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RADIATION THERAPY FOR SUBFOVEAL CHOROIDAL NEOVASCULAR MEMBRANE IN AGE RELATED MACULAR DEGENERATION
MAHESH P SHANMUGAM
Medical Research Foundation, 18, College Road,Chennai 600 006.
Radiation therapy, a treatment with known antiangiogenic properties, has been investigated as a modality to prevent severe visual loss in exudative ARMD. This review article outlines the technique, rationale, toxicity and clinical trials of radiation therapy for CNVM complicating AMD. Laser photocoagulation and photodynamic therapy are the only proven therapy for choroidal Neovascular membranes complicating ARMD. Despite the long-term benefit of laser treatment of subfoveal lesions within the context of the macular photocoagulation studies, the management of subfoveal CNVM in AMD remains controversial because laser treatment results in immediate visual loss after foveal ablation. Photodynamic therapy has been proven to be effective for classic as well as occult choroidal neovascular membranes in selected cases. According to the VIP study results photodynamic therapy is beneficial in occult membranes with recent onset loss of vision, small lesion and with poor visual acuity.[1] However, for a larger occult lesion options are limited. In addition, the cost of photodynamic therapy limits its use. Several alternate treatment modalities have been tried. Transpupillary thermotherapy has been shown to work in both classic and occult membranes but is not supported by a randomised controlled trial. Subfoveal surgery is not suitable for subfoveal membranes due to AMD. Role of antiangiogenic factors is still in an experimental state. Radiation therapy, a treatment of known antiangiogenic property, has been investigated as a modality to prevent severe visual loss in exudative AMD.
Biology of ionising radiation
Electromagnetic radiation is the broad term that encompasses different types of what may be regarded as pure wave forms of energy, including radio waves, microwaves, infrared heat radiation, visible light, ultraviolet waves, X-rays, and g-rays. X-rays are produced in an extranuclear way, by accelerating electrons and then stopping them suddenly in a target. X-rays are produced in an electrical device called accelerator. As X-rays collide with the atoms of a target, high-speed electrons result, which in turn collide with electrons of other atoms, creating more ions. Given enough energy, particulate radiation consisting of charged particles may cause direct ionisation through collisions with electrons of a target atom.
The interaction of radiation with human tissue is multifaceted and extremely complex, with potentially far reaching results. The critical cellular target in human tissue is DNA. Radiation can damage the ability of a cell to reproduce, cause genetic mutations, or kill a cell outright. One of the major goals in radiation therapy is to achieve maximum target damage accompanied by minimum normal tissue damage. Radiation given in a daily fraction over several weeks produced better tumour control balanced with relatively less normal tissue damage then could be achieved with single high dose of radiation.
Radiation therapy techniques
Two terms describing different methods of delivering medical radiation treatment are Teletherapy, Brachytherapy.
Teletherapy, also called external beam therapy refers to external beam radiation to a patient from a large distance. One of the most commonly used devices in external beam radiation therapy is linear accelerator. It uses radio frequency waves to transfer electrons down an accelerator tube. This process yields a high-energy electron beam, and can be used in treatment or sent into a target to produce high-energy X-ray beams. Brachytherapy refers to use of sealed radioactive materials to deliver radiation at a short distance, either in contact with a surface, distributed a short distance from a surface, or within the target tissue.
Stereotactic radiosurgery refers to a techniques of delivering ionising radiation generally of a small volume to stereotactically localized tissue target. At present number of techniques are being used to deliver radiation in treatment of CNVM. These include external beam teletherapy using photons or protons, plaque brachytherapy, stereotactic radiosurgery.
Procedure
After a thorough medical examination of the patent, the diagnosis is confirmed and the patient is referred for radiation therapy. An additional history and examination may take lace in radiation therapy setting the treatment planning can begin. Treatment planning refers to a series of steps that include identification of the area to be treated, followed by the design of a plan to deliver the treatment. Simulation is a major step in this process. A simulation refers to use of a simulator, a machine with a diagnostic X-ray tube attached to a gantry that can be positioned about the patient in the same way as the treatment machine to be used. The simulator can provide a diagnostic quality X-ray of the patient’s anatomy to be treated rendering good anatomic details. During simulation, positioning devices, such a prefabricated head restraints or custom moulded face masks are used to ensure accuracy and reproducibility of positioning. Proposed treatment ports, radiation beam angles, and patient position may be simulated, with appropriate radiographic exposures to follow. For macular external beam radiation treatment, the supine position of the patient is appropriate. A computed tomogram of the patients’ head in the treatment position with head positioning device may be used for detailed small field target localisation. This study provides cross sectional anatomy for treatment planning and can be used to determine radiation port dimensions, beam angle, and target depth.
