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Uveal Melanomas Near the Optic Disc or Fovea
Uveal Melanomas Near the Optic Disc or Fovea Visual Results after Proton Beam Irradiation JOHANNA M. SEDDON, MD,*t EVANGELOS S. GRAGOUDAS, MD,* KATHLEEN M. EGAN, MPH,t ROBERT J. GLYNN, SeD, PhD,t JOHN E. MUNZENRIDER, MD,:j: MARY AUSTIN-SEYMOUR, MD,:j: MICHAEL GOITEIN, PhD,:j: LYNN VERHEY, PhD,:j: MARSHA URIE, PhD,:j: ANDREAS KOEHLER, AM§
Abstract: Proximity to the disc and fovea is a risk factor for visual loss after proton beam irradiation of uveal melanomas. Of 562 eyes treated over a 10 year period with pretreatment visual acuity of 20/200 or better, 363 (64.6%) contained tumors within 2 disc diameters (DD) of the disc or fovea. Rates of visual loss after treatment to worse than 20/200 and causes of visual decline were evaluated using Kaplan-Meier analysis. Cumulative rates of visual loss among subjects with tumors near the disc or fovea were 33 and 47% 1 and 2 years after treatment compared to 17 and 28%, respectively, for subjects with tumors located farther from both structures. The leading cause of visual loss in the first year among eyes with tumors near the disc or fovea was retinal de tachment. Controlling for other predictors of visual loss to worse than 20/200, location near the disc or fovea was independently related to visual loss primarily due to retinal detachment, cataract, and radiation retinopathy. Despite the un favorable location of these tumors, over half of patients with 20/200 or better pretreatment visual acuity had useful vision 2 years after treatment. [Key words: fovea, optic disc, proton beam irradiation, uveal melanoma, visual acuity.] Oph thalmology 94:354-361, 1987
A previous analysis of patients treated by proton beam irradiation has shown that the most important prognostic factors for visual loss to worse than 20/200 are higher tumor height and proximity to the disc, fovea, or both (2 disc diameters [DO] or about 3.0 mm from these struc tures or closer). 1 Also predictive of visual loss using mul tivariate analyses were presence of macular detachment From the Retina Service,* and Epidemiology Unit, t Massachusetts Eye and Ear Infirmary, the Department of Ophthalmology, Harvard Medical School, Boston, the Department of Radiation Medicine,:j: Massachusetts General Hospital, Boston, and Harvard Cyclotron Laboratory,§ Cambridge. Presented at the Ninety-first Annual Meeting of the American Academy of Ophthalmology, New Orleans, Louisiana, November 9-13, 1986. Reprint requests to Johanna M. Seddon, MD, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.
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before treatment, worse pretreatment vision, and higher radiation dose delivered to the disc, fovea, or lens. 1 In another report, which evaluated vision after cobalt plaque therapy, a radiation dose to the disc and fovea of greater than 50 gray (Gy) (5000 rad; 1 Gy = 100 rad) was related to substantial visual loss after 2 to 3 years. Tumors with margins within 5 mm of these structures almost in variably received this higher dose. 2 Although we inform patients who present with tumors close to the disc or fovea of the higher risk of visual loss after irradiation, many still prefer such a treatment rather than enucleation. These patients often request informa tion concerning the likelihood of visual decline and how quickly it will occur. The purpose of this report is to focus on the subgroup of patients with tumors near the optic disc or fovea treated by proton beam irradiation in order to (1) calculate their
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rate of visual loss after treatment, (2) compare the rate of visual loss of patients with these tumors to the rate of visual loss of patients with tumors located elsewhere, (3) evaluate the cause-specific rates ofdecreased visual acuity for patients in this group, and (4) compare them to the cause-specific rates of decreased visual acuity for patients with tumors farther from the disc and fovea.
SUBJECfS AND METHODS STUDY POPULATION
Patients with uveal melanoma of the choroid and/or ciliary body treated by proton beam irradiation at the Harvard Cyclotron Laboratory between July 1975 and March 1985 were considered for inclusion in the analysis. Of the 666 patients (667 eyes) treated during this interval, 442 patients (442 eyes, 66.3%) contained tumors within 2 DD or 3.0 mm ofthe disc, fovea, or both. For all analyses involving posttreatment visual acuity, the following pa tients were excluded: four (0.5%) retreated with proton beam irradiation; two (0.3%) whose tumors had been ex cised before treatment; and 25 (3.7%) who had no visual acuity follow-up available. The majority ofthe latter group consisted of patients from outside the United States (18 patients). For analyses assessing the endpoint of visual decline to worse than 20/200 after treatment among patients starting with 20/200 or better vision, an additional 74 patients ( 11%) with pretreatment visual acuities worse than 20/200 were also excluded. Ofthe remaining 561 patients (562 eyes), 363 patients (363 eyes, 64.6%) had tumors within 2 DD of the disc, fovea, or both. VISUAL ACUITY FOLLOW-UP
Visual acuities were tested with and without pinhole before treatment and at follow-up visits. The majority of patients returned to MEEI 6 and 12 months after treat ment and at yearly intervals thereafter. Twenty-five per cent of patients were followed elsewhere, and posttreat ment visual acuities were obtained from the· referring ophthalmologist for these cases. Follow-up data were col lected through March 31, 1986. For the 562 eyes evaluated for visual outcome worse than 20/200, vision follow-up ranged between 1 month and 10.6 years (median, l. 7 years). Only 16 cases (3%) had less than 6 months of vision follow-up. Seventy-nine cases (14%) had 6 months to 1 year, 175 (31%) had 1 to 2 years, 126 (22%) had 2 to 3 years, and 166 (30%) had more than 3 years of vision follow-up. If patients who required enucleation did not have worse than 20/200 vision before surgery, they were considered to have "no light perception" on the day of enucleation. CAUSES OF VISUAL DECLINE
Causes of initial visual loss to worse than 20/200 were determined by chart review for most patients. Beginning
in September 1985, the reasons for visual acuity loss of more than one line compared to pretreatment visual acu ity were recorded on standardized forms at the time of follow-up examination at MEEI. These were used for data collection for subjects whose initial visual decline to worse than 20/200 occurred after this time. For the patients fol lowed elsewhere, causes of visual loss were provided by the referring ophthalmologist by letter or when contacted by telephone. Posttreatment fluorescein angiography was performed on 70% of cases whose vision declined to worse than 20/200 after treatment. The specific cause of visual loss was coded as due pri marily to radiation-induced cataract (anterior or posterior subcapsular changes), retinal detachment which involved the fovea, radiation retinopathy (retinal vascular changes secondary to radiation causing macular ischemia, macular edema, intraretinal hemorrhages, and/or intraretinal and subretinal exudates), radiation optic neuropathy (hyper emia and edema of optic disc, ischemia of the disc cap illaries, or optic atrophy), vitreous hemorrhage, or glau coma secondary to anterior segment neovascularization (neovascularization ofthe angle with intraocular pressure over 21 mmHg). In some cases, a primary cause of visual decline could not be determined because more than one of the above problems contributed to the decrease in vi sion. These cases were coded as having a combination of the above complications. A few subjects had visual decline due to reasons unrelated to treatment including macular degeneration, open angle glaucoma, and senile cataract which worsened symmetrically with the fellow eye. In some cases, the cause of visual decline could not be de termined. OTHER CLINICAL DATA
Additional clinical information collected and coded onto standardized forms has been described previously 1 and is summarized below. (1) Age at the time of treatment. (2) The largest tumor diameters were grouped into small (~10.0 mm), medium (10.1-15.0 mm), and large (> 15.0 mm). Maximum heights determined by ultraso nography were categorized as low (~5.0 mm), medium (5.1-8.0 mm), or high (>8.0 mm). 1 (3) Location of the anterior margin of the tumor was coded as posterior to the equator, or anterior to the equa tor with or without involvement of the ciliary body. (4) The distance of the closest part of the tumor, apex or base, from the edge of the optic disc and fovea was assessed by indirect ophthalmoscopy. These distances were estimated in terms of disc diameters with 1.0 DD ap proximately equal to 1.5 mm. Data were coded as near both disc and fovea, near the disc only, near the fovea only, or near neither structure. Unless otherwise specified, a tumor was considered to be near a structure if it was less than or equal to 2.0 DD from the structure. The term "near the disc or fovea" implies that the tumor is near one or near both structures. (5) Macular detachment before treatment. (6) In almost all cases, the total dose delivered to the 355
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tumor and a 1.5-mm margin around the tumor was 70 Cobalt Gy Equivalent (CGE) in five treatments over 7 to 10 days (63.6 proton Gy X 1.1 relative biological effec tiveness = 70 CGE). The radiation doses were estimated from the computer treatment planning program. 3 Thera diation doses to the disc and fovea were considered to gether as high dose to disc and fovea, high dose to disc only, high dose to fovea only, or high dose to neither structure. High dose was considered to be 35.5 CGE or greater. The percentage of the lens receiving more than 50% of the total dose was categorized as low (0-33%), medium (34-66%), or high (67-100%). ANALYSES
Initial data analyses used contingency tables with as sociated chi-square tests to examine the differences in proportions or distributions of baseline characteristics among groups. Pearson's correlation coefficient (R) was used to assess the relationship of tumor distances from the disc and fovea to the estimated radiation doses at these sites. The time until a first observation of visual acuity worse than 20/200 was examined using life-table ap proaches to adjust for variable follow-up between indi viduals. Life-table techniques were also used to estimate the probability of recovering vision to 20/200 or better among eyes losing vision to worse than 20/200 after pro ton beam therapy. When visual loss occurred during an interval between two examinations, the time of visual loss was taken to be the midpoint of that interval. Analyses of visual loss for both specific distances from the fovea and disc and for individual causes of visual loss, and anal yses of visual recovery, used the Kaplan-Meier product moment approach to the estimation of survival. 4 This approach allows for estimation of the time until an event without making assumptions about the functional form of the survival curve. Standard errors of estimated per centages maintaining vision at 20/200 or better were ob tained using Greenwood's formula. 5 Time to visual loss curves were compared using the log-rank test. 6 Multivar iate survival analyses used Cox's proportional hazards model 7 to assess the relative importance of a number of variables as predictors of time to visual loss.
