Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

Ranibizumab is a humanized monoclonal antibody fragment, produced in Escherichia coli by recombinant DNA technology. It binds with high affinity to all VEGF isoforms. It results from the insertion of murine anti- VEGF-A complementary-determining regions (CDRs) into a human IgG1 framework.57 The two major phase 3 clinical prospective, randomized, double-blind, sham-controlled trials for ranibizumab are known as MARINA and ANCHOR. The MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration) is a study on safety and efficacy of intravitreal injections of ranibizumab administred every four weeks in patients with minimally classic and occult CNV associated with AMD. The study met its primary endpoint at 12 months when 94.5% of the patients receiving ranibizumab 0.3 mg and 94.6% of those receiving 0.5 mg had lost fewer than 15 letters from baseline, as compared with 62.2% in the sham-injection group. Furthermore, this is the first wet AMD treatment in which not only stabilization but also an increase of visual acuity was observed. At 12 and 24 months, approximately one quarter of patients treated with 0.3 mg of ranibizumab and one third of patients treated with 0.5 mg gained 15 or more letters, as compared with 5% or less of those in the sham-injection group. A subgroup analysis revealed that the most important predictors of visual acuity outcomes were baseline visual acuity score, CNV lesion size, and age.58 In the ANCHOR study (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration) eligible patients were

randomly assigned in a 1:1:1 ratio to receive either 0.3 or 0.5 mg of ranibizumab plus sham verteporfin therapy or sham intravitreal injections plus active verteporfin therapy. All end points with respect to visual acuity in the study eye at 12 months favored ranibizumab treatment over verteporfin therapy. With respect to the primary efficacy end point, 94.3% of patients in the 0.3 mg group and 96.4% in the 0.5 mg group lost fewer than 15 letters from baseline visual acuity, as compared with 64.3% in the verteporfin. In addition, the proportion of patients whose visual acuity improved from baseline by 15 or more letters was significantly greater among those receiving ranibizumab treatment (35.7% in the 0.3 mg group and 40.3% in the 0.5 mg group, as compared with 5.6% in the verteporfin group; P<0.001 for each comparison). In summary, the ANCHOR study showed that ranibizumab administered monthly by intravitreal injection was superior in efficacy to photodynamic therapy with verteporfin in patients with subfoveal, predominantly classic choroidal neovascularization associated with age-related macular degeneration. The 2-year results confirmed the visual acuity gain maintenance in both ranibizumab groups.59 Intravitreal injections of ranibizumab were associated with a low rate of serious ocular adverse events: most common were presumed endophthalmitis and severe intraocular inflammation (reported in less than 0.1% of pooled ranibizumab injections). Patients treated with a 0.5 mg dose had a higher rate of arterial thromboembolic events (mostly with a history of stroke or arrhythmia) than did those who received a 0.3 mg dose or control cases but the difference was not statistically significant.60

Subsequent studies were designed to determine whether a less frequent ranibizumab dosing schedule would prevent loss of visual acuity in patients with AMD reducing the treatment burden for the patients. In the phase IIIb, multicenter, randomized, double-masked PIER trial (Randomized, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-related Macular Degeneration), based on the evidence that farmacodynamic activity of ranibizumab may last 90 days, patients received monthly injections for the first 3 months and then once every three months. While the efficacy in preserving from loss of visual acuity was mantained (-1.6 and -0.2 letters in the ranibizumab 0.3 mg and 0.5 mg groups vs -16.3 in the sham group), the vision gain obtained after 3 months was not observed at 12 months.61

The PrONTO (Prospective Optical coherence tomography imaging of patients with neovascular AMD treated with intra-ocular ranibizumab -Lucentis-) study was a 2-year, open-label, prospective, single center clinical study designed to investigate the efficacy, durability and safety of a variable-dosing regimen with intravitreal ranibizumab, OCTguided, in patients with neovascular AMD. Intravitreal injections of ranibizumab were administered to all patients at baseline, month 1, and month 2. Additional reinjections were given if any of the following changes were observed by the evaluating physician during the first year of the study: VA loss of at least 5 letters with OCT evidence of fluid in the macula, an increase in OCT central retinal thickness of at least 100 μm, new macular hemorrhage, new area of classic CNV, or

