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Small Case Series |

Response to Ranibizumab Following Tachyphylaxis to Bevacizumab in a Patient With Radiation Maculopathy Following Stereotactic Fractionated Radiotherapy for Optic Nerve Meningioma FREE

Gurjeet Jutley, BM, BSc(Hons); Olajumoke A. Shona, FWACS, FRCS; Richard Cheong Leen, MSc, MRCOphth; Nicholas Lee, FRCOphth; Jane M. Olver, FRCOphth; Sheena M. George, FRCOphth
[+] Author Affiliations

Author Affiliations: Western Eye Hospital, Imperial College Healthcare NHS Trust, London, England.


Arch Ophthalmol. 2012;130(11):1466-1470. doi:10.1001/archophthalmol.2012.1542.
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Published online

A 38-year-old man presented to our eye clinic 21 months after radiotherapy for optic nerve meningioma in the left eye. At initial assessment, he had a visual acuity (VA) of 6/36, a central retinal thickness of 531 μm, and minimal disruption of the foveal avascular zone. The decision was made to treat his condition with intravitreal injections of bevacizumab (Avastin; Roche). His left eye's initial response to bevacizumab was very encouraging, with VA improving to 6/12 after 3 injections. However, this response was transient; after 6 injections, he had a VA of 6/18 and a central retinal thickness of 475 μm in the left eye. His treatment was then switched to intravitreal injections of ranibizumab (Lucentis; Novartis), and he experienced a complete resolution of his cystoid macula edema, with a final VA of 6/6 and a central retinal thickness of 264 μm in the left eye. This is an interesting case of tachyphylaxis to bevacizumab in a patient with radiation maculopathy, with full resolution following intravitreal injections of ranibizumab.

A 38-year-old man presented to our eye clinic 21 months after stereotactic fractioned radiotherapy (50 Gy) for optic nerve meningioma in the left eye. He was initially under the care of the oculoplastics team and neurologists from September 2003 following diagnosis of the meningioma, presenting with proptosis, a VA of 6/4, and a constricted visual field. After 4 years of follow-up, in spite of the VA remaining stable, imaging revealed progression of the meningioma and further constriction of the Goldmann visual field; as a result, he was referred for radiotherapy.

Twenty-one months after radiotherapy, his VA remained stable at 6/5. Ophthalmoscopy, however, revealed intraretinal hemorrhages and cotton-wool spots, and a diagnosis of radiation retinopathy was made. Six months later, his VA had deteriorated to 6/36. Optical coherence tomography revealed cystic intraretinal fluid with a central retinal thickness of 531 μm (Figure 1). Fundus fluorescein angiography revealed an enlarged foveal avascular zone (Figure 2).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Optical coherence tomographic scan of left eye of patient showing intraretinal edema and multiple intraretinal cysts (asterisks) prior to bevacizumab treatment. N indicates nasal; T, temporal.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. A, Fundus color photograph showing retinal hemorrhages (black arrowheads) and multiple cotton-wool spots (white arrowheads) before treatment with bevacizumab. B, Fundus fluorescein angiogram at the midvenous phase showing enlarged fovea avascular zone (white arrows) before treatment with bevacizumab. C, Fundus fluorescein angiogram at late venous phase showing macula edema with leakage of dye (white arrowheads) and retinal neovascularization (black arrowhead).

This is a retrospective case report based on the patient's response to therapy. After explaining the risks, benefits, and treatment options, he consented to anti–vascular endothelial growth factor (VEGF) injections.

All of the injections were given in an operating room, under strict sterile conditions. The eye was anesthetized with topical proxymetacaine and prepared with povidone-iodine (10% on the eyelid and periocular region and 5% on the ocular surface). The anti-VEGF treatment was then drawn up using a 1-mL syringe with a 30-gauge needle (for ranibizumab) if not already in a pre-prepared syringe (for bevacizumab). Both drugs are stored at between 2°C and 8°C and are used before their expiration date. Following insertion of the speculum in the eyelid, further topical anesthesia was administered with a pledget over the injection site. Finally, an injection was given through the pars plana in the inferotemporal quadrant, 4 mm from the limbus. Optic nerve perfusion was assessed with indirect ophthalmoscopy, and topical chloramphenicol, 0.5% (4 times a day for 5 days), was prescribed.

Treatment was given in accordance with our department protocol. The patient received 1.25 mg of off-label bevacizumab monthly for 6 consecutive months before being switched to 0.05 mg of ranibizumab.

