Episcleral plaque 125I radiotherapy with episcleral LCF hyperthermia: A prospective randomized trial

Methods and materials From 1991–1998, 35 patients with uveal melanoma were enrolled in a phase II prospective randomized trial of 125 I EPRT combined with episcleral HT. Two groups were closely matched for pre-treatment patient and tumor characteristics. Group 1: N = 16, and Group 2: N = 19. The median dose to the tumor apex for Group 1 was 80.0 Gy and 60.8 Gy for Group 2. Episcleral HT was given once for 45 min immediately prior to EPRT with a median temperature of 44°C for both groups. The median follow-up was 5.5 years for Group 1 and 5.3 years for Group 2. Results The median tumor height decreased 1.7 mm for patients of both groups. The 5- and 8-year probability of local recurrence was 33% for Group 1, and 25% for Group 2, p = 0.73. The 5-year probability of DFS was 54% for Group 1 and 67% for Group 2, p = 0.51. The 5- and 8-year overall survival was 68% and 34%, respectively, for Group 1, and 83% and 50%, respectively, for Group 2, p = 0.60. The rate of distant metastasis at 5- and 8-years for Group 1 was 29% and 62%, respectively, and 17% and 17%, respectively, for Group 2, p = 0.18. The incidence of enucleation was 4 (25%) in Group 1 vs. 4 (22%) in Group 2. The incidence of late complications was similar in either treatment group. The ambulatory visual acuity (>5/200) at last follow-up was slightly better in Group 2 (80%) than Group 1 (64%). Conclusions Treatment outcomes were similar despite a 25% difference in radiation dose. In view of these findings and in an attempt to reduce the incidence of late treatment toxicity a still lower radiation dose in combination with HT needs to be studied. The reported outcomes need to be evaluated with caution due to the small number of patients in this study. Keywords Uveal Melanoma Plaque Thermoradiotherapy Episcleral Introduction There are several treatment options available for the management of patients with uveal melanoma. Enucleation and episcleral plaque radiotherapy (EPRT) are the most commonly used treatment modalities (1, 2) . In the past 20 years, EPRT has established itself as a well-recognized and effective treatment for T1, T2, and selected T3 lesions (3–5) . Results of EPRT have been excellent with consistently reported 5-year actuarial survival of more than 75% (6–9) . The most conclusive evidence for the effectiveness of EPRT for uveal melanoma when compared with enucleation was provided by a multi-institutional, prospective randomized trial of 1317 patients conducted by the Cooperative Ocular Melanoma Study (COMS) (10, 11) . This important report demonstrated a similar 5- and 10-year overall survival for the 660 patients randomized to enucleation and those 657 patients treated with organ preservation (11) . The main problem with EPRT is a well-documented progressive decrease of vision in the treated eye (12) . In the COMS Report No. 16 based on 657 patients, up to 49% of those with medium-sized choroidal melanoma had substantial impairment in visual acuity at 3 years following EPRT (13) . In addition, serious complications occur in the treated eyes of >20% of patients that receive EPRT (4, 14) . The nature and severity of these complications depend on the radiation dose, treatment method, and the tumor size (12, 15) . Approximately 10% of conservatively treated patients will require enucleation to manage the resulting severe post-radiation sequelae (4, 8) . Hyperthermia (HT) has been shown to have a strong synergistic effect when given with radiotherapy in patients with cutaneous primary and metastatic melanoma (12, 16) . This effect has been well demonstrated in a prospective randomized trial of patients with cutaneous melanoma (16) . The use of adjuvant HT in that study resulted in an improved local control and survival when compared with radiotherapy alone (16) . These findings provided a rationale to reduce the radiation dose for patients who receive EPRT in addition to episcleral HT. There was also an expectation that a reduced radiation dose in patients receiving episcleral thermoradiotherapy may decrease the incidence of treatment complications (4, 12, 17, 18) . It has been shown that a reduction of the episcleral radiation dose, if used concurrently with HT, can account for cessation of tumor growth or shrinkage in up to 90% of cases (4, 12, 17) . Decreased incidence of treatment complications in these patients has also been reported (4, 12, 17) . A phase I study of 25 uveal melanoma patients that employed a 30% lower radiation dose concurrent with episcleral