Intravitreal Avastin Maintains Long-term Visual and Anatomic Stability
Anti-VEGF treatment for neovascular AMD still effective after six years.
Luis J. Haddock, MD • Kevin K. Suk, MD • Harry W. Flynn, Jr., MD
Retinal physicians are well acquainted with the success of ranibizumab in blockading vascular endothelial growth factor, first established in 2005,1-3 and that of the drug from which it was derived, bevacizumab, FDA approved in 2004 as an antiangiogenic drug for the treatment of metastatic colorectal cancer.4 The 2005 report by Rosenfeld et al. describing bevacizumab's ability to improve macular appearance and to provide stable visual acuity for four weeks after one intravitreal injection was a watershed moment for the profession.5
In the current report, the six-year follow-up of one of the first patients to be treated with intravitreal injections of bevacizumab for the management of neovascular AMD is presented. This patient has received multiple intravitreal bevacizumab injections on an as-needed regimen since 2005 and has shown remarkable anatomical and visual acuity stability.
A 59-year-old Caucasian male presented in 1994 with sub-foveal CNV in the right eye and marked drusen with RPE atrophy in the left eye secondary to AMD. Over the years, the right eye progressed to a disciform macular scar despite treatment with photodynamic therapy.
|Luis J. Haddock, MD, and Kevin K. Suk, MD, are vitreoretinal fellows at the Bascom Palmer Eye Institute in Miami. Harry W. Flynn, Jr., MD, is professor and J. Donald M. Gass Distinguished Chair of Ophthalmology at Bascom Palmer. None of the authors reports any financial interest in any production mentioned in this article. Dr. Flynn can be reached via e-mail at email@example.com.|
In December 2004, the left eye was found to have occult subfoveal CNV on fluorescein angiography (Figure 1), which was observed as the patient maintained a stable visual acuity of 20/25. However, in September 2005, the patient presented due to a decrease in VA of the left eye to 20/200 and was found to have progression of the occult neovascularization with fluid under the retina on optical coherence tomography (Figure 2).
Figure 1. Fundus photos and FA of left eye in 2005, showing RPE changes, drusen and an occult CNV. FA shows early mottled hyperfluorescence centrally, followed by a late, stippled hyperfluorescence consistent with an occult CNV.
Figure 2. OCT before first bevacizumab injection in September 2005 shows subretinal fluid associated with CNV.
At this visit, the patient was offered an off-label intravitreal injection of 1.25 mg bevacizumab in his left eye. After a lengthy discussion, the patient signed the consent form for the off-label intravitreal injection of bevacizumab, which was administered without complications.
The patient returned one week after the injection with significantly improved VA to 20/30 and an OCT that showed complete resolution of the subretinal fluid (Figure 3). Four weeks after the injection, the patient maintained a stable VA of 20/25 without fluid on OCT. Retreatments were performed on an as-needed PRN regimen, based on signs of active neovascularization, such as fluid on OCT, new hemorrhage, decreased visual acuity as compared to a prior exam, or increased lesion size or leakage on FA.
Figure 3. OCT one week after initial bevacizumab shows nearly complete resolution of subretinal fluid.
In the first year, the patient received a total of three intravitreal injections of bevacizumab on an as-needed basis, while maintaining a VA of 20/25 and stable OCT findings. The patient received a mean of 2.33 (median 2.5) injections per year for a total of 14 injections over 77 months of follow-up.
At the most recent follow up visit, in February 2012, the patient continued to have an excellent VA of 20/20 with a fundus examination and FA showing a stable area of geographic atrophy with central RPE preservation and no evidence of thickening or hemorrhage (Figure 4A), as well as an OCT showing preserved foveal contour without fluid or hemorrhage (Figure 4B).
Figure 4. Fundus photo and FA of left eye in 2011 (A), showing a stable area of geographic atrophy and subretinal fibrosis, with central RPE preservation and no evidence of an active choroidal neovascular membrane. (B) OCT of left eye in 2011, six years after initial treatment with intravitreal bevacizumab for wet AMD, showing a preserved foveal contour without intraretinal or subretinal fluid.
Since the two phase 3 trials showing that ranibizumab was superior to verteporfin in the treatment of predominantly classic neovascular AMD, subsequent studies showed that the use of intravitreal ranibizumab, by OCT-guided variable dosing, was the standard of treatment for neovascular AMD, as this regimen resulted in visual acuity outcomes similar to the phase 3 trials while requiring fewer injections.6,7
Bevacizumab has been used for the treatment of neovascular AMD since 2005, after a report that showed an improvement in VA, on OCT, and on angiographic findings after systemic administration of bevacizumab.8 These findings were followed by a case report that same year that described improved macular OCT appearance and stable visual acuity in the first human patient receiving intravitreal bevacizumab.5
Subsequently, bevacizumab was used as an off-label alternative for the treatment of neovascular AMD while awaiting approval of ranibizumab. Even after FDA approval of ranibizumab in 2006, bevacizumab continued to be used because it was available at a lower cost.9
Recently, the CATT study showed that the two drugs had equivalent effects on visual acuity at all time points throughout the first year of follow-up when given at regular intervals (the results with PRN dosing were not equivalent).10 This large clinical trial provided level 1 evidence-based data of noninferiority of bevacizumab when compared with ranibizumab in the treatment of neovascular AMD.
In the current report, a male Caucasian patient with decreased visual acuity and a subfoveal occult neovascular membrane demonstrated initial and follow-up visual and anatomical stability with six years of repeated intravitreal injections of bevacizumab on an as-needed basis.
This patient was one of the first patients to be treated with intravitreal bevacizumab for neovascular AMD, and his favorable outcome over six years of repeated intravitreal injections supports the efficacy of bevacizumab in preventing vision loss and disease progression.
Finally, this report shows that the strategy of using qualitative OCT changes suggestive of recurrent fluid as the basis for retreatment resulted in anatomical and visual stability and is still effective after six years of anti-VEGF treatment for AMD. RP
1. Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina. 2005; 25:111-118.
2. Rosenfeld PJ, Brown DM, Heier JS, et al.; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-1431.
3. Brown DM, Kaiser PK, Michels M, et al.; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1432-1444.
4. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350:2335-2334.
5. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005; 36:331-335.
6. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007; 143: 566-568.
7. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008; 145:239-248.
8. Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005; 112:1035-1047.
9. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S. Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-for-service part B claims file. Am J Ophthalmol. 2011; 151:887-895.
10. Martin DF, Maguire MG, Ying GS, et al.; CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011; 364:1897-1908.