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UVEAL MELANOMAS
ORGAN PRESERVATION
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UVEAL MELANOMAS Conservation Treatment John E. Munzenrider, MD
Uveal melanoma is the most common primary adult ocular tumor. Approximately 1500 cases are diagnosed annually in the United States. Men and women are affected in equal proportions. Uveal melanomas are much less common than cutaneous melanomas and infrequently occur in blacks. Historically, treatment was by enucleation, which provided a histological diagnosis and effective tumor treatment. These benefits, however, were obtained at the cost of immediate visual loss. The diagnostic accuracy of current noninvasive techniques (indirect ophthalmoscopy, fundus photography, fluorescein angiography, and ultrasonography) is sufficiently high that treatment decisions can routinely be based on clinical evaluation only. In 1532 eyes with a clinical diagnosis of choroidal melanoma enucleated in a multi-institutional study, an independent review of the histology by three independent ophthalmic pathologists confirmed the diagnosis in 99.7% (1527 eyes). Four of the five patients with a false-positive clinical diagnosis of melanoma had metastatic adenocarcinoma, while the fifth had a h e m a n g i ~ m a Re.~~ cently, an analysis of tumor location with respect to retinal topography and light dose distribution on the retinal sphere was reported, based on the study of 420 Massachusetts residents diagnosed between 1984 and 1993 in whom fundus drawings or photographs were available for review. The results suggested that tumor initiation occurred nonuniformly: tumors were concentrated in the macular area and decreased
From the Deparbnent of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA
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monotonically with distance from the macula to the ciliary body. This pattern correlated positively with the dose distribution of solar light on An epidemiologic case-control study had suggested the retinal ~phere.3~ that sunlight exposure to the retina might be related to the development of uveal melanomas,51 although that suggestion has been q~esti0ned.l~ A recent review has discussed the nature of uveal melanoma and its possible causes and treatment.’ TECHNIQUES FOR EYE CONSERVATION
Stallard5‘jfirst demonstrated the potential for conservative treatment of ocular tumors, specifically uveal melanomas, using scleral radionuclide cobalt-60 plaque brachytherapy. That t e c h h u e achieved eye preservation in almost two thirds of surviving patients. Conservative treatment of uveal melanoma patients has become commonplace in recent 45, 56, or charged particle years, with radionuclide plaquesz0, 33, beamss7, l2, 14, 28, 55* ‘j0, @, ‘j7 being most commonly used. Transpupillary thermotherapp53 has also recently been used in selected patients. In addition, internal re~ection,’~, 35 microwave therm~therapy,’~ stereotactic radiosurgery,38and stereotactic radiotherapy61have also been used. @
CHARGED PARTICLE CONSERVATION TREATMENT
Charged particle beams allow more precise focusing of the radiation dose in the target than do X-ray beams and thus are better able to spare noninvolved intraocular and orbital structures. This makes them ideal for treating ocular tumors. Uveal melanomas have been treated for more than a quarter of a century in what has proven to be a most fruitful collaborative effort between the Radiation Oncology Department of Massachusetts General Hospital (MGH), the Retina Service of the Massachusetts Eye and Ear Infirmary (MEEI), and the Harvard Cyclotron Laboratory (HCL). A similar collaboration between the Radiation Oncology Department and the Ocular Oncology Unit of the University of California at San Francisco (UCSF) and the Lawrence Berkeley Laboratory (LBL), using helium ended in 1992 when the accelerator at LBL was shut down. The UCSF group currently uses the Douglas Cyclotron at the University of California, Davis? for the proton treatment of uveal melanomas. Proton beam therapy for uveal melanomas has also been administered in the former Soviet Union: at Clatterbridge, England? at the Paul Shirer Institute (PSI, formerly the Swiss Institute for Nuclear the Gustav Werner Institute Research [SIN]) in Villigen, S~itzerland,6~ in Uppsala, Sweden, in Brussels, Belgium, in Nice and Orsay, France,14
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in Chiba, Japan,6O at TRIUMF in Vancouver, British Columbia, and at Loma Linda University in Calif0rnia.5~ Approximately 9400 patients have been treated with charged particle radiation through 1999 throughout the using similar techniques and doses to those used at HCL. Those planning and treatment techniques, clinical indications, current treatment protocols, and treatment outcome in the MGH-HCL uveal melanoma patients are discussed later. Selected references regarding treatment outcomes with isotope plaque therapy also are summarized. PRECLINICAL STUDIES
Proton doses of 50 to 100 Gy were delivered in a single fraction through 7- or 10-mm-diameter apertures to normal monkey eyes to simulate ocular tumor treatment. Areas of edematous retina and choroid developed in the treated eyes within 20 hours, but the retina and choroid outside the irradiated area remained entirely normal.1° Fractionation showed a marked effect, with 125 Gy/5 fractions producing the same effect at 24 hours and at 1year as 30 Gy in a single pulse.9Normal retinal architecture was preserved immediately outside the discrete retinal scar produced by the proton beam whereas chorioretinal changes persisted within the irradiated area at 42 to 51 months.31 CLINICAL STUDIES
Through October 2000, 2815 uveal melanoma patients were treated at MGH-HCL; 1405 (49.9%) were men, and 1410 (50.1%) were women. Patients ranged in age from 13 to 92 years (mean 58 yrs); 9 (0.3%) were 18 years of age or younger. Using the Collaborative Ocular Melanoma Study (COMS) size ~ategories?~ approximately 20% have had small, 50% medium, and 30% large tumors. PLANNING AND TREATMENT TECHNIQUES
All patients have had planning with a program developed at MGH.= Axial eye length and tumor height are determined ultrasonographically. Tumor configuration is drawn manually on the computer screen, depicting the tumor as shown on sketches drawn by the ophthalmologist or fundus photographs. Surgical tumor localization is used in most uveal melanoma patientsz2,*,26: 2-mm-diameter tantalum rings (Trings) are sutured to the sclera around the perimeter of the tumor,
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which is defined by transillumination or indirect ophthalmoscopy. Tring position for planning is determined from measurements taken during surgery and from simulation radiographs taken on the second or third day after surgery. A transparency with appropriate magnification shows the desired clip position and is overlaid on a radiograph taken in the treatment position at treatment set-up. The light field projection of the proton beam through the treatment aperture onto the front of the eye is used to verlry patient alignment. Anterior ciliary body lesions can be planned for treatment with a light field set-up only, with tumor location being determined by transillumination of the tumor. Dose volume histograms for the globe, lens, ciliary body, retina, macula, and disc are also routinely made available. An individualized brass aperture is fabricated for each patient by a computer-controlled milling machine as specified by the planning program. Treatmen' portals are relatively small, ranging from 10 to 35 mm in diameter. Tissue compensators have not been used for the ocular treatments at HCL. The patient is treated in a seated position, his or her head immobilized with an individually molded face mask and bite block. The eye is immobilized by voluntary patient fixation on a light positioned to define the prescribed fixation angle. The treatment fixation angle is chosen so that the beam enters the eye to the extent possible through the sclera, thereby reducing or eliminating direct irradiation of the cornea, anterior chamber, and lens. Patients who had had T-ring placement for tumor localization have eye position for treatment determined radiographically and verified by visualization of the light field as projected through the treatment aperture onto the front of the eye. A light-field set-up only is used for patients who did not undergo surgical localization. Irradiation of the eyelid is reduced or eliminated by lid retraction. Treatment set-up is routinely accomplished in 5 to 10 minutes, with irradiation times being 1 to 2 minutes. During treatment, eye position is monitored by a video camera. Mean movement during treatment was 0.5 mm k 0.3 mm, as determined during 41 treatments in 11patients; maximum movement was 1.2 mm.@ DOSE AND FOLLOW-UP
The standard dose, 70 CGE (Cobalt Gy Equivalents, CGE = proton 62, ") was given to 95% of patients, 4.0% received 50 Gy times RBE l.la* CGE, and 1% received other doses. Ninety-nine percent received 5 fractions, and 94% completed treatment in 7 to 9 days. Patients have generally been seen at MEEI or by the referring ophthalmologist 6 weeks after completion of treatment, every 3 months during the first year, and on a semiannual or annual schedule thereafter.