HT of a mean temperature of 43.5°C showed an 88% tumor height reduction and a late complication rate of only 8% (4) . This data helped us design a phase II prospective randomized trial to search for an optimal radiation dose in patients treated with episcleral plaque thermoradiotherapy. We elected to compare patients treated with episcleral HT with the use of either 60 or 80 Gy defined at the tumor apex. A dose of 80 Gy at that time was considered a “standard” dose to the tumor apex. This report provides the data on significant outcomes of the above study. Methods and materials From 1991–1998, 35 patients with primary uveal melanoma were enrolled in an Institutional Review Board (IRB) approved phase II prospective randomized trial utilizing 125 I EPRT with episcleral HT. Patients were randomized to two groups: Group 1 received 80 Gy, (N = 16) and Group 2 received 60 Gy, (N = 19). The total number of patients randomized was 38 with 3 patients excluded following the randomization. There were 2 patients excluded from Group 1, this included 1 patient with unexpected extraocular tumor extension and 1 with no proper consent being signed. The third patient who was randomized to Group 2, developed an acute medical condition, which precluded episcleral plaque placement. All of the study patients received the same episcleral HT. Eligibility criteria for this study included: ( 1 ) Diagnosis of uveal melanoma based on imaging and clinical data (9–11, 13, 18) , ( 2 ) visual acuity in the affected eye of 5/200 or better, those with worse visual acuity could be considered for enrollment if they had refused a recommended enucleation, ( 3 ) visual acuity in the other eye of 20/50 or better, ( 4 ) patient age >21 years, ( 5 ) No prior radiotherapy to the region of the treated eye, ( 6 ) patients had to be medically and psychologically capable of tolerating the treatment procedure and agree to the process of follow-up, ( 7 ) informed consent in writing was required. The accurate delineation of tumor by clinical photography, computerized tomography, and echography was obtained in all affected eyes. Details of the pretreatment work-up have been published previously (4, 9, 18, 19) . The two study groups were closely matched for the important pretreatment patient and tumor characteristics ( Tables 1 and 2 ). All patients had a diagnosis of primary choroidal melanoma. Tumors were staged according to the American Joint Committee on Cancer Staging System (5) . The majority of patients in either group had T2 tumors ( Table 1 ). Two patients in Group 2 had previous surgery on their eyes. Detailed pretreatment general and ophthalmic examinations were performed for all patients, and this process is described elsewhere (8, 9, 18) . An increase or decrease of 2 or more lines of vision was considered to be a significant change in visual acuity. Echography was viewed as an essential part of the initial evaluation of all tumors in this study, as well as for follow-up examinations. Both, contact A-scan and B-scan ultrasound were used. The diagnosis of choroidal melanoma was based on multiple factors including: ( 1 ) Tumor appearance on ophthalmological examination, ( 2 ) tumor size with a period of observation required for evidence of tumor growth in small lesions, ( 3 ) Acoustic criteria previously described (19) . In general, diagnostic criteria were very similar to those recommended by COMS (20) . The shape, size, and location of the tumors were all noted and were observed after treatment for indications of either growth or regression, as well as for changes in their internal acoustic characteristics. Tumor surface area was measured as previously reported, with a combination of computerized axial tomography and fundus photography (4) . First, ocular dimensions were measured from computerized axial tomography, and a three-dimensional (3D) model of the eye was constructed. The retinal surface was estimated to a portion of a sphere of radius, extending from the posterior pole to the limbus. Fundus photographs were then digitized and scaled to a retinal diagram representation of the model. The dimensions of, and distance between, anatomic landmarks visible in the fundus photos, such as the optic disc and fovea, provided the scaling and orientation factors. The tumor perimeter was then outlined on the fundus diagram and stored as a polygon. The surface area A of an n-sided polygon on the surface of a sphere (where A is the area, f is the sum of its angles in radians and r is the radius of the sphere) is A = [f−(n−2)π]r 2 . The angles between successive sides