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Long-term outcomes of eye-conserving treatment with Ruthenium106 brachytherapy for choroidal melanoma
Radiotherapy and Oncology 95 (2010) 332–338
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Choroidal melanoma
Long-term outcomes of eye-conserving treatment with Ruthenium106 brachytherapy for choroidal melanoma q Karijn M.S. Verschueren a,1, Carien L. Creutzberg a,*, Nicoline E. Schalij-Delfos b, Martijn Ketelaars a, Floor L.L. Klijsen b, Barbara I. Haeseker b, Sabine M.B. Ligtenberg b, Jan E.E. Keunen c, Corrie A.M. Marijnen a a
Department of Radiation Oncology; and b Department of Ophtalmology, Leiden University Medical Center, Leiden, The Netherlands; c Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
a r t i c l e
i n f o
Article history: Received 24 April 2009 Received in revised form 15 January 2010 Accepted 14 March 2010 Available online 21 April 2010 Keywords: Choroidal melanoma Eye-conserving treatment Brachytherapy Ruthenium-106 plaque brachytherapy Prognostic factors
a b s t r a c t Purpose: To evaluate long-term outcomes of eye-conserving treatment using Ruthenium-106 plaque brachytherapy with or without transpupillary thermotherapy (TTT) for small to intermediate size choroidal melanomas. Methods: Outcomes of 425 consecutive patients were analysed. The median basal tumour diameter was 10.9 mm (range 4.8–15.9 mm), and the median apical height 4.2 mm (range 1.2–9.3 mm). Brachytherapy doses ranged from 400 to 600 Gy with TTT (86%), or from 600 to 800 Gy without TTT (14%), specified at the scleral surface. Kaplan–Meier survival curves, log-rank tests and Cox regression analysis were used for analysis. Results: Median follow-up was 50 months. Five-year actuarial local control was 96%. Five-year overall and metastases-free survival rates were 79.6% and 76.5%. Prognostic factors for metastasis-free survival were peripheral location (p = 0.02) and smaller basal diameter (p < 0.001). No dose effect relationships were found. Radiation side effects were frequent, with 2- and 5-year rates free of radiation complications of 60% and 35%. Five-year enucleation rate was 4.4% (10 for local recurrence, 7 for complications). Cosmetic and functional (visual acuity >0.10) eye preservation rates were 96% and 52% at 5 years. Conclusions: Ruthenium-106 brachytherapy for choroidal melanoma provides excellent rates of local control and eye preservation. Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 95 (2010) 332–338
Choroidal melanoma is the most common primary eye cancer in adults. Until the introduction of plaque brachytherapy in the 1960s, enucleation was standard treatment. From that time on, various eye-conserving treatment modalities such as Ruthenium106 (Ru-106) or Iodine-125 plaque brachytherapy, proton beam radiotherapy, stereotactic radiotherapy, transscleral or transretinal local resection, and phototherapy (photocoagulation or transpupillary thermotherapy, TTT) have been developed with the aim of preserving useful vision without increasing the risk of metastatic spread [1]. Several studies have demonstrated that eye-conserving treatment with plaque brachytherapy does not increase the risk of distant metastases [2,3]. The Collaborative Ocular Melanoma Study (COMS) confirmed the efficacy of plaque brachytherapy in a multi-
q Presented in part at ECCO, the 14th European Cancer Conference, Barcelona, Spain, September 23–27, 2007. * Corresponding author. Address: Department of Clinical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: [email protected] (C.L. Creutzberg). 1 Present address: Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.03.023
center randomised trial including 1317 patients, which did not show any difference between enucleation and I-125 brachytherapy in 5-year survival (81% vs. 82 %) or 5-year rates of death with melanoma metastases (11% vs. 9%) [4]. Although the most important treatment aim for patients with choroidal melanoma is survival free of disease recurrence, both patients and physicians focus on the preservation of useful vision, cosmetic appearance and quality of life as well. Since its introduction, Ru-106 brachytherapy has been increasingly used for treatment of small to medium sized choroidal melanomas [5–7]. Although the benefit of eye preservation may be reduced by impaired vision resulting from radiation toxicity, eye conservation has major functional and cosmetic advantages. Previously, our group has reported outcome data after Ru-106 brachytherapy for choroidal melanoma [8,9], as well as results of the combination of brachytherapy and transpupillary thermotherapy (TTT) [10,11]. This combination therapy (so-called sandwich therapy) was initiated to use lower radiation doses for smaller tumours to reduce the risk of severe radiation toxicities, and on the other hand enable eye-conserving treatment for patients with tumours thicker than 5 mm. Moreover, patients with insufficient tu-
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mour regression after brachytherapy or with tumour recurrence can be retreated with TTT alone. The aims of the present analysis were to determine long-term outcomes of Ru-106 brachytherapy for intermediate size choroidal melanomas in a large series of patients treated in a single referral centre, focusing on tumour control, survival, visual acuity and complications, to identify prognostic factors and to determine if dose–effect relationships could be demonstrated. Specifically, outcomes using Ru-106 brachytherapy with and without TTT were evaluated.
