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Intravitreal Triamcinolone Versus Intravitreal Bevacizumab in the Treatment of Exudative Retinal Detachment Secondary to Posterior Uveal Melanoma
Intravitreal Triamcinolone Versus Intravitreal Bevacizumab in the Treatment of Exudative Retinal Detachment Secondary to Posterior Uveal Melanoma RAFFAELE PARROZZANI, ELISABETTA PILOTTO, ALESSIA DARIO, GIACOMO MIGLIONICO, AND EDOARDO MIDENA ● PURPOSE: To evaluate the efficacy and safety of prompt
intravitreal triamcinolone acetonide injection (4 mg/0.1 mL) vs intravitreal bevacizumab injection (1.25 mg/0.05 mL) compared with observation in the management of extensive exudative retinal detachment secondary to posterior uveal melanoma. ● DESIGN: Retrospective, nonrandomized, interventional case series. ● METHODS: SETTING: Institutional. PATIENTS: Ninetysix patients affected by posterior uveal melanoma with large exudative retinal detachment (>10 mm in largest basal diameter) were included. INTERVENTION: Patients received intravitreal triamcinolone acetonide (32 eyes) or intravitreal bevacizumab (32 eyes) at plaque removal. Thirty-two patients served as controls (observation group). All groups were matched for age, sex, initial tumor thickness and largest basal diameter, largest exudative retinal detachment basal diameter, tumor location, and Bruch membrane rupture. Patients underwent monthly follow-up examinations in the first 6 months and every 3 months thereafter. Follow-up was longer than 24 months. MAIN OUTCOME MEASURE: Exudative retinal detachment resolution (B-scan ultrasonography), steroid-induced cataract, steroid-induced increased IOP. ● RESULTS: Follow-up was 37 ⴞ 7 months. Marked exudative retinal detachment regression was documented in 22 (69%) intravitreal triamcinolone acetonide–treated vs 11 (34%) intravitreal bevacizumab–treated and 9 (28%) untreated eyes (P ⴝ .0007 and P ⴝ .0001, respectively). No statistical significance was found between intravitreal bevacizumab group vs observation group (P ⴝ .45) Steroid-induced cataract was observed in 4 intravitreal triamcinolone acetonide–treated patients (12%). Neither steroid-induced increased IOP nor other short- or long-term side effects were documented. ● CONCLUSION: Intraoperative intravitreal triamcinolone acetonide injection induces earlier and marked exudative retinal detachment resolution after brachytherAccepted for publication Jun 20, 2012. From G.B. Bietti Foundation, IRCCS, Rome, Italy (R.P., E.M.); and Department of Ophthalmology, University of Padova, Padova, Italy (E.P., A.D., G.M., E.M.). Inquiries to Edoardo Midena, Department of Ophthalmology, University of Padova, Via Giustiniani 2, Padova 35128, Italy; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2012.06.026
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apy of posterior uveal melanoma. Risk and benefit should be balanced vs steroid-induced cataract. (Am J Ophthalmol 2013;155:127–133. © 2013 by Elsevier Inc. All rights reserved.)
E
YE-PRESERVING RADIATION TREATMENT HAS EMERGED
as the standard of care for the management of most uveal melanoma since the Collaborative Ocular Melanoma Study confirmed equivalent life prognosis following brachytherapy compared with enucleation in medium-sized tumors.1 Although the goal of treating the tumor and preserving the eye is achieved in most cases, the preservation of vision remains unpredictable.2 This is mainly attributable, at least in medium-to-large tumors, to the persistence (or increase) after brachytherapy of the uveal melanoma–related exudative retinal detachment, with its long-term side effects (mainly retina ischemia and neovascular glaucoma).3 Although exudative retinal detachment can be caused by eye injury, inflammation, or vascular abnormalities, it is clinically detected in up to 75% of eyes with uveal melanoma, and it is considered the most common retinal side effect accompanying this tumor.3 Exudative retinal detachment is characterized by subretinal fluid accumulation secondary to fluid homeostasis alteration across the inner and outer blood-retinal barriers.3–5 Enhanced production of vascular endothelial growth factor (VEGF), nitric oxide, oxidative stress, and inflammation are considered the main factors that increase the permeability of both the inner and outer blood-retinal barriers.4 Several proinflammatory cytokines are significantly expressed in uveal melanoma eyes.6,7 Ly and associates recently suggested that the presence of uveal melanoma leads to the production of a proinflammatory cytokine pattern that promotes tumor survival by creating a new microenvironment.6 Evidence of subclinical inflammation in uveal melanoma eyes was also previously reported by in vivo laser photometry measurements, detecting increased anterior chamber flare in untreated eyes with uveal melanoma.7 An increased flare in uveal melanoma eyes was also strongly correlated with the presence of uveal melanoma– related exudative retinal detachment.7,8 One of the major group of proinflammatory cytokines is the VEGF family.9 VEGF-A is secreted by various types of
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TABLE 1. Uveal Melanoma–Related Exudative Retinal Detachment: Clinical and Demographic Characteristics of Enrolled Patients
N Age (y), mean (range) Sex: male/female Affected eye: right/left Tumor location: choroidal/ciliary body Baseline tumor dimensions Thickness (mm) Largest basal diameter (mm) Baseline exudative retinal detachment dimension: largest basal diameter (mm) Bruch membrane rupture Mean dose rate Mean dose at tumor apex
Intravitreal Triamcinolone Acetonide Group
Intravitreal Bevacizumab Group
Observation Group
All Groups
32 56 ⫾ 14 (33–84) 14/18 (44%/56%) 18/14 (56%/44%) 24/8 (75%/25%)
32 55 ⫾ 15 (30–83) 15/17 (47%/53%) 19/13 (59%/41%) 26/6 (81%19%)
32 58 ⫾ 17 (37–86) 17/15 (53%/47%) 21/11 (66%/34%) 25/7 (78%22%)
96 56 ⫾ 15 (30–86) 46/50 (45%/55%) 58/38 (61%/39%) 75/21 (78%/22%)
6.7 ⫾ 1.9 (range, 4.0–10) 13.6 ⫾ 3.3 (range, 8–18) 15.4 ⫾ 3.5 (range, 10–21)
6.5 ⫾ 1.9 (range, 4.2–10) 12.9 ⫾ 3.4 (range, 7.6–18) 14.6 ⫾ 3.3 (range 10–20)
6.7 ⫾ 2.0 (range, 4.0–10) 13.0 ⫾ 3.5 (range, 7.1–17) 15.5 ⫾ 3.0 (range 10–19)
6.6 ⫾ 1.9 (range, 4.0–10) 13.3 ⫾ 3.4 (range, 7.1–18) 15.1 ⫾ 3.5 (range 10–21)
14 (43.7%) 0.85 ⫾ 0.14 Gy/h 91 ⫾ 5 Gy
15 (46.8%) 0.86 ⫾ 0.14 Gy/h 90 ⫾ 4 Gy
12 (37.5%) 0.86 ⫾ 0.13 Gy/h 91 ⫾ 5 Gy
41 (43%) 0.86 ⫾ 0.14 Gy/h 91 ⫾ 5 Gy
● PATIENTS:
tumor cells and can cause increased vascular permeability, endothelial cell growth, angiogenesis, monocyte activation, and chemotaxis.9 Uveal melanoma is associated with increased concentrations of VEGF-A in the aqueous humor. Recently, Missotten and associates suggested that VEGF-A concentration in the aqueous humor, exudative retinal detachment, and tumor size are interrelated factors.9 A few years ago, we started a prospective pilot study to treat patients with extensive exudative retinal detachment secondary to uveal melanoma with intravitreal bevacizumab or intravitreal triamcinolone acetonide, mainly because of the lack of other truly safe options (see discussion). The aim of this study is to retrospectively evaluate the efficacy and safety of prompt intravitreal triamcinolone acetonide vs intravitreal bevacizumab compared to observation in the management of exudative retinal detachment secondary to posterior uveal melanoma.
