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Ophthalmic and Adnexal Complications of Radiotherapy Acta Ophthalmologica Scandinavica 2007 Review Article Ophthalmic and adnexal complications of radiotherapy Shane R. Durkin,1 Daniel Roos,2 Braden Higgs,2 Robert J. Casson1,3 and Dinesh Selva1,3 1Department of Ophthalmology and Visual Sciences, University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia, Australia 2Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia 3Department of Medicine and Surgery, University of Adelaide, Royal Adelaide Hospital, Adelaide South Australia, Australia ABSTRACT. The efficacy of radiotherapy is The role of radiotherapy in ophthalmic practice continues to grow. This determined by aspects of radiation growth has seen an expansion of indications for radiotherapy, a refinement of delivery and the biological conse- the modalities that can be used and a reduction in the ocular and adnexal com- quences to the tumour and normal tis- plications that result from this form of therapy. The compendium of indica- sues. By giving radiation doses over a tions for radiotherapy in ophthalmology continues to grow and now includes number of fractions, damage to nor- many conditions such as the treatment of lid and adnexal disease, ocular sur- mal tissues can be reduced due to the repair of sublethal damage between face disorders and both benign and malignant disease of the posterior segment fractions and repopulation of cells and optic pathways. The radiotherapeutic modalities employed to manage during the course of treatment. these conditions are numerous and include both radioactive plaques (brachy- Although the radiosensitivity of differ- therapy) and external beam radiation techniques. New techniques such as ster- ent tumours varies considerably (Steel eotactic radiosurgery are delivering benefits in the management of conditions 1997), in general tumour cells are such as optic nerve sheath meningioma, where the treatment of this blinding more susceptible to radiation than and occasionally life-threatening intracranial neoplasm now results in fewer normal tissues as they are less able to adverse affects. The purpose of this review is to give a brief overview of the reduce the amount of DNA damage indications and treatment modalities, and a more in-depth discussion of the inflicted by radiation and have less potential side-effects when radiotherapy is used for ocular and periorbital dis- fidelity of DNA repair. ease. Just as tumour cells differ in their vulnerability to ionizing radiation, so Key words: complications – indications – ocular – orbital – radiotherapy – treatment modalities too do normal tissues. The tolerance dose (TD) 5 ⁄ 5 (probability of a 5% complication rate at 5 years) and the Acta Ophthalmol. Scand. 2007: 85: 240–250 TD 50 ⁄ 5 (probability of a 50% com- ª 2006 The Authors Journal compilation ª 2006 Acta Ophthalmol Scand plication rate at 5 years) are terms used to express this variability in tis- doi: 10.1111/j.1600-0420.2006.00822.x sue sensitivity. In 1991, Emami et al. (1991) reviewed the literature to deter- Introduction lead to either direct damage to DNA mine TD 5 ⁄ 5 and TD 50 ⁄ 5 using con- or indirect injury through interactions ventional fractions of 1.8–2.0 Gy for Radiobiology with nearby molecules (such as water) various structures including the lens, The biological effects of radiation, and subsequent free radical formation retina and optic nerve. Subsequently, particularly at the molecular level, are (Hall 2000; McMillan 2003). Radia- others have published varying toler- becoming increasingly well under- tion can also cause cell death through ance doses, some of which conflict stood. Both photons (X-rays and the induction of apoptosis (pro- with the results published by Emami gamma-rays) and particles (e.g. pro- grammed cell death) (Peltenburg et al. (1991) (Parsons et al. 1983, tons) interact with matter and may 2000). 1994a, 1994b, 1996; Jiang et al. 1994). 240 Acta Ophthalmologica Scandinavica 2007 Table 1. Tolerance doses of the optic nerve, retina, ocular surface and lens. prohibitively large skin dose (Fig. 1). Lower energy kV photons give their Ophthalmic Manifestation of TD 5 ⁄ 5 TD 50 ⁄ 5 structure toxicity (Gy) (Gy) maximum dose at or very near the skin surface and penetrate less deeply Optic nerve Optic neuropathy > 55 > 65 into tissue (Fig. 2). Hence, they are Retina Retinopathy 45–50 55 clinically more useful for superficial Ocular surface Severe dry eye 35 50 tumours such as periocular squamous Lens Cataract 10 18 cell carcinoma (SCC) and basal cell TD ¼ tolerance dose. carcinoma (BCC). Stereotactic radiosurgery (as a large single fraction or multiple fractions) Table 1 represents a synthesis of these tons, electrons and protons. Photons involves the use of multiple, small data. of lower energies (kilovoltage, kV) are MV photon fields (typically < 3–4 cm produced by superficial and orthovolt- diameter). These are delivered through Radiotherapy types age X-ray machines. Higher energy several arcs or fixed fields of radiation The major modalities employed in photons (megavoltage, MV) are pro- centred on the same point to treat ocular radiotherapy are external beam duced by linear accelerators (Linacs). well defined intracranial lesions. The radiotherapy and brachytherapy High-energy MV photons penetrate treatment concentrates the dose in the (application of plaques). The location deeply through tissue and exhibit a target tissue and spares the normal and type of pathology inform the ‘skin-sparing’ property (the surface brain as much as possible. Stereotactic choice of technique (Table 2). dose is less than the dose delivered to fractionated radiotherapy is being the underlying tissue) (Khan 2003), used increasingly in the management External beam radiotherapy which allows for the delivery of ade- of meningiomas in close proximity to External beam radiotherapy (EBRT) quate doses to deep-seated tumours the visual pathway, such as those of utilizes radiation types such as pho- without the limitations imposed by a the optic nerve sheath or parasellar region (Behbehani et al. 2005). Stereo- Table 2. Ophthalmic indications for radiotherapy and their respective treatment options. tactic radiosurgery (gamma-knife) has Ophthalmic indications for radiotherapy Type(s) of radiotherapy used also been used experimentally for uveal melanoma (Mueller et al. Malignant tumours 2000) and for choroidal metastases Primary intraocular tumours (Bellmann et al. 2000) as an alternat- Choroidal melanoma Primary treatment: EBRT (protons), brachytherapy ive to enucleation. It has also been 125I, 198Au, 103Pd, 106Ru Post-enucleation: EBRT (MV photons), employed in the treatment of choroi- brachytherapy dal haemangioma (Shields et al. 2004). Retinoblastoma Primary treatment: EBRT (MV photons), Electron beams are used for treat- brachytherapy (106Ru) ing superficial tumours with a charac- Adenocarcinoma of the RPE Brachytherapy teristic sharp drop-off in dose beyond the tumour. This makes electrons Primary orbital and periocular tumours Tumours of the adnexa EBRT (MV photons) or brachytherapy (electrons) another useful modality for the treat- (e.g. lymphoma, rhabdomyosarcoma) ment of periocular SCC and BCC Lacrimal gland carcinoma EBRT (MV photons) or brachytherapy (Anscher & Montana 1993; Dutton Optic nerve tumours EBRT (MV photons) or stereotactic radiosurgery 1993; Leshin & Yeatts 1993). (e.g. meningioma) Protons deposit their dose very Chiasmal tumours MV photons (EBRT) or stereotactic radiosurgery slowly with depth and then very shar- Pituitary lesions EBRT (MV photons) or stereotactic radiosurgery ply near the end of the range (the Periocular BCC, SCC EBRT (kV photons, MV) characteristic ‘Bragg peak’), before Periocular and conjunctival EBRT (kV photons) or brachytherapy (90Sr) Kaposi’s sarcoma dropping off to an almost zero value beyond (Khan 2003). By confining the Secondary intraocular, orbital or periocular tumours high-dose region to the tumour vol- Choroidal deposits EBRT (MV photons) or brachytherapy (electrons) ume, the dose to surrounding normal Orbital ⁄ periorbital metastases tissue can be minimized. Some Benign conditions researchers consider protons to be the Thyroid ophthalmopathy EBRT (MV photons) treatment of choice for choroidal mel- Pterygium Brachytherapy (90Sr) anoma (Hall 2000). Exudative inflammatory processes EBRT (MV photons) of the posterior segment Brachytherapy Age-related macular degeneration EBRT (MV photons) Plaque brachytherapy involves the use Choroidal haemangioma EBRT (MV photons) or brachytherapy of radioactive sources such as stron- Non-specific orbital EBRT (MV photons) tium-90, ruthenium-106, iodine-125 inflammatory syndrome and palladium-103. These take the RPE ¼ retinal pigment epithelium; EBRT ¼ external beam radiotherapy; MV ¼ megavoltage; form of ophthalmic applicators, which kV ¼ kilovoltage; BCC ¼ basal cell carcinoma; SCC ¼ squamous cell carcinoma. are placed on or sutured to the sclera. 241 Acta Ophthalmologica Scandinavica 2007 (Fig. 4) and madarosis are classed as acute effects, whereas telangiectasia, skin atrophy and depigmentation pre- sent as late effects (Fig. 5A, B). The initial reaction is seen within 2 weeks of fractionated EBRT. This delay correlates with the time required for cell migration from the basal to the keratinized layer of skin (Mettler & Upton 1995). Initially, erythema is observed, and this is soon followed by dry desquamation. The skin at this time can be erythe- matous, warm, and sometimes oede- matous. Microscopically, the upper dermal vessels are dilated and inflam- matory
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