Table 1 Treatment protocols. Period
Tumour prominence (mm)
Dose (Gy)
TTT
N
1993–1997
<3 3–5 >5
600 600 800
No Yes Yes
24 37 12
Total 1997-onwards Central tumours
Materials and methods
Peripheral tumours
Patients and data collection
Total
The records of all 430 consecutive patients who were treated for choroidal melanoma with Ru-06 brachytherapy at Leiden University Medical Center (LUMC) between January 1993 and December 2004 were analysed. Patients treated with Ru-106 brachytherapy for iris and ciliary body melanoma were excluded, as these have been analysed and reported separately. The diagnosis of choroidal melanoma was based on opthalmoscopic and ultrasonographic findings and fluorescein angiography. Patients were eligible for Ru-106 brachytherapy if they had a small or intermediate size melanoma (basal diameter up to 16 mm and tumour prominence up to 8 mm; one exception involved a tumour prominence of 9.3 mm). At time of diagnosis, all patients were evaluated by liver ultrasonography, chest radiography and routine blood tests. Follow-up examinations, conducted 1 month after treatment and at 3- to 6-month intervals, included opthalmoscopy, ultrasonography and, if necessary, fundus photography and visual field examination. Visual acuity was assessed by projection of Snellen characters at a distance of 5 m. Patients were followed in LUMC until 3–5 years after treatment, and by their local ophthalmologist thereafter. Applicators Ru-106 applicators manufactured by Bebig (Eckert & Ziegler BEBIG GmbH, Berlin, Germany) were used. The three applicators most frequently used have diameters of 15.3, 17.9 and 20.2 mm with active diameters of 13.5, 15.8 and 18 mm, respectively (CCA, CCD, CCB). Applicators for treatment of juxtapapillary tumours (tumours located immediately adjacent to the optic nerve), have a section cut out for the optic nerve (COB, CIB). Due to the rapid dose fall-off of Ru-106, 80% of the dose has already been absorbed at 5 mm from the applicator. The distribution of Ru-106 is not completely uniform over the applicator surface, with dose variations of 5–10%. In the past, dose calibration has been hampered by lack of an international dose reference. Since early 2002 Bebig has adopted a more extensive calibration protocol proposed by the National Institute of Standards and Technology (http://www.bebig.de/downloads/augen_ info_dosimetrie_eng.pdf) [12]. In our analysis all doses reported from treatments before 2002 have been recalculated according to this calibration protocol. Treatment Patients were treated according to two different protocols, as shown in Table 1. Before 1997 a protocol was used combining Ru-106 brachytherapy with TTT for tumours with prominence >3 mm. From 1997 onwards, the brachytherapy dose was reduced to 400–600 Gy for combined brachytherapy and TTT. Peripheral tumours, for which TTT could not be used, were treated with doses of 600–800 Gy. The brachytherapy dose was prescribed at the scleral surface and standardized to a dose rate of 100 Gy per 24 h, by cor-
73
400 600 600 800
65 >5 63 >3
Yes Yes No No
229 88 12 23 352
recting the prescribed dose by a factor equal to (standard dose rate/ actual dose rate)0.2, adapted from Ellis [13]. In practice, this resulted in a dose correction of 2–10% (maximum 13%). Dose specification at the scleral surface (as opposed to the tumour apex) has Table 2 Patient and treatment characteristics. Characteristic
N
%
Sex Male Female
205 220
48.2 51.8
Age (years) <50 50–70 P70
87 207 131
20.5 48.7 30.8
Eye involved Left Right
208 217
48.9 51.1
Visual acuity 60.1 0.11–0.32 0.33–0.5 0.51–0.8 >0.8
34 52 79 134 126
8.0 12.2 18.6 31.5 29.6
Pigmentation Melanotic Amelanotic Partly amelanotic
340 76 9
80 17.9 2.1
Proximity to optical nerve Central/juxtapap Peripheral
248 177
58.4 41.6
Basal diameter <8 mm 8–11.49 mm 11.5–14.99 mm P15 mm
37 214 164 10
8.7 50.4 38.6 2.4
Tumour height 63 mm 3.01–5 mm >5 mm
84 203 138
19.8 47.8 32.5
Dose to apex 6100 Gy 100.01–150 Gy 150.01–200 Gy >200 Gy
98 130 87 110
23.1 30.6 20.5 25.9
Dose to sclera 6400 Gy 400.01–600 Gy >600 Gy
124 202 99
29.2 47.5 23.3
TTT used No Yes
59 366
13.9 86.1
TTT = transpupillary thermotherapy.
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Brachytherapy for choroidal melanoma
traditionally been used in our centre. This was considered more accurate since the dose distribution is more homogeneous close to the surface of the Ruthenium applicator, and because measurements of tumour prominence with ultrasonography have a high inter-observer variation. To evaluate and compare these two methods of dose specification, the dose at the tumour apex was calculated as well. The apex was defined as the tumour prominence including the sclera, as measured during ultrasonography. TTT was generally applied 2 months after brachytherapy, and was given using an infrared diode laser, with power ranging from 500 to 1000 mW. In case of incomplete tumour regression, TTT was repeated after 6 months. Outcome measures Vital status of all patients was known from hospital records and oncological registration. Tumour response was evaluated by fundoscopy and ultrasonography, with a flat scar, or a regressed lesion not showing any signs of tumour activity representing tumour control. Local recurrence was defined as insufficient tumour regression with signs of tumour activity on fluorescein angiography, or documented tumour growth. Metastases were detected by routine follow-up investigations (liver ultrasonography and blood chemistry tests) or by evaluation of symptomatic patients. Complications such as retinopathy, maculopathy, optic neuropathy, retinal haemorrhage and exudative retinal detachment were evaluated at each follow-up. For this analysis we focused on the late radiation-induced complications retinopathy, opticopathy and maculopathy. Vision was determined using WHO criteria, with low vision defined as visual acuity less than 1/3, whereas a vision <0.10 equals legal blindness.
TTT or enucleation were used to treat insufficient regression or recurrence. In some cases enucleation was performed for ocular complications. After enucleation, patients were followed for metastases and survival. Statistical methods All outcome analyses were based on data computerized by March 27, 2006. The results were analysed with SPSS software (version 12, SPSS Inc, Chicago, Il). Kaplan–Meier survival curves were used to analyse survival, tumour recurrence, metastases, visual acuity, risk of enucleation and complications as a function of time. Follow-up time was calculated from first day of brachytherapy to date of last information on vital status. Time intervals to death and to local recurrence or metastases were calculated from the first day of brachytherapy to the date of death or diagnosis of recurrence, with censoring at date of last contact. The relationships of these outcomes and independent variables were evaluated using log-rank tests. Statistical significance was defined as a two-sided p-value of less than 0.05. For multivariate analyses, variables with a p-value of 60.10 were entered into Cox regression analyses, and eliminated with a backward-stepwise procedure. Results Patient and treatment characteristics Between January 1993 and December 2004, 430 patients with choroidal melanoma were treated with Ru-106 plaque brachytherapy. Five patients were lost to follow-up, leaving 425 patients in
Local recurrence
Distant metastases
0.5
0.5
0.4
0.4
Number
Number
Events
424
0.3
423
Events 5-yr DM 51
16.6%
5-yr LR
16
3.9%
0.3
0.2
0.2
0.1
0.1
0.0
0.0 0
20
40
60
80
100
120
153
81
34
1
100
120
time in months
20
40
60
236
150
80
time in months
100
120
34
1
No at risk:
No at risk: N = 424
0
355
237
N = 423
358
83
Overall survival 1.0 0.8 0.6 0.4 Number Events
0.2
424
77
5-yr OS 79.6%
0.0 0
20
No at risk: N = 424
363
40
60
243
156
80
time in months
84
35
1
Fig. 1. Kaplan–Meier estimates of local recurrence, metastases and overall survival. LR = local recurrence; DM = distant metastases; OS = overall survival.