of the polygon were calculated and summed, and the surface area calculated. The median surface area of the tumor was 71.5 mm 2 for Group 1 and 94.0 mm 2 for Group 2 patients. The ciliary body was involved in 1 patient from each treatment group. The geometric center of the tumor base was located posterior to the equator in the majority of patients in either group. Retinal detachment associated with the tumor at the time of diagnosis was found in 56% of patients in Group 1, and 68% of patients from Group 2. The tumor was a primary choroidal melanoma in all patients in this study. The tumor reflectivity was low in the majority of patients in either group; 75% of patients in Group 1, and 95% of patients in Group 2. Treatment EPRT was given with the use of 125 I in the previously described custom-built gold plaques (8, 9, 18, 21, 22) . The treatment was optimized with use of 3-D image reconstruction and 3-D radiation dose distribution (22, 23) . The median prescription depth and radiation dose was 5.4 mm and 80 Gy, respectively, for Group 1 and 5.5 mm and 60.8 Gy, respectively, for Group 2 patients ( Table 3 ). The median dose-rate of 52 cGy/h at a tumor apex was the same for both treatment groups. The dose was defined to the tumor apex and was to include wherever possible a 2 mm margin on the retina (4, 9, 18, 22–24) . Prior to 1999, radiation dose at the University of Southern California (USC) was calculated using methodology that was subsequently shown to be equivalent to the NIST 1999 standards recommended for dose calculations. Episcleral HT was delivered with a localized current field system at 500 kHz (18, 24) . The temperature was controlled on the plaque surface with four microthermocouples at a mean of 43.5°C. This mean temperature was easy to obtain and maintain throughout the treatment. It was controlled within a narrow range of the mean (±0.5°C). Details of episcleral HT technique have been described previously (4, 18, 24–26) . Episcleral HT was given once for 45 min, immediately prior to EPRT (18) . This particular approach was implemented based on our clinical experience with the use of HT as well as the outcome of our experimental animal study (4, 18, 25, 26) . The HT temperature ranged from 42.8 to 45.0°C with a median of 45.0°C for Group 1 and 44.1°C for Group 2 ( Table 3 ). The entire episcleral procedure, including plaque placement and removal, was performed on an outpatient basis. Details on surgical techniques as used in this study have been published elsewhere (9, 25) . The first follow-up visit was scheduled 2 weeks after plaque removal. Subsequent visits were scheduled at quarterly intervals for the first post-treatment year, twice a year for the next 4 years and annually thereafter. Details of the follow-up examination process have been published previously (18) . None of the study patients was lost to follow-up. Local recurrence was defined as a tumor progression or the presence of viable tumor cells in the enucleated eye for any reason including treatment complications. The median follow-up for Group 1 patients was 5.5 years with a maximum of 8.0 years and 5.3 years and 8.4 years, respectively, for Group 2 patients. Randomization was done remotely so that security of this process was assured. The agent assigned to carry out the randomization was blinded to the patient's name and characteristics. The data for this publication was obtained by an IRB approved chart review of all patients who entered the study. The level of significance for this study was p<0.05. The statistical analysis was carried out according to the selected treatment. Informed consent was obtained in writing from all study patients. Results At the time of last follow-up, 16 patients in Group 1 and 19 patients in Group 2 were evaluated for a reduction in tumor height following episcleral plaque thermoradiotherapy. There was a median tumor height reduction of 1.7 mm for the patients in either group ( Table 4 ). There was an increase in tumor reflectivity, indicating a favorable response to treatment, in 61% of Group 1 and 89% of Group 2 patients, p = 0.055 ( Table 4 ). The change in tumor reflectivity remained medium to high in 66% of Group 1, and in 94% of Group 2 patients for the remainder of follow-up. The median and 5-year DFS was 6.3 years and 54%, respectively, for Group 1 and 5.8 years and 67%, respectively, for Group 2 patients, p = 0.51 ( Table 5 , Fig. 1 ). The median and 5-year overall survival was 6.7 years and 68%, respectively, for Group 1 and 5.8 years and 83%, respectively, for Group 2 patients, p = 0.60 ( Table 5 , Fig. 