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The purpose of this chapter is to discuss the different treatment modalities that were available in clinical practice before the use of anti–vascular endothelial growth factors (anti-VEGF), according to their date of appearance and their clinical significance. At present, many of these techniques have been abandoned, as the reader will conclude, given their efficacy compared to the modern anti-VEGF treatments available. However, we are still far from having an ideal treatment for wet age-related macular degeneration (AMD), and in some circumstances, history has shown that retaking old treatment strategies and combining them with newer modalities, or rethinking previously used principles, can lead science toward new steps in managing these disorders, thus offering novel treatment strategies and improving visual outcomes.
In this chapter, the reader will find a brief review of the different treatment modalities available for AMD previous to the introduction of anti-VEGF in clinical practice. In each treatment option mentioned, we summarized an introduction, the most relevant multicenter studies, their principle and results, and their current use. In those treatments where no randomized, double-blind, placebo-controlled study data were available, we included those obtained from small case series that had significant results and relevance that lead to their application in different disorders.
PHOTOCOAGULATION FOR CHOROIDAL NEOVASCULARIZATION
Between 1979 and 1994, the Macular Photocoagulation Study Group (MPS) conducted three sets of randomized clinical trials (1–21). The purpose of these studies was to determine if laser photocoagulation was of benefit in preventing or delaying large losses of visual acuity (VA) in comparison with observation without treatment. The Argon and Krypton studies included patients with choroidal neovascularization (CNV) secondary to AMD, presumed ocular histoplasmosis (POH), and idiopathic choroidal neovascularizations (ICNV). The Argon study studied the effectiveness of photocoagulation with argon blue-green laser in eyes with extrafoveal CNV (200–2,500 μm from the center of the foveal avascular zone [FAZ]). The Krypton study examined CNV lesions with the posterior border 1 to 199 μm from the center of the FAZ, and the Foveal study was carried out in patients with new (never treated) or recurrent (previously treated with laser photocoagulation) subfoveal CNV (CNV with blood or blocked fluorescence within 200 μm of the foveal center).
PRINCIPLES OF TREATMENT
Ocular photocoagulation uses heat produced through the absorption of light by ocular pigments. Absorption of light can take place either in the tissue to be photocoagulated or in a neighboring tissue, where heat is then transferred to the tissue of interest by thermal conduction. Therefore, photocoagulation is used to obliterate single blood vessels and neovascular networks such as subretinal neovascularization. The most common light sources used for this type of surgery were argon ion (488 and 514 μm) and krypton ion (568 and 647 μm) (20).
SUMMARIZED MPS RESULTS OF TREATMENT BY LESION LOCATION
Extrafoveal Choroidal Neovascularization
In 1982, the MPS group reported that covering the entire extent of the extrafoveal CNV and contiguous blood reduced the risk of additional severe VA loss when compared with the natural course of the disease (1). The benefits were greatest during the first posttreatment year and persisted over 5 years of follow-up; at that time, 64% of untreated eyes versus 46% of treated eyes progressed to severe visual loss. After 5 years, untreated eyes lost a mean of 7.1 lines of VA, while laser-treated eyes lost 5.2 lines. Unfortunately, persistent or recurrent CNV was observed in 54% of treated eyes, usually on the foveal (posterior) side of the treated lesion (3,4,7,21).
Juxtafoveal Choroidal Neovascularization
The 5-year results for juxtafoveal lesions in AMD were published in 1994. They also demonstrated the benefit of treatment over observation. As compared to no treatment, laser photocoagulation reduced the risk of severe visual loss by approximately 10%. The baseline level of VA was maintained in 25% of the treated eyes, compared to 15% of the untreated eyes over the study period. In addition, more than twice as many treated patients as untreated patients retained VA of 20/40 or better. Unfortunately, by the 5-year follow-up examination, 78% of those treated had either persistent or recurrent CNV involving the foveal center (5,6,15,18,21).
Subfoveal Choroidal Neovascularization
In 1991, the MPS reported that laser treatment of new subfoveal CNV (i.e., no prior laser treatment) was better than observation alone in preventing large losses of VA for eligible lesions. Overall, eyes receiving direct laser treatment to the fovea for new CNV immediately lost more VA than did observed eyes. However, the amount of VA loss in observed eyes increased to the level of loss in treated eyes at 12 months and exceeded the level thereafter. By 24 months, VA still had decreased by six or more lines in 20% of laser-treated eyes compared to 37% of untreated eyes (8–10). Additional follow-up at 4 years continued to show this same trend, despite both treated and untreated eyes losing additional lines of VA (12,21). Eyes with smaller lesions and worse initial VA had greater and earlier benefits of laser treatment (13). Eyes with large subfoveal neovascular lesions and good initial VA were not good candidates for focal laser photocoagulation. In all probability, the wavelength specificity for laser photocoagulation of the CNV was not as critical as the completeness of treatment (16).