K.M.S. Verschueren et al. / Radiotherapy and Oncology 95 (2010) 332–338
the analysis. The median follow-up was 50 months (range 6– 125 months) for patients alive. Patient demographics, tumour and treatment characteristics are summarized in Table 2. The median age was 63 years (range 17– 90). The initial visual acuity in the affected eye was >0.10 in 92% of patients, P0.33 in 80%, and >0.50 in 61%. The median basal tumour diameter was 10.9 mm (range 4.8–15.9 mm), and the median apical height was 4.2 mm (range 1.2–9.3 mm). TTT was used in the treatment of 86% of the patients; 14% were treated without TTT. Local control, distant metastases and survival Local recurrences were diagnosed in 16 patients. The median time to local failure was 17.5 months (range 6.9–87.5 months). The actuarial 5-year local recurrence rate was 3.9% (95% CI 2.1– 5.7%). See Fig. 1. All patients with a local recurrence had received TTT within protocol. Patients who had a local recurrence had significantly more often a centrally or juxtapapillary located tumour, a lower visual acuity before treatment and a larger basal diameter (Table 3). Among the 25 patients with true juxtapapillary tumour location, four (16.0%) had a local recurrence. Treatment for local recurrence consisted of additional TTT (n = 6) or enucleation (n = 10). Among the six patients treated with additional TTT, five had one extra TTT session, and one had three
Table 3 Local recurrence rates by tumour and treatment characteristics. Characteristic
Age (years) <50 50–70 P70
Local recurrence
No local recurrence
N
%
N
%
1 9 6
1.1 4.3 4.6
86 198 125
98.9 95.7 95.4
p
335
extra TTT sessions. Among the 10 patients treated with enucleation, seven had direct surgery for recurrence. One patient had two extra TTT sessions and two had three extra TTT sessions for insufficient regression after first treatment, and subsequently underwent enucleation for documented tumour growth. Six (37.5%) patients with local recurrence died, five of whom with known distant metastases. In one patient distant metastases were diagnosed more or less synchronously with local recurrence (within 2 months), whereas four patients developed metastases 9– 29 months after local recurrence. Distant metastases were diagnosed in 51 patients. The median time to metastases was 30.4 months (range 0–68.4 months). Actuarial metastases-free survival rates were 76.5% at 5 years and 69.1% at 10 years. A total of 77 patients died, 46 with distant metastases and 29 from intercurrent diseases. In two patients (without known metastases) the cause of death was unknown. Actuarial overall survival rates were 79.6% at 5 years and 68.2% at 10 years (Fig. 1).
Complications During the course of time, 234 patients developed ocular complications, resulting in a 2-year actuarial survival rate free from complications of 49.7%, and 5-year rate of 27.8%. 194 of these 234 patients had radiation complications such as retinopathy (n = 56), maculopathy (n = 65), or opticopathy (n = 7), and combinations of these (n = 66). Forty patients had various other complications, such as vitreous haemorrhage or retinal detachment. The actuarial rates free of radiation complications were 60.0% at 2 years and 35.0% at 5 years.
0.25
Visual acuity <0.1 0.11–0.32 0.33–0.5 0.51–0.8 >0.8
1 1 10 3 1
2.9 1.9 12.7 2.2 0.8
33 51 69 131 125
97.1 98.1 87.3 97.8 99.2
Proximity to optical nerve Central/juxtapap Peripheral
16 0
6.5 0
232 177
93.5 100
Basal diameter <8 mm 8–11.5 mm 11.5–15 mm >15 mm
0 6 9 1
0 2.8 5.5 10
37 208 155 9
100 97.2 94.5 90.0
Tumour height <3 mm 3–5 mm >5 mm
2 7 7
2.4 3.4 5.1
82 196 131
97.6 96.6 94.9
Dose to apex <100 Gy 100–150 Gy 150–200 Gy >200 Gy
4 9 1 2
4.1 6.9 1.1 1.8
94 121 86 108
95.9 93.1 98.9 98.2
Dose to sclera <400 Gy 400–600 Gy >600 Gy
5 9 2
4.0 4.5 2.0
119 193 97
96.0 95.5 98.0
TTT used No Yes
0 16
0 4.4
59 350
100 95.6
Treatment date 1993–1997 1997–onwards
2 14
2.7 4.0
71 338
97.3 96.0
Functional eye preservation
0.03
0.001
Among the 391 patients with a pre-treatment visual acuity greater than 0.10, 147 had a deterioration of visual acuity in the treated eye to <0.10, thus to legal blindness. Patients with centrally or juxtapapillary located tumours had more often a poor vision before treatment, as well as greater deterioration after treatment. Actuarial rates of preserved vision greater than 0.10 were 66.9% at 2 years and 51.9% at 5 years. Actuarial rates of preserved vision of at least 0.33 among patients with initial visual acuity of >0.32 were 55.1% at 2 years and 36.6% at 5 years.
0.04
Cosmetic eye preservation
0.29
0.12
0.48
0.1
0.61
Note: Statistically significant values are indicated in bold.
Seventeen patients eventually underwent enucleation, resulting in a 5-year actuarial enucleation rate of 4.4%. Most enucleations (76%) were performed within the first 2 years after treatment. Ten patients underwent enucleation for local recurrence and seven for complications. Ocular complications necessitating enucleation were vitreous haemorrhage in three patients, serous detachment in two, neovascularisation in one, and combined vitreous haemorrhage and retinal detachment in one patient.
Prognostic factors Univariate and multivariate analyses of prognostic factors for overall survival, distant metastases, functional visual outcome and complications were done. Significant favourable prognostic factors for survival free of distant metastases were peripheral tumour location (p = 0.02) and smaller basal diameter (p < 0.001). The number of local recurrences was too small to perform multivariate analysis. As shown in Table 3, trends towards lower risk of local recurrence were found for peripheral tumour location, better initial visual acuity and smaller basal diameter.
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Brachytherapy for choroidal melanoma
Results for visual outcome are shown in Table 4. Significant favourable prognostic factors for preserved visual acuity of 0.33 or greater were peripheral tumour location (p = 0.02), better initial visual acuity (p < 0.001), and lower apical height (p = 0.04), while dose to sclera or apex did not have prognostic significance. Both lower apical height and better initial visual acuity remained significant when analysed separately for peripherally located tumours, while for central tumours only initial visual acuity was significant. A trend for higher rate of preserved visual acuity >0.32 was found for treatment without TTT (52.1 versus 34.5%, p = 0.06 in univariate analysis). Prognostic factors for risk of radiation complications were younger age (p = 0.03) and use of TTT (p = 0.05), while brachytherapy dose, basal diameter and tumour location were not significantly related to risk of complications (Table 5).