RESULTS DESCRIPTIVE CHARACTERISTICS
Table 1 describes the clinical characteristics of the 667 eyes, comparing 442 with tumors near the disc or fovea to 225 with tumors greater than 2 DD from the disc and fovea. Eyes containing tumors within 2 DD of the disc, fovea, or both had poorer pretreatment vision. Sixty-two of 442 eyes (14.0%) with tumors in this location started worse than 20/200 compared to 12 of 225 eyes (5.3%) with tumors at greater distances from the disc and macula. Eyes containing tumors near the disc or fovea were more likely to present with retinal detachment involving the macula. They were also less likely to have tall (>5.0 mm) tumors, compared to tumors farther from these structures. 356
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Two hundred and five of 225 eyes (91.1%) with tumors farther than 2 DD from the disc and fovea received low radiation doses (as defined above) to both disc and fovea. In contrast, 367 of 442 eyes (83%) with tumors near the disc or fovea received a high dose to one ofthese structures. The amount of radiation dose received by the disc and fovea correlated inversely with the distance of the tumor from these structures (R = -0.47, P < 0.001; R = -0.44, P < 0.001, respectively). The lenses of eyes with tumors near the disc or fovea were less likely to receive more than one third of the total dose than lenses of eyes with more distant tumors. Complications requiring enucleation developed in 39 of the treated 667 eyes (6%). Thirty-three of these (85%) had tumors near the disc or fovea. Of these 33 eyes, 18 had tumor diameters greater than 15 mm. Seventy-four eyes ( 11%) had pretreatment visual acu ities worse than 20/200. Vision never improved to 20/200 or better throughout the posttreatment period in 35 of these eyes (47%). Visual improvement to 20/200 or better occurred in 36 eyes (49%), although improvement was temporary in most (25/36). The remaining three eyes had no vision follow-up. Pretreatment and most recent (before March 1986) posttreatment visual acuity categories for 165 subjects with tumors near the disc or fovea followed 2 or more years after treatment are displayed in Table 2. Seventeen of these 165 patients ( 10.3%) improved, 99 (60%) worsened, and the other 49 (29.7%) remained in the same visual acuity category. The corresponding figures were similar for eyes with tumors more than 2 DD from the disc and fovea (11.3% improved, 58.7% worsened, and 30.0% re mained in the same category). Thus, 40% of all cases re tained the same or better visual acuity at least 2 years after treatment. RATES OF VISUAL CHANGE
Visual loss to worse than 20/200. Visual decline to worse than 20/200 among the 562 eyes with initial visual acuity of 20/200 or better occurred in 228 eyes. This end point was the first observed visual acuity worse than 20/200 regardless of subsequent improvement. The most recent visual acuity for these 228 eyes was 20/200 or better for 31 eyes ( 13.6%), 20/300 to count fingers for 111 eyes (48.7%), and hand motions or worse vision for the re maining eyes (37.7%). Ofthe 228 eyes with visual decline, 171 (75%) had tumors near the disc or fovea and 16 of these (9%) had most recent visual acuity of 20/200 or better. Fifty-seven ofthe 228 eyes (25%) had tumors more than 2 DD from both structures and 15 of these (26%) had most recent visual acuity of 20/200 or better. Cumulative probabilities for posttreatment visual acuity loss at intervals after treatment are presented in Table 3. Among the 363 patients with tumors near the disc or fovea, 33% had visual loss to worse than 20/200 by the end of the first year. In contrast, only 17% of the 199 patients with tumors farther from the disc and fovea had the same outcome during this interval. By the end of the second posttreatment year, 47% had similar visual loss compared to 28% of patients with tumors farther from
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Table 1. Clinical Characteristics by Distance to Disc and Fovea Within 2 DD of Disc or Fovea Characteristic Pretreatment visual acuity 20/10-20/40 20/50-20/125 20/160-20/200 Worse than 20/200 Age (yrs) <60 ~60
Largest tumor diameter (mm) :$10.0 10.1-15.0 >15.0 Tumor height (mm) :$5.0 5.1-8.0 >8.0 Pretreatment macular detachment y
N Location of anterior tumor margin Ciliary body Anterior Posterior Dose to optic disc and fovea High to disc and fovea (~35.5 CGE) High to disc High to fovea High to neither (<35.5 CGE) Lens dose (%) 0-33 34-66 67-100 Posttreatment enucleation y
N
>2 DD from Disc and Fovea
x2
df
p
(72.0) (19.6) (3.1) (5.3)
53.9
3
0.001
116 109
(51.6) (48.4)
1.1
(17.6) (49.3) (33.1)
38 95 92
(16.9) (42.2) (40.9)
4.7
2
0.094
223 116 103
(50.5) (26.2) (23.3)
90 81 54
(40.0) (36.0) (24.0)
8.3
2
0.016
124 318
(28.1) (71.9)
21 204
(9.3) (90.7)
29.6
53 111 278
(12.0) (25.1) (62.9)
114 82 29
(50.7) (36.4) (12.9)
176.7
2
0.001
167 54 146 75
(37.8) (12.2) (33.0) (17.0)
4 5 11 205
(1.8) (2.2) (4.9) (91.1)
337.6
3
0.001
313 86 43
(70.8) (19.5) (9.7)
137 65 23
(60.9) (28.9) (10.2)
8.1
2
0.018
33 409
(7.5) (92.5)
6 219
(2.7) (97.3)
5.4
No. of Eyes
(%)
No. of Eyes
(%)
190 141 49 62
(43.0) (31.9) (11.1) (14.0)
162 44 7 12
248 194
(56.1) ' (43.9)
78 218 146
0.301
0.001
0.020
DD = disc diameter; df = degree of freedom; CGE = cobalt gray equivalent.
Table 2. Pretreatment and Most Recent Posttreatment Visual Acuity Among Patients with Uveal Melanoma within 2 DD of Disc or Fovea Followed 2 or More Years Final Posttreatment Visual Acuity 20/10-20/40
20/50-20/125
20/160-20/200
Total
Worse than 20/200
Pretreatment Visual Acuity
No. of Eyes
(%)
No. of Eyes
(%)
No. of Eyes
%
No. of Eyes
%
No. of Eyes
%
20/10-20/40 20/50-20/125 20/160-20/200 Worse than 20/200
22 8 0 0
(27.5) (16.7) (0) (0)
17 10 3 1
(21.3) (20.8) (18.8) (4.8)
10 6 2 5
(12.5) (12.5) (12.5) (23.8)
31 24 11 15
(38.8) (50.0) (68.8) (71.4)
80 48 16 21
(100) (100) (100) (100)
Total
30
(18.2)
31
(18.8)
23
(13.9)
81
(49.1)
165
(100)
DD
=
disc diameter.