evidence of persistent fluid on OCT one month after the previous injection. During the second year, an amendment to the study changed the retreatment criteria to include any qualitative change in the appearance of the OCT images that suggested recurrence of fluid in the macula (e.g. appearance of retinal cysts, subretinal fluid, enlargement of a pigment epithelial detachment). VA improved by 11.1 letters at 24 months with a 95% CI ranging from 7 letters to 15.2 letters, suggesting results comparable with the phase III trial results. Whereas patients in the MARINA and ANCHOR trials received 24 injections over 24 months, the patients in the PrONTO Study received an average of just 9.9 injections with a median of 9.0 injections. 97.5% of patients avoided a 15-letter VA decrease, 43% of patients gained at least 15 letters of VA, 78% of patients didn’t lose any letters. The PrONTO Study suggests that VA outcomes with an OCT-guided treatment with ranibizumab seem to be comparable with the results obtained with monthly injections.62

Current strategies of treatment with ranibizumab will be revisited according to prospective, randomized, double-masked ongoing trial with the aim of reducing the number treatment with visual acuity results comparable to monthly fixed dosing regimen.60

Bevacizumab (Avastin). is a humanized monoclonal antibody binding all isoforms of VEGF. It was designed for intravenous administration and approved in 2004 for the treatment of metastatic colorectal cancer.63 The first use of intravitreal bevacizumab for wet AMD was reported in a single case in 2005.64 Since then, the use of intravitreal

bevacizumab as an off label treatment for neovascular AMD has become widespread. Several small, uncontrolled retrospective and prospective studies ofintravitrealbevacizumab in neovascular AMD have been published.65,66 Recently published results of a prospective study on 51 eyes of 51 patients treated with 2.5 intravitreal bevacizumab over 24 months suggest that this treatment is safe (one patient required surgery for instable angina and no ocular adverse event were reported) and efficacious: mean visual acuity improved significantly from 45.7 letters at baseline to 54.3 letters at 24 months, 92.2% lost fewer than 15 letters.67 Debated is the minimum efficacious dose: dose ranging in published studies is 1 - 2.5 mg, although recently Arevalo suggested that 1.25 mg may have equal efficacy of higher doses.68 Adverse events reported in a registry compiling adverse experiences of 7113 injections69 included ocular complications (more frequent bacterial endophthalmitis in 0.16% and retinal detachments in 0.16%) and systemic complications (acute elevation of bloood pressure in 0.59%, cerebrovascular accidents in 0.5%, myocardial infarction in 0.45 and death in 0.4%). Randomized, controlled trials comparing bevacizumab with approved therapies are still ongoing.70

Combination therapies. An ideal therapy for AMD, taking into account the multifactorial pathogenesis, would eradicate pre-existing neovessels as well as reduce inflammation and VEGF expression to prevent further CNV growth. No single therapy possesses all of these action modalities. Nonetheless, intravitreal anti-VEGF monotherapies must be frequently administered for a prolonged period of time to maintain the VA benefit

and recent clinical data indicate a possible resistance and tolerance to both ranibizumab and bevacizumab.71

Currently, combinations of two or three therapies, compared with anti-VEGF monotherapy are being tested for their ability to reduce the intervention rate with equivalent efficacy and safety results. These include the combination in various ways of PDT, radiation therapy, pegaptanib, ranibizumab, bevacizumab, triamcinolone, dexamethasone.

Large case series have demonstrated the advantages of combining standard PDT and high dose intravitreal triamcinolone but serious adverse complications have been reported.72-74

Efficacy of standard PDT and bevacizumab 1,25 mg (within 14 days) combination treatment has been recently examined in a large retrospective multicenter case series. With one combination treatment at baseline and a mean of 0.6 additional verteporfin PDT retreatments and 2.0 bevacizumab retreatments over a mean follow-up period of 15.0 months, after 12 months (701 cases) 82% of patients had stable or improved vision (loss of <3 lines or a gain in VA), 36% improved by > or =3 lines, and 17% improved by > or =6 lines with a mean vision gain of approximately 1.2 lines of VA from baseline. Patients who were treatment naïve gained significantly more compared with those who had been previously treated.75

Augustin et al treated 104 eyes, with reduced light dose (42 J/cm) of PDT by

verteporfin, 800 μg of dexamethasone and 1.5 mg of bevacizumab intravitreal injection after 16 hours. Five patients received a second PDT and 18 patients had a second bevacizumab injection in 40 weeks of fol- low-up (range, 22-60 weeks) with a mean visual acuity improvement of 1.8 lines, with 39.4% gaining three or more lines and 3.8% losing three or more lines.76 In Yip series of consecutive cases treated with standard fluence PDT and intravitreal injection within one hour of 4mg of triamcinolone and 1.25 mg of bevacizumab, 78% achieved CNV eradication, and 61% achieved visual stabilization at 6 months, with 30% and 28% gaining three or more lines at 3 and 6 months respectively.77 In a recent retrospective cases serie with 13.7 months mean follow-up, same day triple therapy with reduced fluence photodynamic therapy (25 J/cm), intravitreal dexamethasone (200 microg), and intravitreal bevacizumab (1.25 mg) gave good results particularly in naive treated patients.78

