Bevacizumab Fragments: and Antibodies• 32 chapterMonoclonal Therapeutic

the injection. Occlusion of the central retinal artery has not been reported.58

SYSTEMIC COMPLICATION AND TOXICITY

Most of the systemic adverse events probably relate to the antiangiogenic effect of bevacizumab. Those effects are rare and occur at different rates among different studies (written in brackets). Systemic adverse events that could possibly be related to bevacizumab include facial skin redness (0.1%), itchy diffuse rash (0.1%), mild blood pressure increase (0.2–0.5%), iliac artery aneurysm (0.17%), toe amputation (0.17%), myocardial infarctions (0.4%), transient ischemic attack (0.01%), cerebrovascular accident (0.07–0.5%), deep venous thrombosis (0.01%), and death (0.03%). Notably, the patients who suffered severe adverse affects were at high risk of cardiovascular and cerebrovascular disease prior to the intravitreal administration of bevacizumab. In addition, the incidence of those events was not increased from that of the general population at large.56–58

Systemic administration of bevacizumab is known to have a higher incidence of the above-mentioned side-effects. A rare but severe sideeffect is gastrointestinal perforation complicated by intra-abdominal abscesses or fistula formation. This complication has an increased incidence in patients receiving bevacizumab compared to controls. It also increases the rate of hemorrhages, especially hemoptysis in patients with nonsmall cell lung cancer. It can also worsen proteinuria and increase the rate of heart failure related to treatment with chemotherapy. Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in clinical studies (with an incidence of <0.1%) and in postmarketing experience. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurological disturbances. No carcinogenicity data are available for bevacizumab in animals or humans.14

DRUG INTERACTIONS

A study performed on monkeys indicates that the combination of bevacizumab with the chemotherapeutic agents paclitaxel and cisplatin does not result in a pharmacokinetic interaction.59 Concentrations of SN38, the active metabolite of irinotecan, were on average 33% higher in patients receiving a bolus combination treatment of intravenous irinotecan, 5-fluorouracil, and leucovorin (IFL, a common treatment for colorectal carcinoma) in combination with bevacizumab when compared with bolus IFL alone. There are still no data on other drug interactions when administered systemically.14

As mentioned above, there is an additive efficacy during intravitreal administration, although there is no information available about changes in drug levels.

SUMMARY AND KEY POINTS

The pathogenesis of many retinal disorders is based on neovascularization and increased permeability of blood vessels. VEGF is a basic factor mediating those processes. Bevacizumab, a humanized monoclonal antibody that blocks VEGF activity, has been proved in vitro to inhibit vessel growth and neovascularization, promote regression of existing microvessels, and decrease leakage. This enables it to be a considerable treatment for retinal neovascular disease. It has had wide off-label use in ophthalmology during the last decade. Its efficacy was proven in small retrospective and prospective studies in the treatment of cases of AMD, DME, and NVG, and there are many case reports demonstrating its beneficial use in other neovascular retinal disease, as detailed above. Large, prospective, double-blind, placebo-controlled trails are warranted in order to determine the exact role of bevacizumab in the long-term treatment of ocular diseases in which angiogenesis plays a role.

REFERENCES

1.Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27–31.

2.Garner A. Vascular diseases. In: Garner A, Klintworth GK, editors. Pathobiology of ocular disease. New York: Marcel Dekker; 1994. p. 1625–1710.

3.Michaelson IC. The mode of development of the vascular system of the retina with some observations on its significance for certain retinal disorders. Trans Ophthalmol Soc UK 1948;68:137–180.

4.Greenblatt M, Shubik P. Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparent chamber technique. J Natl Cancer Inst 1968;41:111–124.

5.Ehrmann RL, Knoth M. Choriocarcinoma. Transfilter stimulation of vasoproliferation in the hamster cheek pouch. Studied by light and electron microscopy. J Natl Cancer Inst 1968;41:1329–1341.

6.Folkman J, Merler E, Abernathy C, et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971;133:275–288.

7.Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004 Aug;25(4):581–611.

8.Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983–985.

9.Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparinbinding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851–858.

10.Connolly DT, Olander JV, Heuvelman D, et al. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem 1989;264: 20017–20024.