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Table 3. Cumulative Percent of Eyes Losing Vision to Worse than 20/200 at Specific Time Points by Distance to the Disc and Fovea•
6 mos Location All within 2 DD of either structure <1 DD disc and >2 DD fovea 1-2 DD disc and >2 DD fovea <1 DD fovea and >2 DD disc 1-2 DD fovea and >2 DD disc Within 1-2 DD of both structures
>2 DD from both structures
1 yr
2 yrs
3 yrs
%
SE
%
SE
%
SE
Pt
33
3
47
3
61
5
<0.001
8
34
10
55
19
77
22
7
31
8
35
11
47
13
0.066
60
29
6
31
7
48
8
70
11
<0.001
53
26
6
31
7
36
9
36
13
0.16
180
23
3
35
4
52
5
66
7
<0.001
199
12
2
17
6
28
4
33
5
Total
%
363
24
28
21
42
SE
0.008
SE = standard error; DD = disc diameter. • Estimated by the Kaplan-Meier method. t Based on log-rank test comparing each group with tumors within 2 DD from the disc or fovea to the group with tumors greater than 2 DD from both structures.
both structures. Thus 53% of patients with tumors near the disc or fovea with 20/200 or better pretreatment vision had this same visual level 2 years after treatment. Table 3 also shows Kaplan-Meier estimates of rates of posttreatment visual loss accounting in detail for distances from the disc and fovea. Classifying the posterior tumors into five groups according to distances from the disc and fovea, rates of visual loss at 1 year were quite similar (range, 31-35%). At 2 years, the rates ofreaching the visual outcome in these five groups ranged from 35 to 55% with higher rates in groups within 1 DD of either structure or near both structures. Although differences between these percentages were large, fewer subjects were followed after 1 year, and the log-rank test comparing the five subgroups of eyes (all with tumors near the disc or fovea) showed that the differences in rates were not statistically significant (P = 0.293). A Cox multivariate analysis of time to vision worse than 20/200 was conducted for the 363 eyes with tumors near the disc or fovea. Other variables potentially related to visual outcome were controlled for including age, pre treatment visual acuity, largest tumor diameter, tumor height, location of anterior tumor margin, and presence or absence of macular detachment before treatment. Eyes with tumors near both structures had twice the rate of visual loss compared to tumors near the disc only (adjusted rate ratio, 2.07; 95% confidence interval [CI], 1.28-3.35). Eyes with tumors near the fovea only had 1.34 times the rate of visual loss compared to tumors near the disc only (95% CI, 0.83-2.18). This suggests that proximity to the fovea was associated with a slightly higher risk compared to proximity to the disc, but this difference was not sta tistically significant. 358
Causes of visual loss to worse than 20/200. Table 4 describes the cumulative probability of visual loss to worse than 20/200 for specific causes of visual loss among eyes with tumors within or greater than 2 DD from the pos terior structures. By far, the leading cause of visual loss in the first year among patients with tumors near the disc or fovea was retinal detachment. Of the patients in this group, 15% lost vision due to retinal detachment in the first year compared to 6% of patients with tumors farther from these structures. After the first year, there were no cases of retinal detachment as a primary cause of visual decline in either group. Rates of visual loss due to cataract were higher in the first 2 years for individuals with tumors farther from the disc and fovea compared to those with tumors near the disc or fovea. By the third year, the rates were equal in the two groups. Rates of visual loss due to radiation mac ulopathy and optic neuropathy were greater in all 3 years in the group with tumors near the disc or fovea compared to the other group, and the risk continued after the first year. The rate of visual loss over the first 3 years due to radiation maculopathy for tumors near the disc or fovea was four times the rate in the other group, and the rate of visual. loss due to optic nerve damage was 11 times greater in the group with tumors near the disc or fovea. Visual loss due to multiple factors was also more common in individuals with tumors near the posterior structures. The univariate rates presented in Tables 3 and 4 are useful for describing prognosis, but they do not control for potential confounding factors. For example, crude rates for cataract were higher in eyes with tumors farther from the disc and fovea because these tumors were more likely to involve the ciliary body. Rate ratios for the three
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Table 4. Cumulative Percent of Eyes Losing Vision to Worse than 20/200 Due to Specific Causes by Distance to Disc and Fovea* Posttreatment Year
(%) SE
Posttreatment Year
2
3
(%) SE
(%) SE
No. of Eyest
(%) SE
Within 2 DD of Disc or Fovea Retinal detachment Cataract Radiation retinopathy Optic neuropathy Combination Other§ Loss unrelated to treatment
(15) (3) (4) (5) (3) (6)
2 1 1 1 1 2
(2)
(15) (9) (10) (9) (6) (9)
2 3 3 3 2 3
(15) (18) (17) (11) (13) (9)
(2)
2
3
(%) SE
(%) SE
No. of Eyest
P:j:
12 25 5 2 3 7
0.004 0.646 0.001 0.002 0.012 0.073
3
0.487
>2 DO from Disc and Fovea
2 5 5 4 4 3
49 27 28 20 18 22
(6) (7) (1) (1) (1) (2)
(2) 1
7
2 2 1 1 1 1
(6) (14) (3) (1) (2) (5)
(1) 1
(1)
2 4 2 1 2 2
(6) (18) (4) (1) (2) (5)
2 4 2 1 2 2
(1)
DO = disc diameter; SE = standard error. * Estimated by the Kaplan-Meier Method. t Number of eyes with vision worse than 20/200 due to specific cause. :j: Based on log-rank test comparing specific outcomes in eyes with tumors within 2 DO of the disc or fovea to outcomes in eyes with tumors greater than 2 DD from both structures. § Includes vitreous hemorrhage (11 eyes), glaucoma (4), tumor growth into macula (2), central epithelial defect (1 ), and unknown (11 ). Table 5. Rate Ratios for Distance to Disc and Fovea by Leading Causes of Visual Loss to Worse than 20/200 Controlling for Other Factors* Related to Visual Loss Near Fovea Only
Near Disc Only
Near Both
Cause of Visual Loss
RRt
Cl
RRt
Cl
RRt
Cl
Retinal detachment Cataract Radiation retinopathy All causes
2.5 3.2 7.4 3.3
(1.0-5.9) (1.3-8.1) (2.3-24.1) (2.1-5.2)
3.5 2.6 1.6 2.6
(1.6-7.8) (1.4-6.4) (0.3-8.5) (1.6-4.1)
3.7 5.1 4.6 5.2
(1.6-8.9) (1.8-14.4) (1.3-16.5) (3.3-8.1)
RR = rate ratio; Cl = confidence interval. * Location of anterior tumor margin, tumor diameter, tumor height, pretreatment visual acuity and pretreatment macular detachment. t Reference category for RR is location greater than 2 DO from disc and fovea. RR is estimated by the antilogarithm of the regression coefficient from proportional hazards model.
most common causes of visual loss to worse than 20/200 were estimated comparing eyes with tumors near the disc or fovea to eyes with tumors greater than 2 DD from both structures. Potentially confounding factors controlled for in these analyses included pretreatment visual acuity, tu mor diameter and height, location ofanterior tumor mar gin, and presence or absence of macular detachment. These results are shown in Table 5. Rate ratios for the effect of location near the disc or fovea on vision ranged from 1.6 to 7.4 for the causes of visual loss evaluated. The rate ratios were highest for the group of tumors near both structures. Thus, proximity to the disc or fovea was associated with a higher risk of retinal detachment, cat aract (controlling for tumor location ciliary body involve ment), an9. radiation retinopathy. Other risk factors for retinal detachment were tumor height greater than 8.0 mm, pretreatment visual acuity worse than 20/40, and macular detachment before treatment. Other risk factors for cataract were ciliary body involvement, tumor height
greater than 8.0 mm, and pretreatment visual acuity worse than 20/125. Proximity to the fovea or to both disc and fovea was the only risk factor for radiation retinopathy as a cause of decrease in vision. VISUAL RECOVERY
Of the 228 eyes with decreased vision, 31 (13.6%) re gained vision to 20/200 or better as of the most recent visual acuity available. Six patients improved to 20/40 or better, nine were 20/50 to 20/100, and 16 were 20/160 to 20/200. Visual improvement occurred in 26% of eyes with tumors more than 2 DD from the disc and fovea compared to 9% ofeyes with tumors near either structure. Improvement occurred as the result ofcataract extraction (11 eyes), resolution of retinal detachment (8 eyes), res olution of vitreous hemorrhage (2 eyes), improvement of neovascular glaucoma after treatment (2 eyes), or a com bination of factors (l eye). Reasons for improvement could not be determined in the remaining seven cases. 359
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Table 6. Cumulative Percent of Eyes with Visual Improvement at Specific Times after Visual Loss to Worse than 20/200* Months After Visual Loss
No. of Eyest
%:j:
SE
3 6 12 24
192 138 101 40
9 13 14 16
2 3 3
5
SE = standard error. * Estimated by the Kaplan-Meier method. t Number of eyes with visual loss, without visual recovery at the end of the specified interval. :j: Percent regaining 20/200 or better visual acuity by the end of the specified interval.
