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SUBMACULAR SURGERY TRIAL (SST) FOR CHOROIDAL NEOVASCULARIZATION
EYAL MARGALIT, RAJENDRA S APTE
Wilmer Eye Institute, Baltimore, MD.
The submacular surgery trial was initiated to define indications and outcomes of subretinal surgery in ARMD. Three groups of patients are studied - Group B (Blood), Group N (New CNV) and Group H (Histoplasmosis/Idiopathic). Eligible patients are randomised after entry into the study to assure accurate comparisons between eyes subjected to surgery and those managed by other strategies. Standardized visual acuity protocols, standardized surgical protocol, careful long-term follow-up and complete reporting of complications will provide important information regarding the visual outcomes of subretinal surgery and enhance our knowledge of the natural course of eyes with these lesions. A variety of ocular disorders can weaken Bruch’s membrane, allowing growth of capillary tufts and the subsequent proliferation of choroidal neovascular tissue (CNV) beneath the retina. Age-related macular degeneration (AMD) is the main cause of visual loss among adults older than 65 in western countries. Annually, there are approximately 700,000 new patients in the USA who lose vision due to this illness and 10% of these who have the disease become legally blind each year.[1] In AMD, Bruch’s membrane demonstrates diffuse abnormalities, with the accumulation of drusen that predispose to vascular invasion.[2] CNV is the primary cause of vision loss in patients with AMD, particularly when the neovascular lesion underlies the centre of the foveal vascular zone.
In presumed ocular histoplasmosis syndrome (POHS) and other inflammatory conditions, the defects in Bruch’s membrane are usually more discrete and focal.[2] Other disease states such as myopic degeneration and angioid streaks may also have extensive defects or cracks in Bruch’s membrane. Regardless of the underlying cause, visual function usually decline when exudative fluid, haemorrhage, or the neovascular tissue extends beneath the central macula and interferes with the normal metabolic interaction between photoreceptors and the retinal pigment epithelium (RPE).
The macular photocoagulation study group demonstrated that focal laser photocoagulation of well-demarcated CNV reduced the rate of vision loss in patients with neovascular AMD.[3-6] However, the degree of benefit was not very impressive in eyes with new subfoveal CNV,[4] and laser photocoagulation involving the foveal centre typically resulted in an immediate loss of visual acuity.
Surgical removal of CNV, together with associated scar tissue and blood, commonly referred to as submacular surgery, was introduced in the late 1980s as an alternative to focal laser treatment. Unlike laser photocoagulation, surgical removal may not destroy all central macular photoreceptors, some photoreceptors may be preserved despite loss of retinal pigment epithelium and photoreceptor cells that adhere to the extracted CNV complex. Furthermore, submacular surgery does not depend on precise delineation of the boundaries of the neovascular lesion, as is required for effective laser photocoagulation, so that surgery is potentially applicable to a much larger proportion of all patients with CNV.
In 1988, DeJuan and Machemer described vitrectomy techniques for the removal of blood and disciform scars in four patients with end-stage AMD. Vision improved in three, but the best acuity achieved was only 5/200, and two patients developed severe proliferative vitreoretinopathy.[7] Thomas and Kaplan reported an alternative approach to subfoveal CNV in POHS. Instead of a large flap retinotomy, their technique employed a small retinal hole through which instruments were introduced into the subretinal space. The neovascular membrane was dislodged, grasped with forceps, and extracted through the slightly enlarged retinotomy. An air-fluid exchange was followed by endolaser burns around the retinotomy and short-term tamponade with sulphur hexafluoride gas.[8] Later reports[9-13] claimed some benefit for eyes with CNV and submacular haemorrhage associated with AMD. These reports prompted some optimism for submacular surgery in the management of eyes with neovascular age-related macular degeneration.
The surgical technique is still in evolution. This approach is most effective in those cases in which the membrane lies predominantly anterior to the RPE and thus can be removed without extracting large areas of the pigment epithelium. Preservation of foveal RPE appears to be a critical factor in regaining excellent central visual function.[14]
Recently, results of larger studies were reported. Data from the Swedish national survey of surgical excision for submacular CNV was published.[15] The study compared visual outcomes after surgical removal of subfoveal CNV between patients younger or older than 50 years of age. Ninety patients treated between 1992-1999 with a follow-up of 6 months or more were included. The results obtained in 49 patients aged 51-89 years (median = 72 years) were compared with the outcome of 41 patients aged 6-49 years (median = 36 years). The main outcome measure was the improvement or deterioration in visual acuity at 6 months following surgery. The results showed that the level of preoperative visual acuity was not significantly different between younger patients and older patients (p = 0.069). However, visual acuity at 6 months after surgery was better (p = 0.0042) in younger patients than in older patients. Marked visual improvement was seen in 29% of young patients compared to 0% in the older group. It was concluded that surgical removal of submacular CNV does not appear to improve visual acuity in patients older than 50 years of age. However, it may be beneficial for younger patients.
