NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-20-003-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/86905; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.
Release date: February 10, 2020; Expiration date: February 10, 2021
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Uveal Melanoma
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Uveal Melanoma
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant financial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
P. Kumar Rao, MD, Panel Member, has disclosed that he has no relevant financial relationships.
Christopher Barker, MD, Panel Member, has disclosed that he receives grant/research support from Amgen Inc., Merck & Co., Inc., and Elekta; is a scientific advisor for Regeneron Pharmaceuticals, Inc.; and receives other financial benefit from Alpha Tau Medical, Ltd., and Regeneron Pharmaceuticals, Inc.
John A. Thompson, MD, Panel Vice Chair, has disclosed that he receives honoraria from AstraZeneca Pharmaceuticals LP; is a scientific advisor for and receives equity interest/stock options from Alpine Immune Sciences; and receives consulting fees from Calithera Biosciences, Inc. and Synthorx.
Carlo Contreras, MD, Panel Member, has disclosed that he has no relevant financial relationships.
Alison Durham, MD, Panel Member, has disclosed that she has no relevant financial relationships.
Ryan C. Fields, MD, Panel Member, has disclosed that he has no relevant financial relationships.
Brian Gastman, MD, Panel Member, has disclosed that he is a scientific advisor for Merck & Co., Inc., Bristol-Myers Squibb Company, and Quest Imaging, and that he is a speaker for Castle Biosciences.
Douglas Johnson, MD, Panel Member, has disclosed that he is a scientific advisor for Array BioPharma Inc., Bristol-Myers Squibb Company, Merck & Co., Inc., and Novartis Pharmaceuticals LP, and receives grant/research support from Incyte Corporation.
Anthony J. Olszanski, MD, Panel Member, has disclosed that he receives honoraria from Bristol-Myers Squibb Company, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Array BioPharma Inc., and Pfizer Inc.
Nicole R. McMillian, MS, CHES, Guidelines Coordinator, NCCN, has disclosed that she has no relevant financial relationships.
Anita Engh, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from AstraZeneca; Celgene Corporation; Coherus BioSciences; Genentech, a member of the Roche Group; and TESARO, a GSK Company. This activity is supported in part by an educational grant from Bayer Healthcare Pharmaceuticals. This activity is supported by an independent medical education grant from Bristol-Myers Squibb. This activity is supported by a medical education grant from Exelixis, Inc. This activity is supported by an independent educational grant from Merck & Co., Inc.
Overview
The NCCN Guidelines for Uveal Melanoma are the first and only NCCN Guidelines on an ocular cancer, and include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated (page UM-1, available in the full guidelines at NCCN.org). These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma, as shown on UM-2 (see above) and UM-3 (available at NCCN.org), in patients who have already undergone a complete workup.
Treatment of Uveal Melanoma
Treatment of Localized Primary Uveal Melanoma
Most uveal melanomas are localized at first presentation, and only a small percentage of cases present with metastases (<3%).1–6 Local treatment of primary uveal melanoma is effective in preventing local recurrence in >85% of cases,7,8 yet the rate of metastasis within 20 years after treatment is approximately 20% to 70% in patients who present with localized uveal melanoma, depending on tumor stage/size at diagnosis.3,9–11 Although surgical approaches are the mainstay of treatment of localized cutaneous melanoma, and historically most uveal melanomas were treated with surgery, the field has moved away from using surgery in all patients,12,13 because different modalities, primarily various forms of radiation therapy (RT), have been found to be just as safe and effective for those with limited disease, and can preserve the affected eye. Some surgical approaches are still used in patients with extensive local disease, but most patients with localized primary uveal melanoma are treated with some form of radiation.14 A number of other ablative techniques are occasionally used for localized primary melanoma, including laser therapy, cryotherapy, and photodynamic therapy. The NCCN Guidelines Insights describes each of these primary treatment modalities in more detail. Selection among these techniques is guided by many case-specific factors, including the size and location of the tumor, presence of extraocular extension, visual potential, and patient age and preference.
Surgical Options
Prior to the development of effective RT options, surgery was used to treat most uveal melanomas.
Local Resection
A variety of methods for local resection of uveal melanoma are aimed at conserving the eye and useful vision,15–17 including transretinal (endoresection) and transscleral (exoresection) approaches.17 These methods can be technically challenging,17,18 with high rates of immediate postoperative complications, such as hemorrhage, retinal detachment, ocular hypertension, and proliferative vitreoretinopathy, which may require repeat surgery.15–17,19,20
Local resection is not recommended in the NCCN Guidelines for Uveal Melanoma as a primary treatment option for choroidal or ciliary body melanoma. For patients with primary tumors amenable to eye-conserving approaches, radiation-based approaches are preferred. For tumors too large for brachytherapy, enucleation is preferred over local resection, because the latter is technically difficult for large tumors.
Enucleation
Enucleation is a technically less challenging procedure than local resection of uveal melanoma, and historically is the most widely used treatment of uveal melanoma. Results from the prospective Collaborative Ocular Melanoma Study (COMS) suggest that enucleation is associated with a very low risk of local recurrence (∼1%),21,22 notably lower than the rate of local recurrence reported for retrospective studies in patients treated with primary local resection.8,23–31 Enucleation procedures have been standardized; they involve complete removal of the eye and in most cases include insertion of an orbital implant.16,17,32,33 Both porous and nonporous implants have been shown to result in similar outcomes, although there may be a higher incidence of ptosis with acrylic implants, and a greater need for ocularists’ treatment (topical antibiotics, polishing or refitting of prosthesis) with hydroxyapatite implants.34
Complications of enucleation reported in the COMS during or <24 hours after surgery include pain, hemorrhage, nausea/vomiting, cardiovascular or pulmonary issues, urinary retention, fever, local surgical problems.21 Complications 1 to 6 weeks after surgery included pain requiring longer hospital stay, pain requiring medication, conjunctival wound dehiscence, infection, decreased facial sensation, eyelid swelling, inflammation, implant displacement, loss of hair, ptosis, conjunctival chemosis, ecchymosis, and orbital or conjunctival hemorrhage.21 Long-term follow-up has shown that other problems after enucleation include poor motility of prosthesis, poor alignment of prosthesis, severe ptosis, and displacement of implant.21 Enucleation can also result in phantom eye syndrome, including visual sensations, seeing, and pain, which can be distressing to some patients.35
Pre-enucleation radiation is generally not used because results from a COMS randomized trial in large tumors (height ≥2 mm and diameter ≥16 mm; or height ≥10 mm and any diameter; or height ≥8, any diameter, if proximal tumor border <2 mm to optic disc) showed that pre-enucleation radiation had no impact on survival (death from melanoma metastasis, all-cause death) compared with enucleation alone,21,36,37 confirming results of prior retrospective studies.38 The COMS randomized trial for large tumors reported a 5-year tumor-related mortality of 28% for patients treated with enucleation.36
In a COMS randomized trial in medium choroidal melanoma tumors (height 2.5–10 mm, diameter ≤16 mm, no extrascleral extension ≥2.0 mm thick), outcomes (cumulative mortality, melanoma-specific mortality) for enucleation were similar to those for iodine-125 (125I) brachytherapy.39,40 For medium tumors, the 5-year disease-specific survival rate was 11% for patients treated with enucleation (14% and 5% for patients with tumor diameter >11 and ≤11 mm, respectively).40 One prospective and several retrospective studies also found that survival was similar after enucleation versus cobalt plaque brachytherapy,41–45 a mix of brachytherapy plaque types,46 or proton-beam RT.47 Retrospective studies suggest that outcomes (overall survival, metastasis-free survival, melanoma-related mortality) are similar for enucleation versus proton-beam radiation or stereotactic radiosurgery (SRS).48–51 Despite the negative aspects of enucleation (relative to RT therapy), including worse effects on certain visual functions (peripheral vision, night driving, judging distances), greater decrease in role functioning, and larger reductions in physical and functional well-being, some studies have found that patients undergoing enucleation appear to have similar quality of life as those treated with RT.52–57
Based on results of the prospective studies comparing enucleation with brachytherapy, enucleation is generally only recommended for patients with tumors that are unsuitable for brachytherapy treatment, such as those that are too large to be effectively treated by commercially available plaques, or that have optic nerve involvement. For tumors such as these, enucleation is an option, but other types of RT (particle beam, stereotactic radiation) are also possibilities. Enucleation is sometimes reserved for cases that would be difficult to treat using only radiation, such as those with neovascular glaucoma, tumor replacing >50% of the globe, blindness, painful eyes, or extensive extraocular extension. In addition to use as a primary treatment, enucleation is also often used as a secondary therapy for patients who develop local recurrence or complications after eye-sparing primary treatment.
