Bevacizumab Local Complications

Bevacizumab Local Complications Dear Editor: Bevacizumab (Avastin, Genetech, San Francisco, CA) is a recombinant monoclonal antibody (IgG1) that selectively binds and neutralizes the biological activity of vascular endothelial growth factor. Its intravenous administration was approved by the Food and Drug Administration (FDA) in February 2004 as a first-line therapy for metastatic colorectal cancer.1 In the past few years, “off-label” uses in the ophthalmology field have become popular due to its encouraging results in the treatment of vasoproliferative diseases. While no one disputes its apparent effectiveness, the relative effectiveness compared with ranibizumab, and the safety of its intravitreal administration, has recently been debated. This is due to lack of comparative data from large prospective randomized trials, and in part, because of doubts cast by the warnings issued by the FDA and the manufacturer about possible local and systemic adverse effects (AE).2,3 One cause of confusion lies in the multiple AEs reported after intravenous administration (dose of 5 mg/kg). Even though the intravitreal doses are almost 400 times smaller than the intravenous, there is some systemic absorption of the drug (3.3 mg/ml, 8 days after intravitreal injection).4 The fact that this amount of bevacizumab may produce systemic AEs is a major concern for the retinal specialists. Due to the lack of information in the literature regarding the incidence of local complications after its intravitreal administration; we decided to review our experience in the use of this antibody. Our study was approved by the hospital ethics board. We reviewed the clinical records of 3517 consecutive injections in 2863 patients, in a period of time involving 27 months (September 2005 to December 2007). We included all bevacizumab injections, regardless the pretreatment diagnosis or the intravitreal dose. For every case, we recorded the age, gender, diagnosis, type of AE, drug dose, number of injections, best corrected visual acuity (BCVA) before the AE, BCVA in the last follow up, the time between the intravitreal injection and the diagnosis of the AE, the need for surgery, the time until the AE was resolved, and time of follow-up (follow-up time). We also recorded the blood pressure before and after the injection. Descriptive analyses were performed using SPSS software, version 10.1.0 (SPSS Inc., Chicago, IL). We identified 16 AEs that appeared to be directly related to the administration of intravitreal bevacizumab. The general demographic data is summarized in Table 1 (available at http://aaojournal.org). The dose used in all patients was 2.5 mg. Most of the patients had previous injections but not always in the same eye. Only 2 patients had 1 or more injections in the same eye (2 females, 1 developed endophthalmitis and the second developed a tractional retinal detachment). Two male patients (0.05%) presented with anterior chamber inflammation (anterior chamber cells 2⫹), without other clinical sign of infection. Neither of these 2 cases required surgery or additional treatment beside topical nonsteroidal anti-inflammatories. Four female and 2 male patients presented endophthalmitis (0.17%). The mean time between the intravitreal injection and the development of the en-

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dophthalmitis was 3.5⫾1 day. The results of the cultured samples were as follows: 2 cases of Pseudomonas cepacia, 2 cases of gram-positive bacillus, and 2 negative reports. There were 5 cases (0.14%) of tractional retinal detachment, and only 1 patient had a rhegmatogenous retinal detachment (0.02%) 7 days after intravitreal application. All of these patients were diabetic with severe cases of proliferative diabetic retinopathy. Another patient developed a vitreous hemorrhage, and the last one developed vitreous leakage through the injection site, 3 days after the treatment. Both AEs resolved successfully. The median follow-up time of the 3517 cases was 45⫾26 days, during which time there were no reported cases of high blood pressure or any other systemic AE of any kind after intravitreal bevacizumab administration (Figures 1–5 are available at http://aaojournal.org). If cases of systemic AE rated are similar to ranibizumab, with 1% to 2% rates of heart attack or myocardial infarction in 1 year, this short duration of follow-up is not sufficient to detect similar rates. For this reason, our comments focus on the local AEs. Over the last 2 decades, the use of intravitreal injections has gained increasing acceptance in the therapeutic management of many intraocular diseases. After an experience of 3517 bevacizumab injections, we can believe that locally, it is a safe procedure with minimum rates of local AE like endophthalmitis, retinal detachment, or anterior chamber inflammation, rates even smaller than those published by Jager et al.5 The lack of longer follow-up time prevents us from believing the same about the systemic AEs. MAXIMILIANO GORDON-ANGELOZZI, MD Rosario, Argentina RAUL VELEZ-MONTOYA, MD JANS FROMOW-GUERRA, MD GERARDO GARCÍA-AGUIRRE, MD JOSE LUIS GUERRERO-NARANJO, MD Mexico Distrito Federal, México HUGO QUIROZ-MERCADO, MD Denver, Colorado VIRGILIO MORALES-CANTÓN, MD Mexico Distrito Federal, México References 1. Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 2007;12:713– 8. 2. http://www.fda.gov/medwatch/SAFETY/2005/Jan_PI/Avastin_ PI.pdf. Accessed on December 2007. 3. Kernt M, Neubauer AS, Kampik A. Intravitreal bevacizumab (Avastin) treatment is safe in terms of intraocular and blood pressure. Acta Ophthalmol Scand 2007;85:119 –20. 4. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114: 855–9. 5. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina 2004; 24:676 –98.