Patients were affected by posterior uveal melanoma with extensive exudative retinal detachment (⬎10 mm in largest basal diameter) and planned to undergo plaque brachytherapy (iodine-125 [I-125], dose of 85–100 Gy at tumor apex, dose rate of 0.60 –1.05 Gy/h).10 Each patient underwent a baseline (preoperative) full ophthalmologic examination. The ophthalmoscopic aspect of the tumors was documented by fundus photography. Tumor and exudative retinal detachment dimensions were also documented using A- and B-scan ultrasonography. Clinical and demographic characteristics were collected, including age, sex, affected eye, tumor location (choroid vs ciliary body), tumor largest basal diameter (based on B-scan ultrasonography), tumor thickness (based on A-scan ultrasonography), exudative retinal detachment largest basal diameter (based on B-scan ultrasonography performed with patient lying on a stretcher), and presence of Bruch membrane rupture. Liver enzymes and liver ultrasonography were also used to evaluate the presence of metastatic disease at baseline. Ninety-six patients treated with I-125 brachytherapy, with a follow-up longer than 24 months, were included in this retrospective study.
MATERIALS AND METHODS ● SETTING AND DESIGN: This was an institutional, retrospective, nonrandomized, interventional case series. Patients were recruited from those referred to the Ophthalmic Oncology units of both the G.B. Bietti Foundation and the Department of Ophthalmology of the University of Padova. Treated patients were retrospectively recruited from those previously included in a pilot prospective study on safety of intravitreal triamcinolone acetonide and intravitreal bevacizumab in the management of exudative retinal detachment secondary to posterior uveal melanoma.
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● INTERVENTION:
Treated patients received 1 intravitreal triamcinolone acetonide injection at plaque removal (32 eyes) or a loading phase of 3 intravitreal bevacizumab injections (32 eyes), performed at 4-week intervals (the first intravitreal bevacizumab injection was performed during plaque removal). Thirty-two patients served as controls. All groups were matched for age, sex, initial tumor thickness and largest basal diameter, largest exudative retinal detachment basal diameter, tumor location, and Bruch membrane rupture. OF
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TABLE 2. Uveal Melanoma–Related Exudative Retinal Detachment: Treatment Outcome and Follow-up
N Mean injections/group Exudative retinal detachment: marked regression, n (%) Exudative retinal detachment regression time (mo) Follow-up (mo)
Intravitreal Triamcinolone Acetonide Group
Intravitreal Bevacizumab Group
Observation Group
All Groups
32 1.9 (range 1–3)
32 3.7 (range 3–5)
32 NA
96 2.9a (range 1–5)
22 (69%)
11 (34%)
4.5 ⫾ 2.4 39 ⫾ 8 (range 24–55)
7.9 ⫾ 2.7 35 ⫾ 6 (range 24–53)
9 (28%) 11.2 ⫾ 3.5 36 ⫾ 6 (range 24–53)
42 (44%) 6.8 ⫾ 3.9 37 ⫾ 7 (range 24–55)
mo ⫽ month; NA ⫽ not applicable. Excluding observation group.
a
Clinical and demographic characteristics related to different treatment groups are reported in Table 1. Cortico-responder patients were preliminarily excluded by the intravitreal triamcinolone acetonide group on the basis of a preoperative test.11 ● INTRAVITREAL INJECTION: Sterile technique was used to prepare 4.0 mg/0.1 mL of triamcinolone acetonide from a single-use vial of 40 mg (Kenalog; Bristol-MyersSquibb, Princeton, New Jersey, USA), immediately before the injection procedure.12 Bevacizumab injections (1.25 mg/0.05 mL) were prepared in sterile conditions by the hospital pharmacy from a single-use vial of 100 mg (Avastin; Genentech, Cambridge, Massachusetts, USA).13 Solutions were injected using a 27-gauge (intravitreal triamcinolone acetonide) or 30-gauge (intravitreal bevacizumab) needle via standard pars plana approach (3.5– 4.0 mm posterior to the limbus), avoiding retinal quadrants occupied by tumor and/or exudative retinal detachment. Injection was performed at the time of I-125 plaque removal. The injection site was recorded. Fundus was observed for side effects immediately after injection using indirect ophthalmoscopy. Anterior chamber paracentesis was never performed. Patients underwent postoperative examination 1 and 7 days after injection.12,13 ● RETREATMENT:
Retreatment criteria were: (1) no or partial response after first injection (intravitreal triamcinolone acetonide) or loading phase (intravitreal bevacizumab); and (2) partial response after subsequent injections. Retreatment was performed at 3-month intervals. Treatment failure was finally managed by observation alone. Laser photocoagulation was employed to treat reattached ischemic retina in each patient having any response to treatment (partial or marked), or spontaneous resolution (partial or marked) in the observation group.
● MAIN OUTCOME MEASURE: No response was defined as exudative retinal detachment largest basal diameter reduc-
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FIGURE 1. Kaplan–Meier analysis of uveal melanoma–related exudative retinal detachment resolution after intravitreal adjuvant treatment: intravitreal triamcinolone acetonide group vs intravitreal bevacizumab group vs observational group.
tion of less than 20%. Partial response was defined as exudative retinal detachment largest basal diameter reduction between 20% and 80%. Marked response was defined as exudative retinal detachment largest basal diameter reduction of more than 80%. Treatment failure was defined as absence of marked response at the end of treatment. Steroid-induced increased IOP was defined as an IOP elevation to 24 mm Hg or higher.11 Steroid-induced cataract was assessed by slit-lamp examination after dilation of the pupil compared with baseline recorded data. ● FOLLOW-UP: Follow-up examinations were performed every month for the first 6 months and every 3 months thereafter. Each examination included complete ophthalmologic evaluation, A- and B-scan ultrasonography, and IOP measurement. Sites of injections underwent regular slit-lamp examination and photographic follow-up. Liver enzyme analysis and ultrasonography were performed at 6-month intervals. ● DATA ANALYSIS: Statistical analyses (ANOVA, Kaplan-Meier, 2 test, independent-samples t test) were
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FIGURE 2. Uveal melanoma with extensive exudative retinal detachment. (Top) Pretreatment B-scan ultrasonography of 4 cases in the intravitreal triamcinolone acetonide group. (Bottom) B-scan ultrasonography of same patients at 12 months follow-up showing resolution of exudative retinal detachment. Note the intravitreal drug persistence (*) after intravitreal triamcinolone acetonide injection.
TABLE 3. Uveal Melanoma–Related Exudative Retinal Detachment: Clinical and Demographic Characteristics Related to Treatment Outcome
# Age (y), median (mean, range) Sex Male Female Tumor location Choroid Ciliary body Baseline tumor dimensions Thickness (mm), median (mean, range) Largest basal diameter (mm), median (mean, range) Baseline exudative retinal detachment dimension Largest basal diameter (mm), median (mean, range) Bruch membrane rupture a
Exudative Retinal Detachment Marked Regression
Exudative Retinal Detachment Persistence
44 56 (57, 33–84)
52 57 (57, 30–86)
20 (21%) 24 (25%)
26 (27%) 26 (27%)
P Value
.74a .65b
.75b 35 (36%) 9 (9%)
40 (42%) 12 (12%)
6.8 (6.8, 4.2–10) 13.5 (13.5, 7.8–18)
6.4 (6.4, 4.2–10) 13.0 (13.5, 7.6–18)
.25a .32a
15.2 (15.4, 10–21) 18 (19%)
15.0 (15.2, 10–20) 23 (24%)
.38a .74b
Independent-samples t test. test.
b 2
Forty-six patients were male (46%) and 50 female (54%). The right eye was affected in 58 patients (60%) and the left eye in 38 (40%). Seventy-five melanomas were purely choroidal in location (78%), whereas 21 eyes were affected by ciliary body tumors (22%). Mean tumor largest basal diameter was 13.3 ⫾ 3.4 mm (range, 7.6 –18 mm) and mean tumor thickness was 6.6 ⫾ 1.9 mm (range, 4 –10 mm). Mean exudative retinal detachment largest basal diameter was 15.1 ⫾ 3.5 mm (range, 10 –21 mm). The
performed by SAS v.8.2 statistical package (SAS Institute, Cary, North Carolina, USA). A value of P ⬍ .05 was considered statistically significant.