Discussion In this analysis long-term outcomes of Ru-106 brachytherapy with or without TTT were evaluated in a large series of 425 patients with choroidal melanoma. We found excellent local tumour control and eye preservation rates. Five-year actuarial local control and eye preservation were both 96%. These results are comparable to those reported by other groups for small or medium sized tumours. In a series of 270 patients treated with brachytherapy and TTT reported by Shields et al. [14] 5-year local recurrence was 3%, while Damato et al. reported an equally low recurrence rate (2% at 5 and 3% at 7 years) in 458 patients treated with Ru106 brachytherapy, using TTT only in case of uncertain efficacy
[15]. Some authors reported lower 5-year eye preservation rates of 72–82% [7,16,17]. Juxtapapillary choroidal melanomas have inferior outcomes, with lower local control rates (16% recurrence among 25 cases in our series) and higher rates of visual impairment. Sagoo et al. [18] reported 90% local control with I-125 brachytherapy and TTT, but with a 23% enucleation rate; Krema et al. [19] described efficacy of stereotactic radiotherapy with 94% local control, but with significant ocular complications (neovascular glaucoma 42%, cataract 53%, retinopathy 81% and optic neuropathy 64%, and enucleation in 12%). As effective salvage therapies are available, brachytherapy continues to be the preferred treatment option in view of the lower complication rates. Overall and metastases-free survival rates were 79.6% and 76.5%; these rates reflect the fact that this series included patients with small to medium sized melanomas, and again confirm that eye-conserving treatment does not impair survival. Choroidal melanomas are relatively resistant to irradiation, and the brachytherapy doses needed to eradicate these tumours are associated with a substantial risk of radiation damage to the retina and optic nerve. In our analysis the actuarial 2- and 5year rates free of radiation related side effects were 60% and 35%. Especially patients with centrally located tumours experience a gradual decline or loss of visual acuity from retinopathy, maculopathy, opticopathy and other ocular side effects. Radiation induces both an acute transudative and slowly progressive occlusive vasculopathy with neovascularisation and macular oedema, resulting in an deterioration of visual acuity in the affected eye which is ongoing over the years after treatment. In our analysis the probability of retaining visual acuity greater
Table 4 Univariate and multivariate analyses of prognostic factor for visual outcome >0.32 (in patients with initial visual acuity >0.32). Characteristic
N
5-Year rate of vision >0.32
Univariate HR
Age (years) <50 50–70 P70
73 175 91
24.4 42.7 35.5
1 0.7 0.9
Visual acuity 0.33–0.5 0.51–0.8 >0.8
79 134 126
26 31.8 49.9
1 0.5 0.3
Proximity to optical nerve Central/juxtapap Peripheral
184 155
27.5 47.6
1 0.6
Basal diameter <8 mm 8–11.5 mm 11.5–15 mm P15 mm
30 169 133 7
39.2 38.7 32.2 54.6
1 1.3 1.7 1
Tumour height 63 mm 3.01–5 mm >5 mm
74 166 99
40 39.3 32.4
1 1.1 1.7
Dose to apex 6100 Gy 100–150 Gy 150–200 Gy >200 Gy
75 99 69 96
31.1 34.3 29.9 44.4
1 0.8 0.6 0.6
Dose to sclera 6400 Gy 400–600 Gy >600 Gy
104 158 77
38.5 31.3 46.7
1 1.4 1.1
TTT used No Yes
48 291
52.1 34.5
1 1.7
Multivariate 95% CI
p
HR
95% CI
p
0.07 0.5–1.0 0.6–1.3 <0.001
<0.001 1 0.5 0.3
0.3–0.7 0.2–0.4
0.4–0.8 0.2–0.4
0.01
0.02 1 0.7
0.4–0.8
0.5–0.9
0.15 0.7–2.5 0.9–3.3 0.3–3.4 0.02 0.7–1.7 1.1–2.5 0.1 0.5–1.2 0.4–1.0 0.4–0.9 0.09 1.0–2.1 0.7–1.7 0.06
Note: Statistically significant values are indicated in bold.
1.0–2.8
0.04 1 1.1 1.6
0.7–1.7 1.0–2.5
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K.M.S. Verschueren et al. / Radiotherapy and Oncology 95 (2010) 332–338 Table 5 Univariate and multivariate analyses of prognostic factors for radiation complications. Characteristic
N
5-Year rate free of complic.
Univariate HR
Age (years) <50 50–70 P70
87 207 131
28.1 35.9 33.4
1 0.8 0.6
Visual acuity 60.1 0.11–0.32 0.33–0.5 0.51–0.8 >0.8
34 52 79 134 126
38.9 34.4 38.2 36.1 31.4
1 0.8 0.9 1 1.1
248 177
32.0 37.6
1 0.9
37 214 164 10
21.3 36.6 34.4 49.7
1 0.8 0.8 0.5
Tumour height 63 mm 3.01–5 mm >5 mm
84 203 138
26.9 38.9 37.2
1 1 1
Dose to apex 6100 Gy 100–150 Gy 150–200 Gy >200 Gy
98 130 87 110
37.3 41.0 27.2 33.5
1 0.7 1.1 0.9
Dose to sclera 6400 Gy 400–600 Gy >600 Gy
124 202 99
34.1 33.6 36.0
1 1.2 1.1
TTT used No Yes
59 366
41.2 33.4
1 1.6
Proximity to optical nerve Central/juxtapap Peripheral Basal diameter <8 mm 8–11.5 mm 11.5–15 mm P15 mm
Multivariate 95% CI
p
HR
95% CI
0.02 1 0.8 0.6
0.6–1.1 0.4–0.9
p 0.03
0.6–1.1 0.4–0.9
0.63 0.4–1.8 0.5–1.6 0.6–1.8 0.6–1.9 0.58 0.7–1.2 0.61 0.5–1.3 0.5–1.3 0.1–0.6 0.99 0.7–1.4 0.7–1.5 0.16 0.5–1.1 0.7–1.7 0.6–1.4 0.62 0.8–1.6 0.7–1.6 0.05 1.0–2.6
0.05 1 1.6
1.0–2.6
Note: Statistically significant values are indicated in bold.