Rates of visual recovery using the Kaplan-Meier method are shown in Table 6. The likelihood of visual improvement was low after 6 months. The cumulative percent of visual recovery to 20/200 or better among pa tients whose vision declined to worse than 20/200 was 13% at 6 months and 16% at 24 months. The percent of patients recovering after visual loss was compared for tumors close to the disc or fovea versus tumors farther from these structures. Six months after visual decline to worse than 20/200 occurred, 27 ± 7% of eyes with tumors greater than 2 DD from the disc and fovea had visual improvement compared to only 9 ± 3% in the other group (P = 0.001 ). These results were similar at 12 months. At 24 months, 33 ± 12% ofeyes with tumors more than 2 DD from both structures improved, whereas the rate ofimprovement remained low in the other group (10 ± 3%).
DISCUSSION Results of this study demonstrate that although patients with tumors near the optic disc and fovea are at a higher risk of visual deterioration after proton beam therapy be cause of their location and radiation dose delivered to sensitive structures, many retain useful vision. Specifically, 53% of patients with 20/200 or better pretreatment vision retained 20/200 or better vision 2 years after proton beam radiation. Among patients with tumors greater than 2 DD from the disc and fovea, the corresponding percentage was 72. These estimates are based on Kaplan-Meier anal ysis, which accounts for differences in follow-up time. The level of 20/200 or better was chosen to represent a rea sonable visual level that would be considered useful vision considering the alternative of no vision at all. Although in our analysis, the visual level of worse than 20/200 was evaluated as an outcome and referred to as "visual loss," it should be noted that 20/300, 20/400, and counting fin gers vision are included in this category. Knowing the risk of visual loss associated with tumors near the disc or fovea, 360
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many patients still prefer to be irradiated rather than un dergo enucleation. A different approach in evaluating visual outcome is to study patients followed more than a specified number of years and assess changes in visual acuity category from pre- to posttreatment (Table 2). One problem with this approach is the variable length offollow-up which remains among cases even after excluding those followed less than the specified interval. For example, in these data some patients were followed 2.5 years, whereas others were fol lowed 5 years or more. Because some patients whose vision decreases to a cer tain level can subsequently improve, a separate life-table analysis was done for such visual improvement. Of the patients in this report, 13% (31/228) were in this category. Rates of such recovery were highest in the first 6 months after visual decline. It is of interest to evaluate whether proximity to the fovea or proximity to the disc has a greater effect on visual outcome. We studied this by a multivariate analysis con trolling for other variables related to visual decline in cluding pretreatment visual acuity, tumor height, and presence or absence of macular detachment. Proximity to the fovea was associated with a slightly higher risk (rate ratio = 1.34; 95% CI = 0.83-2.18) or a 33% elevated risk compared to location near the disc only. However, this difference was not statistically significant. Primary causes of visual loss were evaluated and com parisons were made between tumors located within 2 DD of the disc or fovea and those located greater than 2 DD from the disc and fovea. Univariate analyses showed that the leading causes of visual loss to worse than 20/200 among eyes with tumors near the disc or fovea were retinal detachment, radiation retinopathy, cataract, and radiation optic neuropathy. The corresponding leading causes for tumors greater than 2 DD from the disc and fovea were cataract and retinal detachment. All of the risk for retinal detachment occurred in the first year, with no risk in the next 2 years. For all other leading causes of visual decline to worse than 20/200, the risk continued after the first year. When discussing visual prognosis with patients, the univariate rates of visual loss and cause-specific rates shown in Tables 3 and 4 are helpful. However, multivar iate analyses are needed to control for other factors that also influence outcome. Table 5 shows the effect estimates for proximity to disc, fovea, or both while controlling for pretreatment vision, tumor diameter and height, anterior location, and macular detachment. This table shows that after such adjustment, proximity to either one or both of these structures is independently associated with the three leading causes of visual decline to worse than 20/200 compared to tumors greater than 2 DD from the disc and fovea. However, proximity to the disc alone was not a statistically significant risk factor for radiation retinopathy causing visual loss. This should be confirmed in other analyses with a larger sample size or a longer follow-up time. Radiation optic neuropathy was not evaluated in Table 5 as an outcome because the small number ofcases
SEDDON et al
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VISION AFTER PROTON IRRADIATION
(22 patients) made it impossible to conduct a meaningful multivariate analysis. Proximity to both the disc and fovea is worse than proximity to one structure alone, as dem onstrated by the highest rate ratios for visual decline and causes of visual loss occurring in this category. A possible limitation of our article is the assignment of cause of visual loss. With multiple causes of visual loss possible, it is sometimes difficult to determine the leading cause of visual decline. We attempted to assess the primary reason for visual loss when the vision first dropped to worse than 20/200. In some cases, there was more than one cause and these cases were recorded as having a com bination of causes. In those in which a primary reason could be identified, other complications that were not an alyzed could have occurred at a later date. In addition, visual acuity could have declined to a level better than 20/200 which was not considered an outcome in the life table analyses and therefore causes of this level of visual decline were not assessed. Limitations are also encountered in other studies which attempt to attribute visual acuity of worse than a certain level to a specific cause. For example, the assignment of cause of visual loss among patients with both macular degeneration and cataract is problematic. Similarly in our study, a decline in visual acuity to worse than 20/200 could have been attributed to cataract when in fact some maculopathy was present as well (but was not detected due to the cataract). This possible misclassification might explain in part why promixity to the disc or fovea was an independent risk factor for cataract as a cause of visual loss to worse than 20/200. There have been only two recent studies addressing the subject of visual acuity after proton beam radiation of uveal melanomas. 1•8 In one report, 1 results of a Cox model analysis for tumors in all locations demonstrated the risk associated with tumors near the disc, fovea, or both. Kap lan-Meier curves were displayed showing the cumulative probability of visual acuity loss according to height and distance of the tumor from the disc and fovea. The other article addressing visual acuity after proton beam irradia tion described 60 patients with macular and paramacular tumors only. 8 The current article focuses on the high-risk group of patients with tumors near the disc or fovea to provide a more detailed description oftheir rates of visual loss and to compare them to rates for tumors in other locations. Only one article that evaluated visual acuity after other types of radiation treatment included life-table analyses. That article by Cruess et ae concerning cobalt plaque therapy differs from this report. It considered 77 patients
with 20/25 or better visual acuity before treatment, and visual results were based on radiation dose delivered to the disc or fovea and not distance of the tumor from these structures. Of 21 eyes with excellent pretreatment vision receiving greater than 50 Gy to the fovea, 48% had 20/ 200 or worse vision after 36 months. Of 26 eyes with excellent pretreatment vision receiving greater than 50 Gy to the disc, 36 months after treatment 35% had 20/ 200 or worse vision. It is stated that tumors with margins closer than 5 mm (3.3 DO) to the fovea and/or optic disc almost invariably received a radiation dose to these sites of greater than 50 Gy (some as high as about 140 Gy). However, in some eyes with tumors farther than 5 mm from the disc or fovea, those structures also received greater than 50 Gy. Those data then are not comparable to our report, which describes rates of visual loss for more unfavorable tumors which are located within only 2 DO of the disc or fovea in eyes with poorer pretreatment vision (2.20/200). It seems reasonable to assess location in terms ofdistance to the posterior structures as a prognostic factor rather than solely dose delivered to these structures be cause location is known while discussing treatment alter natives and prognosis with the patient. Results of the current investigation suggest that patients with tumors near the disc or fovea can be advised that if their vision is 20/200 or better, approximately 53% will retain this level of vision 2 years after treatment.
REFERENCES 1. Seddon JM, Gragoudas ES, Polivogianis L, et al. Visual outcome after proton beam irradiation of uveal melanoma. Ophthalmology 1986; 93: 666-74. 2. Cruess AF, Augsburger JJ, Shields JA, et al. Visual results following cobalt plaque radiotherapy for posterior uveal melanomas. Ophthal mology 1984; 91:131-6. 3. Goitein M, Miller T. Planning protqn therapy of the eye. Med Phys 1983; 10:275-83. 4. Kaplan EL, Meier P. Nonparametric estimation from incomplete ob servations. J Am Stat Assoc 1958; 53:457-81. 5. Greenwood M. The natural duration of cancer. Gr Br Dept of Health Soc Secur. Reports on Public Health and Medical Subjects 1926; 33: 1-26. 6. Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc Series A 1972; 135:185-206. 7. Cox D. Regression models and life tables (with discussion). J R Stat Soc Series B 1972; 34:186-220. 8. Gragoudas ES, Goitein M, Seddon J, et al. Preliminary results of proton beam irradiation of macular and paramacular melanomas. Br J Ophthalmol1984; 68:479-85.