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TREATMENT OUTCOME Local Control and Survival
Tumor was locally controlled within the treated eye in 96.3 f 1.5% and 95.4 f 3.3%at 60 and 84 months: 236 and 82 patients were available for follow-up at those intervals. Two failures were noted after 48 months. In 10 of 12 patients, tumors recurred at the margin of the irradiated volume, with the other patients recurring in the full dose (70 CGE) volume.@ Survival Approximately 80% of patients are surviving at 5 year~.2~,~O in proton-treated patients is at least as good as in those treated primarily with enucleation. Survival was compared between 556 proton-treated patients and two enucleated groups: 238 patients operated during the same 10-year period that the proton treatments were given (July 1975 to December 1984), and 275 patients whose eyes were removed during the preceding decade (January 1965 to June 1975). Estimated Kaplan-Meier survival rates at 5 years were 81 f 2%, 68 f 3%, and 74 f 3%, and at 10 years they were 63 f 5%, 53 f 4%, and 50 f 3'70, respectively, for irradiated patients, patients enucleated in the later period, and those enucleated in the earlier period, respectively. Median follow-up for the three patient groups was 5.3, 8.8, and 17.0 years, respectively?, 49 Previously defined significant prognostic factors for irradiated30and enucleated4 patients were used to classify patients in each treatment group. Younger patients with relatively small posterior tumors were classified as lower risk. Higher risk patients were older and had larger tumors involving the ciliary body, and intermediate risk patients had tumors extending anterior to the equator without involving the ciliary body and were intermediate in tumor size and age. Estimated survival probabilities in each risk category were better for proton-treated patients than for either of the enucleated groups. This data suggest that there was little influence of treatment modality on survival in these three groups of uveal melanoma patients.4sA similarly structured retrospective study compared the survival of 103 enucleated patients with that of 345 patients treated with isotope plaque brachytherapy. As in the proton therapy versus enucleation comparison, there was no survival disadvantage for the irradiated patients. At 15 years, metastasis-free survivals were 57.1%(standard error [SE] 6.4%) and 61.8% (SE 3.3%)for the enucleated and the plaque-treated patients, respectively2 Eye Retention and Survival
Eye retention probability is strongly related to tumor size, being 97y0, %yo, and 78% for patients with small, intermediate, and large
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tumors, respectively. Enucleation rates were significantly greater in patients with large tumors, those with tumor height >8 mm, tumor diameter >16 mm, and ciliary body tumor involvement (P=<.OOOl for all factors). Multivariate analysis identified independent risk factors associated with greater likelihood of eye loss as being involvement of the ciliary body, tumor height >8 mm, and distance between the posterior tumor edge and the fovea. Risk of eye loss was greatest for patients who had two or more risk factors (238 patients), was intermediate for those with one risk factor (569 patients), and least for patients with no risk factor (213 patients). Rates of eye retention at 5 years were 99 ? 1%and 92 k 2% for the low and intermediate riskigroups, respectively, but dropped to 76 ? 7% at 5 years for patients in the highest risk group.16 Pathologic changes in eyes enucleated after proton therapy have been described.l8,36,47,66 There was a relationship between death from metastatic disease and reason for enucleation after proton treatment. Patients whose indication for enucleation was tumor growth (N = 34) were almost four times as likely to die from metastasis as those losing the eye because of complications (N = 103, rate ratios 3.8 versus 0.9, 95% confidence limits 2.3 to 6.3 and 0.6 to 1.4, respectively). Eye retention probability at 10 years, with median follow-up of 8 years for the 1541 patients studied, was 89% ? 2%.17 Treatment-Related Morbidity and Visual Function
Moist eyelid desquamation is the only usual acute reaction, occurring in patients whose lid could not be completely retracted from the irradiation field. Typically, this involves only a small lid segment (2 to 5 mm by 8 to 15 mm). Permanent eyelash loss with late atrophy and scarring usually occurs in the desquamated area, although the acute reaction heals in approximately 4 weeks. Late radiation injuries to anterior ocular structures include rubeosis iridis with neovascular glaucoma and cataract formation. Both of these complications can be treated successfully, with expectation of visual preservation or restoration in some patients.= Lens changes after proton therapy have been studied in 388 patients with clear lenses initially; 42% developed posterior subcapsular opacities (PSC) within 3 years of treatment. Probability of PSC formation was related to lens dose, tumor height, and older age.” Lens opacities were present in 494 of the 1171 patients (42%)treated through December 1987. Eighty-four patients with opacities underwent cataract extraction between 2 months and 11 years after treatment. Visual acuity 1 year after surgery was 20/100 or better in approximately one half of patients and 20/40 or better in approxi-
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mately one third of patients. Larger tumor size was highly correlated with poorer visual outcome after cataract extraction. Six patients were later enucleated, five because of painful blind eyes and one because of a ”ring melanoma’’ diagnosed after surgery.u Treatment options for patients with late radiation injury to posterior ocular structures are limited. Significant loss of visual function can occur because of radiation-induced macular edema, maculopathy, papillopathy, and optic atrophy. Visual morbidity is greater in eyes with larger and with more posterior tumors, although visual acuity is unchanged or improved in more than 50% of treated eyes. Visual prognosis is significantly associated with tumor height, distance of the posterior tumor margin from the optic disc or fovea, pretreatment retinal detachment involving the macula, initial visual acuity, and radiation dose to disc, fovea, and Patients with useful vision (visual acuity 20/200 or better) before treatment experience visual loss caused by cataract progression, retinal detachment, and radiation retinopathy. Visual status at 36 months was significantly related to tumor location with respect ,to posterior ocular structures. Useful vision was preserved in 67Y0 of 199 patients with tumor edge greater than 3 mm from the optic disc and the fovea but in only 39% of 363 patients with tumor edge 3 mm or less from either structure. The disc and/or the fovea received a high dose (>35 CGE) in only 9% of the former group and in 83% of the latter group.5O Generally, similar complication patterns are seen in isotope plaque-treated 33 Focal laser therapy may be beneficial in the short term for some patients.=
CLINICAL TRIALS Dose-Searching Trial to Decrease Radiation Morbidity
Because of the visual morbidity associated with treatment of posterior tumors, a randomized dose de-escalation trial was conducted between October 1989 and July 1994. Patients known to be at high risk of experiencing significant visual morbidity with the standard dose of 70 CGE were selected for the trial. Study subjects had tumors of 15 mm or less in greatest diameter and 5 mm or less in height, located within 6 mm of the optic disc fovea. One hundred eighty-eight patients with small and medium choroidal melanomas, 75% of those meeting the study criteria during the enrollment period, were randomized to receive the standard dose or the experimental dose (50 CGE). Treatment was given to both groups in five fractions over 7 to 9 days. The prognostically favorable characteristics of this population predicted a relatively low