2 ). The median time to local recurrence was 2.1 years for Group 1, and 1.4 years for Group 2, p = 0.78 ( Table 5 , Fig. 3 ). Four patients in each treatment group experienced a local recurrence. The probability of local recurrence at 5 and 8 years was 33% and 33%, respectively, for Group 1, and 25% and 25%, respectively, for Group 2 patients, p = 0.73. All patients who experienced a local recurrence in the treated eye were managed by enucleation, except for 1 patient in Group 2, who was treated with laser ablation. Eight patients ultimately experienced distant metastasis, 5 (31%) in Group 1 and 3 (16%) in Group 2. The median time to distant metastasis was 6.3 and 8.4 years, respectively, for Group 1 and 2 patients ( Table 5 ). The rate of distant metastasis at 5 years for Group 1 was 29%, and for Group 2 was 17%, p = 0.18 ( Table 5 ). A univariate analysis was performed to identify clinical features predictive of disease free survival, overall survival, local recurrence, and the incidence of distant metastasis. There were no features predictive of disease free survival, overall survival, local recurrence, or distant metastases ( Table 6 ). There were only 2 patients with ciliary body involvement, and they had shorter survival than the remaining patients. The summary of visual acuity at last follow-up is shown in Table 7 . At the time of this analysis, 2 patients from each treatment group had unknown pretreatment visual acuity. Three patients from Group 1, and 2 patients from Group 2 had unknown post-treatment visual acuity at last follow-up. Ultimately, 11 patients from Group 1, and 15 patients from Group 2 were evaluated for visual acuity changes. All patients in Group 1 had at least ambulatory vision (>5/200) prior to treatment, while 14 (93%) of patients in Group 2 had ambulatory vision. At the time of last follow-up, 3 (27%) patients from Group 1 had the same visual acuity, while 8 (73%) had worse visual acuity. A total of 7 (64%) patients were able to maintain at least ambulatory vision after treatment. In Group 2, 2 (13%) patients retained the same visual acuity, while 3 (20%) had an improvement, and 10 (67%) had decreased visual acuity. A total of 12 (80%) patients from Group 2 were able to maintain at least ambulatory vision ( Table 7 ). Treatment toxicity This study treatment program was very well tolerated by our patients. Acute toxicity for all patients was of no clinical significance and mostly consisted of mild local pain, relieved by non-narcotic analgesics. At the time of last follow-up, the total incidence of severe late complications was 31% for Group 1 and 26% for Group 2 ( Table 8 ). As expected, cataract formation was the most frequent problem in either group with severe cataract formation affecting only few patients. Moderate to severe vitreous hemorrhage occurred in 31% of Group 1 and in 11% of Group 2 patients ( Table 8 ). The vitreous hemorrhage that occurred in either group was often seen early, which was attributed to a rapid tumor response to HT. Some patients experienced late vitreous hemorrhage associated with vascular complications or tumor regrowth. Severe cases of vitreous hemorrhage were treated with vitrectomy. Severe vitreous detachment occurred in 19% Group 1 and in 11% of Group 2 patients ( Table 8 ). The majority was exudative and resolved spontaneously. Severe radiation retinopathy occurred in 7% of Group 1 and none of Group 2 patients. Retinopathy was diagnosed in all patients in addition to clinical examination by fluorescein angiography. Optic atrophy occurred in about 5% of the patients of either group. Angle closure glaucoma occurred in 2 (13%) Group 1 and 2 (11%) Group 2 patients. This complication leads to a painful eye. In one patient, this could not be controlled and led to an enucleation. There was viable tumor found in this patient's eye at the time of enucleation, and this was scored as a local recurrence. Enucleation was performed in 4 patients of each treatment group ( Table 8 ). Of these 8 patients requiring an enucleation, 7 (87%) were found on histological examination to have viable tumor. Discussion We previously reported treatment results of a phase I trial in patients with uveal melanoma who received episcleral plaque thermoradiotherapy (4, 9) . Long-term survival exceeding 80% was obtained in this group of patients who received 73 Gy to the tumor apex. This represented a 30% radiation dose reduction from the “accepted standard” at the time of the study. This reduction in dose was expected to be associated with a lower incidence of treatment complications such as