The submacular surgery trials pilot study was initiated in November 1993 and consisted primarily of four pilot trials designed to evaluate the feasibility of larger clinical trials of submacular surgery. The methods of the submacular surgery trials pilot study were described in detail in the submacular surgery trials manual of procedures.[16] One of the pilot studies compared laser photocoagulation versus surgery for recurrent CNV secondary to AMD. The other three pilot studies included patients with ‘new CNV in the foveal centre associated with AMD’, or ‘blood (more than 50% of the lesion) and CNV in the foveal centre associated with AMD’, or ‘subfoveal CNV associated with histoplasmosis or with unknown aetiology (idiopathic)’. A recent publication by the investigators of the pilot study of laser photocoagulation versus surgery for recurrent CNV secondary to PMD reported the ophthalmic outcomes of patients at 2 years after enrolment.[17] Of 70 patients enrolled, 36 were assigned to laser photocoagulation and 34 to submacular surgery. Sixty five per cent of the patients in the laser arm versus fifty per cent in the surgery arm had visual acuity that was better than or no more than 1 line worse than the baseline level. Few serious complications were observed in either arm at the time of initial treatment; serious adverse events were rare. During follow-up, 11 laser treated eyes and 18 surgically treated eyes had additional intraocular procedures. Complications are summarized in Table 1. Two patients died during the course of follow-up. Both deaths occurred in the second year of follow-up; neither death appeared to be associated with the treatment received in the pilot trial.
Number (Percent) of patients with adverse events and additional treatment of the study eye during follow-up
Adverse event or treatment
Adverse event Death
Emergency hospitalization
2 (6)
Additional treatment
Laser photocoagulation to CNV Submacular surgery Repair of retinal detachment Cataract surgery Fluid-air exchange Iridectomy Cryo therapy for retinal break Any additional intraocular procedure
Two patients in each treatment arm had an emergency hospitalization. Only one of the four emergency hospitalizations was for an ocular emergency, that is, emergency surgery to repair a retinal detachment more than 1 year after submacular surgery. Eyes treated initially with surgery had more additional treatments than laser-treated eyes. Thomas and Ibanez reported similar complication rates among their 118 patients.[4] Furthermore, submacular surgery entails the expense associated with vitrectomy.
Another report summarizing the quality of life of patients participating in the same study was published recently. Overall, summary scores from the 36-item short-form health survey and changes in scores over 2 years in this pilot trial were consistent with the ophthalmic outcome measures that showed no important differences between the treatment arms.[18]
This data from the pilot trial and other studies suggested no reason to prefer submacular surgery to laser photocoagulation for treatment of patients with recurrent CNV secondary to AMD. In January 1997, an independent data and safety monitoring committee appointed by the director of the national eye institute reviewed the data from each of the pilot trials. The committee recommended postponement of the ‘subfoveal recurrent CNV secondary to AMD’ trial.
In addition to this chain of developments, the SST investigators, along with investigators in any randomized clinical trial, must be aware of and prepared to respond to relevant external events that may affect the design or conduct of these trials. Bressler et al described such an event relevant to the SST.[19] These were the results published by the treatment of age-related macular degeneration with photodynamic therapy (TAP) study group.[20,21] This group reported that in a randomized clinical trial, photodynamic therapy (PDT) with verteporfin reduced the risk of moderate and severe visual acuity loss one year and two years after enrolment in a predefined group of over 200 patients with subfoveal CNV due to AMD, in which the composition of the lesion was predominantly classic CNV on fluorescein angiography (area of classic CNV at least 50% area of entire lesion). Furthermore, a second randomized clinical trial showed that PDT with verteporfin increased the chance of stable or improved visual acuity in 120 patients enrolled with subfoveal CNV due to pathologic myopia.[22] In addition, patients with a lesion composition of all-occult CNV were shown to benefit from treatment with verteporfin.[23]
Thus, ophthalmologists may question whether the SST remains relevant in an era in which laser photocoagulation and photodynamic therapy has been proven effective for treating selected cases of CNV. Nevertheless, data regarding the effectiveness of submacular surgery are limited. No study to date has compared submacular surgery with the natural history of the diseases for which it has been employed, with laser photocoagulation, photodynamic therapy, or other treatments. Thus, the SST data and safety monitoring committee and the SST executive committee responsible for the scientific conduct of the SST recommended three study arms for future study. In accordance with their recommendation, three larger multicentre clinical trials subsequently were initiated with target sample sizes sufficient to provide a valid statistical analysis of the benefits and risks of submacular surgery in comparison to observation without treatment (Table 2). The three groups are group B (Blood), group N (New CNV), group H (Histoplasmosis/idiopathic).[24]
Principal occular eligibility criteria for groups B, N and H
Criteria Group B (Blood) Group N (New CNV) Group H (Histo/Idio) Age Older than 50 y Older than 50 y Older than 18 CNV cause AMD AMD OHS or none Classic CNV Optional Required Required Occult CNV Optional Optional Optional Foveal centre Blood or CNV CNV CNV Lesion size Equal or more than 3.5 disc areas1 Equal or less than 9 disc areas2 Equal or less than 9 disc areas2 Blood Equal or more than 50% of lesion Less than 50% of the lesion No limit Prior laser3 Optional Not allowed Optional Best visual acuity 20/100 20/100 20/50 Worst vision Light perception 20/800 20/800 1. Area of CNV equal or less than 9 dic areas, no limit to lesion size except 75% or more of the blood must be posterior to the equator; 2. If equal or less than 3.5 disc areas, boundaries are poorly demarcated; 3. Prior laser cannot involve foveal centre.