than 0.1 (not being legally blind) was 52% at 5 years, comparable to other large series [20,21]. It is important to note that visual acuity as reported here is only a measure of central vision of the affected eye. Peripheral visual acuity remains at least partly preserved, which is essential for binocular vision and orientation in space. Some authors have investigated the impact of treatment factors such as total dose and dose rate on visual acuity [21–23]. Increased dose and dose rate (exceeding 90–100 cGy/h) to the macula and optic disc, and small distance of the tumour to these structures, were associated with increased toxicity and poor visual outcome [22,24]. In our analysis, central location of the tumour was a significant prognostic factor for loss of visual acuity, but we could not demonstrate dose–response relationships between dose to the sclera or to the tumour apex and poor visual outcome. Recent data suggest that treatment of radiation retinopathy with intravitreal anti-vascular endothelial growth factors such as bevacizumab (Avastin) may decrease neovascularisation, vascular permeability and retinal edema, resulting in stabilization or improvement of visual acuity [25]. In our centre most patients have been treated with Ru-106 brachytherapy in combination with transpupillary thermotherapy (TTT) [9–11]. With TTT necrosis is induced to a depth of 3 mm. The combined use of TTT and brachytherapy was expected to have additive effects, as with TTT the apex of the tumour is treated up to 3 mm, while with brachytherapy the highest dose is given to the tumour base. Combining both treatments would enable treatment of patients with tumour prominences exceeding 5 mm, which was
traditionally regarded as the maximum height suitable for Ru-106 brachytherapy. Furthermore, it was expected that with lower radiation doses the risk of complications would be reduced. We did, however, not find reduced complication rates, nor better visual outcomes with the use of lower brachytherapy doses in conjunction with TTT. A possible explanation could be that the doses used, ranging from 400 to 800 Gy at the scleral surface, are well above the levels with potential dose–effect relationships. In addition, TTT causes deterioration of visual acuity which occurs immediately after treatment, while the effect of brachytherapy on visual outcome slowly increases over time. A trend for higher rates of preserved visual acuity >0.32 was found for treatment without TTT, but this might be related to the peripheral location of these tumours, where treatment has less impact on central visual acuity. At multivariate analysis, however, the use of TTT was associated with increased rates of radiation related complications. Although this analysis was not done to evaluate the efficacy of TTT used in conjunction with brachytherapy, we could not demonstrate any trend towards increased efficacy. Peripheral tumours (most treated without TTT) had better survival rates and a trend for lower relapse rates. It is, however, not possible to draw definite conclusions as peripheral tumour location is by itself a favourable prognostic factor, and the number of patients treated without TTT was small. It should be noted that the apex doses which resulted from dose prescription at the scleral surface in our patients were relatively high (46% had apex doses exceeding 150 Gy). We could not demonstrate a dose–effect relationship for dose to the scleral surface, nor
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Brachytherapy for choroidal melanoma
for dose to the tumour apex. Most authors [4,5,14–17] have used dose levels of 100–120 Gy specified to the tumour apex, often with a maximum of 1000 Gy to the scleral surface. In our analysis 100 Gy at the tumour apex was also found to be an efficacious dose level, but using combination treatment with TTT, even lower apex doses (<100 Gy) did not result in reduced treatment efficacy. Dose specification at the apex has the advantage of giving lower doses to the sclera and retina in patients with smaller tumours, which might reduce complication rates. Apex doses of 100 Gy and greater are effective. Use of TTT in conjunction with adequate apex doses does not seem to improve outcome; on the contrary, TTT seems to increase the risk of ocular complications and, depending on tumour location, results in an immediate deterioration of vision. Therefore, TTT should be reserved for cases with insufficient apex dose or for salvage treatment in case of insufficient tumour regression or a local recurrence after treatment [15]. For treatment of small to medium sized melanoma, we prefer Ru-106 brachytherapy to other radiation modalities, such as charged particle irradiation or stereotactic radiation. Although these methods seem to be equally effective with regard to the risk of metastases and survival, brachytherapy is associated with fewer and less severe local complications [19,26–28]. For larger melanomas, however, these radiation modalities should be considered as effective eye-conserving treatment alternatives. In conclusion, we have confirmed the efficacy of Ruthenium106 brachytherapy for eye-conserving treatment for patients with choroidal melanoma, with excellent rates of local control and eye preservation. Melanomas up to 16 mm diameter and 8 mm prominence can safely be treated. Dose specification at the tumour apex, with TTT reserved for cases with insufficient apex dose and/or insufficient tumour regression, are preferable to reduce the risk of complications and poor visual outcome. Further research should be directed towards strategies to reduce the progressive effects of radiation retinopathy and use of lower brachytherapy doses.
Reference [1] Damato B. Treatment of primary intraocular melanoma. Expert Rev Anticancer Ther 2006;6:493–506. [2] Augsburger JJ, Gamel JW, Sardi VF, Greenberg RA, Shields JA, Brady LW. Enucleation vs cobalt plaque radiotherapy for malignant melanomas of the choroid and ciliary body. Arch Ophthalmol 1986;104:655–61. [3] Brady LW, Shields JA, Shields CL, Glennon PT, Hernandez JC. Organ preservation: choroidal melanoma treated by brachytherapy techniques. Front Radiat Ther Oncol 1993;27:1–19. [4] Diener-West M, Earle JD, Fine SL, Hawkins BS, Moy CS, Reynolds SM, et al. Randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18. Arch Ophthalmol 2001;119:969–82. [5] Lommatzsch PK, Werschnik C, Schuster E. Long-term follow-up of Ru-106/Rh106 brachytherapy for posterior uveal melanoma. Graefes Arch Clin Exp Ophthalmol 2000;238:129–37. [6] Potter R, Janssen K, Prott FJ, Widder J, Haverkamp U, Busse H, et al. Ruthenium106 eye plaque brachytherapy in the conservative treatment of uveal melanoma: evaluation of 175 patients treated with 150 Gy from 1981–1989. Front Radiat Ther Oncol 1997;30:143–9.