radiation retinopathy, in which the main predictor is high radiation dose to the tumor base (12, 27) . Tumor regression was noted in the majority of patients, with 9% ultimately showing tumor progression (4) . The complication rate in this study was 56%, however, ambulatory vision was maintained in 80% of patients (4) . The findings of this phase I study gave an impetus to design a phase II randomized trial with one of the study arms scheduled to receive still lower radiation doses. This study was designed in 1989 and the optimal dose-rate for episcleral plaque radiotherapy was not known. The authors believed at that time that a dose-rate just over 50 cGy/hour is a reasonable compromise between tumor control rate and normal tissue tolerance. Subsequently, higher dose-rates were identified as the more optimal ones for patients treated with episcleral plaque radiotherapy for uveal melanoma. A mean dose-rate to the tumor apex ranged from 70–120 cGy/h (12, 28) . Recently published recommendations of the American Brachytherapy Society include a dose-rate to the tumor apex from 60–105 cGy/h (29) . These higher dose-rates to the tumor apex may improve the incidence of local tumor control. Treatment results of this prospective randomized trial are of interest. There was no significant difference in the main outcomes between the two study groups in spite of a 25% difference in the radiation dose to the tumor apex. We hypothesize that the use of episcleral hyperthermia in addition to episcleral plaque radiotherapy was responsible for these results. Of a concern is the relatively small number of patients in this study requiring cautious evaluation of treatment outcomes. The patients in this study experienced a local recurrence rate somewhat higher than is reported in the literature, which is usually in the range of 10–15% at 5 years (1, 12, 26, 27) . To a large extent this higher incidence of local tumor recurrence is a definition of local recurrence, which includes finding of “viable” tumor cells in an enucleated eye for any reason. Of some concern, is the relatively high rate of distant metastasis for the patients in Group 1 who received 80 Gy to the tumor apex. The reason for this high incidence is not known. It may be in part due to the small sample size. The rate of distant metastasis for the patients in Group 2, however, compares favorably with the literature, where the rate of distant metastasis has been reported to be 22% at 10 years (1,12) . The enucleation rate in our study was 25% for Group 1 and 22% for Group 2. Two patients from Group 1 were enucleated due to treatment complications of optic atrophy, which led to a non-functional eye. One patient was also enucleated due to painful angle closure glaucoma. These are reported as common reasons for enucleation after EPRT (3, 30) . The other 2 patients were enucleated due to tumor progression. In Group 2, 1 patient was enucleated due to optic atrophy and found to have viable tumor cells. Two patients were enucleated due to complications of angle closure glaucoma, but only 1 patient was found to have viable tumor cells in the specimen. Overall, 78% of patients were able to preserve their eyes. The enucleation rate for patients in this study was somewhat higher than that reported in the literature, which is usually in the range of 15–16% (31) . There were no predictive prognostic factors identified in our study. It appears that the 2 patients with ciliary body involvement, fared worse in terms of disease free and overall survival than the other patients. This finding is consistent with the data reported in the literature (32, 33) . Factors predicting treatment outcome in patients with uveal melanoma have been well documented. They include: ( 1 ) Baseline tumor height (>4 mm), ( 2 ) increased circumferential tumor dimension, and ( 3 ) T-stage are important predictors of survival, local recurrence, and distant metastasis (1, 6, 30, 31) . Some studies reported in the literature found no decrease in the incidence of tumor control in patients treated with lower radiation doses (30, 34) . One such report of 48 patients treated with episcleral plaque thermoradiotherapy is of interest (12) . The mean tumor dose to the apex was 52.6 Gy (12) . The local control rate was 94%, with the incidence of distant metastasis of 8.3%. Functional visual acuity was maintained in 69% of patients. In experimental animal study, episcleral HT alone demonstrated substantial tumorocidal activity making a design of further clinical trials with the use of HT-RT combination in patients with uveal melanoma very