361
Abstract: Proximity to the disc and fovea is a risk factor for visual loss after proton beam irradiation of uveal melanomas. Of 562 eyes treated over a 10 year period with pretreatment visual acuity of 20/200 or better, 363 (64.6%) contained tumors within 2 disc diameters (DD) of the disc or fovea. Rates of visual loss after treatment to worse than 20/200 and causes of visual decline were evaluated using Kaplan-Meier analysis. Cumulative rates of visual loss among subjects with tumors near the disc or fovea were 33 and 47% 1 and 2 years after treatment compared to 17 and 28%, respectively, for subjects with tumors located farther from both structures. The leading cause of visual loss in the first year among eyes with tumors near the disc or fovea was retinal de tachment. Controlling for other predictors of visual loss to worse than 20/200, location near the disc or fovea was independently related to visual loss primarily due to retinal detachment, cataract, and radiation retinopathy. Despite the un favorable location of these tumors, over half of patients with 20/200 or better pretreatment visual acuity had useful vision 2 years after treatment. [Key words: fovea, optic disc, proton beam irradiation, uveal melanoma, visual acuity.] Oph thalmology 94:354-361, 1987
A previous analysis of patients treated by proton beam irradiation has shown that the most important prognostic factors for visual loss to worse than 20/200 are higher tumor height and proximity to the disc, fovea, or both (2 disc diameters [DO] or about 3.0 mm from these struc tures or closer). 1 Also predictive of visual loss using mul tivariate analyses were presence of macular detachment From the Retina Service,* and Epidemiology Unit, t Massachusetts Eye and Ear Infirmary, the Department of Ophthalmology, Harvard Medical School, Boston, the Department of Radiation Medicine,:j: Massachusetts General Hospital, Boston, and Harvard Cyclotron Laboratory,§ Cambridge. Presented at the Ninety-first Annual Meeting of the American Academy of Ophthalmology, New Orleans, Louisiana, November 9-13, 1986. Reprint requests to Johanna M. Seddon, MD, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.
354
before treatment, worse pretreatment vision, and higher radiation dose delivered to the disc, fovea, or lens. 1 In another report, which evaluated vision after cobalt plaque therapy, a radiation dose to the disc and fovea of greater than 50 gray (Gy) (5000 rad; 1 Gy = 100 rad) was related to substantial visual loss after 2 to 3 years. Tumors with margins within 5 mm of these structures almost in variably received this higher dose. 2 Although we inform patients who present with tumors close to the disc or fovea of the higher risk of visual loss after irradiation, many still prefer such a treatment rather than enucleation. These patients often request informa tion concerning the likelihood of visual decline and how quickly it will occur. The purpose of this report is to focus on the subgroup of patients with tumors near the optic disc or fovea treated by proton beam irradiation in order to (1) calculate their
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VISION AFTER PROTON IRRADIATION
rate of visual loss after treatment, (2) compare the rate of visual loss of patients with these tumors to the rate of visual loss of patients with tumors located elsewhere, (3) evaluate the cause-specific rates ofdecreased visual acuity for patients in this group, and (4) compare them to the cause-specific rates of decreased visual acuity for patients with tumors farther from the disc and fovea.
SUBJECfS AND METHODS STUDY POPULATION
Patients with uveal melanoma of the choroid and/or ciliary body treated by proton beam irradiation at the Harvard Cyclotron Laboratory between July 1975 and March 1985 were considered for inclusion in the analysis. Of the 666 patients (667 eyes) treated during this interval, 442 patients (442 eyes, 66.3%) contained tumors within 2 DD or 3.0 mm ofthe disc, fovea, or both. For all analyses involving posttreatment visual acuity, the following pa tients were excluded: four (0.5%) retreated with proton beam irradiation; two (0.3%) whose tumors had been ex cised before treatment; and 25 (3.7%) who had no visual acuity follow-up available. The majority ofthe latter group consisted of patients from outside the United States (18 patients). For analyses assessing the endpoint of visual decline to worse than 20/200 after treatment among patients starting with 20/200 or better vision, an additional 74 patients ( 11%) with pretreatment visual acuities worse than 20/200 were also excluded. Ofthe remaining 561 patients (562 eyes), 363 patients (363 eyes, 64.6%) had tumors within 2 DD of the disc, fovea, or both. VISUAL ACUITY FOLLOW-UP
Visual acuities were tested with and without pinhole before treatment and at follow-up visits. The majority of patients returned to MEEI 6 and 12 months after treat ment and at yearly intervals thereafter. Twenty-five per cent of patients were followed elsewhere, and posttreat ment visual acuities were obtained from the· referring ophthalmologist for these cases. Follow-up data were col lected through March 31, 1986. For the 562 eyes evaluated for visual outcome worse than 20/200, vision follow-up ranged between 1 month and 10.6 years (median, l. 7 years). Only 16 cases (3%) had less than 6 months of vision follow-up. Seventy-nine cases (14%) had 6 months to 1 year, 175 (31%) had 1 to 2 years, 126 (22%) had 2 to 3 years, and 166 (30%) had more than 3 years of vision follow-up. If patients who required enucleation did not have worse than 20/200 vision before surgery, they were considered to have "no light perception" on the day of enucleation. CAUSES OF VISUAL DECLINE
Causes of initial visual loss to worse than 20/200 were determined by chart review for most patients. Beginning
in September 1985, the reasons for visual acuity loss of more than one line compared to pretreatment visual acu ity were recorded on standardized forms at the time of follow-up examination at MEEI. These were used for data collection for subjects whose initial visual decline to worse than 20/200 occurred after this time. For the patients fol lowed elsewhere, causes of visual loss were provided by the referring ophthalmologist by letter or when contacted by telephone. Posttreatment fluorescein angiography was performed on 70% of cases whose vision declined to worse than 20/200 after treatment. The specific cause of visual loss was coded as due pri marily to radiation-induced cataract (anterior or posterior subcapsular changes), retinal detachment which involved the fovea, radiation retinopathy (retinal vascular changes secondary to radiation causing macular ischemia, macular edema, intraretinal hemorrhages, and/or intraretinal and subretinal exudates), radiation optic neuropathy (hyper emia and edema of optic disc, ischemia of the disc cap illaries, or optic atrophy), vitreous hemorrhage, or glau coma secondary to anterior segment neovascularization (neovascularization ofthe angle with intraocular pressure over 21 mmHg). In some cases, a primary cause of visual decline could not be determined because more than one of the above problems contributed to the decrease in vi sion. These cases were coded as having a combination of the above complications. A few subjects had visual decline due to reasons unrelated to treatment including macular degeneration, open angle glaucoma, and senile cataract which worsened symmetrically with the fellow eye. In some cases, the cause of visual decline could not be de termined. OTHER CLINICAL DATA
Additional clinical information collected and coded onto standardized forms has been described previously 1 and is summarized below. (1) Age at the time of treatment. (2) The largest tumor diameters were grouped into small (~10.0 mm), medium (10.1-15.0 mm), and large (> 15.0 mm). Maximum heights determined by ultraso nography were categorized as low (~5.0 mm), medium (5.1-8.0 mm), or high (>8.0 mm). 1 (3) Location of the anterior margin of the tumor was coded as posterior to the equator, or anterior to the equa tor with or without involvement of the ciliary body. (4) The distance of the closest part of the tumor, apex or base, from the edge of the optic disc and fovea was assessed by indirect ophthalmoscopy. These distances were estimated in terms of disc diameters with 1.0 DD ap proximately equal to 1.5 mm. Data were coded as near both disc and fovea, near the disc only, near the fovea only, or near neither structure. Unless otherwise specified, a tumor was considered to be near a structure if it was less than or equal to 2.0 DD from the structure. The term "near the disc or fovea" implies that the tumor is near one or near both structures. (5) Macular detachment before treatment. (6) In almost all cases, the total dose delivered to the 355
OPHTHALMOLOGY
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tumor and a 1.5-mm margin around the tumor was 70 Cobalt Gy Equivalent (CGE) in five treatments over 7 to 10 days (63.6 proton Gy X 1.1 relative biological effec tiveness = 70 CGE). The radiation doses were estimated from the computer treatment planning program. 3 Thera diation doses to the disc and fovea were considered to gether as high dose to disc and fovea, high dose to disc only, high dose to fovea only, or high dose to neither structure. High dose was considered to be 35.5 CGE or greater. The percentage of the lens receiving more than 50% of the total dose was categorized as low (0-33%), medium (34-66%), or high (67-100%). ANALYSES
Initial data analyses used contingency tables with as sociated chi-square tests to examine the differences in proportions or distributions of baseline characteristics among groups. Pearson's correlation coefficient (R) was used to assess the relationship of tumor distances from the disc and fovea to the estimated radiation doses at these sites. The time until a first observation of visual acuity worse than 20/200 was examined using life-table ap proaches to adjust for variable follow-up between indi viduals. Life-table techniques were also used to estimate the probability of recovering vision to 20/200 or better among eyes losing vision to worse than 20/200 after pro ton beam therapy. When visual loss occurred during an interval between two examinations, the time of visual loss was taken to be the midpoint of that interval. Analyses of visual loss for both specific distances from the fovea and disc and for individual causes of visual loss, and anal yses of visual recovery, used the Kaplan-Meier product moment approach to the estimation of survival. 4 This approach allows for estimation of the time until an event without making assumptions about the functional form of the survival curve. Standard errors of estimated per centages maintaining vision at 20/200 or better were ob tained using Greenwood's formula. 5 Time to visual loss curves were compared using the log-rank test. 6 Multivar iate survival analyses used Cox's proportional hazards model 7 to assess the relative importance of a number of variables as predictors of time to visual loss.