Radiation Therapy
RT is the most commonly used first-line treatment for uveal melanoma,12 because several approaches have been shown to have similar efficacy as enucleation for reducing the risk of metastasis and death from disease.39–51 Brachytherapy and charged-particle RT are the RT modalities considered appropriate as primary therapy for most cases uveal melanoma, whereas photon RT and stereotactic radiation are less often used as primary treatment for uveal melanoma. SRS is sometimes used for large primary tumors, and photon RT is generally only used as an adjuvant to surgery.
Plaque Brachytherapy
Plaque brachytherapy is a commonly used form of definitive RT for the primary tumor.13,14,58,59 Brachytherapy is often used (for localized primary uveal melanoma) based on results of a large prospective randomized COMS trial showing that long-term outcomes were not significantly different with plaque brachytherapy (n=657) versus enucleation (n=660) in patients with small- to medium-sized choroidal melanomas (2.5–10.0 mm in apical height [2.5–8.0 mm if peripapillary] and ≤16 mm in maximum basal diameter, no extrascleral extension ≥2.0 mm thick).39,40 In this study, the 5-year risk of treatment failure after brachytherapy was 10.3%.60 Treatment failure was defined as tumor expansion (≥15% increase in height, ≥250 μm in any tumor boundary) or extrascleral extension (>2 mm). Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Other more recent studies have reported local failure rates ranging from 0% to approximately 20% for patients treated with 125I plaques, and local failure rates were in this range for patients treated with other types of brachytherapy plaques (ruthenium-106, palladium-103, cesium-131).8,61–64 It is important to note that late treatment failures (up to 12 years) after brachytherapy have been observed.63
In the COMS randomized trial in medium choroidal melanoma tumors (height 2.5–10.0 mm, diameter ≤16 mm, no extrascleral extension ≥2.0 mm thick), after a minimum of 5 years of follow-up (range, 5–15 years), there were no treatment-dependent differences in all-cause mortality or death with confirmed melanoma metastasis.40 There was no difference across arms in the rate of death with histologically confirmed metastasis (enucleation vs brachytherapy, respectively: 11% vs 10% at 5 years and 17% vs 18% at 10 years) or all-cause mortality (19% at 5 years and 35% at 10 years in each arm).40 The only factors correlated with these outcomes were age and maximum basal diameter, but even after adjustment for these variables, there were no treatment-dependent differences in all-cause mortality or mortality with confirmed melanoma metastasis at time of death.40
In the COMS randomized trial in medium choroidal melanoma tumors, intraoperative/immediate postoperative complications observed with similar frequency across brachytherapy and enucleation arms included anesthetic complications; pain requiring medication; other hemorrhage; cardiovascular or pulmonary problems; urinary problems; and local surgical problems.39 Immediate complications seen only in the brachytherapy arm included intraocular hemorrhage, scleral perforation, and vortex vein rupture.39 In the brachytherapy arm, the most common long-term complications were loss of visual acuity and growth of tumor or other indications that lead to enucleation.39 After 3 years of follow-up, approximately half of the patients (49%) treated with brachytherapy lost ≥6 lines of visual acuity (compared with before treatment), and among patients with visual acuity better than 20/200 before treatment, 43% had visual acuity of 20/200 or worse.65 Factors associated with loss of visual acuity included greater baseline tumor apical height, shorter distance between the tumor and the foveal avascular zone, presence of tumor-associated retinal detachment, non–dome-shaped tumor, and patient history of diabetes.65 During the first 5 years of follow-up, cataracts developed in 68% of eyes treated with brachytherapy and 12% had undergone cataract surgery.66 Cataract surgery resulted in visual acuity improving by ≥2 lines in 66% of patients and stabilizing in 26%.66 The 5-year cumulative rate of enucleation was approximately 12%,39,60 most often due to treatment failure during the first 3 years after brachytherapy and to eye pain beyond 3 years after treatment.60
When evaluating patients for brachytherapy, it is important to consider the entry criteria and treatment parameters used in the COMS randomized trial that compared brachytherapy with enucleation, which included only patients with tumors that were choroidal39; those with tumors contiguous with the optic disc were excluded, as were those with metastases from melanoma or another cancer (except nonmelanoma skin cancers).40 Only 16% of patients had tumors <2.0 mm from the optic disc.39 Most of the tumors included were dome-shaped on B-scan ultrasound (77%), and approximately half had nonrhegmatogenous retinal detachment (54%–55%); a few (<1%) had rhegmatogenous retinal detatchment.39
Prospective studies in patients with small choroidal tumors treated with 125I brachytherapy also found that most patients experienced tumor regression (98%),67 <3% experienced recurrence, and 98% achieved globe conservation.68 Melanoma-specific mortality at 5 years was 3.9%.68
Although the plaques used in the COMS randomized trial were all 125I, one prospective and several retrospective studies also found that survival was similar after enucleation versus cobalt plaque41–45 or a mix of brachytherapy plaque types.46 A meta-analysis of studies testing ruthenium plaques in patients with uveal melanoma reported a 5-year melanoma-related mortality rate of 6% for small and medium tumors (T1/T2) and 26% for large tumors (T3).69 Palladium-103 brachytherapy plaques also appear to perform similarly to 125I plaques.70
Recent prospective studies aimed at identifying factors associated with loss of visual acuity after brachytherapy have had varying results. Factors identified in ≥1 studies include applicator size, tumor basal diameter, juxtapapillary location, dose (close to foveola, or retinal), increased tumor height, radiation maculopathy, and radiation optic neuropathy.71–73 Some studies have reported adjustments to technique that may reduce the risk of vision decline.64 One prospective study of 650 patients with medium-sized choroidal melanoma found that retinal hemorrhage in the macular and peripapillary zone, optical disc hemorrhage, microaneurysms, and foveal retinal pigment epithelium atrophy were more prevalent and severe after brachytherapy than before treatment.74 Macular angiographic leakage tended to worsen after brachytherapy, and optic neuropathy was present in 27% of patients 5 years after treatment.74
NCCN Recommendations