UTILITY IN CURRENT CLINICAL PRACTICE
Although photocoagulation treatment could change the natural history of the disease, it would not restore vision, and unfortunately with the appropriate follow-up, persistent or recurrent CNV would be observed in all kinds of extrafoveal, juxtafoveal, and subfoveal CNVs. Therefore, thermal coagulation produces a scar that goes through all layers of the retina and that manifests itself clinically as a visual field defect.
In light of recent findings on anti-VEGF therapy, it seems like at present photocoagulation for CNV should only be applied for small extrafoveal lesions, which accounts for 5% of all patients. There is no doubt that laser photocoagulation is still useful for peripapillary CNV. However, some ophthalmologists are hesitant to treat peripapillary CNV with photocoagulation, fearing that the procedure may lead to thermal damage of the nerve fiber layer in the papillomacular bundle. Others are hesitant because they believe that the natural course of peripapillary lesions might be more benign than the treatment (21). The MPS reported that in those eyes with peripapillary CNV lesions nasal to the fovea and below the papillomacular bundle, 44% of treated eyes versus 29% of untreated eyes would achieve VA of 20/40 or better at 3-year follow-up. In addition, only 9% of treated eyes compared to 54% of untreated eyes lost six or more lines of VA. The MPS group reported that severe VA loss was noted after treatment only when recurrent CNV extended through the center of the fovea (17–21). This finding suggests that severe visual loss only from nerve fiber layer damage after this treatment approach, in the absence of subfoveal recurrence, must be a rare complication.
In order to avoid thermal necrosis of disc tissue and following the MPS photocoagulation technique, one should consider refraining from treatment within 100 to 200 μm of the optic nerve and consider treatment only when at least 1 ½ clock hours of papillomacular bundle on the temporal side of the disc is uninvolved with CNV so that at least 1 ½ clock hours of papillomacular bundle can be spared of treatment (17).
In 1988, De Juan and Machemer (22) described a vitrectomy technique with a large flap retinotomy for the removal of blood and disciform scars in four end-stage cases of AMD. Although three of their patients improved their vision, two of them developed severe proliferative vitreoretinopathy (PVR). Subsequent surgeons reported discouraging results in terms of VA (23). As a result of these experiences, large flap retinotomy was not widely employed. Investigators speculated that the postsurgical absence of retinal pigment epithelium (RPE) was the cause of poor vision, and thus, they attempted to replace subfoveal RPE with autologous or homologous RPE. However, the surgical transplantation of RPE failed to improve vision (23). In January 1991, Thomas and Kaplan (24) reported in two patients an alternative approach to subfoveal neovascularization in POHS, with dramatic improvements in VA from 20/400 to 20/20 and 20/400 to 20/40, respectively. Instead of a large flap retinotomy, their technique employed a small retinal hole through which instruments were introduced into the subretinal space (23,24).
PRINCIPLES OF TREATMENT
The surgery for CNV is appealing because it offers the promise of removing abnormal tissue without causing as much damage to normal tissue (neurosensory retina) as occurs with laser photocoagulation (23). However, it has also been realized that the numerous pre-RPE and sub-RPE attachments of the neovascular complex in AMD (in contrast to the neovascular complex in ocular histoplasmosis that lie predominantly anterior to the RPE and have eccentric ingrowth sites), carry an increased risk of damage to the underlying RPE thereby resulting in poorer visual outcome.
SUMMARIZED MULTICENTER, RANDOMIZED, AND DOUBLE-BLIND CLINICAL TRIAL RESULTS IN SUBMACULAR SURGERY
The Submacular Surgery Trials (SST) was initiated in 1997, prior to the advent of photodynamic therapy (PDT) (25). They were designed to compare the outcome of surgical treatment versus observation in three categories: (a) (SST-N): New subfoveal CNV (without prior laser) secondary to AMD, (b) (SST-H): CNV secondary to POHS or idiopathic etiology, and (c) (SST-B): Thick submacular blood or hematomas associated with AMD. In the three arms, a successful outcome was defined to be either improvement of best-corrected visual acuity or visual acuity no more than 1 line worse at 24-month follow-up. However, none of the three arms showed a benefit over the observation group at the end of the study period (25–28), according to the following results:
SST-N: Forty-four percent of observed eyes and 41% of eyes assigned to surgery had a successful outcome as defined in the study. Median VA loss at 24 months was 2.1 lines in observed eyes and 2.0 lines in eyes assigned to surgery. Median VA declined from 20/100 to 20/400 at 2 years in both groups (26).