RESULTS NINETY-SIX PATIENTS (MEAN AGE, 56 ⫾ 15 YEARS; RANGE,
30 – 86 years) were included in this retrospective study. 130
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rupture of Bruch membrane was present in 41 patients (43%). Mean dose rate and mean dose at tumor apex were not statistically different in the 3 groups (P ⬎ .05) (Table 1). A mean of 3.7 (range, 3–5) intravitreal injections were performed in the intravitreal bevacizumab group vs 1.9 (range, 1–3) in the intravitreal triamcinolone acetonide group. No local or systemic complications were observed during surgical procedure. Mean follow-up was 37 ⫾ 7 months (range, 24 –55 months). Marked exudative retinal detachment regression was documented in 22 of 32 intravitreal triamcinolone acetonide–treated patients (69%) vs 11 of 32 intravitreal bevacizumab–treated patients (34%) and 9 of 32 control patients (28%) (observation group) (Table 2). Of these, regression was complete (absence of any ultrasonographic evidence of exudative retinal detachment) in 18 intravitreal triamcinolone acetonide–treated patients (82%) vs 10 intravitreal bevacizumab–treated patients (91%) and 7 control patients (78%) (observation group). Exudative retinal detachment marked regression was observed 4.5 ⫾ 2.4, 7.9 ⫾ 2.7, and 11.2 ⫾ 3.5 months after brachytherapy, respectively. Statistical analysis showed significant difference between exudative retinal detachment marked regression in the intravitreal triamcinolone acetonide group vs intravitreal bevacizumab and observation groups (P ⫽ .0007 and P ⫽ .0001, respectively) (Figures 1 and 2). No statistical significance was found between the intravitreal bevacizumab group vs observation group (P ⫽ .4501) (Figures 1 and 2). No statistically significant difference was observed between tumors showing exudative retinal detachment regression or persistence vs patient age, sex, tumor location, exudative retinal detachment largest basal diameter, and presence of Bruch membrane rupture (Table 3). Steroid-induced cataract was observed in 4 of 32 intravitreal triamcinolone acetonide–treated patients (12%). Neither steroid-induced increased intraocular pressure nor other short- or longterm side effects were documented. Seven of 96 patients (7.3%) developed neovascular glaucoma (18 ⫾ 3.9 months after brachytherapy). Of these, 3 were in the observation group (43%), 3 were in the intravitreal bevacizumab group (43%), and 1 was in the intravitreal triamcinolone acetonide group (14%) (P ⬎ .05). Eleven of 96 patients developed metastatic disease (11.5%) within an interval of 27 ⫾ 5.7 months after brachytherapy. Of these, 4 were in the observation group (36%), 3 were in the intravitreal bevacizumab group (27%), and 4 were in the intravitreal triamcinolone acetonide group (36%) (P ⬎ .05). Neither local recurrence nor extrascleral/orbital extension was documented during follow-up.
DISCUSSION INCREASED INTRATUMOR CAPILLARY PERMEABILITY, IN-
tratumor inflammation, and necrosis are often present in uveal melanoma, as well as in most solid tumors.14 AssumVOL. 155, NO. 1
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ing a role of VEGF and/or other proinflammatory cytokines in the pathogenesis of uveal melanoma–related exudative retinal detachment, these factors significantly increase after conservative radiation treatment because of radiation effect on tumor cells.14 “Senescence” is the term used to describe a condition of permanent cell-cycle arrest.14 Senescence has been reported to occur in tumor cells in vitro and in experimental tumors in vivo following extensive cellular stress induced by a number of DNA-damaging agents, mainly irradiation.15–17 Clinical evidence of prolonged cytostatic arrest following radiotherapy also indicate senescence as a major mechanism for solid tumor regression.18 Senescent cells acquire extensive alterations in gene expression, including inhibition of genes involved in cell proliferation, homeostasis, and intercellular communication.19 Thus, senescent cells do not divide, but may remain alive and metabolically active for several months.14 Senescent cells have been shown to overexpress and secrete many factors, including a number of cytokines allowing communication between senescent cells and their microenvironment.19 –21 These communications have been reported to induce an intense and prolonged inflammatory response, to increase tumor capillary permeability, and to promote angiogenesis. 9,19 –23 Corticosteroids play a relevant role in many irradiation protocols of different solid tumors.24,25 Corticosteroids are believed to exert their influence on tumors and surrounding tissue by reducing the tumor-associated vasogenic edema, decreasing the pathologically increased tumor capillary permeability, and reducing intratumor inflammation and necrosis.24,25 Anti-VEGF is a potent antiangiogenic monoclonal antibody with different biologic effects, including inhibition of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine regeneration.26 VEGF is both a vascular growth factor and a vascular permeability factor, overexpressed in most solid tumors as well as in uveal melanoma.27 To the best of our knowledge, there are no data on corticosteroids and few data on anti-VEGF’s role in the treatment of uveal melanoma–associated exudative retinal detachment. Newman and associates described, in a pilot study, that systemic bevacizumab was associated with resolution of choroidal melanoma–related exudative retinal detachment as well as transient systemic side effects.28 Conversely, in our study we found no significant bevacizumab efficacy vs observation in the management of extensive exudative retinal detachment secondary to posterior uveal melanoma. This may be explained by different administration method, dosage, and timing (intravenous bevacizumab 10 mg/kg every 2 weeks for 3 or 4 cycles vs intravitreal bevacizumab 1.25 mg/0.05 mL for at least 3 times). Nevertheless, considering the possible related side effects of systemically administered bevacizumab, the intravitreal approach should be preferred. Another possible explanation for the lack of efficacy of the intravitreal bevacizumab– based approach is the use of a modified protocol based on the standard protocol for neovas-
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cular age-related macular degeneration. The decision to use this regimen for uveal melanoma–related exudative retinal detachment appeared reasonable based on the beneficial response observed in most patients with neovascular agerelated macular degeneration.29 However, for uveal melanoma patients who did not respond favorably to a loading phase, it is questionable whether more frequent injections (or prolonged treatment period) may have a long-term beneficial effect. Moreover, looking at the average number of injections in the intravitreal bevacizumab group (3.7 injections/patient), mainly paired to current age-related macular degeneration protocols, we cannot exclude that this treatment may be underdosed in the long-term period, which may explain the lack of statistically significant difference from the observation arm. Nevertheless, the lack of response after 3 intravitreal injections of bevacizumab should raise relevant questions about the efficacy of the intravitreal bevacizumab– based approach. An alternative strategy that should be considered may be to increase the bevacizumab intravitreal dose.29 Retrospective analysis is a relatively common practice in the oncology literature; nevertheless, the possible biases of our study are the retrospective design itself, the lack of consecutive enrollment, and the possible selection bias in the construction of the current cohort. However, our data demonstrate that early intravitreal triamcinolone acetonide injection significantly induces earlier and marked exudative retinal detachment resolution after brachytherapy compared with intravitreal bevacizumab or no treatment. We have considered as the “main result” the concept of marked regression (instead of complete