatment of CNV and macular edemaby the ophthalmologic community.As this drug has not been FDA approved
`for ophthalmic indications,classic clinical trials do not uniformly exist, however convincing data has been published for the most commonly treated
`pathologies.
`
`Age-related Macular Degeneration (neovascular with CNV) - The shaminjection/untreated arm of the Minimally Classic/Occult Trial of the Anti-VEGF
`Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA)!*4trial showed vision loss of 14.9 letters from baseline
`over 24 months, whichis often quoted as the natural history of neovascular AMD. While the Comparison of Age-related Macular Degeneration Treatments
`Trials (CATT)!97] did not have an untreated arm,it was perhaps the most well-structured clinicaltrial involving bevacizumab and showeda7.8 letter gain from
`baseline with monthly adminisration. The Inhibit VEGF in the Age-Related Choroidal Neovascularizationtrial (IVAN)!°8) echoed this positive result.
`
`Diabetic Macular Edema (DME) - The Pan-AmericanCollaborative Retina Study Group (PACORES)!99)trial compared monthly intravitreal bevacizumab with
`macular focal-grid laser photocoagulation (standard of care at that time) and showed an anverageof 11.86 letters gained with bevacizumaband 3.66letters
`gained with focalgrid laser over 24-months.
`
`Macual Edema due to Retinal Vein Occlusion - The untreated macular edema arm (Group M)of the Central Vein Occlusion Study (CVOS)!“4l trial lost
`approximately 5 letters from baseline. The PACOREStrialfor central vein occlusion,44) which did not have a untreated arm buthadsimilarinclusioncriteria,
`showed 19letters of improvementfrom baseline over 12 months with monntly/as-needed intravitreal bevacizumab.
`
`Various other papers have been published showingtheefficacy of intravitreal bevacizumabin control of myopic CNV, proliferative diseases, and various other
`eye diseases.
`
`Adverse Affects and Safety
`General
`Bevacizumabhas3 black box warnings; gastrointestinal perforation, surgery and wound healing complications, and severe or fatal hemorrhage, hemoptysis,
`gastrointestinal bleeding, CNS hemorrhage, and vaginal bleeding. It is unknown whetherintravitreal bevacizumab is associated with the same black box safety
`issues howeverthese types of complications are not included in the known complicationsfollowing intravitreal used of bevacizumab.The risk of these severe
`adverse effects are thought to be very lowastheintravitreal dose is 300-500 times less than the intravenous dose andis administered less frequently.5121)
`However, we do know that systemic/serum levels ofVEGF are reduced withintravitreal administration (IVAN), but the significance ofthis is not yet clear.
`Furthermore, somestudies suggest a fellow eye effect.42)
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`Bevacizumabhas been used in the eye withoutsignificantintraoculartoxicity.!49) Transient elevationof intraocular pressure (IOP)after intravitrealinjection is
`commonandtypically normalizes rapidly withoutintervention.!“4)
`However, some believe this may cause long term increases in IOP, leading to glaucoma.!45) It
`is generally thought that these potential manageable complications are outweighedbythe benefit ofthese injections.
`
`Acuteintraocular inflammation(or ‘sterile endophthalmitis’) is a more serious ocular adverse event, but rarely occurs. At 24-months, the CATTtrial reported
`only twocases of ‘pseudo-endophthalmitis; one case in the bevacizumab group and onecase inthe ranibizumab group.
`
`Bacterial endophthalmitis is rare but is the most serious and vision threatening complication of intravitreal bevacizumaband is associated with the procedure
`rather than the medication.44] At 24-months,the CATT trial reported 11 total cases of bacterial endophthalmitis, yielding an infection rate of0.9%, with 7
`cases inthe bevacizumab groupsand 4 cases in the ranibizumab groups (nostatistical difference). However muchlarger retrospective reviews show the rate of
`infection to be between 0.022% and 0.16%.!47] One suchlarge review,looked at over 26,000 injections of both bevacizumabandranibizumab and showed an
`over allinfection rate of 0.02%. Interestingly, both the bevacizumaband ranibizumab groups had 2 cases ofendophthalmitisfor a 0.02% infection rate for each
`group.
`
`Meta-analysis of clinical trials show serious ocular adverse effects to be less than 1.2% for bevacizumab.!48)
`
`Systemic
`The occurrence of serious systemic adverse effects are rare with intravitreal bevacizumab. The exact systemicrisk attributable to intravitreal bevacizumabis
`unknown. Firstly, due to the fact that large scale randomized placebo-controlled studies have not been conducted on this drug,it is not possible to obtain pure
`safety data to answerthis question. Secondly, even the best studies that collected safety data on bevacizumab did so in non-uniform ways and published the
`data in non-comparable generalities and vary widely. For instance, the IVAN trial showed serious adverse effects (SAE) to be 12.5% in the bevacizumab group
`while the CATT trial showed SAE rate of 40%. The Bevacizumabor Laser Therapy (BOLT)!4%)trial, which compared bevacizumabversus macularlaser, showed
`approximately 5% SAEin the bevacizumab group and 10% in thelaser group. Furthermore, in the |VAN study, the data trended toward bevacizumabbeing the
`safer therapy, while the CATT trial trended toward the opposite.
`
`Interestingly in the IVAN study, there wasa clear trend toward fewer systemic SAEs with continuous monthly treatmentversus as-needed treatment, although
`the significance of this is unknown.