SST-H: Forty-six percent of eyes in the observation arm and 55% of those in the surgery arm had a successful outcome as defined in the study. Median VA at 24 months was 20/250 among eyes in the observation group and 20/160 in the surgery group. A subgroup of eyes with VA worse than 20/100 at baseline had more success with surgery; 76% in the surgery arm versus 50% in the observation arm. However, recurrent CNV developed in 54% of surgically treated eyes at 24 months (27).
SST-B: Forty-one percent of observed eyes and 44% of eyes assigned to surgery achieved a successful outcome as defined in the study (28).
UTILITY IN CURRENT CLINICAL PRACTICE
Vitrectomy surgery for removal of subretinal CNV, whether subfoveal or nonsubfoveal, has not been shown to be more beneficial over laser photocoagulation, PDT, or observation in any prospective clinical trial. However, massive subretinal hemorrhage is a medically untreatable entity that will remain in the domain of surgical treatment.
The use of intravitreal triamcinolone was largely overlooked until 2002 when Jonas et al. (29–31) published their findings on the beneficial effects of the triamcinolone on macular edema, on ocular neovascularization, and during difficult surgical cases. Subsequently, several animal studies showed the benefits of triamcinolone acetonide in the treatment of experimental CNV (32,33). Ciulla et al. (33) noted that the rodents failed to develop iatrogenic created krypton laser CNV if laser photocoagulation was followed by an intravitreal injection of triamcinolone. In contrast, nearly 70% of eyes that received intravitreal saline after laser photocoagulation developed CNV.
Triamcinolone acetonide exerts an anti-inflammatory effect due to the induction of the phospholipase A2 inhibitory proteins. These proteins control the biosynthesis of prostaglandins and leukotrienes by inhibiting the release of arachidonic acid, which is released from membrane phospholipids by phospholipase A2 (34).
In 1994, Dominguez-Collazo (35) detailed the safety and efficacy of intravitreal triamcinolone in the treatment of subfoveal CNV secondary to AMD. One year later, Penfold et al. (36) published the first results from a large series of patients. In the long-term follow-up, intravitreal triamcinolone acetonide (IVTA) as monotherapy had no effect on the risk of severe VA loss, despite a significant antiangiogenic effect found 3 months after the treatment. The first randomized, double-blind, placebo-controlled study in a relatively large study population was reported by Gillies et al. (37) in 2003. They treated patients with a single dose of intravitreal triamcinolone, and after 1 year of follow-up, they found a 35% risk of severe visual loss in both groups (treatment vs. observation). Further studies with conventional (4 mg) and higher doses (20–25 mg) did not show any other beneficial effects (38,39).
UTILITY IN CURRENT CLINICAL PRACTICE
Although an important number of publications were written, several issues remained unsolved regarding the type of CNV that responded best to intravitreal triamcinolone, the dose (from 4 to 25 mg depending on the study), and the frequency of injection (34). The intravitreal administration of steroids alone can no longer be recommended, in view of the results of new VEGF inhibitor treatments and the high rate of complications such as cataract, glaucoma, vitreous hemorrhage, and pseudoendophthalmitis (34). Nowadays, IVTA has been tested as a part of the triple combined treatment (see combined treatment).
Until 1999, no treatment other than laser photocoagulation had been shown to reduce the risk of vision loss in patients with CNV from AMD in large-scale, randomized clinical trials (40). The first experience with the use of PDT in ophthalmology was reported in 1994 treating intraocular tumors and subretinal neovascularization (41,42). The propitious results obtained in the treatment of choroidal melanomas initiated the study of PDT in animal models of CNV (43). In 1998, Schmidt-Erfurth et al. (44) reported the results of 61 patients with subfoveal CNV secondary to AMD treated with PDT in whom a temporary closing of the CNV was observed, and stabilization of VA was achieved. Based on this experiment, phase III randomized clinical trials were designed and developed (45).