Plaque brachytherapy is appropriate as an upfront therapy after initial diagnosis, or after local recurrence following a prior local therapy. Plaque brachytherapy is appropriate for patients with tumors ≤18 mm in largest base diameter and ≤10 mm in thickness, based on the size of the largest commercially available plaques. The plaque margin on the tumor border should be ≥2 mm when feasible (diameter of plaque ≥4 mm larger than largest base diameter of tumor; the plaque should cover the tumor with a ≥2-mm circumferential margin). The exception is for tumors near the optic nerve where it may be impossible to achieve adequate coverage of the margins. The largest commercially available brachytherapy plaque is 22 mm in diameter; thus, plaque brachytherapy is recommended only for tumors with largest basal diameter ≤18 mm. Brachytherapy plaque is a recommended first-line option for all tumors that have a largest diameter of at least 5 mm but no more than 18 mm, with thickness up to 10 mm. Round plaques are most commonly used, although nonround plaques (eg, notched) can be considered for tumors in specific locations (eg, peripapillary). Preliminary data from a prospective study suggest that slotted plaques provide local control of choroidal melanomas adjacent to the optic nerve, but with a high risk of radiation optic neuropathy.75 Plaque brachytherapy should be performed by an experienced multidisciplinary team including an ophthalmic oncologist, radiation oncologist, and brachytherapy physicist.76 Tumor localization for brachytherapy may be performed using indirect ophthalmoscopy, transillumination, light pipe diathermy, and/or ultrasonography (intraoperative and/or preoperative).77 MRI may be used for preoperative planning. A summary of NCCN recommendations regarding brachytherapy, as well as recommended dosing, can be found on UM-B, 1 of 3 (available at NCCN.org).
Particle Beam RT
Particle beam RT includes radiation with protons, carbon ions, or helium ions and is a common form of definitive RT for the primary tumor.58 Prospective studies and a systematic review found that disease-specific survival in patients with uveal melanoma treated with particle beam RT was similar or better compared with those treated with plaque brachytherapy.78–80 Compared with brachytherapy, particle beam RT was associated with higher rates of local control and similar or lower rates of enucleation during follow-up.78–80 Across studies, local recurrence rates reported with charged-particle therapy ranged from 3% to 10%.8,81 However, multivariate analysis of a real-world database found that treatment with protons was associated with poorer overall survival compared with brachytherapy treatment.82
Decrease in visual acuity and loss of vision can occur with particle beam RT.81,83 Toxicities include vitreous hemorrhage, subretinal exudation in macula, posterior subcapsular opacity, radiation keratopathy, rubeosis/neovascular glaucoma, radiation maculopathy, and papillopathy.81,84
NCCN Recommendations
Particle beam RT should be performed by an experienced multidisciplinary team including an ophthalmic oncologist, radiation oncologist, and particle beam physicist.85 In settings where the appropriate expertise is available, particle beam therapy (proton, carbon ion, or helium ion) is appropriate as upfront therapy after initial diagnosis, after margin-positive enucleation, or for intraocular or orbital recurrence. It is important that the clinical team have experience treating uveal melanoma with the specific type of particle beam used (proton, carbon ion, or helium ion). Particle beam RT is an option regardless of the size of the primary lesion, and is the preferred method of RT for tumors that are too large or too near the optic nerve to be effectively treated with brachytherapy. Tumor localization for particle beam RT may be performed using indirect ophthalmoscopy, transillumination, and/or ultrasonography (intraoperative and/or preoperative), MRI, and/or CT. Recommendations regarding particle beam RT, as well as recommended dosing, can be found on UM-B, 1 and 2 of 3 (available at NCCN.org).
Stereotactic Radiation
Stereotactic radiation includes both single-fraction and hypofractionated stereotactic techniques, referred to collectively as SRS in these NCCN Guidelines. Compared with brachytherapy and particle beam RT, there are fewer prospective comparative study data on SRS for treatment of primary uveal melanoma. Available data suggest that SRS may be as effective as other radiation modalities, but may also be associated with a higher risk of complications. One series that compared SRS with 125I brachytherapy found that rates of tumor recurrence, distant metastasis, and secondary enucleation were similar across treatments.86 Risk of cataract appeared similar across treatments, but SRS appeared to be associated with higher rates of certain complications, including neovascular glaucoma, radiation retinopathy, and radiation papillopathy.86,87 Another study also reported similar rates of local control with brachytherapy versus SRS.88 A retrospective study comparing ruthenium-106 brachytherapy versus SRS found a nonsignificant trend toward increased secondary glaucoma after SRS.89 A retrospective study comparing SRS versus proton beam RT reported similar rates of local control and eye retention across treatment, but higher rates of visual acuity decline with SRS.90
Studies using SRS as primary treatment of uveal melanomas have reported local failure rates ranging between 2% to 16%.8,86,88,90–104 Rates of 5-year metastasis-free survival after SRS ranged from 69% to 84%.86,92,94,105 Overall survival 5 years after SRS has been reported to be 55% to 98%.93,94,99,105,106 These large ranges likely reflect differences in the populations studied; thus, in the absence of randomized trial data it is difficult to know whether these outcomes are better or worse than those reported for other treatment modalities.
In studies testing SRS as primary treatment of uveal melanoma, eye retention rates ranged from 73% to 98%.90,93,96,98–101,104–108 In addition to causing decline in visual acuity, complications associated with SRS reported across multiple studies include cataracts, neovascular glaucoma, radiation retinopathy, radiation papillopathy, radiation maculopathy, hemorrhage, macular edema, optic neuropathy, and keratitis sicca (dry eye).86,87,92,93,95,96,101–103,108–112 Some studies have linked the rate and/or severity of complications to the radiation dose, tumor location, tumor size, and visual acuity before treatment.95,98,101,110,113,114
NCCN Recommendations
Due to the lack of randomized prospective data (compared with other RT techniques described earlier), SRS is the least often used form of definitive RT for the treatment of primary or recurrent intraocular tumors. Like particle beam RT, SRS can be used to treat large choroidal melanomas. The choice between these 2 options generally depends on the radiation oncology facilities available. In rare cases when both particle beam RT and SRS facilities are available, some NCCN panel members prefer particle beam RT because of more supporting data for this approach. Tumor localization, fiducial marker use, and planning for SRS are generally consistent with particle beam RT approaches. Using fractionated SRS, 45 to 70 Gy in 2 to 5 fractions should be prescribed. Using single-fraction SRS, 18 to 45 Gy in 1 fraction should be prescribed (UM-B, 2 of 3, available at NCCN.org).
