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Show STATE OF THE ART Radiation Therapy for Visual Pathway Tumors Volker W. Stieber, MD Abstract: The multimodality management of visual pathway tumors frequently involves radiation. Most commonly, photons are delivered via multiple focused beams aimed at the tumor while sparing adjacent tissues. The dose can be delivered in multiple treatments (radiation therapy) or in a single treatment (radiosurgery). Children with visual path-way gliomas should be treated with chemotherapy alone, delaying the use of radiation therapy until progression. Definitive radiation therapy of optic nerve sheath meningiomas results in stable vision in most patients. Radiation therapy or radiosurgery for pituitary tumors can result in control of both tumor growth and hormone hypersecretion. Postoperative radiation therapy or radiosurgery of craniopharyng-iomas significantly improves local control rates compared with surgery alone. Radiation therapy is highly effective for eradicating orbital pseudolym-phoma and lymphoma. The risk of complications from radiation treatment is dependent on the organ at risk, the cumulative dose it receives, and the dose delivered per fraction. (J Neuro-Ophthalmol 2008;28:222-230) Ionizing radiation is a mainstay of the treatment of intracranial lesions. Practitioners of this art have at their command an arsenal of varying tools, all of which serve one purpose: to deliver a specific dose of radiation to a specific target with a specific intent and the lowest pos-sible dose to normal tissues. THE TOOLS Radiation therapy (RT) most commonly uses photon energy generated by linear accelerators or cobalt-60 sources. Photons are delivered as focused beams aimed at the tumor from varying angles. RT can be delivered in multiple treatments or in a single treatment. ‘‘Three-dimensional conformal'' RT (3DCRT) conforms the vol-umetric distribution of the desired dose to the shape of the target. The basic rationale for using conformal delivery is to spare adjacent normal tissue from receiving unnecessary radiation. ‘‘Intensity-modulated'' RT (IMRT) is a special-ized subset of 3DCRT resulting in a non-uniform dose distribution. Stereotactic targeting is used when a very high degree of accuracy and precision is required. ‘‘Image-guided'' RT (IGRT) uses real-time imaging to confirm that the target is localized correctly with respect to the radiation beams. Photons, Electrons, and Protons The three most common types of radiation used in the treatment of tumors are photons, electrons, and particles (protons). Electrons are rarely used as they have poor penetration through the cranium. Photons and particles are delivered as focused beams aimed at the tumor from varying angles. By far most commonly used are photons, which are usually generated using a linear accelerator to accelerate electrons which strike a target and result in the release of a focused beam of photons (1). Cobalt-60 is the second most commonly used source of photon radiation in the treatment of intracranial tumors. It is rarely used in the United States and Western Europe because its low beam energy makes it difficult to treat deeply seated tumors. Protons are the most commonly used particles, also gen-erated in accelerators. Because of their high initial cost, there are very few dedicated clinical proton facilities in the world, and the treatment cost compared with photon therapy is currently estimated to be at least double (2,3). Protons originally held significant promise in the 1980s because of their (at that time unique) ability to achieve very spatially conformal dose distributions while sparing normal tissues. The advent of photon IMRT (discussed below) in the 1990s effectively eliminated this advantage. There are no prospective randomized studies demonstrating that one modality is inherently superior to the other in the ability to safely deliver a desired dose to a specified target, marketing efforts of various vendors notwithstanding. Absorbed dose is measured in Gray (1 Gy = 100 cGy; 1 cGy = 1 rad in the old nomenclature). Dose is prescribed at a percent isodose line (IDL), which is the line Department of Radiation Oncology, Derrick L. Davis Forsyth Regional Cancer Center, Winston-Salem, North Carolina. Address correspondence to Volker W. Stieber, MD, Director of Stereotactic Radiation Oncology, Derrick L. Davis Forsyth Regional Cancer Center, 3333 Silas Creek Parkway, Winston-Salem, NC 27103; E-mail: vwstieber@novanthealth.org 222 J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 encompassing the target on a two-dimensional image along which the delivered dose is the same at every point. (In three dimensions, the term ‘‘isodose cloud'' is used.) The percent IDL is referenced to the dose at a particular point, often the geometric center of the target. Fractionated and Single-Dose Treatments Radiation therapy can be delivered in multiple treatments (‘‘fractions'') or in a single treatment. ‘‘Radio-surgery'' specifically refers to the delivery of a large single dose of radiation given in a highly focused manner to awell-delineated target using a three-dimensional Cartesian coordinate system for targeting. If more than one fraction is delivered in this manner, it is termed ‘‘fractionated stereo-tactic radiation therapy.'' This method is expected to produce the same biological effect as a course of several weeks of fractionated radiation therapy (4). Comparisons of outcomes between fractionated and single-dose treatment are described below under Section III for each applicable diagnosis. In general, the risk-benefit ratio drives the choice of therapy. Only when efficacy and safety are similar does convenience become the deciding factor. Conformal Treatment The basic rationale for using conformal delivery is to spare adjacent normal tissue from receiving unnecessary radiation, the ramifications of which are discussed in Section II below. 