PDT involves the use of a photoactivatable compound (photosensitizer: Benzoporphyrin derivate [BPD-verteporfin; Ciba Vision AG, Balateh, Switzerland & QLT Photherapeutics, Vancouver, Canada]), which accumulates in, and is retained by, proliferating tissues. When injected intravenously and complexed with low-density lipoprotein (LDL), verteporfin may be taken up selectively by rapidly proliferating endothelial cells that have an increased number of LDL receptors active in their plasma membranes. When this molecule is activated by light of appropriate wavelength (laser light of low power to avoid thermal damage), active forms of oxygen and free radicals are generated, causing a photochemical reaction that appears to result in direct cellular injury, including damage to vascular endothelial cells and vessel thrombosis (46).
SUMMARIZED MULTICENTER, RANDOMIZED, AND DOUBLE-BLIND CLINICAL TRIAL RESULTS IN PHOTODYNAMIC THERAPY
The treatment of AMD with photodynamic therapy (TAP) study was carried out in 22 centers in Europe and the United States with 609 patients recruited between December 1996 and October 1997 and randomized in a proportion of two to one (verteporfin to placebo). Cases enrolled were to have subfoveal CNV with a component of classic CNV and a greatest linear dimension ≤5,400 μm. Results at 1 year showed that verteporfin therapy significantly reduced the risk of moderate and severe visual loss compared to placebo (47). At 12-month follow-up examination for primary outcome, 39% of 402 verteporfin-treated patients compared with 54% of 207 placebo-treated patients had three or more lines of VA loss (P < 0.001). Subgroup analysis showed that the treatment benefit was judged to be quite clinically relevant in eyes with predominantly classic CNV (where the classic CNV was ≥50% of the area of the lesion), especially when no occult CNV was present. No VA benefit was noted for cases with classic CNV in which the area of classic CNV was greater than 0 but less than 50% of the area of the lesion. At 24-month follow-up, moderate visual loss was observed in 47% of the patients in the verteporfin group and 62% in the placebo group (P < 0.001) (48). An extension to 36 months demonstrated that the visual results of patients with predominantly classic lesions treated with verteporfin remained stable (49).
The Verteporfin in Photodynamic Therapy (VIP) Study began in 1998 and included 459 patients (120 patients with CNV secondary to myopia and 339 patients with occult CNV secondary to AMD) recruited in 28 centers in Europe and the United States. Results at 1 year showed that 51% of the group treated with verteporfin suffered from moderate visual loss compared to 55% in the placebo group; in other words, verteporfin did not perform any better than letting the disease run its natural course (45). However, at 2 years, the results showed that a smaller percentage of the group treated with verteporfin suffered from moderate visual loss (55% vs. 68%, P = 0.023). Analyzing the group with occult active CNV secondary to AMD, the results showed a benefit when the patient had small lesions (less than 4 MPS disc diameters) with independence of the VA or VA less than 20/50, regardless of the size of the lesion (50).
In those patients with CNV secondary to myopia, the VIP results showed that at 1 year, 72% of the patients treated with verteporfin lost less than 1.5 lines of vision compared with 44% of the patients in the placebo group (P = 0.003) (51). At the conclusion of the 2nd year, 39% of the patients treated with verteporfin versus 13% in the placebo group gained at least one line of VA (52).
The Visudyne in Minimally Classic CNV (VIM) trial was developed because in a retrospective analysis, the group of patients with minimally classic CNV secondary to AMD (with lesions measuring less than 4 MPS disc diameters and visual acuities less than 20/50) lost less vision when they were treated with verteporfin compared to patients who did not receive PDT (42% vs. 63% in the placebo group). Previous studies suggested that diminishing the light fluence could maximize the photodynamic effects of verteporfin. For this reason, a phase II study was designed to compare the application of verteporfin using standard-fluence PDT (600 mW/cm2) compared to low-fluence PDT (300 mW/cm2) (45). After 12 months, it was observed that the group treated with verteporfin had better visual acuities than did the control group (low-fluence PDT compared to placebo P = 0.02; standard-fluence PDT compared to placebo P = 0.08; PDT with verteporfin group compared to placebo P = 0.01) (53).
Other PDT Studies
The Verteporfin in Ocular Histoplasmosis (VOH) Study was developed to evaluate the response of PDT treatment in 26 patients with CNV secondary to ocular histoplasmosis. At 12 months, a mean of seven lines of improvement was observed (54).