regression), because minimal residual serous retinal detachment is relatively common in uveal melanoma, mainly in large tumors with Bruch membrane rupture, and is attributable to direct retinal traction by the tumor. Moreover, when minimal residual serous retinal detachment is present, it is possible to treat reattached retina with laser photocoagulation, preventing long-term side effects related to retinal ischemia. Intravitreal triamcinolone acetonide efficacy may be attributable to the higher anti-inflammatory activity of this drug compared with bevacizumab in the post-RT intraocular tumor microenvironment, suggesting a major role of post-RT tumor inflammation in the pathogenesis of exudative retinal detachment (“senescence syndrome”).12,19 Moreover, it is well known that corticosteroids also have a direct antiangiogenic effect.30 Recently, McAllister and associates reported that intravitreal triamcinolone acetonide directly downregulates VEGF expression.30 This effect may also contribute to the intravitreal triamcinolone acetonide efficacy in reducing uveal melanoma–related exudative retinal detachment. Nevertheless, considering the lack of efficacy of intravitreal bevacizumab, an approach operating in the antiangiogenic pathway alone may be partial and insufficient. 132
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There are few reports on the treatment of postradiation persistent exudative retinal detachment in uveal melanoma. Char and associates reported 11 patients treated by adjuvant post–RT laser–induced tumor hyperthermia, concluding that combined laser-induced hyperthermia and proton irradiation may dissipate exudative retinal detachment more rapidly than irradiation alone.31 The rationale of this modality is to close leaking superficial tumor vessels. Nevertheless, laser-induced hyperthermia is not suitable for uveal melanoma with overlying extensive exudative retinal detachment. Gibran and Kapoor recently reported that timely vitreoretinal surgical intervention for exudative retinal detachments associated with choroidal melanomas may result in significant restoration of vision. Although this technique should be considered as a promising approach, only 6 patients were included in this preliminary report.32 Other proposed modalities, aimed at removing metabolically active tumor cells (the so-called “toxic tumor syndrome”), are ab externo and ab interno tumor resections.33 While ab externo tumor resection is more applicable to anteriorly located tumors with ciliary body and/or iris involvement, endoresection is more suitable for posteriorly located lesions without ciliary body involvement. However, both types of tumor resections are challenging surgical procedures, bearing the risk of early and late intraoperative and postoperative local and systemic complications.33 Conversely, our reported approach is surgically simple and cost-effective. Moreover, we have performed the injection procedure immediately after brachytherapy, avoiding both managing eyes with vital tumor cells and the risk of induce pharmacologic effects on tumor cells during the irradiation period. The lack of steroid-induced increased intraocular pressure after intravitreal triamcinolone acetonide may be explained by the preliminary exclusion of cortico-responder patients.11 Moreover, a second explanation of the lack of increased intraocular pressure in our cohort of patients is the peculiar pathophysiology of eyes with large uveal melanoma: in these eyes intraocular pressure is often low (this was considered a minor diagnostic criterion for uveal melanoma in the past), mainly in large lesions with large serous retinal detachment. The major side effect of intravitreal triamcinolone acetonide is steroid-induced cataract. Visual acuity was not an endpoint in this study because of tumors and exudative retinal detachment dimensions (radiation retinopathy, maculopathy, and optic neuropathy are often present after treatment in these lesions). Nevertheless, before starting treating patients with small or medium tumors and limited exudative retinal detachment, risk and benefit should be balanced vs steroid-induced cataract. In conclusion, intraoperative intravitreal triamcinolone acetonide injection induces earlier and marked exudative retinal detachment resolution after brachytherapy in large uveal melanoma with extensive exudative retinal detachment compared with intravitreal bevacizumab or observation groups, causing limited local and no systemic side effects. OF
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ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF Interest and none were reported. The authors indicate no funding support. Involved in design and conduct of the study (R.P., E.M.); collection, management, analysis, and interpretation of the data (R.P., E.P., A.D., G.M., E.M.); and preparation, review, or approval of the manuscript (R.P., E.P., A.D., G.M., E.M.). Informed consent for both the treatment and participation in the research for this prospective study (Study N.: 1302P, Regione del Veneto, Azienda Ospedaliera di Padova, Struttura Interaziendale Marketing e Sviluppo) was approved by the institutional review board (Prot. N. 65819, November 23, 2006). Informed consent for both the treatment and participation in the research was obtained from each patient and the research was conduced according to the provisions of the Declaration of Helsinki, 1995 (as revised in Edinburgh, 2000).
REFERENCES 1. Hawkins BS. Collaborative Ocular Melanoma Study randomized trial of I-125 brachytherapy. Clin Trials 2011;8(5):661–673. 2. Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for uveal melanoma: long-term visual outcome in 1106 consecutive patients. Arch Ophthalmol 2000;118(9):1219 –1228. 3. Gibran SK, Kapoor KG. Management of exudative retinal detachment in choroidal melanoma. Clin Experiment Ophthalmol 2009;37(7):654 – 659. 4. Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res 2008;27(6):622– 647. 5. Kivelä T, Eskelin S, Mäkitie T, Summanen P. Exudative retinal detachment from malignant uveal melanoma: predictors and prognostic significance. Invest Ophthalmol Vis Sci 2001;42(9):2085– 2093. 6. Ly LV, Bronkhorst IH, van Beelen E, et al. Inflammatory cytokines in eyes with uveal melanoma and relation with macrophage infiltration. Invest Ophthalmol Vis Sci 2010;51(11):5445–5451. 7. Castella AP, Bercher L, Zografos L, Egger E, Herbort CP. Study of the blood-aqueous barrier in choroidal melanoma. Br J Ophthalmol 1995;79(4):354 –357. 8. Lumbroso L, Desjardins L, Levy C, et al. Intraocular inflammation after proton beam irradiation for uveal melanoma. Br J Ophthalmol 2001;85(11):1305–1308. 9. Missotten GS, Notting IC, Schlingemann RO, et al. Vascular endothelial growth factor A in eyes with uveal melanoma. Arch Ophthalmol 2006;124(10):1428 – 434. 10. Nag S, Quivey JM, Earle JD, et al. The American Brachytherapy Society recommendations for brachytherapy of uveal melanomas. Int J Radiat Oncol Biol Phys 2003;56(1):544 –555. 11. Breusegem C, Vandewalle E, Van Calster J, Stalmans I, Zeyen T. Predictive value of a topical dexamethasone provocative test before intravitreal triamcinolone acetonide injection. Invest Ophthalmol Vis Sci 2009;50(2):573–576. 12. Tao Y, Jonas JB. Intravitreal triamcinolone. Ophthalmologica 2011;225(1):1–20. 13. Gunther JB, Altaweel MM. Bevacizumab (Avastin) for the treatment of ocular disease. Surv Ophthalmol 2009;54(3):372–400. 14. Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol 2010;31(4):363–372. 15. Gewirtz DA, Holt SE, Elmore LW. Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochem Pharmacol 2008;76(8):947–957. 16. Jones KR, Elmore LW, Jackson-Cook C, et al. P53-dependent accelerated senescence induced by ionizing radiation in breast tumour cells. Int J Radiat Biol 2005;81(6):445– 458. 17. Lehmann BD, McCubrey JA, Jefferson HS, Paine MS, Chappell WH, Terrian DM. A dominant role for p53dependent cellular senescence in radiosensitization of human prostate cancer cells. Cell Cycle 2007;6(5):595– 605.