attractive (35) . In our study, patients treated with 60 Gy had a slightly improved functional visual acuity (80%) compared to those treated with 80 Gy (64%). In a recent report of the COMS randomized trial, only 55% of patients were able to maintain visual acuity better than 20/200, 3 years after 125 I brachytherapy (13) . The dose prescribed to the tumor apex in that study was 85 Gy. It is of interest to note the results of a dose searching prospective randomized trial using proton beam radiotherapy (34) . This trial consisted of 188 patients with small- or medium-size choroidal melanomas treated with proton beam to either 50 CGE (cobalt Gray equivalent) or 70 CGE. The incidence of local tumor recurrence and distant metastasis was similar in both study groups. Treatment results obtained with EPRT + EPHT has been shown to be equivalent to those obtained with proton beam therapy in terms of local control, but with a lower incidence of complications (12, 18, 30, 33, 34, 36) . A major effort has been made to optimize radiation dose distribution in EPRT. A part of this effort relates to a routine use of 3-D simulation and treatment planning (22, 37, 38) . A recent study shows the importance of careful dosimetry and treatment planning in treatment outcomes (39) . Another substantial dosimetric improvement was obtained with the development of conformal episcleral plaque radiotherapy (23) . The newly designed episcleral plaque utilizes individually collimated 125 I sources, with the goal of substantially (>30%) reducing the dose to the sclera, while maintaining a tumoricidal dose to the lesion. Additional benefits with the use of this plaque include much “sharper” radiation dose distribution allowing for: ( 1 ) The treatment of tumors in close proximity to the fovea or optic disc with much reduced radiation doses to these structures when compared with the COMS plaques, and ( 2 ) reduced radiation dose to the uninvolved retina when compared with the COMS plaques (23, 37) . The treatment planning program for patients with uveal melanoma developed at USC helps the ophthalmologist with a more precise placement of the plaque on the sclera, thus reducing the time required for surgery. Conclusion Lowering the radiation dose for patients treated with episcleral plaque thermoradiotherapy appears feasible, and may result in a further decrease in treatment complications. Treatment results obtained in our randomized trial need to be interpreted with caution due to a limited number of patients in this study. Based on the outcome of our studies and the data of other relevant reports, the dose of radiation to the tumor apex of 60 Gy appears acceptable. There is a need to design a prospective randomized trial(s) to compare this dose to a 45–50 Gy dose level. These new trials should include the new ABS recommendations relevant to episcleral plaque radiotherapy (29) . Since we know that EPRT is a curative treatment modality equaling survival rates to those obtained following enucleation, more effort needs to be directed toward improvement of quality of life of the patients treated (11) . References [1] K Gunduz C.L Shields J.A Shields Radiation complications and tumor control after plaque radiotherapy of choroidal melanoma with macular involvement Am J Ophthalmol 127 1999 579 589 [2] P.T Finger Tumour location affects the incidence of cataract and retinopathy after ophthalmic plaque radiation therapy Br J Ophthalmol 84 2000 1068 1070 [3] C.L Shields J.A Shields U.L.F Karlsson Reasons for enucleation after plaque radiotherapy for posterior uveal melanoma Ophthalmology 96 1989 919 924 [4] Z Petrovich M Pike M.A Astrahan Episcleral plaque thermoradiotherapy of posterior uveal melanomas Am J Clin Oncol 19 1996 207 211 [5] American Joint Committee on Cancer Malignant melanoma of the uvea F.L Greene L.D Page I.D Fleming Manual for staging of cancer 6 th ed. 2002 Springer-Verlag New York 365 368 [6] J.J Augsburger J.W Gamel J.A Shields Post-irradiation regression of choroidal melanomas as a risk factor for death from metastatic disease Ophthalmology 94 1987 1173 1177 [7] J.A Shields C.L Shields Management of posterior uveal melanoma J.A Shields C.L Shields Intraocular tumors 1992 WB Saunders Philadelphia 171 205 [8] E.K Lean D.M Cohen P.E Liggett Episcleral radioactive plaque therapy: Initial clinical experience with 56 patients Am J Clin Oncol 13 1990 185 190 [9] Z Petrovich G Luxton B Langholz Episcleral plaque radiotherapy in the treatment of uveal melanomas Int J Radiat Oncol Biol Phys 24 1992 247 251 [10] B.R Straatsma S.L Fine J.D Earle Enucleation