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risk of death from metastatis or of eye loss caused by radiation complications, with the expectation that most patients would be available for follow-up. End points for the trial were visual loss, retinopathy, and local control. Baseline characteristics of the two groups were generally similar. The control group, however, had a larger proportion of male patients (63%vs 44%, P = .04), a smaller average largest tumor diameter (10 mm versus 11 mm, P = .03), and a smaller proportion of patients with tumor extending anterior to the equator (6% versus l6%, P = .04). The average dose to the optic disc and the macula was 31.2 and 45 CGE, respectively, for the 50 CGE group, and 42 and 67.9 CGE, respectively, for the 70 CGE group. Baseline median visual acuity was 20/32 for both groups. Local tumor regrowth occurred in 2 and 3 patients, and metastasis occurred in 7 and 8 patients at the lower and higher dose levels, respectively ( P > .99 and .79, for the two comparisons).Median visual acuity progressively declined at each annual follow-up interval from 12 to 48 months for both groups, being 20/100 at the latter milestone. At 60 months, median acuity had declined further to 20/160 for the 50 CGE group but remained stable at 20/100 for the higher dose group. There was no difference in the proportion of patients retaining useful vision at 5 years, with approximately 55% in both groups having visual acuity of 20/200 or better ( P = .81). Radiation maculopathy rates were similar for both dose groups, occurring in approximately 75% of patients with tumors 1.5 mm or less from the macula and in 40% of patients with tumors 1.5 mm or more from the macula, respectively. Radiation papillopathy rates were nonsignificantly decreased for the lower dose group ( P = .20). There was significantly less visual field deficit following treatment for patients receiving the lower dose. Four and five patients in the lower and higher dose groups, respectively, underwent enucleation for radiation complications following treatment. Other radiation complications were not significantly different in the two groups. Mean tumor heights, initially 3.05 and 3.04 mm for the lower and higher dose groups, respectively, by 60 months had declined to 1.59 and 1.54 mm, res~ectively.2~ That a 30% reduction in dose was not associated with a greater degree of visual preservation suggested that even the lower dose (50 CGE) exceeded the radiation tolerance of the macula. A lesser degree of visual field loss and of radiation papillopathy with the lower dose did, however, suggest some visual benefit for the lower radiation dose. The demonstration that local tumor failure rates were not increased by the significantly lower dose used in this study suggests that even lower doses could be studied in an attempt to reduce visual morbidity. Further dose reductions must be undertaken with great care because increased local failure rates could result in greater rates of eye loss and distant failure. The author is currently preparing to investigate an altered frac-
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tionation program in this patient population, in which the study group would receive a smaller radiation dose per fraction and a larger number of treatment fractions, resulting in a larger total dose than that given to the control group. Such an approach would have the potential to reduce the effective dose to normal ocular structures, while still preserving a high degree of tumor control. Adjuvant Interferon in Patients at High Risk for Metastasis
A significantly greater median survival and median relapse-free survival has been demonstrated in cutaneous melanoma patients at high risk for recurrence who were randomized to receive interferon-alpha2b (INF), relative to patients randomized to observation In a nonrandomized clinical trial, 130 patients with one or more risk factors for metastasis (tumor 215 mm diameter, ciliary body involvement, and age older than 65) have been offered INF following standard dose proton beam radiotherapy. Survival rates in the INF-treated patients will be compared with a historical control group of patients matched for known prognostic factors who were treated with protons only. An interim report on this study is planned for June 2001. Particle Beam Therapy versus Radionuclide Plaque Brachytherapy
Patients with melanomas less than 10 mm in height and less than 15 mm in diameter were randomized by the LBL-UCSF group to receive 70 GyE in five treatments with helium ions, or 70 Gy to the tumor apex with iodine-125 (lz5I)episcleral plaque brachytherapy. In the initial report of this trial, local control rates were 100% and 87% with helium ions and with lEI plaque, respectively. Enucleation rates were significantly higher in plaque-treated patients whereas anterior segment complications were more common in particle-treated patients.* In a retrospective nonrandomized study, treatment outcome was compared for patients treated with proton beam therapy (PBRT) and with episcleral plaque brachytherapy using two different isotopes. The risk of local recurrence was significantly greater for patients treated with ruthenium-106 (lo6Ru)than with '=I or with PBRT.& SUMMARY
Eye conservation can be achieved in patients with uveal melanomas by several techniques, with external beam charged particle (proton)
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therapy and episcleral radionuclide plaque therapy being used most commonly. The probability of visual preservation and of eye retention with either technique is related to tumor size and location. If vision is poor or absent in the fellow eye, even very large tumors can be treated with the proton beam, with a 75% to 80% probability of eye salvage and preservation of some degree of visual function. Local control is achieved in a large proportion of treated eyes with either technique probably because of the large doses that can be focally administered to these relatively small tumors with those techniques. Achieving local control may also contribute to improved survival in some patients.17Survival clearly has not been compromised?, 49 Useful vision is preserved in eyes with tumors occurring in a favorable location with respect to the optic disc or macula.32,51A dose-searching trial, aimed at improving visual outcome in patients with tumors in unfavorable locations, has been completedz7and has provided data to aid in designing future trials. Successfully treating uveal melanoma without removal of the involved eye is one of the major oncologic triumphs of the latter part of the 20th century. Very high rates of local control can be achieved with heavy charged particle external beam radiotherapy or '=I episcleral plaque brachytherapy, with preservation of a functionally useful eye in many patients. The excellent results in the eye melanoma patients treated with external beam proton therapy also demonstrate that almost all the patients can successfully cooperate in their treatment by voluntarily fixating the eye on a particular point during treatment, so that their tumor is positioned properly in the beam during treatment. Conservative treatment can achieve local control rates similar to or superior to those achieved with radiation therapy alone in other commonly treated solid tumors, including early stage carcinomas of the breast, vocal cord, and prostate. Continued careful follow-up of conservatively treated patients will provide even better understanding of the radiation effects on uveal melanomas and on normal ocular structures. It is also impressive that these gains have not been achieved at a cost of increased mortality: survival rates in irradiated patients are at least as good as after enucleation.25 49 Further observation will reveal whether these initial dramatic and encouraging results will be maintained. The COMS Study may provide additional data in this regard at least regarding survival after brachytherapy relative to e n u ~ l e a t i o n . 5 ~ ~ ~ It will not, however, clardy indications for the two types of radiotherapy (brachytherapy and charged particle therapy) nor will it allow direct comparisons of acute and chronic ocular effects of those therapeutic modalities. The UCSF-LBL trial mentioned previously, which compared helium ion therapy with lEI episcleral plaque treatment, has documented the superiority of charged particle therapy to plaque therapy in terms
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of local tumor control and eye retention.* Of interest is a recent survey reporting that choice of treatment for uveal melanoma did not seem to be associated with large differences in quality of life when assessed at long-term follow-up.11 The distant failures and metastatic deaths in uveal melanoma patients, more common with larger and more anteriorly located tumors, are most distressing. A randomized clinical trial of adjuvant systemic therapy is clearly indicated but has not been mounted because of the relatively poor results obtained with systemic therapy in metastatic melanoma patients. The recent report of improved survival in cutaneous melanoma patients at high risk for metastasis who were treated with interferon is en~ouraging,3~ and it led to the initiation of the nonrandomized study described previously, which uses interferon following proton eye irradiation for patients with increased risk of metastasis. Other trials would clearly be indicated if more effective systemic therapies become available.