[7] Seregard S, Aft Trampe E, Lax I, Kock E, Lundell G. Results following episcleral ruthenium plaque radiotherapy for posterior uveal melanoma. The Swedish experience. Acta Ophthalmol Scand 1997;75:11–6. [8] Tjho-Heslinga RE, Kakebeeke-Kemme HM, Davelaar J, de Vroomea H, Bleeker JC, Oosterhuis JA, et al. Results of ruthenium irradiation of uveal melanoma. Radiother Oncol 1993;29:33–8. [9] Tjho-Heslinga RE, Davelaar J, Kemme HM, de VH, Oosterhuis JA, Bleeker JC, et al. Results of ruthenium irradiation of uveal melanomas: the Dutch experience. Radiother Oncol 1999;53:133–7. [10] Bartlema YM, Oosterhuis JA, Journee-de Korver JG, Tjho-Heslinga RE, Keunen JE. Combined plaque radiotherapy and transpupillary thermotherapy in choroidal melanoma: 5 years’ experience. Br J Ophthalmol 2003;87: 1370–3. [11] Journee-de Korver JG, Keunen JE. Thermotherapy in the management of choroidal melanoma. Prog Retin Eye Res 2002;21:303–17. [12] Kaulich TW, Zurheide J, Haug T, Budach W, Nusslin F, Bamberg M. On the actual state of industrial quality assurance procedures with regard to (106)Ru ophthalmic plaques. Strahlenther Onkol 2004;180:358–64. [13] Ellis F, Sorensen A. A method of estimating biological effect of combined intracavitary low dose rate radiation with external radiation in carcinoma of the cervix uteri. Radiology 1974;110:681–6. [14] Shields CL, Cater J, Shields JA, Chao A, Krema H, Materin M, et al. Combined plaque radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor control and treatment complications in 270 consecutive patients. Arch Ophthalmol 2002;120:933–40. [15] Damato B, Patel I, Campbell IR, Mayles HM, Errington RD. Local tumor control after 106Ru brachytherapy of choroidal melanoma. Int J Radiat Oncol Biol Phys 2005;63:385–91. [16] Bergman L, Nilsson B, Lundell G, Lundell M, Seregard S. Ruthenium brachytherapy for uveal melanoma, 1979–2003: survival and functional outcomes in the Swedish population. Ophthalmology 2005;112:834–40. [17] Isager P, Ehlers N, Urbak SF, Overgaard J. Visual outcome, local tumour control, and eye preservation after 106Ru/Rh brachytherapy for choroidal melanoma. Acta Oncol 2006;45:285–93. [18] Sagoo MS, Shields CL, Mashayekhi A, Freire J, Emrich J, Reiff J, et al. Plaque radiotherapy for juxtapapillary choroidal melanoma overhanging the optic disc in 141 consecutive patients. Arch Ophthalmol 2008;126:1515–22. [19] Krema H, Somani S, Sahgal A, Xu W, Heydarian M, Payne D, et al. Stereotactic radiotherapy for treatment of juxtapapillary choroidal melanoma: 3-year follow-up. Br J Ophthalmol 2009;93:1172–6. [20] Damato B, Patel I, Campbell IR, Mayles HM, Errington RD. Visual acuity after Ruthenium(106) brachytherapy of choroidal melanomas. Int J Radiat Oncol Biol Phys 2005;63:392–400. [21] Melia BM, Abramson DH, Albert DM, Boldt HC, Earle JD, Hanson WF, et al. Collaborative ocular melanoma study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3 years COMS report no. 16. Ophthalmology 2001;108:348–66. [22] Jensen AW, Petersen IA, Kline RW, Stafford SL, Schomberg PJ, Robertson DM. Radiation complications and tumor control after 125I plaque brachytherapy for ocular melanoma. Int J Radiat Oncol Biol Phys 2005;63:101–08. [23] Summanen P, Immonen I, Kivela T, Tommila P, Heikkonen J, Tarkkanen A. Radiation related complications after ruthenium plaque radiotherapy of uveal melanoma. Br J Ophthalmol 1996;80:732–9. [24] Jones R, Gore E, Mieler W, Murray K, Gillin M, Albano K, Erickson B. Posttreatment visual acuity in patients treated with episcleral plaque therapy for choroidal melanomas: dose and dose rate effects. Int J Radiat Oncol Biol Phys 2002;52:989–95. [25] Finger PT. Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin). Int J Radiat Oncol Biol Phys 2008;70:974–77. [26] Shields JA, Shields CL. Current management of posterior uveal melanoma. Mayo Clin Proc 1993;68:1196–200. [27] Muller K, Nowak PJ, de PC, Marijnissen JP, Paridaens DA, Levendag P, Luyten GP. Effectiveness of fractionated stereotactic radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 2005;63:116–22. [28] Modorati G, Miserocchi E, Galli L, Picozzi P, Rama P. Gamma knife radiosurgery for uveal melanoma: 12 years of experience. Br J Ophthalmol 2009;93: 40–4.
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Choroidal melanoma
Long-term outcomes of eye-conserving treatment with Ruthenium106 brachytherapy for choroidal melanoma q Karijn M.S. Verschueren a,1, Carien L. Creutzberg a,*, Nicoline E. Schalij-Delfos b, Martijn Ketelaars a, Floor L.L. Klijsen b, Barbara I. Haeseker b, Sabine M.B. Ligtenberg b, Jan E.E. Keunen c, Corrie A.M. Marijnen a a
Department of Radiation Oncology; and b Department of Ophtalmology, Leiden University Medical Center, Leiden, The Netherlands; c Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
a r t i c l e
i n f o
Article history: Received 24 April 2009 Received in revised form 15 January 2010 Accepted 14 March 2010 Available online 21 April 2010 Keywords: Choroidal melanoma Eye-conserving treatment Brachytherapy Ruthenium-106 plaque brachytherapy Prognostic factors
a b s t r a c t Purpose: To evaluate long-term outcomes of eye-conserving treatment using Ruthenium-106 plaque brachytherapy with or without transpupillary thermotherapy (TTT) for small to intermediate size choroidal melanomas. Methods: Outcomes of 425 consecutive patients were analysed. The median basal tumour diameter was 10.9 mm (range 4.8–15.9 mm), and the median apical height 4.2 mm (range 1.2–9.3 mm). Brachytherapy doses ranged from 400 to 600 Gy with TTT (86%), or from 600 to 800 Gy without TTT (14%), specified at the scleral surface. Kaplan–Meier survival curves, log-rank tests and Cox regression analysis were used for analysis. Results: Median follow-up was 50 months. Five-year actuarial local control was 96%. Five-year overall and metastases-free survival rates were 79.6% and 76.5%. Prognostic factors for metastasis-free survival were peripheral location (p = 0.02) and smaller basal diameter (p < 0.001). No dose effect relationships were found. Radiation side effects were frequent, with 2- and 5-year rates free of radiation complications of 60% and 35%. Five-year enucleation rate was 4.4% (10 for local recurrence, 7 for complications). Cosmetic and functional (visual acuity >0.10) eye preservation rates were 96% and 52% at 5 years. Conclusions: Ruthenium-106 brachytherapy for choroidal melanoma provides excellent rates of local control and eye preservation. Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 95 (2010) 332–338