Treatment of Extraocular/Extrascleral Extension
Extraocular/extrascleral extension has been reported to be present in approximately 3% of patients at uveal melanoma diagnosis,115–118 is more common among tumors with higher T stage (12% of T4 tumors),9 and is associated with poor prognosis.7,10,119–122 Extrascleral/extraocular extension can be detected by preoperative imaging, or found or confirmed at the time of enucleation.21,123 Sometimes the evidence of extraocular extension is microscopically positive or close margins after enucleation, without clinical, intraoperative, or radiographic evidence of gross residual disease to the orbit. In other cases, extraocular tumor is visible intraoperatively or intraoperative findings suggest that there may be gross disease to the orbit. In the COMS trial of patients with large uveal melanomas that tested enucleation with versus without pre-enucleation radiation, unexpected extrascleral extension was found in 2% of patients who underwent enucleation, despite extensive clinical and imaging workup.21,37
Orbital Exenteration
Orbital exenteration is surgical removal of the globe and adjacent orbital contents, for cases with extraocular extension and/or orbital invasion.18,76,124–127 Retrospective studies of large databases suggest that exenteration is used in <1% of patients,10 and among patients undergoing enucleation, 2.5% need orbital exteneration.128 The value of orbital exenteration is disputed in the literature, largely based on low-quality data such as case reports and retrospective studies. Some studies support orbital exenteration because it provided superior outcomes to other (nonsurgical) approaches,129 whereas others report poor outcomes after orbital exenteration, arguing that it may not be justified.130,131
RT for Extraocular/Extrascleral Extension
A retrospective study (n=202) found that in patients treated with enucleation, postoperative RT improved survival, particularly in young patients (age <30 years) and those with choroidal tumor height >3 mm.128 Another retrospective study (n=17) reported a local recurrence rate of 6% in patients with extrascleral extension who were treated with enucleation followed by adjuvant external-beam RT to the orbit.132 For patients with limited extraocular extension <3 mm thick, brachytherapy may also be an option based on a retrospective study (n=17) showing no intraocular or extraocular tumor relapse after a median follow-up of 63 months (range, 23–164 months).133
NCCN Recommendations for Treatment of Localized Uveal Melanoma
After workup and staging, patients with localized uveal melanoma should be treated. Treatment options depend on tumor size (diameter and thickness) and proximity to the optic nerve (UM-2, page 122).
Tumor Size: Largest Diameter 5–18 mm and Thickness <2.5 mm
For thin tumors (<2.5 mm) with largest diameter ranging from 5 to 18 mm, recommended preferred primary treatment options are brachytherapy plaque or particle beam RT. For patients who are not good candidates for brachytherapy or particle beam RT, other options to consider include laser therapy or enucleation.
Tumor Size: Largest Diameter ≤18 mm and Thickness 2.5–10 mm
Brachytherapy and particle beam RT are also options for treating tumors with largest diameter ≤18 mm and thickness 2.5 to 10 mm. If there is concern that adequate response was not achieved from initial radiation, then further treatment should be considered. Recommended options for further treatment include laser therapy or cryotherapy. In highly select cases, resection is sometimes considered. Tumors in this size range may also be treated with enucleation. Although there is a trend toward avoiding enucleation, it is recommended for patients with neovascular glaucoma, tumor replacing >50% of globe, or blind, painful eyes. Enucleation should also be considered in cases of extensive extraocular extension.
Tumors Not Appropriate for Brachytherapy
Given the limitations in the size and RT penetrance of commercially available brachytherapy plaques (diameter ≤22 mm), this method is not appropriate (and not recommended) for tumors that are too large in diameter (>18 mm; any thickness), too thick (>10 mm; any diameter), or have optic nerve involvement and thickness >8 mm (any diameter). RT options for such tumors include particle beam RT and SRS. The choice between these 2 RT modalities usually depends on which modality is available at the treating institution. In the rare scenario that the institution has both SRS and particle beam facilities, some practitioners would opt for particle beam because there are more data supporting its efficacy. Enucleation is also a recommended option, especially in cases with extensive extraocular extension, neovascular glaucoma, tumor replacing >50% of globe, or blind, painful eyes.
Additional Treatment Considerations
An essential feature of high-quality care is that clinical decisions are informed by a variety of case-specific factors (eg, patient preferences and characteristics, such as age; status of the other eye; disease characteristics; medical history), such that for some patients the best clinical approach may not be one of the listed options. The recommended treatment options are largely based on data from choroidal melanomas. For small ciliary body and iris tumors (<3 clock hours), surgical excision may be considered.
Additional Primary Treatment of Extraocular Extension
For patients with limited extraocular extension, brachytherapy with scleral patch graft should be considered. For patients treated with enucleation for their primary tumor, additional treatment may be needed if extraocular extension is present (UM-3, available at NCCN.org). For patients with microscopically positive or close margins after enucleation, but no clinical, intraoperative, or radiographic evidence of gross residual disease to the orbit, recommended options include observation (no further treatment), mapping biopsy, and/or consideration of RT to the orbit (using particle beam or photon beam therapy). For patients with visible extraocular tumor or suspicion of gross disease in the orbit at the time of enucleation, biopsy of the extraocular tissue is recommended, if possible. Additional treatment options to consider include one or more of the following: intraoperative cryotherapy, orbital exenteration, and/or RT to orbit using particle beam or photon beam therapy. For photon or proton beam RT to the orbit (after enucleation), a dose of 20 to 30 Gy in 5 fractions should be prescribed to the clinical target volume at risk for recurrence21,134 using intensity-modulated or conformal techniques with image guidance.
NCCN Recommendations for Treatment of the Primary Tumor in Patients With Metastatic Disease
Palliative local therapy to the primary tumor may be considered in the setting of metastatic disease. In general, if the metastatic disease is being treated, the primary tumor should also be treated. Patients who present with advanced metastatic disease and limited life expectancy may elect to have no treatment to their primary tumor. Recommendations for treatment of distant metastatic disease in patients with uveal melanoma can be found on UM-6 (available at NCCN.org).
Conclusions
Most uveal melanomas are localized at first presentation, and local treatment of primary uveal melanoma is effective in preventing local recurrence in most patients but fail to prevent distant metastasis. Although historically most primary uveal melanomas were treated with surgery, RT has been shown to be equally effective, and is now more widely used than surgical approaches. Due to technical limitations with RT approaches, selection of primary treatment depends largely on the size and location of the primary tumor. Clinical decisions should also take into account case-specific factors (eg, patient preferences and characteristics, such as age; status of the other eye; disease characteristics; medical history).
References
- 1.↑
Freton A, Chin KJ, Raut R, et al.. Initial PET/CT staging for choroidal melanoma: AJCC correlation and second nonocular primaries in 333 patients. Eur J Ophthalmol 2012;22:236–243.