References 1. Albert D M The ocular melanoma story: LIII Edward Jackson Memorial Lecture: part 11. Am J Ophthalmol 123:729-741,1997 2. Augsburger JJ, Schneider S, Freire J, et al: Survival following enucleation versus plaque
radiotherapy in statistically matched subgroups of patients with choroidal melanomas: Results in patients treated between 1980 and 1987. Graefes Arch Clin Exp Ophthalmol 237558-567, 1999 . 3. Bonnet DE, Kacperek A, Sheen MA, et al: The 62 MeV proton beam for the treatment of ocular melanoma at Clatterbridge. Br J Radio1 66907-914, 1993 4. Brovkina AF, Zarubei G D Ciliochoroidal melanomas treated with a narrow medical proton beam. Arch Ophthalmol 104:402404, 1986 5. Castro JR, Char DH, Petti PL, et al: 15 years experience with helium ion radiotherapy for uveal melanoma. Int J Radiation Oncology Biol Phys 39:989-996, 1997 6. Castro JR, Petti PL, Blakely EA, et al: Particle radiation therapy. In Leibel SA, Phillips TL (eds): Textbook of Radiotherapy. Philadelphia, WB, Saunders, 1998, pp 1223-1240 7. Char DH, Kroll SM, Castro J R Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 125S1-89, 1998 8. 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 1001547-1554, 1993 9. Constable IJ, Goitein M, Koehler AM, et al: Small field irradiation of monkey eyes with protons and photons. Radiation Research 65:304-314,1976 10. Constable IJ, Koehler AM, Schmidt RA: Proton irradiation of simulated ocular tumors. Investig Ophthalmol 14:547-555,1975 11. Cruickshanks KJ, Fryback DG, Nondahl DM, et al: Treatment choice and quality of life in patients with choroidal melanoma. Arch Ophthalmol 117:461467, 1999 12. Daftari IK, Char DH, Verhey LJ, et al: Anterior segment sparing to reduce charged particle radiotherapy complications in uveal melanoma. Int J Radiation Oncology Biol Phys 39~997-1010,1997 13. Damato B, Groenwald C, McGalliard J, et al: Endoresection of choroidal melanoma. Br J Ophthalmol 82:213-218, 1998 14. Desjardins L, Levy C, d’Hermies F, et al: Initial results of proton therapy in choroidal
melanoma at the d'Orsey Ceter for Proton Therapy: The first 464 patients. Cancer Radiother 1:222-226,1997 15. Dolin P, Foss A, Hungerford J: Uveal melanoma: Is solar W radiation a risk factor? Ophthalmic Epidemiol1:27-30,1994 16. Egan K, Gragoudas ES, Seddon JM, et al: The risk of enucleation after proton beam irradiation of uveal melanoma. Ophthalmology 96:1377-1383, 1989 17. Egan KM, Ryan LM, Gragoudas ES Survival implications of enucleation after definitive radiotherapy for choroidal melanoma: An example of regression on time-dependent covariates. Arch Ophthalmol 116:36&370,1998 18. Ferry AP, Blair CJ, Gragoudas ES, et a1 Pathologic examination of ciliary body melanoma treated with proton beam irradiation. Arch Ophthalmol103:1849-1853,1985 19. Finger PT:Microwave thermoradiotherapy for uveal melanoma: Results of a 10-year study. Ophthalmology 104:1794-1803,1997 20. Finger PT, Berson A, Szechter A. Palladium-103 plaque radiotherapy for choroidal melanoma: Results of 7-year study. Ophthalmology 106606-613, 1999 21. Garretson BR, Robertson DM, Earle JK: Choroidal melanoma treatment with iodine125 brachytherapy. Arch Ophthalmol 105:1394-1397,1987 22. Goiten M, Miller T: Planning proton therapy of the eye. Med Phys 10:275-283, 1983 23. Gragoudas ES, Egan Kh4, Arrigg PG, et ak Cataract extraction after proton beam irradiation for malignant melanoma of the eye. Arch Ophthalmol 110475479,1992 24. Gragoudas ES, Egan Kh4, Walsh SM, et a1 Lens changes after proton beam irradiation for uveal melanoma. Am J Ophthalmol 119:157-164,1995 25. Gragoudas ES, Goitein M, Koehler AM, et a1 Proton irradiation of small choroidal malignant melanomas. Am J Ophthalmol83655-673,1977 26. Gragoudas ES, Goitein M, Verhey LJ, et ak Proton beam irradiation: An alternative to enudeation for intraocular melanoma. Ophthalmology 87571-581,1980 27. Gragoudas ES, Lane AM, Regan S, et ak A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma. Arch Ophthalmol 11877% 778,2000 Egan K, et ak Long-term results of proton beam irradiated 28. Gragoudas ES, Seddon JM, uveal melanomas. Arch Ophthalmol94349-353,1987 29. Gragoudas ES, Seddon JM, Egan JSM, et ak Metastasis from weal melanoma after proton beam irradiation. Ophthalmology 95992-999,1988 30. Gragoudas ES, Seddon JM, Polivogianis LL, et al: Prognostic factors for metastasis following proton beam irradiation of weal melanomas. Ophthalmology 93675-680, 1986 31. Gragoudas ES, Zakov NZ, Albert DM, et al: Long term observations of protonirradiated monkey eyes. Arch Ophthalmol972184-2191, 1979 32. Gunduz K, Shields CL, Shields JA, et a1 Radiation complications and tumor control after plaque radiotherapy of choroidal melanomas with macular involvement. Am J Ophthalmol 127579-589,1999 33. Gunduz K, Shields CL, Shields JA, et ak Radiation retinop[athy following plaque radiotherapy of choroidal melanomas for posterior uveal melanoma. Arch Ophthalmol 117609414,1999 34. Hykin PG, Shields CL, Shields JA, et ak The efficacy of focal laser therapy in radiationinduced macular edema. Ophthalmology 1051425-1429, 1998 35. Kertes PJ, Johnson JC, Peyman G A Internal resection of posterior uveal melanomas. Br J Ophthalmol821147-1153, 1998 36. Kincaid MC, Folberg R, Torczynski E, et ak Complications after proton beam therapy for weal malignant melanoma. Ophthalmology 95:982-991,1988 37. Kirkwood JM, Strawderman MH, Emstoff MS, et al: Interferon Alpha-2b adjuvant therapy of high risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin On~0114:7-17,1996 38. Leung SW, Hsiung CY, Chen HC, et al: Management of choroidal melanomas with linear accelerator-based stereotactic radiosurgery. Acta Ophthalmol m62-65, 1999 39. Li W, Judge H, Gragoudas ES, et al: Patterns of tumor initiation in choroidal melanoma. Cancer Res 603757-3760,2000 40. Lommatzsch PK, Werschnik C, Schuster E: Long-term follow-up of Ru-106/Rh-106