RESULTS DESCRIPTIVE CHARACTERISTICS
Table 1 describes the clinical characteristics of the 667 eyes, comparing 442 with tumors near the disc or fovea to 225 with tumors greater than 2 DD from the disc and fovea. Eyes containing tumors within 2 DD of the disc, fovea, or both had poorer pretreatment vision. Sixty-two of 442 eyes (14.0%) with tumors in this location started worse than 20/200 compared to 12 of 225 eyes (5.3%) with tumors at greater distances from the disc and macula. Eyes containing tumors near the disc or fovea were more likely to present with retinal detachment involving the macula. They were also less likely to have tall (>5.0 mm) tumors, compared to tumors farther from these structures. 356
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Two hundred and five of 225 eyes (91.1%) with tumors farther than 2 DD from the disc and fovea received low radiation doses (as defined above) to both disc and fovea. In contrast, 367 of 442 eyes (83%) with tumors near the disc or fovea received a high dose to one ofthese structures. The amount of radiation dose received by the disc and fovea correlated inversely with the distance of the tumor from these structures (R = -0.47, P < 0.001; R = -0.44, P < 0.001, respectively). The lenses of eyes with tumors near the disc or fovea were less likely to receive more than one third of the total dose than lenses of eyes with more distant tumors. Complications requiring enucleation developed in 39 of the treated 667 eyes (6%). Thirty-three of these (85%) had tumors near the disc or fovea. Of these 33 eyes, 18 had tumor diameters greater than 15 mm. Seventy-four eyes ( 11%) had pretreatment visual acu ities worse than 20/200. Vision never improved to 20/200 or better throughout the posttreatment period in 35 of these eyes (47%). Visual improvement to 20/200 or better occurred in 36 eyes (49%), although improvement was temporary in most (25/36). The remaining three eyes had no vision follow-up. Pretreatment and most recent (before March 1986) posttreatment visual acuity categories for 165 subjects with tumors near the disc or fovea followed 2 or more years after treatment are displayed in Table 2. Seventeen of these 165 patients ( 10.3%) improved, 99 (60%) worsened, and the other 49 (29.7%) remained in the same visual acuity category. The corresponding figures were similar for eyes with tumors more than 2 DD from the disc and fovea (11.3% improved, 58.7% worsened, and 30.0% re mained in the same category). Thus, 40% of all cases re tained the same or better visual acuity at least 2 years after treatment. RATES OF VISUAL CHANGE
Visual loss to worse than 20/200. Visual decline to worse than 20/200 among the 562 eyes with initial visual acuity of 20/200 or better occurred in 228 eyes. This end point was the first observed visual acuity worse than 20/200 regardless of subsequent improvement. The most recent visual acuity for these 228 eyes was 20/200 or better for 31 eyes ( 13.6%), 20/300 to count fingers for 111 eyes (48.7%), and hand motions or worse vision for the re maining eyes (37.7%). Ofthe 228 eyes with visual decline, 171 (75%) had tumors near the disc or fovea and 16 of these (9%) had most recent visual acuity of 20/200 or better. Fifty-seven ofthe 228 eyes (25%) had tumors more than 2 DD from both structures and 15 of these (26%) had most recent visual acuity of 20/200 or better. Cumulative probabilities for posttreatment visual acuity loss at intervals after treatment are presented in Table 3. Among the 363 patients with tumors near the disc or fovea, 33% had visual loss to worse than 20/200 by the end of the first year. In contrast, only 17% of the 199 patients with tumors farther from the disc and fovea had the same outcome during this interval. By the end of the second posttreatment year, 47% had similar visual loss compared to 28% of patients with tumors farther from
SEDDON et al •
VISION AFTER PROTON IRRADIATION
Table 1. Clinical Characteristics by Distance to Disc and Fovea Within 2 DD of Disc or Fovea Characteristic Pretreatment visual acuity 20/10-20/40 20/50-20/125 20/160-20/200 Worse than 20/200 Age (yrs) <60 ~60
Largest tumor diameter (mm) :$10.0 10.1-15.0 >15.0 Tumor height (mm) :$5.0 5.1-8.0 >8.0 Pretreatment macular detachment y
N Location of anterior tumor margin Ciliary body Anterior Posterior Dose to optic disc and fovea High to disc and fovea (~35.5 CGE) High to disc High to fovea High to neither (<35.5 CGE) Lens dose (%) 0-33 34-66 67-100 Posttreatment enucleation y
N
>2 DD from Disc and Fovea
x2
df
p
(72.0) (19.6) (3.1) (5.3)
53.9
3
0.001
116 109
(51.6) (48.4)
1.1
(17.6) (49.3) (33.1)
38 95 92
(16.9) (42.2) (40.9)
4.7
2
0.094
223 116 103
(50.5) (26.2) (23.3)
90 81 54
(40.0) (36.0) (24.0)
8.3
2
0.016
124 318
(28.1) (71.9)
21 204
(9.3) (90.7)
29.6
53 111 278
(12.0) (25.1) (62.9)
114 82 29
(50.7) (36.4) (12.9)
176.7
2
0.001
167 54 146 75
(37.8) (12.2) (33.0) (17.0)
4 5 11 205
(1.8) (2.2) (4.9) (91.1)
337.6
3
0.001
313 86 43
(70.8) (19.5) (9.7)
137 65 23
(60.9) (28.9) (10.2)
8.1
2
0.018
33 409
(7.5) (92.5)
6 219
(2.7) (97.3)
5.4
No. of Eyes
(%)
No. of Eyes
(%)
190 141 49 62
(43.0) (31.9) (11.1) (14.0)
162 44 7 12
248 194
(56.1) ' (43.9)
78 218 146
0.301
0.001
0.020
DD = disc diameter; df = degree of freedom; CGE = cobalt gray equivalent.
Table 2. Pretreatment and Most Recent Posttreatment Visual Acuity Among Patients with Uveal Melanoma within 2 DD of Disc or Fovea Followed 2 or More Years Final Posttreatment Visual Acuity 20/10-20/40
20/50-20/125
20/160-20/200
Total
Worse than 20/200
Pretreatment Visual Acuity
No. of Eyes
(%)
No. of Eyes
(%)
No. of Eyes
%
No. of Eyes
%
No. of Eyes
%
20/10-20/40 20/50-20/125 20/160-20/200 Worse than 20/200
22 8 0 0
(27.5) (16.7) (0) (0)
17 10 3 1
(21.3) (20.8) (18.8) (4.8)
10 6 2 5
(12.5) (12.5) (12.5) (23.8)
31 24 11 15
(38.8) (50.0) (68.8) (71.4)
80 48 16 21
(100) (100) (100) (100)
Total
30
(18.2)
31
(18.8)
23
(13.9)
81
(49.1)
165
(100)
DD
=
disc diameter.