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18. Shay JW, Roninson IB. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 2004;23(16):2919 –2933. 19. Rodier F, Coppé JP, Patil CK, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 2009;11(8):973–979. 20. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 2010;5:99 –118. 21. Novakova Z, Hubackova S, Kosar M, et al. Cytokine expression and signaling in drug-induced cellular senescence. Oncogene 2010;29(2):273–284. 22. Mashayekhi A, Tuncer S, Shields CL, Shields JA. Tumorrelated lipid exudation after plaque radiotherapy of choroidal melanoma: the role of Bruch’s membrane rupture. Ophthalmology 2010;117(5):1013–1023. 23. Harbour JW, Ahmad S, El-Bash M. Rate of resolution of exudative retinal detachment after plaque radiotherapy for uveal melanoma. Arch Ophthalmol 2002;120(11):1463–1469. 24. Koehler PJ. Use of corticosteroids in neuro-oncology. Anticancer Drugs 1995;6(1):19 –33. 25. Sturdza A, Millar BA, Bana N, et al. The use and toxicity of steroids in the management of patients with brain metastases. Support Care Cancer 2008;16(9):1041–1048. 26. Pradeep CR, Sunila ES, Kuttan G. Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies. Integr Canc Ther 2005;4(4):315– 321. 27. Missotten GS, Schlingemann RO, Jager MJ. Angiogenesis and vascular endothelial growth factors in intraocular tumors. Dev Ophthalmol 2010;46:123–132. 28. Newman H, Finger PT, Chin KJ, Pavlick AC. Systemic bevacizumab (Avastin) for exudative retinal detachment secondary to choroidal melanoma. Eur J Ophthalmol. 2011;21(6): 796 – 801. 29. Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor trap-eye). Retina 2012;32(3):434 – 457. 30. McAllister IL, Vijayasekaran S, Chen SD, Yu DY. Effect of triamcinolone acetonide on vascular endothelial growth factor and occludin levels in branch retinal vein occlusion. Am J Ophthalmol 2009;147(5):838 – 846. 31. Char DH, Bove R, Phillips TL. Laser and proton radiation to reduce uveal melanoma-associated exudative retinal detachments. Am J Ophthalmol 2003;136(1):180 –182. 32. Gibran SK, Kapoor KG. Management of exudative retinal detachment in choroidal melanoma. Clin Experiment Ophthalmol 2009;37(7):654 – 659. 33. Gündüz K, Bechrakis NE. Exoresection and endoresection for uveal melanoma. Middle East Afr J Ophthalmol 2010;17(3):210– 216.
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Biosketch Edoardo Midena was born in Venice, Italy. He graduated in Medicine and Surgery, and received his PhD from the University of Padova, Italy. He is a Full Professor of Ophthalmology at the University of Padova, and Chairman of the Department of Ophthalmology, Padova University Hospital. He is member of the scientific board of the GB Bietti Foundation, IRCCS (Roma, Italy). He has published more than 300 contributes. His primary research interests are ocular oncology and chorioretinal diseases.
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Biosketch Raffaele Parrozzani was born in 1980, in Montebelluna, Italy. He graduated in Medicine and Surgery (2005) and received his degree in Ophthalmology (2010) from the University of Padova. In 2010 he started the fellowships in General and Surgical Oncology. He actually works for the G.B Bietti Eye Foundation, IRCCS, in the Ocular Oncology Center and in the Multidisciplinary Center for Ocular and Orbital Disorders, Padova, Italy. His primary research interests are ocular oncology and toxicology.
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intravitreal triamcinolone acetonide injection (4 mg/0.1 mL) vs intravitreal bevacizumab injection (1.25 mg/0.05 mL) compared with observation in the management of extensive exudative retinal detachment secondary to posterior uveal melanoma. ● DESIGN: Retrospective, nonrandomized, interventional case series. ● METHODS: SETTING: Institutional. PATIENTS: Ninetysix patients affected by posterior uveal melanoma with large exudative retinal detachment (>10 mm in largest basal diameter) were included. INTERVENTION: Patients received intravitreal triamcinolone acetonide (32 eyes) or intravitreal bevacizumab (32 eyes) at plaque removal. Thirty-two patients served as controls (observation group). All groups were matched for age, sex, initial tumor thickness and largest basal diameter, largest exudative retinal detachment basal diameter, tumor location, and Bruch membrane rupture. Patients underwent monthly follow-up examinations in the first 6 months and every 3 months thereafter. Follow-up was longer than 24 months. MAIN OUTCOME MEASURE: Exudative retinal detachment resolution (B-scan ultrasonography), steroid-induced cataract, steroid-induced increased IOP. ● RESULTS: Follow-up was 37 ⴞ 7 months. Marked exudative retinal detachment regression was documented in 22 (69%) intravitreal triamcinolone acetonide–treated vs 11 (34%) intravitreal bevacizumab–treated and 9 (28%) untreated eyes (P ⴝ .0007 and P ⴝ .0001, respectively). No statistical significance was found between intravitreal bevacizumab group vs observation group (P ⴝ .45) Steroid-induced cataract was observed in 4 intravitreal triamcinolone acetonide–treated patients (12%). Neither steroid-induced increased IOP nor other short- or long-term side effects were documented. ● CONCLUSION: Intraoperative intravitreal triamcinolone acetonide injection induces earlier and marked exudative retinal detachment resolution after brachytherAccepted for publication Jun 20, 2012. From G.B. Bietti Foundation, IRCCS, Rome, Italy (R.P., E.M.); and Department of Ophthalmology, University of Padova, Padova, Italy (E.P., A.D., G.M., E.M.). Inquiries to Edoardo Midena, Department of Ophthalmology, University of Padova, Via Giustiniani 2, Padova 35128, Italy; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2012.06.026
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apy of posterior uveal melanoma. Risk and benefit should be balanced vs steroid-induced cataract. (Am J Ophthalmol 2013;155:127–133. © 2013 by Elsevier Inc. All rights reserved.)