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brachytherapy for posterior uveal melanoma. Graefes Arch Clin Exp Ophthalmol 238~129-137, 2000 41. Marcoe AM, Brady LW, Shields J, et a1 Radioactive eye plaque therapy versus enucleation for the treatment of posterior uveal malignant melanoma. Radiology 156801803, 1985 42. Miller D W A review of proton beam radiotherapy. Med Phys 22:1943-1954, 1995 43. Munzenrider JE, Verhey L, Gragoudas ES, et al: Conservative treatment of uveal melanoma: Dose distribution to tumors with local recurrence after proton beam therapy. Int J Radiation Oncology Biol Phys 17493498,1989 44. Oosterhuis JA, Journec-de-Korver HG, Keunen JE: Transpupillary thermotherapy: Results in 50 patients with choroidal melanoma. Arch Ophthalmol 116:157-162, 1998 45. Rotman M, Long RS, Packer S, et al: Radiation therapy of uveal melanomas. Trans Ophthalmol SOCUK 97431435, 1977 46. Seddon JM, Albert DM, Lavin P, et al: A prognostic factor study of disease-free interval and survival following enucleation for uveal melanoma. Arch Ophthalmol 101:1894-1899,1983 47. Seddon JM, Gragoudas ES, Albert DM: Ciliary body and choroidal melanomas treated by proton beam irradiation: Histopathologic study of eyes. Arch Ophthalmol101:14021408, 1983 48. Seddon JM, Gragoudas ES, Albert DM, et al: Comparison of survival rates for patients with uveal melanoma after treatment with proton beam irradiation or enucleation. Am J Ophthalmol99:282-290, 1985 49. Seddon Jh4,Gragoudas ES, Egan KM, et al: Relative survival rates after alternative therapies for uveal melanoma. Ophthalmology 97769-777, 1990 50. Seddon JM, Gragoudas ES, Egan KM, et al: Uveal melanomas near the optic disc or fovea: Visual results after proton beam irradiation. Ophthalmology 94354-361, 1987 51. Seddon JM, Gragoudas ES, Glynn RJ, et al: Host factors: UV radiation and risk of uveal melanoma: A case-control study. Arch Ophthalmol 10831274-1280, 1990 52. Seddon JM, Gragoudas ES, Polivogianis L, et al: Visual outcome after proton beam irradiation of uveal melanoma. Ophthalmology 93:666-674, 1986 53. Shields CL, Shields JA, Carter J, et a1 Transpupillary thermotherapy for choroidal melanoma: Tumor control and visual results in 100 consecutive cases. Ophthalmology 105~581-590,1998 54. Sisterson J: Ion beam therapy: Overview of the world experience. Application of Acdelerators in Research and Industry. Proceedings of the Sixteenth International Conference, Denton, TX, November 3, 2000 55. Slater JM, Archambeau JO, Miller DW, et al: The proton treatment center at Loma Linda University Medical Center: Rationale for and description of its development. Int J Radiat Oncol Biol Phys 22383-389, 1992 56. Stallard HB: Malignant melanoblastoma of the choroid. Mod Prob Ophthalmol 71638, 1966 57. The Collaborative Ocular Melanoma Study Group: Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. COMS Report No. 1Ophthalmol 108:1268-1273, 1990 58. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma I 1 Initial mortality findings. COMS report no. 10. Am J Ophthalmol 125:779-796, 1998 59. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma I11 Local complications and observations, following enucleation COMS report no. 11. Am J Ophthalmol 126:362-372, 1998 60. Tsunemoto H, Morita S, Kawachi K, et al: Clinical results of proton radiotherapy in Japan. Proceedings of the 8th International Cong of Rad Research, Edinburgh, 1987, pp 922-927 61. Tokuuye K, Akine Y, Sumi M, et al: Fractionated stereotactic radiotherapy for choroidal melanoma. Radiother Oncol43:87-91, 1997 62. Urano M, Goitein M, Verhey LJ, et al: Relative biological effectiveness of modulated proton beams in various murine tissues. Int J Radiat Oncol Biol Phys 10:509-514,1984
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63. Verhey LJ, Goitein M, Munzenrider JE, et al: Precise positioning of patients for radiation therapy. Int J Radiat Oncol Biol8289-294,1982 64. Wilson W ,Hungerford JL: Comparison of plaque and proton beam radiation therapy for treatment of choroidal melanoma. Ophthalmology 106157947,1999 65. Yashkin PN, Silin DI, Zolotov VA, et a1 Medical beam at Moscow Synchotron determined by the Chinese hamster cells assay. Int J Radiat Oncol Biol Phys 313535540,1995 66. Zinn KM, Stein-Pokomy K, Jakobiec F, et ak Proton beam irradiated epithelial cell me!anoma of the ciliary body. Ophthalmology 881315-1321,1981 67. Zografos L, Perret C, Egger E, et al: Proton beam irradiation of weal melanomas at Paul Scherrer Institute (former SIN).Strahlenther Onkol 166114, 1990
Address reprint requests to John E. Munzenrider, MD Department of Radiation Oncology Massachusetts General Hospital 100 Blossom Street Boston, MA 02114-2617
0889-8588/01 $15.00
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UVEAL MELANOMAS Conservation Treatment John E. Munzenrider, MD
Uveal melanoma is the most common primary adult ocular tumor. Approximately 1500 cases are diagnosed annually in the United States. Men and women are affected in equal proportions. Uveal melanomas are much less common than cutaneous melanomas and infrequently occur in blacks. Historically, treatment was by enucleation, which provided a histological diagnosis and effective tumor treatment. These benefits, however, were obtained at the cost of immediate visual loss. The diagnostic accuracy of current noninvasive techniques (indirect ophthalmoscopy, fundus photography, fluorescein angiography, and ultrasonography) is sufficiently high that treatment decisions can routinely be based on clinical evaluation only. In 1532 eyes with a clinical diagnosis of choroidal melanoma enucleated in a multi-institutional study, an independent review of the histology by three independent ophthalmic pathologists confirmed the diagnosis in 99.7% (1527 eyes). Four of the five patients with a false-positive clinical diagnosis of melanoma had metastatic adenocarcinoma, while the fifth had a h e m a n g i ~ m a Re.~~ cently, an analysis of tumor location with respect to retinal topography and light dose distribution on the retinal sphere was reported, based on the study of 420 Massachusetts residents diagnosed between 1984 and 1993 in whom fundus drawings or photographs were available for review. The results suggested that tumor initiation occurred nonuniformly: tumors were concentrated in the macular area and decreased
From the Deparbnent of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
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monotonically with distance from the macula to the ciliary body. This pattern correlated positively with the dose distribution of solar light on An epidemiologic case-control study had suggested the retinal ~phere.3~ that sunlight exposure to the retina might be related to the development of uveal melanomas,51 although that suggestion has been q~esti0ned.l~ A recent review has discussed the nature of uveal melanoma and its possible causes and treatment.’ TECHNIQUES FOR EYE CONSERVATION
Stallard5‘jfirst demonstrated the potential for conservative treatment of ocular tumors, specifically uveal melanomas, using scleral radionuclide cobalt-60 plaque brachytherapy. That t e c h h u e achieved eye preservation in almost two thirds of surviving patients. Conservative treatment of uveal melanoma patients has become commonplace in recent 45, 56, or charged particle years, with radionuclide plaquesz0, 33, beamss7, l2, 14, 28, 55* ‘j0, @, ‘j7 being most commonly used. Transpupillary thermotherapp53 has also recently been used in selected patients. In addition, internal re~ection,’~, 35 microwave therm~therapy,’~ stereotactic radiosurgery,38and stereotactic radiotherapy61have also been used. @