- 2.↑
Bagger M, Andersen MT, Andersen KK, et al.. The prognostic effect of American Joint Committee on Cancer staging and genetic status in patients with choroidal and ciliary body melanoma. Invest Ophthalmol Vis Sci 2014;56:438–444.
- 3.↑
Shields CL, Kaliki S, Furuta M, et al.. American Joint Committee on Cancer classification of uveal melanoma (anatomic stage) predicts prognosis in 7,731 patients: the 2013 Zimmerman lecture. Ophthalmology 2015;122:1180–1186.
- 4.↑
The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma I: characteristics of patients enrolled and not enrolled. COMS report no. 9. Am J Ophthalmol 1998;125:767–778.
- 5.↑
Mahendraraj K, Shrestha S, Lau CS, et al.. Ocular melanoma-when you have seen one, you have not seen them all: a clinical outcome study from the Surveillance, Epidemiology and End Results (SEER) database (1973-2012). Clin Ophthalmol 2017;11:153–160.
- 6.↑
Mahendraraj K, Lau CS, Lee I, et al.. Trends in incidence, survival, and management of uveal melanoma: a population-based study of 7,516 patients from the Surveillance, Epidemiology, and End Results database (1973-2012). Clin Ophthalmol 2016;10:2113–2119.
- 7.↑
Ophthalmic Oncology Task Force. Local recurrence significantly increases the risk of metastatic uveal melanoma. Ophthalmology 2016;123:86–91.
- 8.↑
Chang MY, McCannel TA. Local treatment failure after globe-conserving therapy for choroidal melanoma. Br J Ophthalmol 2013;97:804–811.
- 9.↑
Shields CL, Kaliki S, Furuta M, et al.. American Joint Committee on Cancer classification of posterior uveal melanoma (tumor size category) predicts prognosis in 7731 patients. Ophthalmology 2013;120:2066–2071.
- 10.↑
Shields CL, Furuta M, Thangappan A, et al.. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol 2009;127:989–998.
- 11.↑
AJCC Ophthalmic Oncology Task Force. International validation of the American Joint Committee on Cancer's 7th edition classification of uveal melanoma. JAMA Ophthalmol 2015;133:376–383.
- 12.↑
Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology 2011;118:1881–1885.
- 13.↑
Isager P, Ehlers N, Overgaard J. Have choroidal and ciliary body melanomas changed during the period 1955–2000? Acta Ophthalmol Scand 2004;82:509–516.
- 14.↑
Rao YJ, Sein J, Badiyan S, et al.. Patterns of care and survival outcomes after treatment for uveal melanoma in the post-coms era (2004-2013): a surveillance, epidemiology, and end results analysis. J Contemp Brachytherapy 2017;9:453–465.
- 16.↑
Dogrusöz M, Jager MJ, Damato B. Uveal melanoma treatment and prognostication. Asia Pac J Ophthalmol (Phila) 2017;6:186–196.
- 17.↑
Grisanti S, Tura A. Uveal melanoma. In: Scott JF, Gerstenblith MR, eds. Noncutaneous Melanoma. Brisbane, AU: Codon Publications; 2018. https://doi.org/10.15586/codon.noncutaneousmelanoma.2018.ch1
- 18.↑
Kaliki S, Shields CL. Uveal melanoma: relatively rare but deadly cancer. Eye (Lond) 2017;31:241–257.
- 19.↑
Krantz BA, Dave N, Komatsubara KM, et al.. Uveal melanoma: epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol 2017;11:279–289.
- 20.↑
Yang J, Manson DK, Marr BP, et al.. Treatment of uveal melanoma: where are we now? Ther Adv Med Oncol 2018;10:1758834018757175.
- 21.↑
The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma III: local complications and observations following enucleation COMS report no. 11. Am J Ophthalmol 1998;126:362–372.
- 22.↑
Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. Arch Ophthalmol 2001;119:670–676.
- 23.↑
Vidoris AAC, Maia A, Lowen M, et al.. Outcomes of primary endoresection for choroidal melanoma. Int J Retina Vitreous 2017;3:42.
- 24.↑
Konstantinidis L, Groenewald C, Coupland SE, et al.. Long-term outcome of primary endoresection of choroidal melanoma. Br J Ophthalmol 2014;98:82–85.
- 25.↑
Caminal JM, Mejia K, Masuet-Aumatell C, et al.. Endoresection versus iodine-125 plaque brachytherapy for the treatment of choroidal melanoma. Am J Ophthalmol 2013;156:334–342.e1.
- 26.↑
García-Arumí J, Zapata MA, Balaguer O, et al.. Endoresection in high posterior choroidal melanomas: long-term outcome. Br J Ophthalmol 2008;92:1040–1045.
- 27.↑
Kertes PJ, Johnson JC, Peyman GA. Internal resection of posterior uveal melanomas. Br J Ophthalmol 1998;82:1147–1153.
- 28.↑
Damato B, Groenewald C, McGalliard J, et al.. Endoresection of choroidal melanoma. Br J Ophthalmol 1998;82:213–218.
- 29.↑
Bechrakis NE, Petousis V, Willerding G, et al.. Ten-year results of transscleral resection of large uveal melanomas: local tumour control and metastatic rate. Br J Ophthalmol 2010;94:460–466.
- 30.↑
Damato BE, Paul J, Foulds WS. Risk factors for residual and recurrent uveal melanoma after trans-scleral local resection. Br J Ophthalmol 1996;80:102–108.
- 31.↑
Shields JA, Shields CL, Shah P, et al.. Partial lamellar sclerouvectomy for ciliary body and choroidal tumors. Ophthalmology 1991;98:971–983.
- 32.↑
Weis E, Salopek TG, McKinnon JG, et al.. Management of uveal melanoma: a consensus-based provincial clinical practice guideline. Curr Oncol 2016;23:e57–64.
- 33.↑
Van Acker E, De Potter P. [Porous polyethylene (Medpor) orbital implant. Prospective study of 75 primary implantations]. J Fr Ophtalmol 2001;24:1067–1073.
- 34.↑
Ho VWM, Hussain RN, Czanner G, et al.. Porous versus nonporous orbital implants after enucleation for uveal melanoma: a randomized study. Ophthal Plast Reconstr Surg 2017;33:452–458.
- 35.↑
Hope-Stone L, Brown SL, Heimann H, et al.. Phantom eye syndrome: patient experiences after enucleation for uveal melanoma. Ophthalmology 2015;122:1585–1590.
- 36.↑
Hawkins BS. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS report number 24. Am J Ophthalmol 2004;138:936–951.
- 37.↑
The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma II: initial mortality findings. COMS report no. 10. Am J Ophthalmol 1998;125:779–796.
- 38.↑
Augsburger JJ, Lauritzen K, Gamel JW, et al.. Matched group study of preenucleation radiotherapy versus enucleation alone for primary malignant melanoma of the choroid and ciliary body. Am J Clin Oncol 1990;13:382–387.
- 39.↑
Diener-West M, Earle JD, Fine SL, et al.. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS report no. 18. Arch Ophthalmol 2001;119:969–982.