versus plaque irradiation for choroidal melanoma Ophthalmology 95 1988 1000 1004 [11] The Collaborative Ocular Melanoma Study Group The COMS randomized trial of 125 Iodine brachytherapy for choroidal melanoma III. Initial mortality findings. COMS Report No. 18 Arch Ophthalmol 119 2001 969 982 [12] P.T Finger Microwave thermoradiotherapy for uveal melanoma: Results of a 10 year study Ophthalmology 104 1997 1794 1803 [13] Collaborative Ocular Melanoma Study Group Collaborative ocular melanoma study (COMS) randomized trial of 125 I brachytherapy for medium choroidal melanoma I. Visual acuity after 3 years. COMS Report No. 16 Ophthalmology 108 2001 348 366 [14] L.W Brady A.M Markoe B.E Amendola The treatment of primary intraocular malignancy Int J Radiat Oncol Biol Phys 15 1988 1355 1361 [15] N.A Kindy-Degnan J.R Char S Kroll Effect of various doses of radiation for uveal melanoma on regression, visual acuity, complications, and survival Am J Ophthalmol 107 1989 114 120 [16] J Overgaard D Gonzalez-Gonzalez M.C.C.M Hulshof Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma Lancet 345 1995 540 543 [17] P.T Finger Microwave plaque thermoradiotherapy for choroidal melanoma Br J Ophthalmol 76 1992 358 364 [18] Z Petrovich M.A Astrahan G Luxton Episcleral plaque thermoradiotherapy in patients with choroidal melanoma Int J Radiat Oncol Biol Phys 23 1992 599 603 [19] K.C Ossoinig Standardized echography: Basic principles, clinical applications, and results Int Opthalmol Clin 19 1979 127 210 [20] The Collaborative Ocular Melanoma Study Group Accuracy of diagnosis of choroidal melanomas The Collaborative Ocular Melanoma Study. COMS Report No. 1 Arch Ophthalmol 108 1990 1268 1273 [21] Z Petrovich P Liggett G Luxton Radioactive plaque therapy in the management of primary malignant ocular melanoma: An overview Endocurietherapy/Hyperthermia Oncology 6 1990 131 141 [22] M.A Astrahan G Luxton G Jozsef An interactive treatment planning system for ophthalmic plaque radiotherapy Int J Radiat Oncol Biol Phys 18 1990 679 687 [23] M.A Astrahan G Luxton Q Pu Conformal episcleral plaque therapy Int J Radiat Oncol Biol Phys 39 1997 505 519 [24] M Astrahan P Liggett Z Petrovich A 500 kHz localized current field hyperthermia system for use with ophthalmic plaque radiotherapy Int J Hyperthermia 3 1987 423 432 [25] P.E Liggett C Ma M Astrahan Combined localized current field hyperthermia and irradiation for intraocular tumors Ophthalmology 98 1991 1830 1836 [26] P.E Liggett K.J Pince M Astrahan Localized current field hyperthermia: Effect on normal ocular tissue Int J Hyperthermia 6 1990 517 527 [27] K Gunduz C.L Shields J.A Shields Radiation retinopathy following plaque radiotherapy for posterior uveal melanoma Arch Ophthalmol 117 1999 609 614 [28] J.M Quivey J Augsburger L Snelling 125 I plaque therapy for uveal melanoma: Analysis of impact of time and dose factors on local control Cancer 77 1996 2356 2362 [29] S Nag J.M Quivey J.D Earle The American Brachytherapy Society recommendations for brachytherapy of uveal melanomas Int J Radiat Oncol Biol Phys 56 2003 544 555 [30] P De Potter C.L Shields J.A Shields Plaque radiotherapy for juxtapapillary choroidal melanoma. Visual acuity and survival outcome Arch Ophthalmol 114 1996 1357 1365 [31] P.T Finger Radiation therapy for choroidal melanoma Surv Ophthalmol 42 1997 215 232 [32] C.L Shields J.A Shields P De Potter Diffuse choroidal melanoma: Clinical features predictive of metastasis Arch Ophthalmol 114 1996 956 963 [33] K Gunduz C.L Shields J.A Shields Plaque radiotherapy of Uveal Melanoma with predominant ciliary body involvement Arch Ophthalmol 117 1999 170 177 [34] W Li E.S Gragoudas K.M Egan Metastatic melanoma death rates by anatomic site after proton beam irradiation for uveal melanoma Arch Ophthalmol 118 2000 1066 1070 [35] P.S Swift P.R Stauffer P.D Fries Microwave hyperthermia for choroidal melanoma in rabbits Invest Ophthalmol Vis Sci 31 1990 1754 1760 [36] E.S Gragoudas A.M Lane S Regan A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma Arch Ophthalmol 118 2000 773 778 [37] M.W Wilson J.L Hungerford Comparison of episcleral plaque and proton beam radiation therapy for the treatment of choroidal melanoma Ophthalmology 106 1999 1579 1587 [38] S Knutsen R Hafslund O.R Monge Dosimetric verification of a dedicated 3D treatment planning system for episcleral plaque therapy Int J Radiat Oncol Biol Phys 51 2001 1159 1166 [39] A.L Krintz W.F Hanson G.S Ibbott A reanalysis of the Collaborative Ocular melanoma Study medium tumor trial eye plaque dosimetry Int J Radiat Oncol Biol Phys 56 2003 889 898