CHARGED PARTICLE CONSERVATION TREATMENT
Charged particle beams allow more precise focusing of the radiation dose in the target than do X-ray beams and thus are better able to spare noninvolved intraocular and orbital structures. This makes them ideal for treating ocular tumors. Uveal melanomas have been treated for more than a quarter of a century in what has proven to be a most fruitful collaborative effort between the Radiation Oncology Department of Massachusetts General Hospital (MGH), the Retina Service of the Massachusetts Eye and Ear Infirmary (MEEI), and the Harvard Cyclotron Laboratory (HCL). A similar collaboration between the Radiation Oncology Department and the Ocular Oncology Unit of the University of California at San Francisco (UCSF) and the Lawrence Berkeley Laboratory (LBL), using helium ended in 1992 when the accelerator at LBL was shut down. The UCSF group currently uses the Douglas Cyclotron at the University of California, Davis? for the proton treatment of uveal melanomas. Proton beam therapy for uveal melanomas has also been administered in the former Soviet Union: at Clatterbridge, England? at the Paul Shirer Institute (PSI, formerly the Swiss Institute for Nuclear the Gustav Werner Institute Research [SIN]) in Villigen, S~itzerland,6~ in Uppsala, Sweden, in Brussels, Belgium, in Nice and Orsay, France,14
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in Chiba, Japan,6O at TRIUMF in Vancouver, British Columbia, and at Loma Linda University in Calif0rnia.5~ Approximately 9400 patients have been treated with charged particle radiation through 1999 throughout the using similar techniques and doses to those used at HCL. Those planning and treatment techniques, clinical indications, current treatment protocols, and treatment outcome in the MGH-HCL uveal melanoma patients are discussed later. Selected references regarding treatment outcomes with isotope plaque therapy also are summarized. PRECLINICAL STUDIES
Proton doses of 50 to 100 Gy were delivered in a single fraction through 7- or 10-mm-diameter apertures to normal monkey eyes to simulate ocular tumor treatment. Areas of edematous retina and choroid developed in the treated eyes within 20 hours, but the retina and choroid outside the irradiated area remained entirely normal.1° Fractionation showed a marked effect, with 125 Gy/5 fractions producing the same effect at 24 hours and at 1year as 30 Gy in a single pulse.9Normal retinal architecture was preserved immediately outside the discrete retinal scar produced by the proton beam whereas chorioretinal changes persisted within the irradiated area at 42 to 51 months.31 CLINICAL STUDIES
Through October 2000, 2815 uveal melanoma patients were treated at MGH-HCL; 1405 (49.9%) were men, and 1410 (50.1%) were women. Patients ranged in age from 13 to 92 years (mean 58 yrs); 9 (0.3%) were 18 years of age or younger. Using the Collaborative Ocular Melanoma Study (COMS) size ~ategories?~ approximately 20% have had small, 50% medium, and 30% large tumors. PLANNING AND TREATMENT TECHNIQUES
All patients have had planning with a program developed at MGH.= Axial eye length and tumor height are determined ultrasonographically. Tumor configuration is drawn manually on the computer screen, depicting the tumor as shown on sketches drawn by the ophthalmologist or fundus photographs. Surgical tumor localization is used in most uveal melanoma patientsz2,*,26: 2-mm-diameter tantalum rings (Trings) are sutured to the sclera around the perimeter of the tumor,
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which is defined by transillumination or indirect ophthalmoscopy. Tring position for planning is determined from measurements taken during surgery and from simulation radiographs taken on the second or third day after surgery. A transparency with appropriate magnification shows the desired clip position and is overlaid on a radiograph taken in the treatment position at treatment set-up. The light field projection of the proton beam through the treatment aperture onto the front of the eye is used to verlry patient alignment. Anterior ciliary body lesions can be planned for treatment with a light field set-up only, with tumor location being determined by transillumination of the tumor. Dose volume histograms for the globe, lens, ciliary body, retina, macula, and disc are also routinely made available. An individualized brass aperture is fabricated for each patient by a computer-controlled milling machine as specified by the planning program. Treatmen' portals are relatively small, ranging from 10 to 35 mm in diameter. Tissue compensators have not been used for the ocular treatments at HCL. The patient is treated in a seated position, his or her head immobilized with an individually molded face mask and bite block. The eye is immobilized by voluntary patient fixation on a light positioned to define the prescribed fixation angle. The treatment fixation angle is chosen so that the beam enters the eye to the extent possible through the sclera, thereby reducing or eliminating direct irradiation of the cornea, anterior chamber, and lens. Patients who had had T-ring placement for tumor localization have eye position for treatment determined radiographically and verified by visualization of the light field as projected through the treatment aperture onto the front of the eye. A light-field set-up only is used for patients who did not undergo surgical localization. Irradiation of the eyelid is reduced or eliminated by lid retraction. Treatment set-up is routinely accomplished in 5 to 10 minutes, with irradiation times being 1 to 2 minutes. During treatment, eye position is monitored by a video camera. Mean movement during treatment was 0.5 mm k 0.3 mm, as determined during 41 treatments in 11patients; maximum movement was 1.2 mm.@ DOSE AND FOLLOW-UP
The standard dose, 70 CGE (Cobalt Gy Equivalents, CGE = proton 62, ") was given to 95% of patients, 4.0% received 50 Gy times RBE l.la* CGE, and 1% received other doses. Ninety-nine percent received 5 fractions, and 94% completed treatment in 7 to 9 days. Patients have generally been seen at MEEI or by the referring ophthalmologist 6 weeks after completion of treatment, every 3 months during the first year, and on a semiannual or annual schedule thereafter.