The Visudyne with Altered (delayed) Light in Occult CNV Trial (VALIO) was designed to determine if delayed laser application (30 minutes) had a positive impact on the visual and angiographic results of patients with occult CNV. The results at 6 months did not show any difference (55).
The Visudyne Early Retreatment (VER) Trial was to determine if earlier retreatments reduced the risk of moderate visual loss in patients with subfoveal predominantly classic CNV secondary to AMD. Re-treating the patients every 6 weeks during the first 6 months and later every 3 months until 2 years did not show any difference after 12 months of follow-up when comparing the results with the control group (45).
UTILITY IN CURRENT CLINICAL PRACTICE
After the introduction of PDT, the location of lesions to be treated (extrafoveal, juxtafoveal, or subfoveal) became irrelevant. Instead, the composition of the lesion was more important (classic or occult). In other words, when PDT with verteporfin was initiated, a reduction of the risk of moderate and severe visual loss in patients with classic CNV and some occult CNVs was achieved, regardless of the localization of the CNV. However, later studies showed that PDT with verteporfin could cause choroidal ischemia with the subsequent stimulation of VEGF expression (56). For this reason and as a result of newer modalities like anti-VEGF therapy, the PDT treatment of CNV secondary to AMD patients evolved to double (PDT + verterporfin + intravitreal steroids) or triple (PDT + verterporfin + intravitreal steroids + anti-VEGF) combination therapies. At present, PDT with verteporfin alone is particularly useful in choroidal hemangioma and central serous chorioretinopathy among other disorders.
The first experience with the use of transpupillary thermotherapy (TTT) in ophthalmology was reported by Journee-de Kover and Oosterhuis (57) in 1992 for the treatment of choroidal melanomas. The beneficial results obtained in the treatment of choroidal melanomas initiated the study of TTT in CNV secondary to AMD (58–62). It was particularly indicated in patients with purely occult CNV where PDT + verteporfin treatment had not shown any advantage over untreated patients according to the 1-year follow-up VIP results.
TTT is a low irradiance (810 nm), large spot size (3 mm), long pulse (60 seconds in a continuous mode), infrared diode laser photocoagulation technique that is poorly absorbed by hemoglobin and xanthophylls, allowing transmission through preretinal and subretinal hemorrhage, and reducing nerve fiber layer damage. Melanin in the RPE and choroid converts laser radiation into heat energy, which increases the temperature of the treated tissue. Vascular damage most likely occurs by heat conversion from the pigmented targets of the irradiation, including the RPE cells and choroidal melanocytes.
Summarized Multicenter, Randomized, and Double-Blind Clinical Trial Results in TTT
The preliminary results of a multicenter, randomized, double-blind clinical trial were presented at the American Academy of Ophthalmology (AAO) Annual Meeting in 2004. The TTT4CNV compared TTT to sham for subfoveal occult CNV caused by AMD. In its preliminary results in 303 patients enrolled, TTT, as applied in this trial, did not result in a significantly advantageous effect relative to sham. However, a subgroup analysis of eyes with poorer baseline VA (20/100 or worse) indicated a statistically significant treatment benefit. Improvement in VA (by two or more lines) was significantly greater (P = 0.03) in TTT-treated eyes at 12 months (19% vs. 0%) and at 18 months (17% vs. 0%). The best results occurred in TTT-treated eyes that were not re-treated (63).
Indocyanine Green–Enhanced Diode Laser Transpupillary Thermotherapy (i-TTT)
i-TTT is a technique that requires intravenous injection of a photosensitizing agent (ICG dye) that accumulates in neovascular tissue. This photosensitized tissue is then irradiated by light at the absorption peak of the dye (805 nm), which is close to the peak emission (810 nm) of the conventional diode laser. ICG is an anionic tricarbocyanine dye with a large protein-bound component that provides a selective intravascular retention advantage in the large choroidal vessels (with a great concentration of ICG) compared to retinal vessels. In exudative AMD, there is less melanin pigment in the proliferative pigment epithelium that covers the CNV, and this less-pigmented RPE absorbs little laser light. However, the therapy is still effective because ICG becomes a new chromophore and absorbs the infrared light, which leads to vascular toxicity.
i-TTT results are quite similar to TTT alone (66). A possible explanation for this might include differences between adjustments in ICG concentration during i-TTT, laser power, and/or the timing of laser application following ICG infusion (67).