- 40.↑
Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report no. 28. Arch Ophthalmol 2006;124:1684–1693.
- 41.↑
Augsburger JJ, Gamel JW, Sardi VF, et al.. Enucleation vs cobalt plaque radiotherapy for malignant melanomas of the choroid and ciliary body. Arch Ophthalmol 1986;104:655–661.
- 42.↑
Augsburger JJ, Corrêa ZM, Freire J, et al.. Long-term survival in choroidal and ciliary body melanoma after enucleation versus plaque radiation therapy. Ophthalmology 1998;105:1670–1678.
- 43.↑
Augsburger JJ, Gamel JW, Lauritzen K, et al.. Cobalt-60 plaque radiotherapy vs enucleation for posterior uveal melanoma. Am J Ophthalmol 1990;109:585–592.
- 44.↑
Adams KS, Abramson DH, Ellsworth RM, et al.. Cobalt plaque versus enucleation for uveal melanoma: comparison of survival rates. Br J Ophthalmol 1988;72:494–497.
- 45.↑
Markoe AM, Brady LW Jr, Shields JA, et al.. Malignant melanoma of the eye: treatment of posterior uveal lesions by Co-60 plaque radiotherapy versus enucleation. Radiology 1985;156:801–803.
- 46.↑
Brady LW, Hernandez JC. Brachytherapy of choroidal melanomas. Strahlenther Onkol 1992;168:61–65.
- 47.↑
Seddon JM, Gragoudas ES, Egan KM, et al.. Relative survival rates after alternative therapies for uveal melanoma. Ophthalmology 1990;97:769–777.
- 48.↑
Mosci C, Lanza FB, Barla A, et al.. Comparison of clinical outcomes for patients with large choroidal melanoma after primary treatment with enucleation or proton beam radiotherapy. Ophthalmologica 2012;227:190–196.
- 49.↑
Dinca EB, Yianni J, Rowe J, et al.. Survival and complications following γ knife radiosurgery or enucleation for ocular melanoma: a 20-year experience. Acta Neurochir (Wien) 2012;154:605–610.
- 50.↑
Furdova A, Slezak P, Chorvath M, et al.. No differences in outcome between radical surgical treatment (enucleation) and stereotactic radiosurgery in patients with posterior uveal melanoma. Neoplasma 2010;57:377–381.
- 51.↑
Cohen VM, Carter MJ, Kemeny A, et al.. Metastasis-free survival following treatment for uveal melanoma with either stereotactic radiosurgery or enucleation. Acta Ophthalmol Scand 2003;81:383–388.
- 52.↑
Melia M, Moy CS, Reynolds SM, et al.. Quality of life after iodine 125 brachytherapy vs enucleation for choroidal melanoma: 5-year results from the Collaborative Ocular Melanoma Study: COMS QOLS report no. 3. Arch Ophthalmol 2006;124:226–238.
- 53.↑
van Beek JGM, Buitendijk GHS, Timman R, et al.. Quality of life: fractionated stereotactic radiotherapy versus enucleation treatment in uveal melanoma patients. Acta Ophthalmol 2018;96:841–848.
- 54.↑
Damato B, Hope-Stone L, Cooper B, et al.. Patient-reported outcomes and quality of life after treatment of choroidal melanoma: a comparison of enucleation versus radiotherapy in 1596 patients. Am J Ophthalmol 2018;193:230–251.
- 55.↑
Brandberg Y, Kock E, Oskar K, et al.. Psychological reactions and quality of life in patients with posterior uveal melanoma treated with ruthenium plaque therapy or enucleation: a one year follow-up study. Eye (Lond) 2000;14:839–846.
- 56.↑
Klingenstein A, Fürweger C, Mühlhofer AK, et al.. Quality of life in the follow-up of uveal melanoma patients after enucleation in comparison to CyberKnife treatment. Graefes Arch Clin Exp Ophthalmol 2016;254:1005–1012.
- 57.↑
Cruickshanks KJ, Fryback DG, Nondahl DM, et al.. Treatment choice and quality of life in patients with choroidal melanoma. Arch Ophthalmol 1999;117:461–467.
- 58.↑
Abrams MJ, Gagne NL, Melhus CS, et al.. Brachytherapy vs. external beam radiotherapy for choroidal melanoma: survival and patterns-of-care analyses. Brachytherapy 2016;15:216–223.
- 59.↑
Desjardins L, Levy-Gabriel C, Lumbroso-Lerouic L, et al.. [Prognostic factors for malignant uveal melanoma. Retrospective study on 2,241 patients and recent contribution of monosomy-3 research]. J Fr Ophtalmol 2006;29:741–749.
- 60.↑
Jampol LM, Moy CS, Murray TG, et al.. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no. 19. Ophthalmology 2002;109:2197–2206.
- 61.↑
Echegaray JJ, Bechrakis NE, Singh N, et al.. Iodine-125 brachytherapy for uveal melanoma: a systematic review of radiation dose. Ocul Oncol Pathol 2017;3:193–198.
- 62.↑
Rospond-Kubiak I, Kociecki J, Damato B. Clinical evaluation of a paper chart for predicting ruthenium plaque placement in relation to choroidal melanoma. Eye (Lond) 2018;32:421–425.
- 63.↑
Sánchez-Tabernero S, García-Alvarez C, Muñoz-Moreno MF, et al.. Pattern of local recurrence after i-125 episcleral brachytherapy for uveal melanoma in a spanish referral ocular oncology unit. Am J Ophthalmol 2017;180:39–45.
- 64.↑
McCannel TA, Kamrava M, Demanes J, et al.. 23-mm iodine-125 plaque for uveal melanoma: benefit of vitrectomy and silicone oil on visual acuity. Graefes Arch Clin Exp Ophthalmol 2016;254:2461–2467.
- 65.↑
Melia BM, Abramson DH, Albert DM, et al.. Collaborative ocular melanoma study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3 years COMS report no. 16. Ophthalmology 2001;108:348–366.
- 66.↑
Collaborative Ocular Melanoma Study Group. Incidence of cataract and outcomes after cataract surgery in the first 5 years after iodine 125 brachytherapy in the Collaborative Ocular Melanoma Study: COMS report no. 27. Ophthalmology 2007;114:1363–1371.
- 67.↑
Pilotto E, Vujosevic S, De Belvis V, et al.. Long-term choroidal vascular changes after iodine brachytherapy versus transpupillary thermotherapy for choroidal melanoma. Eur J Ophthalmol 2009;19:646–653.
- 68.↑
Sobrin L, Schiffman JC, Markoe AM, et al.. Outcomes of iodine 125 plaque radiotherapy after initial observation of suspected small choroidal melanomas: a pilot study. Ophthalmology 2005;112:1777–1783.
- 69.↑
Seregard S. Long-term survival after ruthenium plaque radiotherapy for uveal melanoma. A meta-analysis of studies including 1,066 patients. Acta Ophthalmol Scand 1999;77:414–417.
- 70.↑
Finger PT, Berson A, Szechter A. Palladium-103 plaque radiotherapy for choroidal melanoma: results of a 7-year study. Ophthalmology 1999;106:606–613.