11.Ferrara N, Houck KA, Jakeman LB, et al. The vascular endothelial growth factor family of polypeptides. J Cell Biochem 1991;47:211–218.

12.Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006 Oct 5;355(14):1432–1444.

13.Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006 Oct 5;355(14):1432–1444.

14.http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf.

15.Lu JF, Bruno R, Eppler S, et al. Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol 2008 Jan 19.

16.Bender JL, Adamson PC, Reid JM, et al. Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol 2008 Jan 20;26(3):399–405.

17.Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007 May;114(5):855–859.

18.Beer PM, Wong SJ, Hammad AM, et al. Vitreous levels of unbound bevacizumab and unbound vascular endothelial growth factor in two patients. Retina 2006 Oct;26(8):871–876.

19.Dib E, Maia M, Longo-Maugeri IM, et al. Subretinal bevacizumab detection after intravitreous injection in rabbits. Invest Ophthalmol Vis Sci 2008 Mar;49(3):1097–1100.

20.Youssoufian H, Hicklin DJ, Rowinsky EK. Review: monoclonal antibodies to the vascular endothelial growth factor receptor-2 in cancer therapy. Clin Cancer Res 2007 Sep 15;13(18 Pt 2):5544s-5548s.

21.Willett CG, Boucher Y, Di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145–147.

22.Gutierrez M, Giaccone G. Antiangiogenic therapy in nonsmall cell lung cancer. Curr Opin Oncol 2008 Mar;20(2):176–182.

23.Scott LJ. Bevacizumab: in first-line treatment of metastatic breast cancer, Drugs 2007;67(12):1793–1799.

24.Wells JA, Murthy R, Chibber R, et al: Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br J Ophthalmol 1996;80:363–366.

25.Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–1487.

26.Moshfeghi AA, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study. Ophthalmology 2006 Nov;113(11):2002.e1–2002.e12. Epub 2006 Oct 5.

27.Cleary CA, Jungkim S, Ravikumar K, et al. Intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration, 6- and 9-month results. Eye 2008 Jan;22(1):82–86.

28.Madhusudhana KC, Hannan SR, Williams CP, et al. Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: results from 118 cases. Br J Ophthalmol 2007 Dec;91(12):1716–1717.

29.Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol 2008 Feb;145(2):249–256. Epub 2007 Dec 11.

30.Falkenstein IA, Cheng L, Morrison VL, et al. Standardized visual acuity results associated with primary versus secondary bevacizumab (Avastin) treatment for choroidal neovascularization in age-related macular degenerationm. Retina 2007 Jul–Aug;27(6):701.

31.Jorge R, Costa RA, Calucci D, et al. Intravitreal bevacizumab (Avastin) for persistent new vessels in diabetic retinopathy (IBEPE study). Retina 2006 Nov–Dec;26(9):1006–1013.

32.Ishikawa K, Honda S, Tsukahara Y, et al. Preferable use of intravitreal bevacizumab as a pretreatment of vitrectomy for severe proliferative diabetic retinopathy. Eye 2009;23:108–111.

33.Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 2007 Apr;114(4):743–750.

34.Scott IU, Edwards AR, Beck RW, et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema, Ophthalmology 2007 Oct;114(10):1860–1867.

35.Badalà F. The treatment of branch retinal vein occlusion with bevacizumab. Curr Opin Ophthalmol 2008 May;19(3):234–238.

36.Wu L, Arevalo JF, Roca JA, et al. Comparison of two doses of intravitreal bevacizumab (Avastin) for treatment of macular edema secondary to branch retinal vein occlusion: results from the Pan-American Collaborative Retina Study Group at 6 months of follow-up. Retina 2008 Feb;28(2): 212–219.

37.Kriechbaum K, Michels S, Prager F, et al. Intravitreal Avastin for macular oedema secondary to retinal vein occlusion: a prospective study. Br J Ophthalmol 2008 Apr;92(4):518–522.

38.Priglinger SG, Wolf AH, Kreutzer TC, et al. Intravitreal bevacizumab injections for treatment of central retinal vein occlusion: six-month results of a prospective trial. Retina 2007 Oct;27(8):1004–1012.

39.Mackensen F, Heinz C, Becker MD, et al. Intravitreal bevacizumab (Avastin) as a treatment for refractory macular edema in patients with uveitis: a pilot study. Retina 2008 Jan;28(1):41–45.