`
`Considerations and Comparison
`Thereis a large debate over the use of bevacizumabversusranibizumabfor ocular pathology. Somekey areas of comparisonarelisted here.
`
`Ranibizumabis a Fab of an antibody and is about one-third the size of bevacizumab, whichisa full length antibody (48 vs 149 kilodaltons). Theoretically, a
`smaller molecule size mayallow betterretinal penetration after intravitreal injection. Studies in rabbits and monkeys demonstrated that smaller antibody
`moieties such as Fabs have better tissue penetration thanfull-length antibodies.) However,in the CATT andIVANtrials, no difference in treatmenteffect
`was shown betweenthese two drugs in AMD.Recently, the SCORE2 study showed "nodifference" in the meanvisual acuity between bevacizumab and
`aflibercept (non-inferiority trial at 6 months (primary outcomepoint).
`
`per molecule, while ranibizumab only
`Ranibizumabhasa higher affinity to binding VEGF than does bevacizumab, however bevacizumab has twobinding sites
`has one. It has been shownthatatclinical doses, bevacizumaband ranibizumabare equally potentat binding VEGF,211221123151)[52)
`
`Theincidenceof serious systemic adverse effects are rare with bothintravitreal bevacizumaband ranibizumab.!“4) The large head-to-head clinicaltrials show
`no statistical difference in serious artheriorthrombotic eventsorall-cause-death between bevacizumab and ranibizumab!®II53) [n the 24-month CATT and
`IVANreports, there was a trend toward ranibizumabhaving less systemic adverse effects, althoughnotstatistically significant. However, in 24-month CATT
`trial, the category of “One or moreserious adverse events” showed a statistically significant outcome of ranibizumab having less such events (31.7% versus
`39.9%), representing the only statistically significant difference in safety outcome in these trials. A 'serious systemic event' was defined as death from any
`cause, arteriothrombotic event, nonfatal myocardial infarction, nonfatal stroke, death from vascular causes, venous thrombotic event, transient ischemic
`attack and hypertension.[51154] [55]
`
`Bevacizumabhas a longer systemic half-life than ranibizumab (20hvs. 4h). This means that bevacizumab maypersist longer in the eye than ranibizumab.
`However, the CATT and IVANtrials showed nodifference in treatment effect between these two drugs in AMD. However, dueto the longerhalf-life,
`bevacizumabalso persists longer systemically in the serum,4! [57] which may be an explanation for the increased systemic adverse effects seen inthe CATT
`trial inthe bevacizumab groups,if indeed this wasa realeffect.
`
`An other explanationfor possible differences in systemic adverse effects may be rates of systemic absorption. Animal and humanstudies have shown that
`systemic absorption does occur,56158] The IVANtrial, which examined VEGFlevels in serum showed areduction from 173 to 151 pg/ml(15% reduction) inthe
`ranibizumab group and a reduction from 203 to 83 pg/ml (60% reduction) in the bevacizumabgroup. This might be explained by the longer half-life of
`bevacizumab.
`
`Large well-structured clinicaltrials, such as CATT and IVAN, indicate that both medications are equally effective in the treatment of CNV in AMD.
`Furthermore, both drugs are effective in DME and vein occlusions and both are commonlyusedbyclinicians although head to headtrials have not yet been
`published.Thereis little debate that both drugs are effective within the ophthalmic community. The debatestill remains unsettled as to the true difference in
`systemic adverse effects between the two drugs, with the focus being 1) the addedrisk from the necessity to compound bevacizumaband 2)the inherent
`systemic risk of each compound.
`
`Bevacizumabwasavailable and used intravenously for cancer treatment before the approvalof ranibizumab.Off-label use of the intravenous formulation of
`bevacizumab was compoundedfortheintravitreal route in the treatmentof ocular disorders around mid-2005.'59I [6] Ranibizumabwas not approved until
`June 2006.
`
`Complicating matters in this debateis the fact that ranibizumabis more than 50 times more expensive than bevacizumab.The cost for one dose of intravitreal
`bevacizumabas reimbursed by Medicareis $64.62, while one dose of ranibizumabis reimbursed $1,986.29,(61)
`
`Thecost difference is a potential reason why the manufacturerof both the drugs, Roche are against theintraocular use of the cheaper drug Avastin. The
`financial benefit of the company may have prevented the companyto apply for an FDA approvalfor intraocular use ofAvastin which has been shown to be
`equally effective, safe and affordable than the much costlier alternative Lucentis.
`
`Additionally, thereis a significant net revenuedifferential between the two drugs due to the 6% mark-up allowed for in-office medication administration.
`
`Overall, it is still unclear if either ranibizumab or bevacizumab offers a treatmentor safety advantageto the patient.
`
`Additional Resources
`© Turbert D,Janigian RH. Avastin (https://www.aao.org/eye-health/drugs/avastin-list). American Academy of Ophthalmology. EyeSmart® Eye health.
`https://www.aao.org/eye-health/drugs/avastin-list. Accessed March 07, 2019.
`© Turbert D, Vemulakonda GA. Anti-VEGF Treatments (htt ps://www.aao.org/eye-health/drugs/anti-vegf-treatments-list). American Academy of
`Ophthalmology. EyeSmart® Eye health. https://www.aao.org/eye-health/drugs/anti-vegf-treatments-list. Accessed March 07, 2019.
`
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