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Table 3. Cumulative Percent of Eyes Losing Vision to Worse than 20/200 at Specific Time Points by Distance to the Disc and Fovea•
6 mos Location All within 2 DD of either structure <1 DD disc and >2 DD fovea 1-2 DD disc and >2 DD fovea <1 DD fovea and >2 DD disc 1-2 DD fovea and >2 DD disc Within 1-2 DD of both structures
>2 DD from both structures
1 yr
2 yrs
3 yrs
%
SE
%
SE
%
SE
Pt
33
3
47
3
61
5
<0.001
8
34
10
55
19
77
22
7
31
8
35
11
47
13
0.066
60
29
6
31
7
48
8
70
11
<0.001
53
26
6
31
7
36
9
36
13
0.16
180
23
3
35
4
52
5
66
7
<0.001
199
12
2
17
6
28
4
33
5
Total
%
363
24
28
21
42
SE
0.008
SE = standard error; DD = disc diameter. • Estimated by the Kaplan-Meier method. t Based on log-rank test comparing each group with tumors within 2 DD from the disc or fovea to the group with tumors greater than 2 DD from both structures.
both structures. Thus 53% of patients with tumors near the disc or fovea with 20/200 or better pretreatment vision had this same visual level 2 years after treatment. Table 3 also shows Kaplan-Meier estimates of rates of posttreatment visual loss accounting in detail for distances from the disc and fovea. Classifying the posterior tumors into five groups according to distances from the disc and fovea, rates of visual loss at 1 year were quite similar (range, 31-35%). At 2 years, the rates ofreaching the visual outcome in these five groups ranged from 35 to 55% with higher rates in groups within 1 DD of either structure or near both structures. Although differences between these percentages were large, fewer subjects were followed after 1 year, and the log-rank test comparing the five subgroups of eyes (all with tumors near the disc or fovea) showed that the differences in rates were not statistically significant (P = 0.293). A Cox multivariate analysis of time to vision worse than 20/200 was conducted for the 363 eyes with tumors near the disc or fovea. Other variables potentially related to visual outcome were controlled for including age, pre treatment visual acuity, largest tumor diameter, tumor height, location of anterior tumor margin, and presence or absence of macular detachment before treatment. Eyes with tumors near both structures had twice the rate of visual loss compared to tumors near the disc only (adjusted rate ratio, 2.07; 95% confidence interval [CI], 1.28-3.35). Eyes with tumors near the fovea only had 1.34 times the rate of visual loss compared to tumors near the disc only (95% CI, 0.83-2.18). This suggests that proximity to the fovea was associated with a slightly higher risk compared to proximity to the disc, but this difference was not sta tistically significant. 358
Causes of visual loss to worse than 20/200. Table 4 describes the cumulative probability of visual loss to worse than 20/200 for specific causes of visual loss among eyes with tumors within or greater than 2 DD from the pos terior structures. By far, the leading cause of visual loss in the first year among patients with tumors near the disc or fovea was retinal detachment. Of the patients in this group, 15% lost vision due to retinal detachment in the first year compared to 6% of patients with tumors farther from these structures. After the first year, there were no cases of retinal detachment as a primary cause of visual decline in either group. Rates of visual loss due to cataract were higher in the first 2 years for individuals with tumors farther from the disc and fovea compared to those with tumors near the disc or fovea. By the third year, the rates were equal in the two groups. Rates of visual loss due to radiation mac ulopathy and optic neuropathy were greater in all 3 years in the group with tumors near the disc or fovea compared to the other group, and the risk continued after the first year. The rate of visual loss over the first 3 years due to radiation maculopathy for tumors near the disc or fovea was four times the rate in the other group, and the rate of visual. loss due to optic nerve damage was 11 times greater in the group with tumors near the disc or fovea. Visual loss due to multiple factors was also more common in individuals with tumors near the posterior structures. The univariate rates presented in Tables 3 and 4 are useful for describing prognosis, but they do not control for potential confounding factors. For example, crude rates for cataract were higher in eyes with tumors farther from the disc and fovea because these tumors were more likely to involve the ciliary body. Rate ratios for the three
SEDDON et al •
VISION AFTER PROTON IRRADIATION
Table 4. Cumulative Percent of Eyes Losing Vision to Worse than 20/200 Due to Specific Causes by Distance to Disc and Fovea* Posttreatment Year
(%) SE
Posttreatment Year
2
3
(%) SE
(%) SE
No. of Eyest
(%) SE
Within 2 DD of Disc or Fovea Retinal detachment Cataract Radiation retinopathy Optic neuropathy Combination Other§ Loss unrelated to treatment
(15) (3) (4) (5) (3) (6)
2 1 1 1 1 2
(2)
(15) (9) (10) (9) (6) (9)
2 3 3 3 2 3
(15) (18) (17) (11) (13) (9)
(2)
2
3
(%) SE
(%) SE
No. of Eyest
P:j:
12 25 5 2 3 7
0.004 0.646 0.001 0.002 0.012 0.073
3
0.487
>2 DO from Disc and Fovea
2 5 5 4 4 3
49 27 28 20 18 22
(6) (7) (1) (1) (1) (2)
(2) 1
7
2 2 1 1 1 1
(6) (14) (3) (1) (2) (5)
(1) 1
(1)
2 4 2 1 2 2
(6) (18) (4) (1) (2) (5)
2 4 2 1 2 2
(1)
DO = disc diameter; SE = standard error. * Estimated by the Kaplan-Meier Method. t Number of eyes with vision worse than 20/200 due to specific cause. :j: Based on log-rank test comparing specific outcomes in eyes with tumors within 2 DO of the disc or fovea to outcomes in eyes with tumors greater than 2 DD from both structures. § Includes vitreous hemorrhage (11 eyes), glaucoma (4), tumor growth into macula (2), central epithelial defect (1 ), and unknown (11 ). Table 5. Rate Ratios for Distance to Disc and Fovea by Leading Causes of Visual Loss to Worse than 20/200 Controlling for Other Factors* Related to Visual Loss Near Fovea Only
Near Disc Only
Near Both
Cause of Visual Loss
RRt
Cl
RRt
Cl
RRt
Cl
Retinal detachment Cataract Radiation retinopathy All causes
2.5 3.2 7.4 3.3
(1.0-5.9) (1.3-8.1) (2.3-24.1) (2.1-5.2)
3.5 2.6 1.6 2.6
(1.6-7.8) (1.4-6.4) (0.3-8.5) (1.6-4.1)
3.7 5.1 4.6 5.2
(1.6-8.9) (1.8-14.4) (1.3-16.5) (3.3-8.1)
RR = rate ratio; Cl = confidence interval. * Location of anterior tumor margin, tumor diameter, tumor height, pretreatment visual acuity and pretreatment macular detachment. t Reference category for RR is location greater than 2 DO from disc and fovea. RR is estimated by the antilogarithm of the regression coefficient from proportional hazards model.
most common causes of visual loss to worse than 20/200 were estimated comparing eyes with tumors near the disc or fovea to eyes with tumors greater than 2 DD from both structures. Potentially confounding factors controlled for in these analyses included pretreatment visual acuity, tu mor diameter and height, location ofanterior tumor mar gin, and presence or absence of macular detachment. These results are shown in Table 5. Rate ratios for the effect of location near the disc or fovea on vision ranged from 1.6 to 7.4 for the causes of visual loss evaluated. The rate ratios were highest for the group of tumors near both structures. Thus, proximity to the disc or fovea was associated with a higher risk of retinal detachment, cat aract (controlling for tumor location ciliary body involve ment), an9. radiation retinopathy. Other risk factors for retinal detachment were tumor height greater than 8.0 mm, pretreatment visual acuity worse than 20/40, and macular detachment before treatment. Other risk factors for cataract were ciliary body involvement, tumor height
greater than 8.0 mm, and pretreatment visual acuity worse than 20/125. Proximity to the fovea or to both disc and fovea was the only risk factor for radiation retinopathy as a cause of decrease in vision. VISUAL RECOVERY
Of the 228 eyes with decreased vision, 31 (13.6%) re gained vision to 20/200 or better as of the most recent visual acuity available. Six patients improved to 20/40 or better, nine were 20/50 to 20/100, and 16 were 20/160 to 20/200. Visual improvement occurred in 26% of eyes with tumors more than 2 DD from the disc and fovea compared to 9% ofeyes with tumors near either structure. Improvement occurred as the result ofcataract extraction (11 eyes), resolution of retinal detachment (8 eyes), res olution of vitreous hemorrhage (2 eyes), improvement of neovascular glaucoma after treatment (2 eyes), or a com bination of factors (l eye). Reasons for improvement could not be determined in the remaining seven cases. 359
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Table 6. Cumulative Percent of Eyes with Visual Improvement at Specific Times after Visual Loss to Worse than 20/200* Months After Visual Loss
No. of Eyest
%:j:
SE
3 6 12 24
192 138 101 40
9 13 14 16
2 3 3
5
SE = standard error. * Estimated by the Kaplan-Meier method. t Number of eyes with visual loss, without visual recovery at the end of the specified interval. :j: Percent regaining 20/200 or better visual acuity by the end of the specified interval.