International multicenter double-masked placebo controlled trials are currently ongoing with the aim of better understanding advantages and disadvantages of combination therapies with currently usable drugs.

SURGICAL TREATMENT OF WET AMD

Limits of current therapies of AMD are well known: necessity of repeated injections over several months, high costs, poor patient compliance, organizational problems for medical facilities, and in some cases, treatment failures. Alternative therapies are therefore still under investigation.

Few surgical options have been proposed, for the time being, confined to advanced cases, non-responders to other treatments and treatment failures often complicated by large hemorrhages.

CNV excision. The Submacular Surgery Trial (SST) has shown that subretinal neovascular membrane excision is not advantageous in AMD.79,80 Bottoni and colleagues81 have further shown that the affected part of the RPE increases, on average, 19.5 times compared to the affected area before surgery.

Therefore, most surgeons have moved to complex surgical procedures enabling a rotation of the macular neural retina over a healthy RPE area.

Macular Translocation. In Macular Translocation (MT) a iatrogenic retinal detachment is induced, followed by the removal of the neovascular membrane and relocation of the fovea to an unaffected part of the RPE and choroid.82-84

In full macular translocation (FMT) or 360° translocation, a complete peripheral retinotomy enables the rotation of the whole retina allowing a wide displacement of the fovea (usually upwards).85-89

In Limited Macular Translocation (LMT) the fovea is moved by punctate retinomies once a local detachment of the posterior pole is induced, with or without a scleral shortening from the outside (‘infolding’ or ‘outfolding’).89-93

FMT allows to move the fovea up to 3300 micron or more compared to little more than 1000 micron in LMT, and is thus more indicated in more advanced CNV cases.94 MT surgical procedure is complex, requires a highly experienced surgeon, and the complications are numerous, both intraoperatively (retinal ruptures, ocular hypotony, macular folds and vitreous, retinal and choroidal hemorrhages) and postoperatively (hemorrhages, relapse of the neovascularization, torsional diplopia, ocular hypotony, macular holes and retinal detachment with PVR).79-87

Presently, only limited case studies are reported and a recent analysis published on the Cochrane Database of Systematic Review95 concludes that at the moment there is not sufficient scientific evidence, based on randomized and controlled trials, to extend the use of this surgical procedure.

The most encouraging results have been achieved by small studies comparing the efficacy of LMT and PDT in myopic patients: in the LMT group 55% of the patients showed an increase of 3 or more lines in BCVA and 60% had an improvement of at least 5 letters compared to 10% and 40% in the PDT group.96

Figure 3: Autologous transplantation of a peripheral RPE-choroid patch that is inserted underneath the macula following surgical CNV excision.

Autologous pigment epithelium transplant. The necessity of restoring a healthy RPE underneath the foveal area has led to autologous transplantation of a peripheral RPE-choroid patch that is inserted underneath the macula following surgical CNV excision (Figure 3). The transplanted tissue grafts onto the new area in most cases and patch vitality can be shown by angiography and autofluorescence (AF). Revascularization of the transplanted RPE and choroid allows a functional improvement in some cases.

However, the rate of complications, which may be serious, leading to more interventions, appears significant and can be higher than

60%.97-99

A recent study100 compares the long-term results of MT and RPE transplantation (patch graft, PG) and shows that after 3-year fol- low-up the MT group maintained functional results that were superior to the PG group showing a progressive loss of retinal function. The authors attribute this effect to major surgical trauma and to the failed perfusion of the part transplanted in the first few days postop with a permanent damage to the foveal receptors.

Relocation and drainage of subretinal hemorrhages. The onset of a massive subretinal hemorrhage is one of the most serious complications in patients with wet AMD, and causes a sudden and substantial vision loss. Occasionally, visual acuity is recovered spontaneously but generally the prognosis is negative. Experimental studies demonstrate that permanent changes of the retina start to develop 24 hours after the bleeding, with loss of photoreceptors due to mechanical, metabolic and toxic damage.