Rationale for radiation therapy in ARMD
Radiation therapy has been proposed as an alternative treatment for exudative AMD because of known radiosensitivity of vascular endothelial cells. Ionising radiation is used in neoplasia to inhibit cellular proliferation and in particularly lethal for rapidly dividing cells. The radio sensitivity of capillary endothelium had long been recognised, and susceptibility is increased in young or new vessels where endothelial cells are proliferating.[2] Low dose radiation has been shown to inhibit neovascularization. In tissue culture, single dose of 8.7 gray prevent endothelial cell division.[3] Retinal endothelial is also radiosensitive, a single radiation dose of approximately 5 gray being sufficient to arrest division in 99% of cultured endothelial retinal cells. After low dose radiation vascular endothelium demonstrated morphologic and DNA changes, inhibition of replication, decreased prostaglandin and prostacyclin production, increased cell permeability, increased cell adhesion molecule synthesis and apoptosis. Chakravarthy and co-workers demonstrated in animal model properties of radiation therapy, which can be utilized in treatment of CNVM.[4,5]
Radiosensitivity of vascular endothelial cells
Radioresistance of neural retina
Selective choriocapillary closure
Sparing of large choroidal vessels
Radiation toxicity
Although the endothelial radiosensitivity observed is the foundation for employing radiation therapy in CNVM, analysis of radiotoxicity and resistance is necessary to support its use and to elucidate the dose at which a therapeutic window may exist. The potential advantage of radiation therapy is that surrounding normal retina and choroid are relatively radioresistant compared with normal endothelium or proliferating endothelium of CNVM.[6] The relative susceptibility of proliferating endothelium must be weighed against the potential toxic effects of higher doses on normal ocular vasculature and tissues. The main factor that influences the development of radiation retinopathy and optic neuropathy include the total dose delivered, daily fraction size, pre-existing microangiography, previous or concurrent chemotherapy and irradiation field design. In humans although radiation induced retinal changes may occur at 30-35 grays radiation retinopathy has been reported rarely as a clinically detectable injury at or below 45-60 grays in standard fractions of approximately 2 grays.[7] The standard fractionation of external beam radiation usually refers to daily fraction sizes of 2 grays. Extramacular sparing techniques with external beam radiations offer the opportunity to minimize radiation induced extramacular complications.
RADIATION THERAPY FOR ARMD - CLINICAL EXPERIENCE
Non-randomized clinical studies
The antiangiogenic properties of ionising radiation, led Chakravarthy, Hudson and Archer to treat 19 patients with subfoveal CNVM complicating ARMD.[8] These investigators used external beam radiations at a dose of 10-15 gy in fractions of 2-3 gy. They reported that visual acuity stabilised or improved in 78% and 63% of eyes at 6 and 12-month follow up respectively. Fluorescein angiographic features of CNVM regression were noted in 83% of patients at 12 months follow up. The authors concluded that low dose radiation could maintain central vision and incidence regression of CNVM. In 1995-96 numerous and uncontrolled, non-randomised studies were reported.
Spaide, and colleagues[9] treated 91 patients who had subfoveal CNVM with 10Gy in 5Gy fractions. The authors concluded that the patient should not be treated with this dose and that no patient should be treated outside of a research protocol.
Stalmans, leys and Limberger[10] treated 111 eyes with external beam radiation, 20Gy in 2Gy fractions. These investigators noted fast growth of classic or mixed CNVM, slowly progressive growth of occult CNVM, and mild increase in growth of vascularized pigment epithelial detachment despite treatment with radiation. Visual acuity declined in majority of patients. The authors concluded that radiotherapy was ineffective in this uncontrolled study.
A peer-reviewed literature on radiation therapy indicates that although this treatment remains promising, there is an absence of definitive proof that benefit exists. The study summarised, suffer from lack of adequate control group absence of randomisation, and short follow-up. The radiation study does not, however, reflect the strict entry criteria for MPS, and therefore any comparison is invalid and may be misleading.
Randomised clinical trials
The first randomised well-controlled clinical trial assessing radiotherapy for subfoveal CNVM complicating AMD was reported by Bergink and co-workers.[11] They randomised 74 patients with classic, mixed or occult CNVM to observation versus external beam irradiation. Six non standard fractions of 4Gy (total 24 Gy) were used. Greater beneficial treatment effect was found for mixed or occult CNVM then for classic CNVM. The authors concluded that visual acuity preservation was significantly better for the radiation group at one year follow up. The authors cautioned that radiotherapy did not prevent visual loss in all patients and that long-term effects are unknown.
Holz FG, Engenhart-Cabillic R, et al,[12] in a prospective, randomized, double masked clinical trial have shown that, the mean reduction in visual acuity was 3.5 ± 4.7 lines in patients of 8- x 2- Gy treatment group and 3.7± 3.8 lines in patients of 8- x 0-Gy control group. The authors concluded that in this randomised study, radiation therapy at the dose of 16 Gy applied in 8 fractions of 2 Gy provided no benefit as a treatment for subfoveal CNVM secondary to ARMD AT 1 year.
Marcus DM, et al[13] in a prospective, double masked, randomised clinical trial have shown that median distance visual acuity in radiation treated eyes decreased from 20/80 at baseline to 20/320 (4.14 mean line loss rate) at one year follow-up. Authors concluded that, at 1 year follow-up, low dose external beam irradiation in standard fractions (14 Gy in 7 fractions) is neither beneficial nor harmful for subfoveal CNVM complicating AMD.
Hart PM, Archer DB[14] studied 11 eyes with bilateral disease. The visual outcome and scar size and morphology in the two eyes of each of these patients were compared. Scars in radiotherapy treated eyes occupied an area that was approximately one third of that in untreated fellow eyes (3.8 mm2 v 11.7 mm2).
CONCLUSION
Radiation therapy is a promising experimental treatment. Though the results of randomised controlled trials are disappointing, radiation therapy can be used as a treatment modality in a trial setting. More randomised controlled clinical trials are necessary to determine if a therapeutic window exists.
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