E
YE-PRESERVING RADIATION TREATMENT HAS EMERGED
as the standard of care for the management of most uveal melanoma since the Collaborative Ocular Melanoma Study confirmed equivalent life prognosis following brachytherapy compared with enucleation in medium-sized tumors.1 Although the goal of treating the tumor and preserving the eye is achieved in most cases, the preservation of vision remains unpredictable.2 This is mainly attributable, at least in medium-to-large tumors, to the persistence (or increase) after brachytherapy of the uveal melanoma–related exudative retinal detachment, with its long-term side effects (mainly retina ischemia and neovascular glaucoma).3 Although exudative retinal detachment can be caused by eye injury, inflammation, or vascular abnormalities, it is clinically detected in up to 75% of eyes with uveal melanoma, and it is considered the most common retinal side effect accompanying this tumor.3 Exudative retinal detachment is characterized by subretinal fluid accumulation secondary to fluid homeostasis alteration across the inner and outer blood-retinal barriers.3–5 Enhanced production of vascular endothelial growth factor (VEGF), nitric oxide, oxidative stress, and inflammation are considered the main factors that increase the permeability of both the inner and outer blood-retinal barriers.4 Several proinflammatory cytokines are significantly expressed in uveal melanoma eyes.6,7 Ly and associates recently suggested that the presence of uveal melanoma leads to the production of a proinflammatory cytokine pattern that promotes tumor survival by creating a new microenvironment.6 Evidence of subclinical inflammation in uveal melanoma eyes was also previously reported by in vivo laser photometry measurements, detecting increased anterior chamber flare in untreated eyes with uveal melanoma.7 An increased flare in uveal melanoma eyes was also strongly correlated with the presence of uveal melanoma– related exudative retinal detachment.7,8 One of the major group of proinflammatory cytokines is the VEGF family.9 VEGF-A is secreted by various types of
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TABLE 1. Uveal Melanoma–Related Exudative Retinal Detachment: Clinical and Demographic Characteristics of Enrolled Patients
N Age (y), mean (range) Sex: male/female Affected eye: right/left Tumor location: choroidal/ciliary body Baseline tumor dimensions Thickness (mm) Largest basal diameter (mm) Baseline exudative retinal detachment dimension: largest basal diameter (mm) Bruch membrane rupture Mean dose rate Mean dose at tumor apex
Intravitreal Triamcinolone Acetonide Group
Intravitreal Bevacizumab Group
Observation Group
All Groups
32 56 ⫾ 14 (33–84) 14/18 (44%/56%) 18/14 (56%/44%) 24/8 (75%/25%)
32 55 ⫾ 15 (30–83) 15/17 (47%/53%) 19/13 (59%/41%) 26/6 (81%19%)
32 58 ⫾ 17 (37–86) 17/15 (53%/47%) 21/11 (66%/34%) 25/7 (78%22%)
96 56 ⫾ 15 (30–86) 46/50 (45%/55%) 58/38 (61%/39%) 75/21 (78%/22%)
6.7 ⫾ 1.9 (range, 4.0–10) 13.6 ⫾ 3.3 (range, 8–18) 15.4 ⫾ 3.5 (range, 10–21)
6.5 ⫾ 1.9 (range, 4.2–10) 12.9 ⫾ 3.4 (range, 7.6–18) 14.6 ⫾ 3.3 (range 10–20)
6.7 ⫾ 2.0 (range, 4.0–10) 13.0 ⫾ 3.5 (range, 7.1–17) 15.5 ⫾ 3.0 (range 10–19)
6.6 ⫾ 1.9 (range, 4.0–10) 13.3 ⫾ 3.4 (range, 7.1–18) 15.1 ⫾ 3.5 (range 10–21)
14 (43.7%) 0.85 ⫾ 0.14 Gy/h 91 ⫾ 5 Gy
15 (46.8%) 0.86 ⫾ 0.14 Gy/h 90 ⫾ 4 Gy
12 (37.5%) 0.86 ⫾ 0.13 Gy/h 91 ⫾ 5 Gy
41 (43%) 0.86 ⫾ 0.14 Gy/h 91 ⫾ 5 Gy
● PATIENTS:
tumor cells and can cause increased vascular permeability, endothelial cell growth, angiogenesis, monocyte activation, and chemotaxis.9 Uveal melanoma is associated with increased concentrations of VEGF-A in the aqueous humor. Recently, Missotten and associates suggested that VEGF-A concentration in the aqueous humor, exudative retinal detachment, and tumor size are interrelated factors.9 A few years ago, we started a prospective pilot study to treat patients with extensive exudative retinal detachment secondary to uveal melanoma with intravitreal bevacizumab or intravitreal triamcinolone acetonide, mainly because of the lack of other truly safe options (see discussion). The aim of this study is to retrospectively evaluate the efficacy and safety of prompt intravitreal triamcinolone acetonide vs intravitreal bevacizumab compared to observation in the management of exudative retinal detachment secondary to posterior uveal melanoma.
Patients were affected by posterior uveal melanoma with extensive exudative retinal detachment (⬎10 mm in largest basal diameter) and planned to undergo plaque brachytherapy (iodine-125 [I-125], dose of 85–100 Gy at tumor apex, dose rate of 0.60 –1.05 Gy/h).10 Each patient underwent a baseline (preoperative) full ophthalmologic examination. The ophthalmoscopic aspect of the tumors was documented by fundus photography. Tumor and exudative retinal detachment dimensions were also documented using A- and B-scan ultrasonography. Clinical and demographic characteristics were collected, including age, sex, affected eye, tumor location (choroid vs ciliary body), tumor largest basal diameter (based on B-scan ultrasonography), tumor thickness (based on A-scan ultrasonography), exudative retinal detachment largest basal diameter (based on B-scan ultrasonography performed with patient lying on a stretcher), and presence of Bruch membrane rupture. Liver enzymes and liver ultrasonography were also used to evaluate the presence of metastatic disease at baseline. Ninety-six patients treated with I-125 brachytherapy, with a follow-up longer than 24 months, were included in this retrospective study.
MATERIALS AND METHODS ● SETTING AND DESIGN: This was an institutional, retrospective, nonrandomized, interventional case series. Patients were recruited from those referred to the Ophthalmic Oncology units of both the G.B. Bietti Foundation and the Department of Ophthalmology of the University of Padova. Treated patients were retrospectively recruited from those previously included in a pilot prospective study on safety of intravitreal triamcinolone acetonide and intravitreal bevacizumab in the management of exudative retinal detachment secondary to posterior uveal melanoma.
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● INTERVENTION:
Treated patients received 1 intravitreal triamcinolone acetonide injection at plaque removal (32 eyes) or a loading phase of 3 intravitreal bevacizumab injections (32 eyes), performed at 4-week intervals (the first intravitreal bevacizumab injection was performed during plaque removal). Thirty-two patients served as controls. All groups were matched for age, sex, initial tumor thickness and largest basal diameter, largest exudative retinal detachment basal diameter, tumor location, and Bruch membrane rupture. OF
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TABLE 2. Uveal Melanoma–Related Exudative Retinal Detachment: Treatment Outcome and Follow-up
N Mean injections/group Exudative retinal detachment: marked regression, n (%) Exudative retinal detachment regression time (mo) Follow-up (mo)
Intravitreal Triamcinolone Acetonide Group
Intravitreal Bevacizumab Group
Observation Group
All Groups
32 1.9 (range 1–3)
32 3.7 (range 3–5)
32 NA
96 2.9a (range 1–5)
22 (69%)
11 (34%)
4.5 ⫾ 2.4 39 ⫾ 8 (range 24–55)
7.9 ⫾ 2.7 35 ⫾ 6 (range 24–53)
9 (28%) 11.2 ⫾ 3.5 36 ⫾ 6 (range 24–53)
42 (44%) 6.8 ⫾ 3.9 37 ⫾ 7 (range 24–55)
mo ⫽ month; NA ⫽ not applicable. Excluding observation group.
a
Clinical and demographic characteristics related to different treatment groups are reported in Table 1. Cortico-responder patients were preliminarily excluded by the intravitreal triamcinolone acetonide group on the basis of a preoperative test.11 ● INTRAVITREAL INJECTION: Sterile technique was used to prepare 4.0 mg/0.1 mL of triamcinolone acetonide from a single-use vial of 40 mg (Kenalog; Bristol-MyersSquibb, Princeton, New Jersey, USA), immediately before the injection procedure.12 Bevacizumab injections (1.25 mg/0.05 mL) were prepared in sterile conditions by the hospital pharmacy from a single-use vial of 100 mg (Avastin; Genentech, Cambridge, Massachusetts, USA).13 Solutions were injected using a 27-gauge (intravitreal triamcinolone acetonide) or 30-gauge (intravitreal bevacizumab) needle via standard pars plana approach (3.5– 4.0 mm posterior to the limbus), avoiding retinal quadrants occupied by tumor and/or exudative retinal detachment. Injection was performed at the time of I-125 plaque removal. The injection site was recorded. Fundus was observed for side effects immediately after injection using indirect ophthalmoscopy. Anterior chamber paracentesis was never performed. Patients underwent postoperative examination 1 and 7 days after injection.12,13 ● RETREATMENT:
Retreatment criteria were: (1) no or partial response after first injection (intravitreal triamcinolone acetonide) or loading phase (intravitreal bevacizumab); and (2) partial response after subsequent injections. Retreatment was performed at 3-month intervals. Treatment failure was finally managed by observation alone. Laser photocoagulation was employed to treat reattached ischemic retina in each patient having any response to treatment (partial or marked), or spontaneous resolution (partial or marked) in the observation group.