The patient's initial response after 3 injections of bevacizumab was observed, and his VA improved to 6/12. However, with subsequent injections, there was no further improvement: his left eye's VA and central retinal thickness worsened to 6/18 and 475 μm, respectively (Figure 3).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Optical coherence tomographic scan of left eye of patient showing increased intraretinal edema after 6 months of consecutive injections of bevacizumab. N indicates nasal; T, temporal.

He was switched to ranibizumab, and after 7 injections given on a pro re nata regime, his VA improved to 6/6, and he had a final central retinal thickness of 264 μm. There was no evidence of maculopathy (Figures 4 and 5).

Place holder to copy figure label and caption
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Figure 4. Optical coherence tomographic scan of left eye of patient showing complete resolution of intraretinal edema after 7 intravitreal injections of ranibizumab. N indicates nasal; T, temporal.

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Graphic Jump Location

Figure 5. Fundus color photograph showing resolution of cotton-wool spots and retinal hemorrhage after ranibizumab therapy.

Ever since its description by Stallard in 1933,1 radiation retinopathy has been known as a clinical entity in its own right. It occurs after irradiation for tumors or for inflammation of the choroid, retina, orbit, or paranasal sinuses. Although there is no definitive threshold, the risk of radiation retinopathy is related to the dose administered, with incidences increasing at doses greater than 45 Gy.2 Comorbidities and the use of other agents (such as chemotherapy) increase the risk of developing radiation retinopathy.2 From a morphological perspective, it can be characterized by retinal changes seen in any insult to the blood vessels and by ensuing hypoxia (more specifically, by microangiopathy, intraretinal hemorrhage, cotton-wool spots, cystoid macular edema, and neovascularization). This disease can cause irreversible loss of vision if the macula is involved; one study3 suggests that rates of radiation maculopathy are up to 23% from plaque radiotherapy.

Recent advances have revolutionized the traditional modalities of treating radiation retinopathy.46 Previously, nonsteroidal anti-inflammatories, laser photocoagulation (both focal macular and scatter), hyperbaric oxygen, and steroids delivered by different methods had been used, all with limited success.7,8 The theory behind anti-VEGF therapy is to inhibit the formation of new vessels, which will go on to leak and to decrease vascular permeability by reducing endothelial cell fenestrations through upregulating occludin.9

In 2007, Finger and Chin4 showed that bevacizumab was effective in treating radiation maculopathy. They produced a consecutive case series of 6 patients using a mean number of 3 bevacizumab injections and analyzed response at a mean follow-up of 4.7 months. They noted a marked improvement in leakage from vessels, stable or improved VA, and almost complete resolution of macular edema.4 No objective measurements of foveal thickness were given in their study.4 In the same year, Ziemssen et al10 published a case report that showed an improvement in foveal thickness from 335 to 243 μm after 1 month of treatment with bevacizumab injections, with a corresponding improvement in VA from 20/100 to 20/40. For a 61-year-old woman who presented with a gradual decrease in left eye VA 29 months after proton beam radiotherapy for choroidal melanoma, Loukianou et al11 observed a sustained benefit from bevacizumab treatment 18 months after 3 consecutive injections. The foveal thickness in her left eye improved from 458 to 334 μm, and her best-corrected VA improved from 2/10 to 3/10.

In contrast to these encouraging results, the results from a case series of patients treated with bevacizumab were inconsistent.12 In this consecutive case series of 6 patients, marked variations were noted after treatment with respect to VA and macular edema.12 It was shown that younger patients with new-onset maculopathy responded better. Mason et al13 treated 10 patients with bevacizumab, and these patients were observed for 4 months after treatment. They found that the mean foveal thickness decreased from 482 to 449 μm; however, there was only a modest improvement in VA.13 Indeed, Wen and McCannel published a review7 in 2009 in which they analyzed treatments for radiation retinopathy. They exclusively looked at bevacizumab in the anti-VEGF agents group and surmised that the improvements in VA after injections appeared to be minimal, with the exception of the results achieved by the Finger and Chin.4 Wen and McCannel7 suggest that the role of bevacizumab was limited.

Our case differs from those already mentioned in that, initially, there was some benefit seen with the injections of bevacizumab. It is well recognized that some patients with age-related macular degeneration seem to have a decreased response after repeated treatments and that others seem have no response at all. Tachyphylaxis is a rapidly decreasing therapeutic response to a pharmacologically active substance following the initial doses.14 Eghøj and Sørensen14 observed that, in 976 patients (1076 eyes), 2% developed tachyphylaxis on reactivation of previously treated choroidal neovascularization.