3DCRT refers to a specialized situation in which the volumetric distribution of the desired dose (isodose cloud) accurately mimics the shape of the target. Both fractionated radiation therapy and radiosurgery may be delivered in this fashion. IMRT is a subset of 3DCRT delivery; the intensity of the photon flux within the treat-ment field(s) is modulated during each treatment, resulting in a non-uniform dose distribution. IMRT is frequently ‘‘inverse-planned,'' that is, dose constraints of target tissues are predefined by the clinician and the treatment planning software optimization algorithm generates a plan to meet those goals. This often results in a more conformal dose distribution to the target and better sparing of select adjacent dose-limiting structures. The trade-off is that a larger volume of normal tissue receives a very low dose of radiation, the late effects of which are not fully understood. A similar effect can be achieved with protons by varying the depth of the Bragg peak, the point in the tissues at which these particles deposit the majority of their therapeutic energy. Stereotactic Treatment The term ‘‘stereotactic'' refers to a specialized method of targeting the three-dimensional treatment (whether fractionated or radiosurgery) whereby the target lesion is referenced not to the patient but to a reproducible x,y,z coordinate system. This method of targeting is used when a very high degree of accuracy and precision is required, because the coordinate system is affixed (usually inva-sively) to the patient. The Leksell neurosurgical headframe is the most common example of such a device. It immo-bilizes the patient's head and provides the reference coor-dinate system required for targeting. In general, any type of treatment can be delivered stereotactically. A number of other stereotactic systems have been derived from this con-cept, including a system of implanted screws to which a headframe can be reproducibly fixed and removed (5,6), a system that utilizes implanted fiducial markers which are then tracked in real time by a camera (6), a non-invasive system using an infrared-detectable diode array attached to a bite block (7-10), and a relocatable non-invasive stereo-tactic headframe (11-14). Practically speaking, stereotactic delivery is useful when extremely tight margins of error are required because critical normal structures are extremely close to a well-demarcated target and would otherwise receive an excessive dose of radiation. Stereotactic targeting is considered mandatory for radiosurgery, because there is only one fraction, in other words, only one opportunity to ‘‘get it right.'' Image-Guided Treatment IGRT is the newest development in radiation delivery systems. The treatment of intracranial lesions is based on three-dimensional volumetric data sets obtained from CT and MRI to delineate the target for the computer-aided planning and simulation of treatment. True IGRT acquires another three-dimensional volumetric data set at the time of treatment delivery, ideally using the treatment machine itself to confirm that the target is localized correctly with respect to the radiation beams (15). This is useful when dealing with targets that may have shifted during the time between treatment simulation and treatment delivery. Such shifting rarely applies to intracranial lesions. Some devices advertised as ‘‘imaged guided'' obtain only a set of orthogonal X-ray films for localization of the target center, lacking the true spatial information of a three-dimensional data set. Such films do not permit subtle corrections of position at the time of treatment. The Machines There are many treatment machines on the market. A brief list of the most common device trade names and their manufacturers follows. It will undoubtedly be partially out of date by the time this article appears. The Leksell Gamma Knife (Elekta, Stockholm, Sweden) in its tradi-tional configuration uses 201 stationary cobalt sources to deliver a single focused ellipsoid sphere of radiation dose with a mechanical reproducibility of #0.2 mm, making it the gold standard in terms of accuracy and precision (16) 223 Radiation Therapy J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 (Fig. 1). The newest configuration of the device (Perfexion) uses fewer sources to achieve a higher degree of confor-mality than previously possible. The Cyberknife (Accuray, Sunnyvale, CA) is a small linear accelerator mounted on a robotic arm. It can focus a single photon beam of fixed shape at a tumor from a wide variety of angles. This system incorporates orthogonal imaging for two-dimensional