● MAIN OUTCOME MEASURE: No response was defined as exudative retinal detachment largest basal diameter reduc-
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FIGURE 1. Kaplan–Meier analysis of uveal melanoma–related exudative retinal detachment resolution after intravitreal adjuvant treatment: intravitreal triamcinolone acetonide group vs intravitreal bevacizumab group vs observational group.
tion of less than 20%. Partial response was defined as exudative retinal detachment largest basal diameter reduction between 20% and 80%. Marked response was defined as exudative retinal detachment largest basal diameter reduction of more than 80%. Treatment failure was defined as absence of marked response at the end of treatment. Steroid-induced increased IOP was defined as an IOP elevation to 24 mm Hg or higher.11 Steroid-induced cataract was assessed by slit-lamp examination after dilation of the pupil compared with baseline recorded data. ● FOLLOW-UP: Follow-up examinations were performed every month for the first 6 months and every 3 months thereafter. Each examination included complete ophthalmologic evaluation, A- and B-scan ultrasonography, and IOP measurement. Sites of injections underwent regular slit-lamp examination and photographic follow-up. Liver enzyme analysis and ultrasonography were performed at 6-month intervals. ● DATA ANALYSIS: Statistical analyses (ANOVA, Kaplan-Meier, 2 test, independent-samples t test) were
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FIGURE 2. Uveal melanoma with extensive exudative retinal detachment. (Top) Pretreatment B-scan ultrasonography of 4 cases in the intravitreal triamcinolone acetonide group. (Bottom) B-scan ultrasonography of same patients at 12 months follow-up showing resolution of exudative retinal detachment. Note the intravitreal drug persistence (*) after intravitreal triamcinolone acetonide injection.
TABLE 3. Uveal Melanoma–Related Exudative Retinal Detachment: Clinical and Demographic Characteristics Related to Treatment Outcome
# Age (y), median (mean, range) Sex Male Female Tumor location Choroid Ciliary body Baseline tumor dimensions Thickness (mm), median (mean, range) Largest basal diameter (mm), median (mean, range) Baseline exudative retinal detachment dimension Largest basal diameter (mm), median (mean, range) Bruch membrane rupture a
Exudative Retinal Detachment Marked Regression
Exudative Retinal Detachment Persistence
44 56 (57, 33–84)
52 57 (57, 30–86)
20 (21%) 24 (25%)
26 (27%) 26 (27%)
P Value
.74a .65b
.75b 35 (36%) 9 (9%)
40 (42%) 12 (12%)
6.8 (6.8, 4.2–10) 13.5 (13.5, 7.8–18)
6.4 (6.4, 4.2–10) 13.0 (13.5, 7.6–18)
.25a .32a
15.2 (15.4, 10–21) 18 (19%)
15.0 (15.2, 10–20) 23 (24%)
.38a .74b
Independent-samples t test. test.
b 2
Forty-six patients were male (46%) and 50 female (54%). The right eye was affected in 58 patients (60%) and the left eye in 38 (40%). Seventy-five melanomas were purely choroidal in location (78%), whereas 21 eyes were affected by ciliary body tumors (22%). Mean tumor largest basal diameter was 13.3 ⫾ 3.4 mm (range, 7.6 –18 mm) and mean tumor thickness was 6.6 ⫾ 1.9 mm (range, 4 –10 mm). Mean exudative retinal detachment largest basal diameter was 15.1 ⫾ 3.5 mm (range, 10 –21 mm). The
performed by SAS v.8.2 statistical package (SAS Institute, Cary, North Carolina, USA). A value of P ⬍ .05 was considered statistically significant.
RESULTS NINETY-SIX PATIENTS (MEAN AGE, 56 ⫾ 15 YEARS; RANGE,
30 – 86 years) were included in this retrospective study. 130
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rupture of Bruch membrane was present in 41 patients (43%). Mean dose rate and mean dose at tumor apex were not statistically different in the 3 groups (P ⬎ .05) (Table 1). A mean of 3.7 (range, 3–5) intravitreal injections were performed in the intravitreal bevacizumab group vs 1.9 (range, 1–3) in the intravitreal triamcinolone acetonide group. No local or systemic complications were observed during surgical procedure. Mean follow-up was 37 ⫾ 7 months (range, 24 –55 months). Marked exudative retinal detachment regression was documented in 22 of 32 intravitreal triamcinolone acetonide–treated patients (69%) vs 11 of 32 intravitreal bevacizumab–treated patients (34%) and 9 of 32 control patients (28%) (observation group) (Table 2). Of these, regression was complete (absence of any ultrasonographic evidence of exudative retinal detachment) in 18 intravitreal triamcinolone acetonide–treated patients (82%) vs 10 intravitreal bevacizumab–treated patients (91%) and 7 control patients (78%) (observation group). Exudative retinal detachment marked regression was observed 4.5 ⫾ 2.4, 7.9 ⫾ 2.7, and 11.2 ⫾ 3.5 months after brachytherapy, respectively. Statistical analysis showed significant difference between exudative retinal detachment marked regression in the intravitreal triamcinolone acetonide group vs intravitreal bevacizumab and observation groups (P ⫽ .0007 and P ⫽ .0001, respectively) (Figures 1 and 2). No statistical significance was found between the intravitreal bevacizumab group vs observation group (P ⫽ .4501) (Figures 1 and 2). No statistically significant difference was observed between tumors showing exudative retinal detachment regression or persistence vs patient age, sex, tumor location, exudative retinal detachment largest basal diameter, and presence of Bruch membrane rupture (Table 3). Steroid-induced cataract was observed in 4 of 32 intravitreal triamcinolone acetonide–treated patients (12%). Neither steroid-induced increased intraocular pressure nor other short- or longterm side effects were documented. Seven of 96 patients (7.3%) developed neovascular glaucoma (18 ⫾ 3.9 months after brachytherapy). Of these, 3 were in the observation group (43%), 3 were in the intravitreal bevacizumab group (43%), and 1 was in the intravitreal triamcinolone acetonide group (14%) (P ⬎ .05). Eleven of 96 patients developed metastatic disease (11.5%) within an interval of 27 ⫾ 5.7 months after brachytherapy. Of these, 4 were in the observation group (36%), 3 were in the intravitreal bevacizumab group (27%), and 4 were in the intravitreal triamcinolone acetonide group (36%) (P ⬎ .05). Neither local recurrence nor extrascleral/orbital extension was documented during follow-up.