- 71.↑
Miguel D, de Frutos-Baraja JM, López-Lara F, et al.. Visual outcome after posterior uveal melanoma episcleral brachytherapy including radiobiological doses. J Contemp Brachytherapy 2018;10:123–131.
- 72.↑
Heilemann G, Fetty L, Blaickner M, et al.. Retina dose as a predictor for visual acuity loss in 106Ru eye plaque brachytherapy of uveal melanomas. Radiother Oncol 2018;127:379–384.
- 73.↑
Tsui I, Beardsley RM, McCannel TA, et al.. Visual acuity, contrast sensitivity and color vision three years after iodine-125 brachytherapy for choroidal and ciliary body melanoma. Open Ophthalmol J 2015;9:131–135.
- 74.↑
Boldt HC, Melia BM, Liu JC, et al.. I-125 brachytherapy for choroidal melanoma photographic and angiographic abnormalities: the Collaborative Ocular Melanoma Study: COMS report no. 30. Ophthalmology 2009;116:106–115.e1.
- 75.↑
Finger PT, Chin KJ, Tena LB. A five-year study of slotted eye plaque radiation therapy for choroidal melanoma: near, touching, or surrounding the optic nerve. Ophthalmology 2012;119:415–422.
- 76.↑
American Brachytherapy Society - Ophthalmic Oncology Task Force. The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma. Brachytherapy 2014;13:1–14.
- 77.↑
Almony A, Breit S, Zhao H, et al.. Tilting of radioactive plaques after initial accurate placement for treatment of uveal melanoma. Arch Ophthalmol 2008;126:65–70.
- 78.↑
Wang Z, Nabhan M, Schild SE, et al.. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys 2013;86:18–26.
- 79.↑
Mishra KK, Quivey JM, Daftari IK, et al.. Long-term results of the UCSF-LBNL randomized trial: charged particle with helium ion versus iodine-125 plaque therapy for choroidal and ciliary body melanoma. Int J Radiat Oncol Biol Phys 2015;92:376–383.
- 80.↑
Char DH, Quivey JM, Castro JR, et al.. Helium ions versus iodine 125 brachytherapy in the management of uveal melanoma. A prospective, randomized, dynamically balanced trial. Ophthalmology 1993;100:1547–1554.
- 81.↑
Gragoudas ES, Lane AM, Regan S, et al.. A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma. Arch Ophthalmol 2000;118:773–778.
- 82.↑
Lin AJ, Rao YJ, Acharya S, et al.. Patterns of care and outcomes of proton and eye plaque brachytherapy for uveal melanoma: review of the National Cancer Database. Brachytherapy 2017;16:1225–1231.
- 83.↑
Castro JR, Char DH, Petti PL, et al.. 15 years experience with helium ion radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 1997;39:989–996.
- 84.↑
Tsuji H, Ishikawa H, Yanagi T, et al.. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a phase I/II dose-escalation study. Int J Radiat Oncol Biol Phys 2007;67:857–862.
- 85.↑
Hrbacek J, Mishra KK, Kacperek A, et al.. Practice patterns analysis of ocular proton therapy centers: the international OPTIC survey. Int J Radiat Oncol Biol Phys 2016;95:336–343.
- 86.↑
Krema H, Heydarian M, Beiki-Ardakani A, et al.. A comparison between (1)(2)(5)iodine brachytherapy and stereotactic radiotherapy in the management of juxtapapillary choroidal melanoma. Br J Ophthalmol 2013;97:327–332.
- 87.↑
Krema H, Heydarian M, Beiki-Ardakani A, et al.. Dosimetric and late radiation toxicity comparison between iodine-125 brachytherapy and stereotactic radiation therapy for juxtapapillary choroidal melanoma. Int J Radiat Oncol Biol Phys 2013;86:510–515.
- 88.↑
Georgopoulos M, Zehetmayer M, Ruhswurm I, et al.. Tumour regression of uveal melanoma after ruthenium-106 brachytherapy or stereotactic radiotherapy with gamma knife or linear accelerator. Ophthalmologica 2003;217:315–319.
- 89.↑
Siedlecki J, Reiterer V, Leicht S, et al.. Incidence of secondary glaucoma after treatment of uveal melanoma with robotic radiosurgery versus brachytherapy. Acta Ophthalmol 2017;95:e734–739.
- 90.↑
Sikuade MJ, Salvi S, Rundle PA, et al.. Outcomes of treatment with stereotactic radiosurgery or proton beam therapy for choroidal melanoma. Eye (Lond) 2015;29:1194–1198.
- 91.↑
Furdova A, Horkovicova K, Justusova P, et al.. Is it sufficient to repeat LINEAR accelerator stereotactic radiosurgery in choroidal melanoma? Bratisl Lek Listy 2016;117:456–462.
- 92.↑
Muller K, Naus N, Nowak PJ, et al.. Fractionated stereotactic radiotherapy for uveal melanoma, late clinical results. Radiother Oncol 2012;102:219–224.
- 93.↑
Modorati G, Miserocchi E, Galli L, et al.. Gamma knife radiosurgery for uveal melanoma: 12 years of experience. Br J Ophthalmol 2009;93:40–44.
- 94.↑
Fakiris AJ, Lo SS, Henderson MA, et al.. Gamma-knife-based stereotactic radiosurgery for uveal melanoma. Stereotact Funct Neurosurg 2007;85:106–112.
- 95.↑
Simonová G, Novotný J Jr, Liscák R, et al.. Leksell gamma knife treatment of uveal melanoma. J Neurosurg 2002;97(5, Suppl):635–639.
- 96.↑
Mueller AJ, Talies S, Schaller UC, et al.. Stereotactic radiosurgery of large uveal melanomas with the gamma-knife. Ophthalmology 2000;107:1381–1387, discussion 1387–1388.
- 97.↑
Muller K, Nowak PJ, de Pan C, et al.. Effectiveness of fractionated stereotactic radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 2005;63:116–122.
- 98.↑
Zehetmayer M, Kitz K, Menapace R, et al.. Local tumor control and morbidity after one to three fractions of stereotactic external beam irradiation for uveal melanoma. Radiother Oncol 2000;55:135–144.
- 99.↑
Haji Mohd Yasin NA, Gray AR, Bevin TH, et al.. Choroidal melanoma treated with stereotactic fractionated radiotherapy and prophylactic intravitreal bevacizumab: the Dunedin Hospital experience. J Med Imaging Radiat Oncol 2016;60:756–763.
- 100.↑
Wackernagel W, Holl E, Tarmann L, et al.. Local tumour control and eye preservation after gamma-knife radiosurgery of choroidal melanomas. Br J Ophthalmol 2014;98:218–223.
- 101.↑
Dunavoelgyi R, Zehetmayer M, Gleiss A, et al.. Hypofractionated stereotactic photon radiotherapy of posteriorly located choroidal melanoma with five fractions at ten Gy—clinical results after six years of experience. Radiother Oncol 2013;108:342–347.