IGRT (17). The Synergy and Axesse (Elekta) represent standard-size medical linear accelerators mounted on rotating gan-tries that, in combination with a moving table, can deliver a photon beam that can be shaped and have its flux modulated (Fig. 2). This system incorporates CT for three-dimensional IGRT (15). The Trilogy (Varian, Palo Alto, CA) is a standard-size medical linear accelerator rotating on a fixed axis that, in combination with a moving table, can deliver a photon beam that can be shaped and have its flux modulated. This system incorporates orthogonal imaging for two-dimensional IGRT. The Novalis (Brain- LAB, Feldkirchen, Germany) is a dedicated stereotactic linear accelerator. Proton beamfacilities (Optivus Technology, Inc., San Bernardino, CA; Ion Beam Applications, Louvain-la- Neuve, Belgium) consist of very large gantry-mounted single-beam delivery systems and mobile patient tables to deliver a focused particle beam from a wide variety of angles. With these tools, a wide variety of treatment options can be tailored to patients' particular diagnoses, such as fractionated stereotactic IMRT or IGRT. Each device vendor claims to have the superior technology. The effect is that patients shop around for technology they have seen advertised regardless of its appropriateness to their condition. The concern is that ‘‘hype'' about devices may result in the inappropriate use of a particular device for a specific indication when another device may have been better suited. COMPLICATIONS The risk of complications typically depends on three parameters: the organ at risk (OAR) receiving the dose, the total dose received, and the dose delivered per fraction. The decision to select a particular treatment from several of similar efficacy will be heavily based on the risk profile. Fractionated Treatment With fractionated radiation therapy, the absolute incidence of damage to the optic chiasm and nerves is 0.3% at doses #60 Gy, as long as the daily fraction size is kept below 2 Gy. At 10 years, patients treated with daily doses of 180 cGy to a total dose of 45 Gy can expect no risk of visual impairment from therapy, and most recent series report no symptomatic visual injury below 55 Gy (18). Single-Dose Treatment With single-dose radiosurgery, injury to the optic apparatus is highly dose-dependent, with 0-2% incidence of optic neuropathy at doses below 10 Gy, a 27% incidence at doses between 10 and 15 Gy, and a 78% incidence at doses above 14 Gy (19). Thus, tumors in very close prox-imity (<2-3 mm) to the optic chiasm and optic nerves may not be suitable targets for single-fraction radiosurgery. Depending on diagnosis, typical doses delivered will range from 10 to 25 Gy. THE TUMORS Optic Glioma In general, patients with visual pathway gliomas (VPGs) do not die from the local effects of their tumors and cause-specific survival rates approach 100%. Therefore, the FIG. 1. Leksell Gamma Knife. Cour-tesy of Elekta, Inc. 224 q 2008 Lippincott Williams & Wilkins J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 Stieber multidisciplinary management of VPGs emphasizes min-imizing the sequelae of treatment. Radiation therapy results in 10-year survival rates ranging from 40% to 93% but at significant potential cost to young children (20-25). Risks may include endocrine disorders, neurodevelopmental dis-orders, moyamoya syndrome, and second malignancy. These risks are significant enough that children of any age should be treated with chemotherapy alone, delaying the use of radiation therapy until progression is documented (26). Typically a median delay of 2.5-3 years can be achieved using this approach, with 5-year progression-free and overall survival rates of 56% and 90%, respectively (27-29). When radiation therapy is required, typical doses range from 45 to 60 Gy in 1.8- to 2.0-Gy fractions (30,31). Prospective randomized phase III trials have shown that non-VPG low-grade gliomas do not exhibit a radiation dose response; that is, higher doses do not result in improved outcomes (32,33). Thus, most clinicians extrapolate from these data when treating VPGs, preferring to use doses in the lower end of this range. Three-dimensional treatment planning is mandatory to minimize dose to uninvolved structures. However, stereotactic positioning is not required even if the tumor is close to an uninvolved contralateral optic nerve, because at 45 Gy in 1.8-Gy fractions, the (admittedly statistical) risk of treatment-induced optic neuropathy is zero (34,35). Moyamoya syndrome develops in 3.5% of children after cranial irradiation, with patients with neurofibromatosis type 1 (NF-1) having a 3-fold higher risk than patients without this diagnosis (36,37). Increasing radiation dose is associated with a higher risk of moyamoya syndrome; 50% of patients experience its onset more than 4 years after treatment. The use of IMRT in children is controversial, because it potentially delivers a low dose of radiation to a large intracranial volume, which hypothetically could increase the risk of late malignancy. Radiosurgery has no defined role in the management of this disease. Meningioma The diagnosis of meningioma can be reliably made in most cases by a classic MRI appearance. The classic findings include a dural-based extra-axial