Thus, in these cases an early relocation or drainage of the hemorrhage is fundamental for a better functional prognosis. A gas tamponade with Sulfur Hexafluoride (SF6) with or without a Recombinant Tissue Plasminogen Activator (r-TPA) injection seems advisable for achieving better vision. Nevertheless, the penetration of intravitreally injected r-TPA through the retina and the necessity of injection in the subretinal space are still debated.

In a meta-analysis of the results achieved by various surgical procedures for wet AMD, Falkner and colleagues101 compared SST data with VA outcomes of MT, RPE transplantation and removal of major subretinal hemorrhages, using data from 88 studies published between 1992 and 2004. The Authors concluded that removal of neovascularization, macular translocation and RPE transplantation, show a rate of improvement of 2 ETDRS lines or more similar to the percent of cases with VA decline of 2 or more ETDRS lines with high a frequency of complications (50-80%). Subretinal hemorrhage removal show a significant favorable effect on functional prognosis: 62% improvement versus 13% decline, and a 37% rate of complications.

Epiretinal brachytherapy. Attempts to use external radiation of the posterior pole to inhibit or slow down the proliferation of subretinal neovascular vessels have produced disappointing results both in terms of efficacy and safety because of radiation effects on the adjacent tissues (lens, optic nerve, ocular adnexa) and on the retina itself (radiation retinopathy).

Recently, a new epiretinal brachytherapy procedure was developed: during a vitrectomy, a probe with strontium-90 beta isotope (Neovista®) allows to exclusively radiate the macular area to a depth of only 3 mm and covering an area of 5 mm in diameter with a limited application of 24 Gy (Figure 4). The use of epiretinal brachytherapy combined with intravitreous anti-VEGF agents injections has shown promising safety and efficacy profiles in pilot studies. In a recent report on 34 patients with follow-up of 12 months, 96% of

patients lost 15 or fewer letters, with a mean VA increase at the end of the follow-up of 10.7 letters.102 Furthermore, at the end of the follow-up there was no evidence of radiation retinopathy but an increase of the crystalline opacity, possibly related to the surgical procedure. Multicenter randomized and controlled studies are under way, aiming to compare the efficacy of this new procedure with the standard of care therapies with anti-VEFG agents.

Suprachoroidal infusion of drugs. The therapeutic effect of pharmacological combinations may be amplified by administration in the suprachoroidal space thanks to a purposely conceived microcatheter (iTrack TM-iScience

Interventional Corp., Menlo Park, CA) while reducing the possible systemic absorption of these drugs.

Preliminary studies on an animal model show that the microcatheter allows the injection of triamcinolone acetonide in the posterior suprachoroidal space with a low incidence of complications, and although the drug remains in the injection spot for at least 120 days, the systemic levels are minimal.103

A pilot study is ongoing to establish the safety and feasibility of suprachoroidal administration of 4mg (0.16ml) of bevacizumab and 4mg(0.1ml)oftriamcinoloneacetonidethrough the ophthalmic microcatheter inserted via an

anterior scleral incision in the suprachoroidal space and moved to the area corresponding to the macula (Figure 5).

exudative AMD. Nonetheless, visual acuity recovery is still partial and the treatment burden for patients and Health Care Systems has significantly increased.

CONCLUSIONS

In the last decade PDT with verteporfin andtheanti-VEGFpegaptanibandranibizumab have significantly improved the prognosis of

New pharmacogenetic evidences show that genetic variants might significantly affect the response to treatments. Two retrospective analyses from the same group reported that patients with the CFH CC genotype responded

to treatment with intravitreal bevacizumab and verteporfin PDT significantly worse than did those with the CFH TC and TT genotypes while no association in treatment response was related to LOC387715 A69S variant.104,105

New drugs are in clinical trials: VEGF Trap is a receptor decoy that targets VEGF with higher affinity than other available antiVEGF agents.106 Other promising therapeutic strategies are focused on ameliorating delivery of drugs and on new molecules designed to inhibit VEGF production by silencing RNAs (SiRNA) or block VEGF post-receptorial cascade via tyrosine kinase inhibitors. Moreover inhibitors of other proangiogenic molecules involved in the neovascular process (particularly interesting is E10030, an anti platelet derived growth factor studied in combination with anti-VEGF) are under development.106-110

Future AMD strategies will be chosen upon single patient conditions on the base of a better knowledge of genetic and environmental risk factors and with multi-approach surgical and medical treatment options.102

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