SST Group H Protocol : Photodynamic therapy with verteporfin has not been shown to be beneficial in eyes with neovascular lesions attributed to OHS or to idiopathic causes. The SST investigators have concluded that published findings from the TAP investigation are not applicable to patients participating in or eligible to be enrolled in the SST Group H Protocol. Presently the SST Research Group is continuing the clinical trial to compare submacular surgery with observation for cases eligible to enrol into the SST Group H Protocol.
SST Group B Protocol : Photodynamic therapy clinical trials have not included lesions that were predominantly blood because it is unlikely that the laser light used to activate the drug to cause a photodynamic effect can penetrate typical amounts of blood present in cases eligible for the Group B Protocol. The SST Research Group is continuing the clinical trial to compare submacular surgery to observation for cases eligible to enrol in the SST Group B Protocol.
SST Group N Protocol : Patients with fluorescein angiography characteristics of minimally classic CNV experienced no visual acuity benefit with verteporfin therapy compared to observation.[20] If such patients are eligible for the Group N Protocol, they are assigned randomly to submacular surgery or observation. With respect to patients eligible for the Group N Protocol who have predominantly classic lesions, for which PDT has been shown to reduce the risk of moderate and service vision loss for at least 2 years, it was recommended that all such patients will be informed about PDT. Each patient then decides whether to elect PDT or enrol in the SST.
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12.Mandelcorn MS, Menezes AV. Surgical removal of subretinal hemorrhage and choroidal neovascular membranes in acute hemorrhagic age-related macular degeneration. Can J Ophthalmol 1993; 28 (1) : 19-23.
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14. Thomas MA, Ibanez HE. Surgical excision of subfoveal neovascular membrances and subretinal strands. Duane’s ophthalmology. Hagerstown, MD : Lippincott Williams and Wilkins, 2000.
15. Berglin L, Algvere P, Olivestedt G, Crafoord S, Stenkula S, Hansson LJ, et al. The Swedish national survey of surgical excision for submacular choroidal neovascularization (CNV). Acta Ophthalmol Scand 2001; 79 (6) : 580-4.
16.Submacular Surgery Trials Research Group. Submacular surgery trials (SST) manual of procedures. Department of Commerce, National Technical Information Service, Springfield, Virginia, USA. 1998.
17.Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration : I. Ophthalmic outcomes submacular surgery trials pilot study report number 1. Am J Ophthalmol 2000; 130 (4) : 387-407.
18.Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration : II. Quality of life outcomes submacular surgery trials pilot study report number 2. Am J Ophthalmol 2000; 130 (4) : 408-18.
19.Bressler NM, Hawkins BS, Sternberg P Jr, McDonald HR, Steinberg P Jr. Are the submacular surgery trials still relevant in an era of photodynamic therapy? Ophthalmology 2001; 108 (3) : 435-6.
20.Bressler NM. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Arch Ophthalmol 2001; 119 (2) : 198-207.
21.Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials-TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) study group. Arch Ophthalmol 1999; 117 (10) : 1329-45.
22.Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial-VIP report no. 1. Ophthalmology 2001; 108 (5) : 841-52.
23.Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovasculatization-verteporfin in photodynamic therapy report 2. Am J Ophthalmol 2001; 131 (5) : 541-60.
24.Submacular surgery trials (SST). Bethesda MD: NIH, National Eye Institute. 1997. Available from URL: http://www.nei.nih.gov/neitrials_script/studydtl.asp?Id=52.
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