In the eye, cellular mechanisms play a predominant role in this type of drug tolerance. For instance, a possible cause for this tachyphylaxis response is the development of circulating antibodies against bevacizumab. Forooghian et al15 showed that levels of neutralizing antibodies increase with repeated injections and that the median time to develop tachyphylaxis is 100 weeks. Another suggested cause is a greater production of VEGF by local macrophages to negate the effect of the agent.

An alternative theory proposed by Schaal et al16 focuses on other mediators playing a role in propagating disease. They performed a small study whereby 15 eyes were treated with bevacizumab, 11 eyes were treated with triamcinolone, and 17 eyes were treated with both drugs, for subfoveal choroidal neovascularization secondary to age-related macular degeneration.16 In the bevacizumab group, approximately 3 injections were required for the efficacy of the treatment to decrease to 50% of the initial response; conversely, in the combination group, the mean number of injections was 5.1.16 Schaal et al16 suggested that other signaling pathways, such as fibroblast growth factor, could compensate for the blocked activity of VEGF when using bevacizumab alone.

Interestingly, there are reports in the literature of patients who develop tachyphylaxis to one anti-VEGF agent but respond to another. Hoffman and Taylor17 described this as one of the methods to reduce or avoid tachyphylaxis. Gasperini et al18 described 10 patients with age-related macular degeneration (3 classic lesions and 7 occult lesions) who were switched to ranibizumab after an average of 7 injections for apparent tachyphylaxis. Eight of these 10 patients had a positive therapeutic response after switching agents (4 after only 1 injection with ranibizumab). Two patients with classic lesions and 2 patients with occult lesions had complete resolution of subretinal fluid.18

As can be appreciated, all the reports related to anti-VEGF treatment and tachyphylactic responses concerned patients with age-related macular degeneration, and, as such, they had pathogeneses that were different from the pathogenesis in our patient with radiation maculopathy. It is our understanding that there is nothing in the literature with respect to tachyphylaxis for anti-VEGF treatment of radiation maculopathy. There is, however, evidence to advocate the role of open-label ranibizumab (Lucentis) in treating radiation maculopathy. Finger and Chin19 performed a consecutive case series to analyze the effect of ranibizumab with respect to safety profile, change in VA, and resolution of maculopathy. All 5 patients had either 8 or 9 injections of ranibizumab. Their 8-month analysis showed a mean 35% reduction in foveal thickness and a mean improvement in best-corrected VA of 6 letters.19

Yuan and Singh20 described their experience in treating a 49-year-old women for metastatic breast cancer after she underwent brain radiation therapy. She received dual therapy, initially with panretinal photocoagulation and then intravitreal ranibizumab, because there was no improvement in VA after laser treatment. After 2 injections, her VA improved in the left eye by 4 lines, which did not correspond to improvement in foveal thickness, unlike the reports from Finger and Chin.19 For our patient, we had been monitoring his progress and basing our decisions for further injections partly on the optical coherence tomographic foveal thickness measurement; the data from Yuan and Singh20 suggest that perhaps one should not give too much credence to this parameter but should rather be more concerned with the VA.

Future studies are required to address the long-term course of the disease after anti-VEGF treatment. For instance, when should these patients be followed up? How many injections should they have, and over what time interval? When should a different form of management be considered? To our knowledge, the literature has hitherto been unable to answer these questions. In summary, we present a case of a 38-year-old man with radiation maculopathy who responded to intravitreal injections of ranibizumab after developing tachyphylaxis to intravitreal injections of bevacizumab.

Correspondence: Dr George, Western Eye Hospital, Imperial College Healthcare NHS Trust, Marylebone Road, London NW1 5QH, England (sheena.george@nhs.net).

Author Contributions: Dr Shona and Mr Jutley contributed equally to this work and should be considered as co–first authors.

Conflict of Interest Disclosures: None reported.