- 102.↑
Dunavoelgyi R, Dieckmann K, Gleiss A, et al.. Local tumor control, visual acuity, and survival after hypofractionated stereotactic photon radiotherapy of choroidal melanoma in 212 patients treated between 1997 and 2007. Int J Radiat Oncol Biol Phys 2011;81:199–205.
- 103.↑
Dieckmann K, Georg D, Zehetmayer M, et al.. LINAC based stereotactic radiotherapy of uveal melanoma: 4 years clinical experience. Radiother Oncol 2003;67:199–206.
- 104.↑
Suesskind D, Scheiderbauer J, Buchgeister M, et al.. Retrospective evaluation of patients with uveal melanoma treated by stereotactic radiosurgery with and without tumor resection. JAMA Ophthalmol 2013;131:630–637.
- 105.↑
Yazici G, Kiratli H, Ozyigit G, et al.. Stereotactic radiosurgery and fractionated stereotactic radiation therapy for the treatment of uveal melanoma. Int J Radiat Oncol Biol Phys 2017;98:152–158.
- 106.↑
Furdova A, Babal P, Kobzova D, et al.. Uveal melanoma survival rates after single dose stereotactic radiosurgery. Neoplasma 2018;65:965–971.
- 107.↑
van den Bosch T, Vaarwater J, Verdijk R, et al.. Risk factors associated with secondary enucleation after fractionated stereotactic radiotherapy in uveal melanoma. Acta Ophthalmol 2015;93:555–560.
- 108.↑
Sarici AM, Pazarli H. Gamma-knife-based stereotactic radiosurgery for medium- and large-sized posterior uveal melanoma. Graefes Arch Clin Exp Ophthalmol 2013;251:285–294.
- 109.↑
Eibl-Lindner K, Fürweger C, Nentwich M, et al.. Robotic radiosurgery for the treatment of medium and large uveal melanoma. Melanoma Res 2016;26:51–57.
- 110.↑
Zahorjanová P, Furdová A, Waczulíková I, et al.. Radiation maculopathy after one-day session stereotactic radiosurgery in patients with ciliary body and choroidal melanoma. Cesk Slov Oftalmol 2019;75:3–10.
- 111.↑
Horwath-Winter J, Schneider MR, Wackernagel W, et al.. Influence of single-fraction gamma-knife radiosurgery on ocular surface and tear function in choroidal melanoma patients. Br J Ophthalmol 2013;97:466–470.
- 112.↑
Dunavoelgyi R, Dieckmann K, Gleiss A, et al.. Radiogenic side effects after hypofractionated stereotactic photon radiotherapy of choroidal melanoma in 212 patients treated between 1997 and 2007. Int J Radiat Oncol Biol Phys 2012;83:121–128.
- 113.↑
Gigliotti CR, Modorati G, Di Nicola M, et al.. Predictors of radio-induced visual impairment after radiosurgery for uveal melanoma. Br J Ophthalmol 2018;102:833–839.
- 114.↑
Dunavoelgyi R, Georg D, Zehetmayer M, et al.. Dose-response of critical structures in the posterior eye segment to hypofractionated stereotactic photon radiotherapy of choroidal melanoma. Radiother Oncol 2013;108:348–353.
- 115.↑
Vidal JL, Bacin F, Albuisson E, et al.. [“Melanoma 92”. epidemiological study of uveal melanoma in France]. J Fr Ophtalmol 1995;18:520–528.
- 116.↑
Shields CL, Kaliki S, Furuta M, et al.. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina 2012;32:1363–1372.
- 117.↑
Collaborative Ocular Melanoma Study Group. Comparison of clinical, echographic, and histopathological measurements from eyes with medium-sized choroidal melanoma in the Collaborative Ocular Melanoma Study: COMS report no. 21. Arch Ophthalmol 2003;121:1163–1171.
- 118.↑
Bellmann C, Lumbroso-Le Rouic L, Levy C, et al.. Uveal melanoma: management and outcome of patients with extraocular spread. Br J Ophthalmol 2010;94:569–574.
- 119.↑
Kujala E, Damato B, Coupland SE, et al.. Staging of ciliary body and choroidal melanomas based on anatomic extent. J Clin Oncol 2013;31:2825–2831.
- 120.↑
Shields CL, Sioufi K, Robbins JS, et al.. Large uveal melanoma (≥10 mm thickness): clinical features and millimeter-by-millimeter risk of metastasis in 1311 cases. The 2018 Albert E. Finley Lecture. Retina 2018;38:2010–2022. https://doi.org/10.1097/IAE.0000000000002144
- 122.↑
van Beek JG, Koopmans AE, Vaarwater J, et al.. The prognostic value of extraocular extension in relation to monosomy 3 and gain of chromosome 8q in uveal melanoma. Invest Ophthalmol Vis Sci 2014;55:1284–1291.
- 123.↑
Blanco G. Diagnosis and treatment of orbital invasion in uveal melanoma. Can J Ophthalmol 2004;39:388–396.
- 124.↑
Chattopadhyay C, Kim DW, Gombos DS, et al.. Uveal melanoma: from diagnosis to treatment and the science in between. Cancer 2016;122:2299–2312.
- 125.↑
Pereira PR, Odashiro AN, Lim LA, et al.. Current and emerging treatment options for uveal melanoma. Clin Ophthalmol 2013;7:1669–1682.
- 126.↑
Rodríguez A, Dueñas-Gonzalez A, Delgado-Pelayo S. Clinical presentation and management of uveal melanoma. Mol Clin Oncol 2016;5:675–677.
- 127.↑
Shields JA, Shields CL. Current management of posterior uveal melanoma. Mayo Clin Proc 1993;68:1196–1200.
- 128.↑
Mirkiewicz-Sieradzka B, Zygulska-Mach H, Romanowska B, et al.. [Attempts of orbit irradiation after enucleation of the eye with malignant choroidal melanoma. Part I]. Klin Oczna 1999;101:287–290.
- 129.↑
Shammas HF, Blodi FC. Orbital extension of choroidal and ciliary body melanomas. Arch Ophthalmol 1977;95:2002–2005.
- 130.↑
Kersten RC, Tse DT, Anderson RL, et al.. The role of orbital exenteration in choroidal melanoma with extrascleral extension. Ophthalmology 1985;92:436–443.
- 131.↑
Pach JM, Robertson DM, Taney BS, et al.. Prognostic factors in choroidal and ciliary body melanomas with extrascleral extension. Am J Ophthalmol 1986;101:325–331.
- 132.↑
Hykin PG, McCartney AC, Plowman PN, et al.. Postenucleation orbital radiotherapy for the treatment of malignant melanoma of the choroid with extrascleral extension. Br J Ophthalmol 1990;74:36–39.
- 133.↑
Gündüz K, Shields CL, Shields JA, et al.. Plaque radiotherapy for management of ciliary body and choroidal melanoma with extraocular extension. Am J Ophthalmol 2000;130:97–102.
- 134.↑
Ang KK, Peters LJ, Weber RS, et al.. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys 1994;30:795–798.
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