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TREATMENT OUTCOME Local Control and Survival
Tumor was locally controlled within the treated eye in 96.3 f 1.5% and 95.4 f 3.3%at 60 and 84 months: 236 and 82 patients were available for follow-up at those intervals. Two failures were noted after 48 months. In 10 of 12 patients, tumors recurred at the margin of the irradiated volume, with the other patients recurring in the full dose (70 CGE) volume.@ Survival Approximately 80% of patients are surviving at 5 year~.2~,~O in proton-treated patients is at least as good as in those treated primarily with enucleation. Survival was compared between 556 proton-treated patients and two enucleated groups: 238 patients operated during the same 10-year period that the proton treatments were given (July 1975 to December 1984), and 275 patients whose eyes were removed during the preceding decade (January 1965 to June 1975). Estimated Kaplan-Meier survival rates at 5 years were 81 f 2%, 68 f 3%, and 74 f 3%, and at 10 years they were 63 f 5%, 53 f 4%, and 50 f 3'70, respectively, for irradiated patients, patients enucleated in the later period, and those enucleated in the earlier period, respectively. Median follow-up for the three patient groups was 5.3, 8.8, and 17.0 years, respectively?, 49 Previously defined significant prognostic factors for irradiated30and enucleated4 patients were used to classify patients in each treatment group. Younger patients with relatively small posterior tumors were classified as lower risk. Higher risk patients were older and had larger tumors involving the ciliary body, and intermediate risk patients had tumors extending anterior to the equator without involving the ciliary body and were intermediate in tumor size and age. Estimated survival probabilities in each risk category were better for proton-treated patients than for either of the enucleated groups. This data suggest that there was little influence of treatment modality on survival in these three groups of uveal melanoma patients.4sA similarly structured retrospective study compared the survival of 103 enucleated patients with that of 345 patients treated with isotope plaque brachytherapy. As in the proton therapy versus enucleation comparison, there was no survival disadvantage for the irradiated patients. At 15 years, metastasis-free survivals were 57.1%(standard error [SE] 6.4%) and 61.8% (SE 3.3%)for the enucleated and the plaque-treated patients, respectively2 Eye Retention and Survival
Eye retention probability is strongly related to tumor size, being 97y0, %yo, and 78% for patients with small, intermediate, and large
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tumors, respectively. Enucleation rates were significantly greater in patients with large tumors, those with tumor height >8 mm, tumor diameter >16 mm, and ciliary body tumor involvement (P=<.OOOl for all factors). Multivariate analysis identified independent risk factors associated with greater likelihood of eye loss as being involvement of the ciliary body, tumor height >8 mm, and distance between the posterior tumor edge and the fovea. Risk of eye loss was greatest for patients who had two or more risk factors (238 patients), was intermediate for those with one risk factor (569 patients), and least for patients with no risk factor (213 patients). Rates of eye retention at 5 years were 99 ? 1%and 92 k 2% for the low and intermediate riskigroups, respectively, but dropped to 76 ? 7% at 5 years for patients in the highest risk group.16 Pathologic changes in eyes enucleated after proton therapy have been described.l8,36,47,66 There was a relationship between death from metastatic disease and reason for enucleation after proton treatment. Patients whose indication for enucleation was tumor growth (N = 34) were almost four times as likely to die from metastasis as those losing the eye because of complications (N = 103, rate ratios 3.8 versus 0.9, 95% confidence limits 2.3 to 6.3 and 0.6 to 1.4, respectively). Eye retention probability at 10 years, with median follow-up of 8 years for the 1541 patients studied, was 89% ? 2%.17 Treatment-Related Morbidity and Visual Function
Moist eyelid desquamation is the only usual acute reaction, occurring in patients whose lid could not be completely retracted from the irradiation field. Typically, this involves only a small lid segment (2 to 5 mm by 8 to 15 mm). Permanent eyelash loss with late atrophy and scarring usually occurs in the desquamated area, although the acute reaction heals in approximately 4 weeks. Late radiation injuries to anterior ocular structures include rubeosis iridis with neovascular glaucoma and cataract formation. Both of these complications can be treated successfully, with expectation of visual preservation or restoration in some patients.= Lens changes after proton therapy have been studied in 388 patients with clear lenses initially; 42% developed posterior subcapsular opacities (PSC) within 3 years of treatment. Probability of PSC formation was related to lens dose, tumor height, and older age.” Lens opacities were present in 494 of the 1171 patients (42%)treated through December 1987. Eighty-four patients with opacities underwent cataract extraction between 2 months and 11 years after treatment. Visual acuity 1 year after surgery was 20/100 or better in approximately one half of patients and 20/40 or better in approxi-
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mately one third of patients. Larger tumor size was highly correlated with poorer visual outcome after cataract extraction. Six patients were later enucleated, five because of painful blind eyes and one because of a ”ring melanoma’’ diagnosed after surgery.u Treatment options for patients with late radiation injury to posterior ocular structures are limited. Significant loss of visual function can occur because of radiation-induced macular edema, maculopathy, papillopathy, and optic atrophy. Visual morbidity is greater in eyes with larger and with more posterior tumors, although visual acuity is unchanged or improved in more than 50% of treated eyes. Visual prognosis is significantly associated with tumor height, distance of the posterior tumor margin from the optic disc or fovea, pretreatment retinal detachment involving the macula, initial visual acuity, and radiation dose to disc, fovea, and Patients with useful vision (visual acuity 20/200 or better) before treatment experience visual loss caused by cataract progression, retinal detachment, and radiation retinopathy. Visual status at 36 months was significantly related to tumor location with respect ,to posterior ocular structures. Useful vision was preserved in 67Y0 of 199 patients with tumor edge greater than 3 mm from the optic disc and the fovea but in only 39% of 363 patients with tumor edge 3 mm or less from either structure. The disc and/or the fovea received a high dose (>35 CGE) in only 9% of the former group and in 83% of the latter group.5O Generally, similar complication patterns are seen in isotope plaque-treated 33 Focal laser therapy may be beneficial in the short term for some patients.=
CLINICAL TRIALS Dose-Searching Trial to Decrease Radiation Morbidity
Because of the visual morbidity associated with treatment of posterior tumors, a randomized dose de-escalation trial was conducted between October 1989 and July 1994. Patients known to be at high risk of experiencing significant visual morbidity with the standard dose of 70 CGE were selected for the trial. Study subjects had tumors of 15 mm or less in greatest diameter and 5 mm or less in height, located within 6 mm of the optic disc fovea. One hundred eighty-eight patients with small and medium choroidal melanomas, 75% of those meeting the study criteria during the enrollment period, were randomized to receive the standard dose or the experimental dose (50 CGE). Treatment was given to both groups in five fractions over 7 to 9 days. The prognostically favorable characteristics of this population predicted a relatively low