Stallard HB. Radiant energy as (a) pathogenic and (b) a therapeutic agent in ophthalmic disorders.  Br J Ophthalmol. 1933;1:70
Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR. Radiation retinopathy after external-beam irradiation: analysis of time-dose factors.  Int J Radiat Oncol Biol Phys. 1994;30(4):765-773
PubMed   |  Link to Article
Haye C, Desjardins L, Bouder P, Schlienger P, Dorval T. Maculopathy caused by irradiation in patients treated for choroid melanoma.  Ophtalmologie. 1990;4(3):229-231
PubMed
Finger PT, Chin KJ. Anti-vascular endothelial growth factor bevacizumab (Avastin) for radiation retinopathy.  Arch Ophthalmol. 2007;125(6):751-756
PubMed   |  Link to Article
Finger PT. Anti-VEGF bevacizumab (Avastin) for radiation optic neuropathy.  Am J Ophthalmol. 2007;143(2):335-338
PubMed   |  Link to Article
Finger PT. Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin).  Int J Radiat Oncol Biol Phys. 2008;70(4):974-977
PubMed   |  Link to Article
Wen JC, McCannel TA. Treatment of radiation retinopathy following plaque brachytherapy for choroidal melanoma.  Curr Opin Ophthalmol. 2009;20(3):200-204
PubMed   |  Link to Article
Horgan N, Shields CL, Mashayekhi A, Shields JA. Classification and treatment of radiation maculopathy.  Curr Opin Ophthalmol. 2010;21(3):233-238
PubMed   |  Link to Article
Rosenfeld PJ, Schwartz SD, Blumenkranz MS,  et al.  Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration.  Ophthalmology. 2005;112(6):1048-1053
PubMed   |  Link to Article
Ziemssen F, Voelker M, Altpeter E, Bartz-Schmidt KU, Gelisken F. Intravitreal bevacizumab treatment of radiation maculopathy due to brachytherapy in choroidal melanoma.  Acta Ophthalmol Scand. 2007;85(5):579-580
PubMed   |  Link to Article
Loukianou E, Brouzas D, Georgopoulou E, Koutsandrea C, Apostolopoulos M. Intravitreal bevacizumab for macular edema due to proton beam radiotherapy: favorable results shown after eighteen months follow-up.  Ther Clin Risk Manag. 2010;6:249-252
PubMed   |  Link to Article
Gupta A, Muecke JS. Treatment of radiation maculopathy with intravitreal injection of bevacizumab (Avastin).  Retina. 2008;28(7):964-968
PubMed   |  Link to Article
Mason JO III, Albert MA Jr, Persaud TO, Vail RS. Intravitreal bevacizumab treatment for radiation macular edema after plaque radiotherapy for choroidal melanoma.  Retina. 2007;27(7):903-907
PubMed   |  Link to Article
Eghøj MS, Sørensen TL. Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab.  Br J Ophthalmol. 2012;96(1):21-23
PubMed   |  Link to Article
Forooghian F, Chew EY, Meyerle CB, Cukras C, Wong WT. Investigation of the role of neutralizing antibodies against bevacizumab as mediators of tachyphylaxis.  Acta Ophthalmol. 2011;89(2):e206-e207
PubMed   |  Link to Article
Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration?  Ophthalmology. 2008;115(12):2199-2205
PubMed   |  Link to Article
Hoffman BB, Taylor P. Neurotransmission: the autonomic and somatic motor nervous systems. In: Goodman LS, Hardman JG, Limbird LE, Gilman AG, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:115-154
Gasperini JL, Fawzi AA, Khondkaryan A,  et al.  Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation.  Br J Ophthalmol. 2012;96(1):14-20
PubMed   |  Link to Article
Finger PT, Chin KJ. Intravitreous ranibizumab (Lucentis) for radiation maculopathy.  Arch Ophthalmol. 2010;128(2):249-252
PubMed   |  Link to Article
Yuan A, Singh RP. Radiation maculopathy treated with ranibizumab.  J Clin Exp Ophthalmol. 2011;2(2):1-4Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Optical coherence tomographic scan of left eye of patient showing intraretinal edema and multiple intraretinal cysts (asterisks) prior to bevacizumab treatment. N indicates nasal; T, temporal.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. A, Fundus color photograph showing retinal hemorrhages (black arrowheads) and multiple cotton-wool spots (white arrowheads) before treatment with bevacizumab. B, Fundus fluorescein angiogram at the midvenous phase showing enlarged fovea avascular zone (white arrows) before treatment with bevacizumab. C, Fundus fluorescein angiogram at late venous phase showing macula edema with leakage of dye (white arrowheads) and retinal neovascularization (black arrowhead).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Optical coherence tomographic scan of left eye of patient showing increased intraretinal edema after 6 months of consecutive injections of bevacizumab. N indicates nasal; T, temporal.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 4. Optical coherence tomographic scan of left eye of patient showing complete resolution of intraretinal edema after 7 intravitreal injections of ranibizumab. N indicates nasal; T, temporal.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 5. Fundus color photograph showing resolution of cotton-wool spots and retinal hemorrhage after ranibizumab therapy.