Letters to the Editor Table 1. Demographic, Follow-up and Treatment Summary

Patient

Age

Gender

Diagnosis CRVO ⫹ ME PDR ⫹ CSME RDP ⫹ VH PDR PDR PDR ⫹ CSME CNV high miopia PDR PDR PDR CNV high miopia CNV AMD PDR PDR PDR ⫹ CSME PDR ⫹ CSME

Patient Patient Patient Patient Patient Patient Patient

1 2 3 4 5 6 7

74 66 24 44 76 80 32

F F F M F M F

Patient Patient Patient Patient

8 9 10 11

68 46 39 56

F F M F

Patient Patient Patient Patient Patient

12 13 14 15 16

81 49 57 62 69

M M F M M

Mean Age Female Male

57.69⫾17.34 9 (56%) 7 (44%)

Type of Complication

No. of Previous Injections

BCVA BCVA Before After AE AE

Time Between Time Between Injection and AE Diagnosis AE and Presentation Resolution

Treatment

Endophthalmitis 2 20/1250 Endophthalmitis 1 (fellow eye) 20/200 TRD 0 20/63 TRD 1 20/32 TRD 0 20/500 AC Immflamation 0 20/630 Vitreous Leakage 0 20/100

LP CF 20/200 20/63 CF 20/630 20/63

5 3 8 31 32 1 3

15 18 6 6 8 7 11

Vitrectomy Vitrectomy Vitrectomy Vitrectomy Vitrectomy NSAID Contact lens

Endophthalmitis TRD RRD Endophthalmitis

0 0 0 0

20/160 HM 20/40 20/800

20/400 20/800 20/250 HM

3 32 7 4

18 8 5 17

Vitrectomy Vitrectomy Vitrectomy Intravitreal AB

AC Immflamation TRD VH Endophthalmitis Endophthalmitis

0 0 0 0 0

20/25 LP 20/32 20/400 20/100

20/25 LP 20/32 HM 20/800

3 35 2 4 2

12 8 14 20 17

NSAID Vitrectomy Position Intravitreal AB Intravitreal AB

TRD: Endoph: RRD:

5 (0.18%) 6 (0.17%) 1 (0.04%)

AC Imm: VH: VL:

2 (0.07%) 1 (0.04%) 1 (0.04%)

AC ⫽ anterior chamber; AE ⫽ adverse effects; BCVA ⫽ best corrected visual acuity; CF ⫽ count fingers; CNV ⫽ choroidal neovascularization; CRVO ⫽ central retinal vein occlusion; CSME ⫽ clinical significant macular edema; F ⫽ female; HM ⫽ hand movements; LP ⫽ light perception; M ⫽ male; ME ⫽ macular edema; NSAID ⫽ non-steroidal anti-inflammatory drugs; PDR ⫽ proliferative diabetic retinopathy; TRD ⫽ tractional retinal detachment; VH ⫽ vitreous hemorrhage.

Figure 1. Patient 11: A, Subretinal fluid due to a choroidal neovascularization. B, Acute endophthalmitis with vitreitis. C, Endophthalmitis resolved after intravitreal antibiotics.

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Ophthalmology Volume 116, Number 11, November 2009

Figure 2. Patient 11: Mode-B ultrasound scanning showing severe vitreous cells and formation of pseudomembranes.

Figure 3. Patient 5: A, Severe proliferative diabetic retinopathy with abundant fibrovascular tissue, 2 weeks before bevacizumab intravitreal administration. B, Thirty-two days after injection, a tractional retinal detachment with macular involvement was observed. B, Same eye, 8 days after vitrectomy. Retina is reattached and silicon oil was used as a tamponade agent.

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Letters to the Editor

Figure 4. Patient 9: A, Right eye fundus images. Proliferative diabetic retinoopathy with fibrovascular tissue over the optic nerve head and in the superior-temporal quadrant. B, One week after the intravitreal injection of bevacizumab with tractional retinal detachment. C, Fluorescein angiogram of the same eye, showing the retinal detachment.

Figure 5. Patient 7: Right eye (arrow), showing the injection site, and the leakage of vitreous fluid through it, stained with fluorescein.

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