Utility in Current Clinical Practice
Like PDT + verteporfin, the TTT and i-TTT therapies evolved into combined treatment modalities with intravitreal steroids or anti-VEGF therapy. TTT and i-TTT are still popular methods for the treatment of small and medium-sized choroidal melanomas.
Combination therapy for wet AMD started after V-PDT was approved for use in 2000. The first dual combinations involved V-PDT plus intravitreal triamcinolone (68). When the anti-VEGF agent pegaptanib became the first agent in its class approved for use, studies of combination therapies of this drug plus V-PDT followed (69,70). Subsequent availability of the anti-VEGF agent ranibizumab generated considerable excitement because it demonstrated meaningful vision benefit for the first time in patients with wet AMD. Combination therapy with ranibizumab or the similar agent bevacizumab and a steroid, V-PDT, or both, followed.
Combining various treatment modalities for exudative AMD targets multiple components of CNV. The intent is to provide different and complementary mechanisms of action to decrease inflammation, destroy existing CNV, prevent the formation of new CNV, and inhibit further VEGF production. This approach has the potential for improving efficacy and reducing treatment frequency.
Summarized Results in Combination Therapies
This chapter is focused on treatments available previous to the introduction of the new anti-VEGF agents, so it is beyond the scope of this review to analyze each of these modalities. However, the double therapy of PDT + verteporfin plus intravitreal triamcinolone is included here because it was done before the appearance of anti-VEGF therapies.
Double Therapy with PDT + Verteporfin Plus Intravitreal Triamcinolone
A large number of publications confirmed the positive synergic role of combining TA and PDT therapies for the treatment of all types of CNV (71,72). However, the advantages registered with the use of IVTA plus PDT compared to PDT alone were partially limited by the side effects, such as the rapid evolution of cataract. Furthermore, in large, randomized, clinical trials on combination therapy of TA and standard and low-fluence PDT, VA failed to show an improvement, even though the lesion size and subretinal fluid had decreased, compared to controls treated with PDT alone (73–76).
UTILITY IN CURRENT CLINICAL PRACTICE
The treatment options have expanded considerably over the past decade. Currently, combination therapies including ranibizumab or bevacizumab plus V-PDT (verteporfin photodynamic therapy) with and without steroids are being exhaustively investigated. The overall goal is to produce vision benefits comparable to those produced with ranibizumab monotherapy but with a reduced need for re-treatment. Dual combination trials comparing V-PDT plus ranibizumab with either V-PDT or ranibizumab monotherapy include FOCUS, PROTECT, MONT BLANC, and DENALI. Triple combinations with V-PDT, an anti-VEGF agent, and a steroid represent the next logical step in treating wet AMD. The RADICAL is a triple combination trial comparing V-PDT plus ranibizumab plus or minus dexamethasone with ranibizumab monotherapy.
Choroidal Feeder Vessel Photocoagulation Therapy
Feeder vessel photocoagulation therapy (FVT) is not a new technique in ophthalmology and has existed for more than 30 years (77). In fact, it was recommended in the guideline for MPS treatment published in 1991 (10). However, its use had been limited by difficulties in identifying the actual feeder vessel. The development of high-speed dynamic video indocyanine green angiography (HSICGA) allows identification of these feeder vessels as the afferent or arteriolar arm of the CNV complex in up to 90% of eyes regardless of the type of leakage (78).
The concept of treating feeder vessels is based upon the concept that a single vessel often controls the majority of blood flow to an area of neovascularization within the choroid. The attenuation of the feeder vessel induces remodeling and maturation of the CNV complex resulting in resolution of exudative manifestations such as subretinal fluid, subretinal hemorrhage, and retinal edema (79,80). By treating only the afferent vessel, rather than the entire lesion, trauma to surrounding tissue is minimized.
FVT has been successfully used in patients with classic, occult CNV and in several situations where a subfoveal CNV exists, since the feeder vessel itself is usually extrafoveal (79,81,82). Although there are no multicenter, double-blind, and randomized studies in large populations that would result in clinically relevant conclusions, in small series, application of FVT in classic CNV has shown improvements of more than two lines varying from 38% to 50% with recurrences between 13% and 19% of eyes according to a few available studies (81,82). In occult CNV, Roh and Glaser (83) reported improvements greater than three lines in 24.3% of 37 eyes included for analysis. Other successful results with regression of subretinal fluid and retinal edema have also been reported in pigment epithelial detachments, recurrent CNV, retinal–choroidal anastomosis, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation (80,84–87).