Choroidal melanoma is the most common primary eye cancer in adults. Until the introduction of plaque brachytherapy in the 1960s, enucleation was standard treatment. From that time on, various eye-conserving treatment modalities such as Ruthenium106 (Ru-106) or Iodine-125 plaque brachytherapy, proton beam radiotherapy, stereotactic radiotherapy, transscleral or transretinal local resection, and phototherapy (photocoagulation or transpupillary thermotherapy, TTT) have been developed with the aim of preserving useful vision without increasing the risk of metastatic spread [1]. Several studies have demonstrated that eye-conserving treatment with plaque brachytherapy does not increase the risk of distant metastases [2,3]. The Collaborative Ocular Melanoma Study (COMS) confirmed the efficacy of plaque brachytherapy in a multi-
q Presented in part at ECCO, the 14th European Cancer Conference, Barcelona, Spain, September 23–27, 2007. * Corresponding author. Address: Department of Clinical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: [email protected] (C.L. Creutzberg). 1 Present address: Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.03.023
center randomised trial including 1317 patients, which did not show any difference between enucleation and I-125 brachytherapy in 5-year survival (81% vs. 82 %) or 5-year rates of death with melanoma metastases (11% vs. 9%) [4]. Although the most important treatment aim for patients with choroidal melanoma is survival free of disease recurrence, both patients and physicians focus on the preservation of useful vision, cosmetic appearance and quality of life as well. Since its introduction, Ru-106 brachytherapy has been increasingly used for treatment of small to medium sized choroidal melanomas [5–7]. Although the benefit of eye preservation may be reduced by impaired vision resulting from radiation toxicity, eye conservation has major functional and cosmetic advantages. Previously, our group has reported outcome data after Ru-106 brachytherapy for choroidal melanoma [8,9], as well as results of the combination of brachytherapy and transpupillary thermotherapy (TTT) [10,11]. This combination therapy (so-called sandwich therapy) was initiated to use lower radiation doses for smaller tumours to reduce the risk of severe radiation toxicities, and on the other hand enable eye-conserving treatment for patients with tumours thicker than 5 mm. Moreover, patients with insufficient tu-
333
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mour regression after brachytherapy or with tumour recurrence can be retreated with TTT alone. The aims of the present analysis were to determine long-term outcomes of Ru-106 brachytherapy for intermediate size choroidal melanomas in a large series of patients treated in a single referral centre, focusing on tumour control, survival, visual acuity and complications, to identify prognostic factors and to determine if dose–effect relationships could be demonstrated. Specifically, outcomes using Ru-106 brachytherapy with and without TTT were evaluated.
Table 1 Treatment protocols. Period
Tumour prominence (mm)
Dose (Gy)
TTT
N
1993–1997
<3 3–5 >5
600 600 800
No Yes Yes
24 37 12
Total 1997-onwards Central tumours
Materials and methods
Peripheral tumours
Patients and data collection
Total
The records of all 430 consecutive patients who were treated for choroidal melanoma with Ru-06 brachytherapy at Leiden University Medical Center (LUMC) between January 1993 and December 2004 were analysed. Patients treated with Ru-106 brachytherapy for iris and ciliary body melanoma were excluded, as these have been analysed and reported separately. The diagnosis of choroidal melanoma was based on opthalmoscopic and ultrasonographic findings and fluorescein angiography. Patients were eligible for Ru-106 brachytherapy if they had a small or intermediate size melanoma (basal diameter up to 16 mm and tumour prominence up to 8 mm; one exception involved a tumour prominence of 9.3 mm). At time of diagnosis, all patients were evaluated by liver ultrasonography, chest radiography and routine blood tests. Follow-up examinations, conducted 1 month after treatment and at 3- to 6-month intervals, included opthalmoscopy, ultrasonography and, if necessary, fundus photography and visual field examination. Visual acuity was assessed by projection of Snellen characters at a distance of 5 m. Patients were followed in LUMC until 3–5 years after treatment, and by their local ophthalmologist thereafter. Applicators Ru-106 applicators manufactured by Bebig (Eckert & Ziegler BEBIG GmbH, Berlin, Germany) were used. The three applicators most frequently used have diameters of 15.3, 17.9 and 20.2 mm with active diameters of 13.5, 15.8 and 18 mm, respectively (CCA, CCD, CCB). Applicators for treatment of juxtapapillary tumours (tumours located immediately adjacent to the optic nerve), have a section cut out for the optic nerve (COB, CIB). Due to the rapid dose fall-off of Ru-106, 80% of the dose has already been absorbed at 5 mm from the applicator. The distribution of Ru-106 is not completely uniform over the applicator surface, with dose variations of 5–10%. In the past, dose calibration has been hampered by lack of an international dose reference. Since early 2002 Bebig has adopted a more extensive calibration protocol proposed by the National Institute of Standards and Technology (http://www.bebig.de/downloads/augen_ info_dosimetrie_eng.pdf) [12]. In our analysis all doses reported from treatments before 2002 have been recalculated according to this calibration protocol. Treatment Patients were treated according to two different protocols, as shown in Table 1. Before 1997 a protocol was used combining Ru-106 brachytherapy with TTT for tumours with prominence >3 mm. From 1997 onwards, the brachytherapy dose was reduced to 400–600 Gy for combined brachytherapy and TTT. Peripheral tumours, for which TTT could not be used, were treated with doses of 600–800 Gy. The brachytherapy dose was prescribed at the scleral surface and standardized to a dose rate of 100 Gy per 24 h, by cor-
73
400 600 600 800
65 >5 63 >3
Yes Yes No No
229 88 12 23 352
recting the prescribed dose by a factor equal to (standard dose rate/ actual dose rate)0.2, adapted from Ellis [13]. In practice, this resulted in a dose correction of 2–10% (maximum 13%). Dose specification at the scleral surface (as opposed to the tumour apex) has Table 2 Patient and treatment characteristics. Characteristic
N
%
Sex Male Female
205 220
48.2 51.8
Age (years) <50 50–70 P70
87 207 131
20.5 48.7 30.8
Eye involved Left Right
208 217
48.9 51.1
Visual acuity 60.1 0.11–0.32 0.33–0.5 0.51–0.8 >0.8
34 52 79 134 126
8.0 12.2 18.6 31.5 29.6
Pigmentation Melanotic Amelanotic Partly amelanotic
340 76 9
80 17.9 2.1
Proximity to optical nerve Central/juxtapap Peripheral
248 177
58.4 41.6
Basal diameter <8 mm 8–11.49 mm 11.5–14.99 mm P15 mm
37 214 164 10
8.7 50.4 38.6 2.4
Tumour height 63 mm 3.01–5 mm >5 mm
84 203 138
19.8 47.8 32.5
Dose to apex 6100 Gy 100.01–150 Gy 150.01–200 Gy >200 Gy
98 130 87 110
23.1 30.6 20.5 25.9
Dose to sclera 6400 Gy 400.01–600 Gy >600 Gy
124 202 99
29.2 47.5 23.3
TTT used No Yes
59 366
13.9 86.1
TTT = transpupillary thermotherapy.