Tables

References

Stallard HB. Radiant energy as (a) pathogenic and (b) a therapeutic agent in ophthalmic disorders.  Br J Ophthalmol. 1933;1:70
Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR. Radiation retinopathy after external-beam irradiation: analysis of time-dose factors.  Int J Radiat Oncol Biol Phys. 1994;30(4):765-773
PubMed   |  Link to Article
Haye C, Desjardins L, Bouder P, Schlienger P, Dorval T. Maculopathy caused by irradiation in patients treated for choroid melanoma.  Ophtalmologie. 1990;4(3):229-231
PubMed
Finger PT, Chin KJ. Anti-vascular endothelial growth factor bevacizumab (Avastin) for radiation retinopathy.  Arch Ophthalmol. 2007;125(6):751-756
PubMed   |  Link to Article
Finger PT. Anti-VEGF bevacizumab (Avastin) for radiation optic neuropathy.  Am J Ophthalmol. 2007;143(2):335-338
PubMed   |  Link to Article
Finger PT. Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin).  Int J Radiat Oncol Biol Phys. 2008;70(4):974-977
PubMed   |  Link to Article
Wen JC, McCannel TA. Treatment of radiation retinopathy following plaque brachytherapy for choroidal melanoma.  Curr Opin Ophthalmol. 2009;20(3):200-204
PubMed   |  Link to Article
Horgan N, Shields CL, Mashayekhi A, Shields JA. Classification and treatment of radiation maculopathy.  Curr Opin Ophthalmol. 2010;21(3):233-238
PubMed   |  Link to Article
Rosenfeld PJ, Schwartz SD, Blumenkranz MS,  et al.  Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration.  Ophthalmology. 2005;112(6):1048-1053
PubMed   |  Link to Article
Ziemssen F, Voelker M, Altpeter E, Bartz-Schmidt KU, Gelisken F. Intravitreal bevacizumab treatment of radiation maculopathy due to brachytherapy in choroidal melanoma.  Acta Ophthalmol Scand. 2007;85(5):579-580
PubMed   |  Link to Article
Loukianou E, Brouzas D, Georgopoulou E, Koutsandrea C, Apostolopoulos M. Intravitreal bevacizumab for macular edema due to proton beam radiotherapy: favorable results shown after eighteen months follow-up.  Ther Clin Risk Manag. 2010;6:249-252
PubMed   |  Link to Article
Gupta A, Muecke JS. Treatment of radiation maculopathy with intravitreal injection of bevacizumab (Avastin).  Retina. 2008;28(7):964-968
PubMed   |  Link to Article
Mason JO III, Albert MA Jr, Persaud TO, Vail RS. Intravitreal bevacizumab treatment for radiation macular edema after plaque radiotherapy for choroidal melanoma.  Retina. 2007;27(7):903-907
PubMed   |  Link to Article
Eghøj MS, Sørensen TL. Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab.  Br J Ophthalmol. 2012;96(1):21-23
PubMed   |  Link to Article
Forooghian F, Chew EY, Meyerle CB, Cukras C, Wong WT. Investigation of the role of neutralizing antibodies against bevacizumab as mediators of tachyphylaxis.  Acta Ophthalmol. 2011;89(2):e206-e207
PubMed   |  Link to Article
Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration?  Ophthalmology. 2008;115(12):2199-2205
PubMed   |  Link to Article
Hoffman BB, Taylor P. Neurotransmission: the autonomic and somatic motor nervous systems. In: Goodman LS, Hardman JG, Limbird LE, Gilman AG, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:115-154
Gasperini JL, Fawzi AA, Khondkaryan A,  et al.  Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation.  Br J Ophthalmol. 2012;96(1):14-20
PubMed   |  Link to Article
Finger PT, Chin KJ. Intravitreous ranibizumab (Lucentis) for radiation maculopathy.  Arch Ophthalmol. 2010;128(2):249-252
PubMed   |  Link to Article
Yuan A, Singh RP. Radiation maculopathy treated with ranibizumab.  J Clin Exp Ophthalmol. 2011;2(2):1-4Link to Article

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