40.Sakaguchi H, Ikuno Y, Gomi F, et al. Intravitreal injection of bevacizumab for choroidal neovascularisation associated with pathological myopia. Br J Ophthalmol 2007 Feb;91(2):161–165.

41.Travassos A, Teixeira S, Ferreira P, et al. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers Imaging 2007 May–Jun;38(3):233–237.

42.Chung EJ, Kim JH, Ahn HS, et al. Combination of laser photocoagulation and intravitreal bevacizumab (Avastin) for aggressive zone I retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2007 Nov;245(11):1727–1730.

43.Dell’omo R, Kulkarni A, Franks WA. Intravitreal and intracameral bevacizumab to treat neovascular complications of retinopathy of prematurity. Acta Ophthalmol 2008;86:698–700.

44.Charbel Issa P, Holz FG, Scholl HP. Findings in fluorescein angiography and optical coherence tomography after intravitreal bevacizumab in type 2 idiopathic macular telangiectasia. Ophthalmology 2007 Sep;114(9): 1736–1742.

45.Maia Júnior OO, Bonanomi MT, Takahashi WY, et al. Intravitreal bevacizumab for foveal detachment in idiopathic perifoveal telangiectasia. Am J Ophthalmol 2007 Aug;144(2):296–299.

46.Wakabayashi T, Oshima Y, Sakaguchi H, et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008;115:1571–1580.

47.Chalam KV, Gupta SK, Grover S, et al. Intracameral Avastin dramatically resolves iris neovascularization and reverses neovascular glaucoma. Eur J Ophthalmol 2008 Mar–Apr;18(2):255–262.

48.Mason 3rd JO, Vail RS, Albert Jr MA, et al. Intravitreal bevacizumab treatment for radiation macular edema after plaque radiotherapy for choroidal melanoma. Retina 2007 Sep;27(7):903–907.

49.Finger PT, Chin K, Anti-vascular endothelial growth factor bevacizumab (avastin) for radiation retinopathy. Arch Ophthalmol 2007 Jun;125(6):751–756.

50.Arevalo JF, Garcia-Amaris RA, Roca JA, et al. Primary intravitreal bevacizumab for the management of pseudophakic cystoid macular edema: pilot study of the Pan-American Collaborative Retina Study Group.

J Cataract Refract Surg 2007 Dec;33(12):2098–2105.

51.Spitzer MS, Ziemssen F, Yoeruek E, et al. Efficacy of intravitreal bevacizumab in treating postoperative pseudophakic cystoid macular edema. J Cataract Refract Surg 2008 Jan;34(1):70–75.

52.Weigert G, Michels S, Sacu S, et al. Intravitreal bevacizumab (Avastin) therapy versus photodynamic therapy plus intravitreal triamcinolone for neovascular age-related macular degeneration: 6-month results of a prospective, randomized, controlled clinical study. Br J Ophthalmol 2008 Mar;92(3):356–360.

53.Bashshur ZF, Schakal A, Hamam RN, et al. Intravitreal bevacizumab vs verteporfin photodynamic therapy for neovascular age-related macular degeneration. Arch Ophthalmol 2007 Oct;125(10):1357–1361.

54.Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina 2007 Nov–Dec;27(9):1187–1195.

55.Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 2006 Nov;90(11):1344–1349.

56.Wu L, Martínez-Castellanos MA, Quiroz-Mercado H, et al. Twelve-month safety of intravitreal injections of bevacizumab (Avastin(R)): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 2008 Jan;246(1):81–87.

57.Shima C, Sakaguchi H, Gomi F, et al. Complications in patients after intravitreal injection of bevacizumab. Acta Ophthalmol Scand 2008;886:372–376.

58.Falkenstein IA, Cheng L, Freeman WR Changes of intraocular pressure after intravitreal injection of bevacizumab (Avastin). Retina 2007 Oct;27(8):1044–1047.

59.Xu L, Zuch CL, Lin YS, et al. Pharmacokinetics and safety of bevacizumab administered in combination with cisplatin and paclitaxel in cynomolgus monkeys. Cancer Chemother Pharmacol 2008 Apr;61(4):607–614.

Diseases Retinal in Mechanisms and Drugs • 4 section