DISCUSSION INCREASED INTRATUMOR CAPILLARY PERMEABILITY, IN-
tratumor inflammation, and necrosis are often present in uveal melanoma, as well as in most solid tumors.14 AssumVOL. 155, NO. 1
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ing a role of VEGF and/or other proinflammatory cytokines in the pathogenesis of uveal melanoma–related exudative retinal detachment, these factors significantly increase after conservative radiation treatment because of radiation effect on tumor cells.14 “Senescence” is the term used to describe a condition of permanent cell-cycle arrest.14 Senescence has been reported to occur in tumor cells in vitro and in experimental tumors in vivo following extensive cellular stress induced by a number of DNA-damaging agents, mainly irradiation.15–17 Clinical evidence of prolonged cytostatic arrest following radiotherapy also indicate senescence as a major mechanism for solid tumor regression.18 Senescent cells acquire extensive alterations in gene expression, including inhibition of genes involved in cell proliferation, homeostasis, and intercellular communication.19 Thus, senescent cells do not divide, but may remain alive and metabolically active for several months.14 Senescent cells have been shown to overexpress and secrete many factors, including a number of cytokines allowing communication between senescent cells and their microenvironment.19 –21 These communications have been reported to induce an intense and prolonged inflammatory response, to increase tumor capillary permeability, and to promote angiogenesis. 9,19 –23 Corticosteroids play a relevant role in many irradiation protocols of different solid tumors.24,25 Corticosteroids are believed to exert their influence on tumors and surrounding tissue by reducing the tumor-associated vasogenic edema, decreasing the pathologically increased tumor capillary permeability, and reducing intratumor inflammation and necrosis.24,25 Anti-VEGF is a potent antiangiogenic monoclonal antibody with different biologic effects, including inhibition of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine regeneration.26 VEGF is both a vascular growth factor and a vascular permeability factor, overexpressed in most solid tumors as well as in uveal melanoma.27 To the best of our knowledge, there are no data on corticosteroids and few data on anti-VEGF’s role in the treatment of uveal melanoma–associated exudative retinal detachment. Newman and associates described, in a pilot study, that systemic bevacizumab was associated with resolution of choroidal melanoma–related exudative retinal detachment as well as transient systemic side effects.28 Conversely, in our study we found no significant bevacizumab efficacy vs observation in the management of extensive exudative retinal detachment secondary to posterior uveal melanoma. This may be explained by different administration method, dosage, and timing (intravenous bevacizumab 10 mg/kg every 2 weeks for 3 or 4 cycles vs intravitreal bevacizumab 1.25 mg/0.05 mL for at least 3 times). Nevertheless, considering the possible related side effects of systemically administered bevacizumab, the intravitreal approach should be preferred. Another possible explanation for the lack of efficacy of the intravitreal bevacizumab– based approach is the use of a modified protocol based on the standard protocol for neovas-
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cular age-related macular degeneration. The decision to use this regimen for uveal melanoma–related exudative retinal detachment appeared reasonable based on the beneficial response observed in most patients with neovascular agerelated macular degeneration.29 However, for uveal melanoma patients who did not respond favorably to a loading phase, it is questionable whether more frequent injections (or prolonged treatment period) may have a long-term beneficial effect. Moreover, looking at the average number of injections in the intravitreal bevacizumab group (3.7 injections/patient), mainly paired to current age-related macular degeneration protocols, we cannot exclude that this treatment may be underdosed in the long-term period, which may explain the lack of statistically significant difference from the observation arm. Nevertheless, the lack of response after 3 intravitreal injections of bevacizumab should raise relevant questions about the efficacy of the intravitreal bevacizumab– based approach. An alternative strategy that should be considered may be to increase the bevacizumab intravitreal dose.29 Retrospective analysis is a relatively common practice in the oncology literature; nevertheless, the possible biases of our study are the retrospective design itself, the lack of consecutive enrollment, and the possible selection bias in the construction of the current cohort. However, our data demonstrate that early intravitreal triamcinolone acetonide injection significantly induces earlier and marked exudative retinal detachment resolution after brachytherapy compared with intravitreal bevacizumab or no treatment. We have considered as the “main result” the concept of marked regression (instead of complete regression), because minimal residual serous retinal detachment is relatively common in uveal melanoma, mainly in large tumors with Bruch membrane rupture, and is attributable to direct retinal traction by the tumor. Moreover, when minimal residual serous retinal detachment is present, it is possible to treat reattached retina with laser photocoagulation, preventing long-term side effects related to retinal ischemia. Intravitreal triamcinolone acetonide efficacy may be attributable to the higher anti-inflammatory activity of this drug compared with bevacizumab in the post-RT intraocular tumor microenvironment, suggesting a major role of post-RT tumor inflammation in the pathogenesis of exudative retinal detachment (“senescence syndrome”).12,19 Moreover, it is well known that corticosteroids also have a direct antiangiogenic effect.30 Recently, McAllister and associates reported that intravitreal triamcinolone acetonide directly downregulates VEGF expression.30 This effect may also contribute to the intravitreal triamcinolone acetonide efficacy in reducing uveal melanoma–related exudative retinal detachment. Nevertheless, considering the lack of efficacy of intravitreal bevacizumab, an approach operating in the antiangiogenic pathway alone may be partial and insufficient. 132
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There are few reports on the treatment of postradiation persistent exudative retinal detachment in uveal melanoma. Char and associates reported 11 patients treated by adjuvant post–RT laser–induced tumor hyperthermia, concluding that combined laser-induced hyperthermia and proton irradiation may dissipate exudative retinal detachment more rapidly than irradiation alone.31 The rationale of this modality is to close leaking superficial tumor vessels. Nevertheless, laser-induced hyperthermia is not suitable for uveal melanoma with overlying extensive exudative retinal detachment. Gibran and Kapoor recently reported that timely vitreoretinal surgical intervention for exudative retinal detachments associated with choroidal melanomas may result in significant restoration of vision. Although this technique should be considered as a promising approach, only 6 patients were included in this preliminary report.32 Other proposed modalities, aimed at removing metabolically active tumor cells (the so-called “toxic tumor syndrome”), are ab externo and ab interno tumor resections.33 While ab externo tumor resection is more applicable to anteriorly located tumors with ciliary body and/or iris involvement, endoresection is more suitable for posteriorly located lesions without ciliary body involvement. However, both types of tumor resections are challenging surgical procedures, bearing the risk of early and late intraoperative and postoperative local and systemic complications.33 Conversely, our reported approach is surgically simple and cost-effective. Moreover, we have performed the injection procedure immediately after brachytherapy, avoiding both managing eyes with vital tumor cells and the risk of induce pharmacologic effects on tumor cells during the irradiation period. The lack of steroid-induced increased intraocular pressure after intravitreal triamcinolone acetonide may be explained by the preliminary exclusion of cortico-responder patients.11 Moreover, a second explanation of the lack of increased intraocular pressure in our cohort of patients is the peculiar pathophysiology of eyes with large uveal melanoma: in these eyes intraocular pressure is often low (this was considered a minor diagnostic criterion for uveal melanoma in the past), mainly in large lesions with large serous retinal detachment. The major side effect of intravitreal triamcinolone acetonide is steroid-induced cataract. Visual acuity was not an endpoint in this study because of tumors and exudative retinal detachment dimensions (radiation retinopathy, maculopathy, and optic neuropathy are often present after treatment in these lesions). Nevertheless, before starting treating patients with small or medium tumors and limited exudative retinal detachment, risk and benefit should be balanced vs steroid-induced cataract. In conclusion, intraoperative intravitreal triamcinolone acetonide injection induces earlier and marked exudative retinal detachment resolution after brachytherapy in large uveal melanoma with extensive exudative retinal detachment compared with intravitreal bevacizumab or observation groups, causing limited local and no systemic side effects. OF
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ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF Interest and none were reported. The authors indicate no funding support. Involved in design and conduct of the study (R.P., E.M.); collection, management, analysis, and interpretation of the data (R.P., E.P., A.D., G.M., E.M.); and preparation, review, or approval of the manuscript (R.P., E.P., A.D., G.M., E.M.). Informed consent for both the treatment and participation in the research for this prospective study (Study N.: 1302P, Regione del Veneto, Azienda Ospedaliera di Padova, Struttura Interaziendale Marketing e Sviluppo) was approved by the institutional review board (Prot. N. 65819, November 23, 2006). Informed consent for both the treatment and participation in the research was obtained from each patient and the research was conduced according to the provisions of the Declaration of Helsinki, 1995 (as revised in Edinburgh, 2000).
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Biosketch Edoardo Midena was born in Venice, Italy. He graduated in Medicine and Surgery, and received his PhD from the University of Padova, Italy. He is a Full Professor of Ophthalmology at the University of Padova, and Chairman of the Department of Ophthalmology, Padova University Hospital. He is member of the scientific board of the GB Bietti Foundation, IRCCS (Roma, Italy). He has published more than 300 contributes. His primary research interests are ocular oncology and chorioretinal diseases.
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Biosketch Raffaele Parrozzani was born in 1980, in Montebelluna, Italy. He graduated in Medicine and Surgery (2005) and received his degree in Ophthalmology (2010) from the University of Padova. In 2010 he started the fellowships in General and Surgical Oncology. He actually works for the G.B Bietti Eye Foundation, IRCCS, in the Ocular Oncology Center and in the Multidisciplinary Center for Ocular and Orbital Disorders, Padova, Italy. His primary research interests are ocular oncology and toxicology.
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