lesion often mani-festing a dural tail. The lesions usually enhance brightly and homogeneously. Benign tumors rarely have necrosis asso-ciated with them because they are slowly growing. Patients with multiple meningiomas or (or schwannomas) should undergo a workup for neurofibromatosis type 2; multiple dural-based lesions could also be metastatic (38,39). The factors that predict meningioma recurrence include subtotal resection, optic nerve sheath location, $4 mitoses per high-power field, male gender, age <40 years, and microscopic brain invasion (40,41). Respectively, average 5-year and 10-year progression-free survival rates are 88% and 75% for patients with a gross-total removal (GTR) and 61% and 39% for patients who have less than a GTR (41-43). The five-year recurrence rate after resection for benign menin-gioma is 12%, for atypical meningioma is 41%, and for brain-invasive meningioma is 56% (44). Most authors now recommend fractionated radiation therapy for definitive management of optic nerve sheath meningiomas (45,46). For all intracranial benign (World Health Organization [WHO] grade I) meningiomas, doses at or above 50-53 Gy in conventional fractionation are required for durable control (47-49). There are no useful data to suggest that encasement of the optic nerve by a nerve sheath meningioma is a contraindication to radi-ation therapy. Stable or improved visual fields and visual acuity can be expected in 95%-100% of patients treated with definitive radiation therapy, from which this author infers that tumor control is the primary factor in main-taining functional vision (46,50-52). Atypical features are found in approximately 5%-20% of intracranial meningi-omas and are indicative of a more aggressive biologic potential (44,53). Local recurrence rates for patients with atypical meningiomas are higher than the rates for those with benign tumors, (40% at 5 years (44,54)), and it is common practice to offer patients with atypical meningi-omas adjuvant irradiation. Most authors recommend 54-60 Gy for WHO grades II-III (49,55,56). Radiosurgery is one of the standards of care for well-circumscribed WHO grade I intracranial meningiomas (57). It is not considered definitive therapy for WHO grade II or higher grade lesions because of the high risk of failure outside the treated volume (58). Thus, for higher-grade lesions, radiosurgery should be considered only FIG. 2. Linear accelerator with three-dimensional image guidance. Courtesy of Elekta, Inc. 225 Radiation Therapy J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 a temporizing measure or as palliation after failure of conventional fractionated radiation therapy. Local control rates are similar to those seen with GTR, subtotal resection followed by radiation therapy, or definitive radiation therapy (58,59). Most authors advocate doses of 11-18 Gy at the isodose prescription line encompassing the tumor volume (marginal dose) (57,59-63). It is recommended that the optic chiasm and nerves receive no more than 10 Gy to any segment (19,64). This practice keeps the risk of symptom-atic optic neuropathy to 2% or less. At the doses required to treat meningiomas, the incidence of optic neuropathy rises to 27% (see Section II) and radiosurgery is thus not typically considered standard therapy for optic nerve sheath meningiomas. Particularly challenging is the management of the subtotally resected meningioma. Overall, one third of intracranial meningiomas are not fully resectable (43). The extent of surgical resection as defined by Simpson (64) is related to the local recurrence risk, with 5-year, 10-year and 15-year recurrence rates of 7%-12%, 20%-25%, and 24%- 32%, and second operation rates of 6%, 15%, and 20%, respectively, among patients with GTR (41-43). Re-currence rates after subtotal resection (STR) are sub-stantially higher (65). Overall, approximately 40%-50% of patients with STR who do not receive adjuvant therapy develop local progression within 5 years, 60%-83% within 10 years, and at least 70% within 15 years (42,66,67). Patients with subtotally resected atypical tumors achieve 5- year relapse-free survival rates of 48% with fractionated radiation therapy and 83% with radiosurgery, respectively (58,68). Although not randomized, these comparisons suggest that patients with subtotally resected meningiomas should be offered the option of additional treatment. Pituitary Adenoma The multidisciplinary management of pituitary adenoma is complex and controversial, without prospective trials to provide guidance. A conservative single-institution treatment algorithm is shown in Figure 3. In general, the treatment of choice for large tumors presenting with mass effect is surgical resection, potentially followed by fractionated radiation therapy or single-dose radiosurgery. [Some institutions prefer to withhold radiation therapy until progression after initial resection (69)]. The intent of radiation therapy/radiosurgery is control of tumor growth and hormone hypersecretion, not eradication of tumor mass. Although radiation therapy alone is effective in selected patients, surgical decompression plus postopera-tive irradiation provides better results in patients with moderately advanced visual field deficits. With very large invasive tumors for