Rates of visual recovery using the Kaplan-Meier method are shown in Table 6. The likelihood of visual improvement was low after 6 months. The cumulative percent of visual recovery to 20/200 or better among pa tients whose vision declined to worse than 20/200 was 13% at 6 months and 16% at 24 months. The percent of patients recovering after visual loss was compared for tumors close to the disc or fovea versus tumors farther from these structures. Six months after visual decline to worse than 20/200 occurred, 27 ± 7% of eyes with tumors greater than 2 DD from the disc and fovea had visual improvement compared to only 9 ± 3% in the other group (P = 0.001 ). These results were similar at 12 months. At 24 months, 33 ± 12% ofeyes with tumors more than 2 DD from both structures improved, whereas the rate ofimprovement remained low in the other group (10 ± 3%).
DISCUSSION Results of this study demonstrate that although patients with tumors near the optic disc and fovea are at a higher risk of visual deterioration after proton beam therapy be cause of their location and radiation dose delivered to sensitive structures, many retain useful vision. Specifically, 53% of patients with 20/200 or better pretreatment vision retained 20/200 or better vision 2 years after proton beam radiation. Among patients with tumors greater than 2 DD from the disc and fovea, the corresponding percentage was 72. These estimates are based on Kaplan-Meier anal ysis, which accounts for differences in follow-up time. The level of 20/200 or better was chosen to represent a rea sonable visual level that would be considered useful vision considering the alternative of no vision at all. Although in our analysis, the visual level of worse than 20/200 was evaluated as an outcome and referred to as "visual loss," it should be noted that 20/300, 20/400, and counting fin gers vision are included in this category. Knowing the risk of visual loss associated with tumors near the disc or fovea, 360
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many patients still prefer to be irradiated rather than un dergo enucleation. A different approach in evaluating visual outcome is to study patients followed more than a specified number of years and assess changes in visual acuity category from pre- to posttreatment (Table 2). One problem with this approach is the variable length offollow-up which remains among cases even after excluding those followed less than the specified interval. For example, in these data some patients were followed 2.5 years, whereas others were fol lowed 5 years or more. Because some patients whose vision decreases to a cer tain level can subsequently improve, a separate life-table analysis was done for such visual improvement. Of the patients in this report, 13% (31/228) were in this category. Rates of such recovery were highest in the first 6 months after visual decline. It is of interest to evaluate whether proximity to the fovea or proximity to the disc has a greater effect on visual outcome. We studied this by a multivariate analysis con trolling for other variables related to visual decline in cluding pretreatment visual acuity, tumor height, and presence or absence of macular detachment. Proximity to the fovea was associated with a slightly higher risk (rate ratio = 1.34; 95% CI = 0.83-2.18) or a 33% elevated risk compared to location near the disc only. However, this difference was not statistically significant. Primary causes of visual loss were evaluated and com parisons were made between tumors located within 2 DD of the disc or fovea and those located greater than 2 DD from the disc and fovea. Univariate analyses showed that the leading causes of visual loss to worse than 20/200 among eyes with tumors near the disc or fovea were retinal detachment, radiation retinopathy, cataract, and radiation optic neuropathy. The corresponding leading causes for tumors greater than 2 DD from the disc and fovea were cataract and retinal detachment. All of the risk for retinal detachment occurred in the first year, with no risk in the next 2 years. For all other leading causes of visual decline to worse than 20/200, the risk continued after the first year. When discussing visual prognosis with patients, the univariate rates of visual loss and cause-specific rates shown in Tables 3 and 4 are helpful. However, multivar iate analyses are needed to control for other factors that also influence outcome. Table 5 shows the effect estimates for proximity to disc, fovea, or both while controlling for pretreatment vision, tumor diameter and height, anterior location, and macular detachment. This table shows that after such adjustment, proximity to either one or both of these structures is independently associated with the three leading causes of visual decline to worse than 20/200 compared to tumors greater than 2 DD from the disc and fovea. However, proximity to the disc alone was not a statistically significant risk factor for radiation retinopathy causing visual loss. This should be confirmed in other analyses with a larger sample size or a longer follow-up time. Radiation optic neuropathy was not evaluated in Table 5 as an outcome because the small number ofcases
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(22 patients) made it impossible to conduct a meaningful multivariate analysis. Proximity to both the disc and fovea is worse than proximity to one structure alone, as dem onstrated by the highest rate ratios for visual decline and causes of visual loss occurring in this category. A possible limitation of our article is the assignment of cause of visual loss. With multiple causes of visual loss possible, it is sometimes difficult to determine the leading cause of visual decline. We attempted to assess the primary reason for visual loss when the vision first dropped to worse than 20/200. In some cases, there was more than one cause and these cases were recorded as having a com bination of causes. In those in which a primary reason could be identified, other complications that were not an alyzed could have occurred at a later date. In addition, visual acuity could have declined to a level better than 20/200 which was not considered an outcome in the life table analyses and therefore causes of this level of visual decline were not assessed. Limitations are also encountered in other studies which attempt to attribute visual acuity of worse than a certain level to a specific cause. For example, the assignment of cause of visual loss among patients with both macular degeneration and cataract is problematic. Similarly in our study, a decline in visual acuity to worse than 20/200 could have been attributed to cataract when in fact some maculopathy was present as well (but was not detected due to the cataract). This possible misclassification might explain in part why promixity to the disc or fovea was an independent risk factor for cataract as a cause of visual loss to worse than 20/200. There have been only two recent studies addressing the subject of visual acuity after proton beam radiation of uveal melanomas. 1•8 In one report, 1 results of a Cox model analysis for tumors in all locations demonstrated the risk associated with tumors near the disc, fovea, or both. Kap lan-Meier curves were displayed showing the cumulative probability of visual acuity loss according to height and distance of the tumor from the disc and fovea. The other article addressing visual acuity after proton beam irradia tion described 60 patients with macular and paramacular tumors only. 8 The current article focuses on the high-risk group of patients with tumors near the disc or fovea to provide a more detailed description oftheir rates of visual loss and to compare them to rates for tumors in other locations. Only one article that evaluated visual acuity after other types of radiation treatment included life-table analyses. That article by Cruess et ae concerning cobalt plaque therapy differs from this report. It considered 77 patients
with 20/25 or better visual acuity before treatment, and visual results were based on radiation dose delivered to the disc or fovea and not distance of the tumor from these structures. Of 21 eyes with excellent pretreatment vision receiving greater than 50 Gy to the fovea, 48% had 20/ 200 or worse vision after 36 months. Of 26 eyes with excellent pretreatment vision receiving greater than 50 Gy to the disc, 36 months after treatment 35% had 20/ 200 or worse vision. It is stated that tumors with margins closer than 5 mm (3.3 DO) to the fovea and/or optic disc almost invariably received a radiation dose to these sites of greater than 50 Gy (some as high as about 140 Gy). However, in some eyes with tumors farther than 5 mm from the disc or fovea, those structures also received greater than 50 Gy. Those data then are not comparable to our report, which describes rates of visual loss for more unfavorable tumors which are located within only 2 DO of the disc or fovea in eyes with poorer pretreatment vision (2.20/200). It seems reasonable to assess location in terms ofdistance to the posterior structures as a prognostic factor rather than solely dose delivered to these structures be cause location is known while discussing treatment alter natives and prognosis with the patient. Results of the current investigation suggest that patients with tumors near the disc or fovea can be advised that if their vision is 20/200 or better, approximately 53% will retain this level of vision 2 years after treatment.
REFERENCES 1. Seddon JM, Gragoudas ES, Polivogianis L, et al. Visual outcome after proton beam irradiation of uveal melanoma. Ophthalmology 1986; 93: 666-74. 2. Cruess AF, Augsburger JJ, Shields JA, et al. Visual results following cobalt plaque radiotherapy for posterior uveal melanomas. Ophthal mology 1984; 91:131-6. 3. Goitein M, Miller T. Planning protqn therapy of the eye. Med Phys 1983; 10:275-83. 4. Kaplan EL, Meier P. Nonparametric estimation from incomplete ob servations. J Am Stat Assoc 1958; 53:457-81. 5. Greenwood M. The natural duration of cancer. Gr Br Dept of Health Soc Secur. Reports on Public Health and Medical Subjects 1926; 33: 1-26. 6. Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc Series A 1972; 135:185-206. 7. Cox D. Regression models and life tables (with discussion). J R Stat Soc Series B 1972; 34:186-220. 8. Gragoudas ES, Goitein M, Seddon J, et al. Preliminary results of proton beam irradiation of macular and paramacular melanomas. Br J Ophthalmol1984; 68:479-85.
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