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risk of death from metastatis or of eye loss caused by radiation complications, with the expectation that most patients would be available for follow-up. End points for the trial were visual loss, retinopathy, and local control. Baseline characteristics of the two groups were generally similar. The control group, however, had a larger proportion of male patients (63%vs 44%, P = .04), a smaller average largest tumor diameter (10 mm versus 11 mm, P = .03), and a smaller proportion of patients with tumor extending anterior to the equator (6% versus l6%, P = .04). The average dose to the optic disc and the macula was 31.2 and 45 CGE, respectively, for the 50 CGE group, and 42 and 67.9 CGE, respectively, for the 70 CGE group. Baseline median visual acuity was 20/32 for both groups. Local tumor regrowth occurred in 2 and 3 patients, and metastasis occurred in 7 and 8 patients at the lower and higher dose levels, respectively ( P > .99 and .79, for the two comparisons).Median visual acuity progressively declined at each annual follow-up interval from 12 to 48 months for both groups, being 20/100 at the latter milestone. At 60 months, median acuity had declined further to 20/160 for the 50 CGE group but remained stable at 20/100 for the higher dose group. There was no difference in the proportion of patients retaining useful vision at 5 years, with approximately 55% in both groups having visual acuity of 20/200 or better ( P = .81). Radiation maculopathy rates were similar for both dose groups, occurring in approximately 75% of patients with tumors 1.5 mm or less from the macula and in 40% of patients with tumors 1.5 mm or more from the macula, respectively. Radiation papillopathy rates were nonsignificantly decreased for the lower dose group ( P = .20). There was significantly less visual field deficit following treatment for patients receiving the lower dose. Four and five patients in the lower and higher dose groups, respectively, underwent enucleation for radiation complications following treatment. Other radiation complications were not significantly different in the two groups. Mean tumor heights, initially 3.05 and 3.04 mm for the lower and higher dose groups, respectively, by 60 months had declined to 1.59 and 1.54 mm, res~ectively.2~ That a 30% reduction in dose was not associated with a greater degree of visual preservation suggested that even the lower dose (50 CGE) exceeded the radiation tolerance of the macula. A lesser degree of visual field loss and of radiation papillopathy with the lower dose did, however, suggest some visual benefit for the lower radiation dose. The demonstration that local tumor failure rates were not increased by the significantly lower dose used in this study suggests that even lower doses could be studied in an attempt to reduce visual morbidity. Further dose reductions must be undertaken with great care because increased local failure rates could result in greater rates of eye loss and distant failure. The author is currently preparing to investigate an altered frac-
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tionation program in this patient population, in which the study group would receive a smaller radiation dose per fraction and a larger number of treatment fractions, resulting in a larger total dose than that given to the control group. Such an approach would have the potential to reduce the effective dose to normal ocular structures, while still preserving a high degree of tumor control. Adjuvant Interferon in Patients at High Risk for Metastasis
A significantly greater median survival and median relapse-free survival has been demonstrated in cutaneous melanoma patients at high risk for recurrence who were randomized to receive interferon-alpha2b (INF), relative to patients randomized to observation In a nonrandomized clinical trial, 130 patients with one or more risk factors for metastasis (tumor 215 mm diameter, ciliary body involvement, and age older than 65) have been offered INF following standard dose proton beam radiotherapy. Survival rates in the INF-treated patients will be compared with a historical control group of patients matched for known prognostic factors who were treated with protons only. An interim report on this study is planned for June 2001. Particle Beam Therapy versus Radionuclide Plaque Brachytherapy
Patients with melanomas less than 10 mm in height and less than 15 mm in diameter were randomized by the LBL-UCSF group to receive 70 GyE in five treatments with helium ions, or 70 Gy to the tumor apex with iodine-125 (lz5I)episcleral plaque brachytherapy. In the initial report of this trial, local control rates were 100% and 87% with helium ions and with lEI plaque, respectively. Enucleation rates were significantly higher in plaque-treated patients whereas anterior segment complications were more common in particle-treated patients.* In a retrospective nonrandomized study, treatment outcome was compared for patients treated with proton beam therapy (PBRT) and with episcleral plaque brachytherapy using two different isotopes. The risk of local recurrence was significantly greater for patients treated with ruthenium-106 (lo6Ru)than with '=I or with PBRT.& SUMMARY
Eye conservation can be achieved in patients with uveal melanomas by several techniques, with external beam charged particle (proton)
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therapy and episcleral radionuclide plaque therapy being used most commonly. The probability of visual preservation and of eye retention with either technique is related to tumor size and location. If vision is poor or absent in the fellow eye, even very large tumors can be treated with the proton beam, with a 75% to 80% probability of eye salvage and preservation of some degree of visual function. Local control is achieved in a large proportion of treated eyes with either technique probably because of the large doses that can be focally administered to these relatively small tumors with those techniques. Achieving local control may also contribute to improved survival in some patients.17Survival clearly has not been compromised?, 49 Useful vision is preserved in eyes with tumors occurring in a favorable location with respect to the optic disc or macula.32,51A dose-searching trial, aimed at improving visual outcome in patients with tumors in unfavorable locations, has been completedz7and has provided data to aid in designing future trials. Successfully treating uveal melanoma without removal of the involved eye is one of the major oncologic triumphs of the latter part of the 20th century. Very high rates of local control can be achieved with heavy charged particle external beam radiotherapy or '=I episcleral plaque brachytherapy, with preservation of a functionally useful eye in many patients. The excellent results in the eye melanoma patients treated with external beam proton therapy also demonstrate that almost all the patients can successfully cooperate in their treatment by voluntarily fixating the eye on a particular point during treatment, so that their tumor is positioned properly in the beam during treatment. Conservative treatment can achieve local control rates similar to or superior to those achieved with radiation therapy alone in other commonly treated solid tumors, including early stage carcinomas of the breast, vocal cord, and prostate. Continued careful follow-up of conservatively treated patients will provide even better understanding of the radiation effects on uveal melanomas and on normal ocular structures. It is also impressive that these gains have not been achieved at a cost of increased mortality: survival rates in irradiated patients are at least as good as after enucleation.25 49 Further observation will reveal whether these initial dramatic and encouraging results will be maintained. The COMS Study may provide additional data in this regard at least regarding survival after brachytherapy relative to e n u ~ l e a t i o n . 5 ~ ~ ~ It will not, however, clardy indications for the two types of radiotherapy (brachytherapy and charged particle therapy) nor will it allow direct comparisons of acute and chronic ocular effects of those therapeutic modalities. The UCSF-LBL trial mentioned previously, which compared helium ion therapy with lEI episcleral plaque treatment, has documented the superiority of charged particle therapy to plaque therapy in terms
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of local tumor control and eye retention.* Of interest is a recent survey reporting that choice of treatment for uveal melanoma did not seem to be associated with large differences in quality of life when assessed at long-term follow-up.11 The distant failures and metastatic deaths in uveal melanoma patients, more common with larger and more anteriorly located tumors, are most distressing. A randomized clinical trial of adjuvant systemic therapy is clearly indicated but has not been mounted because of the relatively poor results obtained with systemic therapy in metastatic melanoma patients. The recent report of improved survival in cutaneous melanoma patients at high risk for metastasis who were treated with interferon is en~ouraging,3~ and it led to the initiation of the nonrandomized study described previously, which uses interferon following proton eye irradiation for patients with increased risk of metastasis. Other trials would clearly be indicated if more effective systemic therapies become available.
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