which radical removal would be associated with a high mortality and morbidity, reliance should be primarily on radiation therapy, although subtotal resection may be required as an urgent debulking measure if vision is severely compromised. Pituitary adenomas show dose-response rates that are dependent on tumor type. Nonfunctioning tumors are usually controlled with 45-50.4 Gy of conventionally fractionated external beam radiation therapy or stereotactic radiosurgery delivering 20-25 Gy to the tumor margin, with control rates in the 95% range. Functioning tumors require slightly higher doses, typically 50-54 Gy of conventionally fractionated external beam radiation therapy or stereotactic radiosurgery delivering 25-30 Gy to the tumor margin. Control rates are slightly lower than for nonfunctioning tumors (70-89). A summary of dosing guidelines is shown in Table 1. Uncommonly used forms of radiation therapy include proton and a-particle radiation therapy and implantation of radioactive sources (90Yor 198Au). Like stereotactic radio-surgery, these methods also attempt to deliver very large doses to highly restricted volumes within the pituitary gland. Their application is thus limited to small, essentially intrasellar tumors. Craniopharyngioma Because radical surgical resection of craniopharyng-ioma is associated with a high rate of visual loss and impaired hormone function requiring replacement therapy, FIG. 3. The author's suggested multidisciplinarymanagement of pitu-itary tumors. EBRT, external beam radiation therapy; SRS, stereotactic radiosurgery. 226 q 2008 Lippincott Williams & Wilkins J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 Stieber many authors recommend minimal surgery (subtotal resection or biopsy) followed by radiation therapy, as long as the diagnosis can be made radiographically with reasonable accuracy and extensive surgery is not required to reverse mass effect. After incomplete resection followed by irradiation, treatment-related toxicity includes impair-ment of hormone function, but the interval between treatment and onset of the disorder is much longer and less severe than it is with extensive surgery (91). Impair-ment of vision is reported for less than 10% of all patients treated with incomplete resection followed by irradiation compared with impairment in up to 20% after complete resection (92). Radiation therapy to a median dose of 52.2 Gy results in 10-year local control rates of 84%-100% compared with a rate of 42% with surgery alone The overall survival rate is approximately 85% regardless of whether radiation therapy is delivered immediately postoperatively or delayed until the event of progression (93,94). A growing body of evidence suggests that radiosurgery alone is effective therapy as well. With doses in the range of 10-12 Gy, the actuarial 10-year survival rate is 91%, the progression-free survival rate is 54%, and the local control at a median follow-up time of 5.5 years is 80% (95). The dose to the optic chiasm and nerves should be maintained below 10 Gy; if it cannot be maintained below that level, fractionated radiation therapy is the treatment of choice. Orbital Pseudolymphoma (Lymphoid Hyperplasia) and Lymphoma Orbital pseudolymphomas are benign masses of lymphoid hyperplasia localized to the orbit. True orbital lymphomas present as painless, slowly enlarging lesions arising from the eyelid, orbit, lacrimal gland, or conjunc-tiva; 75% are unilateral. Orbital lymphoma is the most common primary orbital malignancy (55%) It may repre-sent the only manifestation of the disease (96,97) or be part of multicentric systemic lymphoma, with 31% of lymphoid tumors of the conjunctiva associated with systemic lymphoma (98). Hence, the diagnosis requires a biopsy and systemic staging workup. Fifteen percent of patients with localized orbital disease subsequently develop systemic lymphoma (97). The risk of disseminated disease is related to histology and location. Thus, lymphomas of the conjunctiva or deep orbit have the lowest risk of dis-semination (21%-24%) compared with 38% for the lacri-mal gland and 50% for the eyelid (99). Good prognostic features are complete remission in response to initial treatment, primary radiotherapy, and older age (100). Orbital radiation therapy is highly effective in eradication of orbital lymphoma. A dose of 20-40 Gy is used for pseudolymphoma and low-grade lymphoma; 30-50 Gy is used for high-grade lymphoma (100-104). Five-year survival rates range from 70% to 89% for patients with pseudolymphoma and low-grade lymphoma (105). The five-year survival rate is only 33% for those patients with high-grade lymphoma (103). Recurrence after radiation therapy is 25% for low-grade and 75% for intermediate- and high-grade lymphomas. The addition of chemotherapy (usually R-CHOP [rituximab, cyclophosphamide, doxorubicin, vin-cristine, and prednisolone]) to radiation therapy reduces the risk of recurrence to 33%for intermediate-grade and 50%for high-grade lymphomas (106). Thus, radiation therapy as single-modality treatment should be reserved for low-grade localized tumors. Disseminated and secondary orbital lymphomas are often treated with chemotherapy alone. REFERENCES 1. Thwaites DI, Tuohy JB. 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