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Brachytherapy for choroidal melanoma
traditionally been used in our centre. This was considered more accurate since the dose distribution is more homogeneous close to the surface of the Ruthenium applicator, and because measurements of tumour prominence with ultrasonography have a high inter-observer variation. To evaluate and compare these two methods of dose specification, the dose at the tumour apex was calculated as well. The apex was defined as the tumour prominence including the sclera, as measured during ultrasonography. TTT was generally applied 2 months after brachytherapy, and was given using an infrared diode laser, with power ranging from 500 to 1000 mW. In case of incomplete tumour regression, TTT was repeated after 6 months. Outcome measures Vital status of all patients was known from hospital records and oncological registration. Tumour response was evaluated by fundoscopy and ultrasonography, with a flat scar, or a regressed lesion not showing any signs of tumour activity representing tumour control. Local recurrence was defined as insufficient tumour regression with signs of tumour activity on fluorescein angiography, or documented tumour growth. Metastases were detected by routine follow-up investigations (liver ultrasonography and blood chemistry tests) or by evaluation of symptomatic patients. Complications such as retinopathy, maculopathy, optic neuropathy, retinal haemorrhage and exudative retinal detachment were evaluated at each follow-up. For this analysis we focused on the late radiation-induced complications retinopathy, opticopathy and maculopathy. Vision was determined using WHO criteria, with low vision defined as visual acuity less than 1/3, whereas a vision <0.10 equals legal blindness.
TTT or enucleation were used to treat insufficient regression or recurrence. In some cases enucleation was performed for ocular complications. After enucleation, patients were followed for metastases and survival. Statistical methods All outcome analyses were based on data computerized by March 27, 2006. The results were analysed with SPSS software (version 12, SPSS Inc, Chicago, Il). Kaplan–Meier survival curves were used to analyse survival, tumour recurrence, metastases, visual acuity, risk of enucleation and complications as a function of time. Follow-up time was calculated from first day of brachytherapy to date of last information on vital status. Time intervals to death and to local recurrence or metastases were calculated from the first day of brachytherapy to the date of death or diagnosis of recurrence, with censoring at date of last contact. The relationships of these outcomes and independent variables were evaluated using log-rank tests. Statistical significance was defined as a two-sided p-value of less than 0.05. For multivariate analyses, variables with a p-value of 60.10 were entered into Cox regression analyses, and eliminated with a backward-stepwise procedure. Results Patient and treatment characteristics Between January 1993 and December 2004, 430 patients with choroidal melanoma were treated with Ru-106 plaque brachytherapy. Five patients were lost to follow-up, leaving 425 patients in
Local recurrence
Distant metastases
0.5
0.5
0.4
0.4
Number
Number
Events
424
0.3
423
Events 5-yr DM 51
16.6%
5-yr LR
16
3.9%
0.3
0.2
0.2
0.1
0.1
0.0
0.0 0
20
40
60
80
100
120
153
81
34
1
100
120
time in months
20
40
60
236
150
80
time in months
100
120
34
1
No at risk:
No at risk: N = 424
0
355
237
N = 423
358
83
Overall survival 1.0 0.8 0.6 0.4 Number Events
0.2
424
77
5-yr OS 79.6%
0.0 0
20
No at risk: N = 424
363
40
60
243
156
80
time in months
84
35
1
Fig. 1. Kaplan–Meier estimates of local recurrence, metastases and overall survival. LR = local recurrence; DM = distant metastases; OS = overall survival.
K.M.S. Verschueren et al. / Radiotherapy and Oncology 95 (2010) 332–338
the analysis. The median follow-up was 50 months (range 6– 125 months) for patients alive. Patient demographics, tumour and treatment characteristics are summarized in Table 2. The median age was 63 years (range 17– 90). The initial visual acuity in the affected eye was >0.10 in 92% of patients, P0.33 in 80%, and >0.50 in 61%. The median basal tumour diameter was 10.9 mm (range 4.8–15.9 mm), and the median apical height was 4.2 mm (range 1.2–9.3 mm). TTT was used in the treatment of 86% of the patients; 14% were treated without TTT. Local control, distant metastases and survival Local recurrences were diagnosed in 16 patients. The median time to local failure was 17.5 months (range 6.9–87.5 months). The actuarial 5-year local recurrence rate was 3.9% (95% CI 2.1– 5.7%). See Fig. 1. All patients with a local recurrence had received TTT within protocol. Patients who had a local recurrence had significantly more often a centrally or juxtapapillary located tumour, a lower visual acuity before treatment and a larger basal diameter (Table 3). Among the 25 patients with true juxtapapillary tumour location, four (16.0%) had a local recurrence. Treatment for local recurrence consisted of additional TTT (n = 6) or enucleation (n = 10). Among the six patients treated with additional TTT, five had one extra TTT session, and one had three
Table 3 Local recurrence rates by tumour and treatment characteristics. Characteristic
Age (years) <50 50–70 P70
Local recurrence
No local recurrence
N
%
N
%
1 9 6
1.1 4.3 4.6
86 198 125
98.9 95.7 95.4
p
335
extra TTT sessions. Among the 10 patients treated with enucleation, seven had direct surgery for recurrence. One patient had two extra TTT sessions and two had three extra TTT sessions for insufficient regression after first treatment, and subsequently underwent enucleation for documented tumour growth. Six (37.5%) patients with local recurrence died, five of whom with known distant metastases. In one patient distant metastases were diagnosed more or less synchronously with local recurrence (within 2 months), whereas four patients developed metastases 9– 29 months after local recurrence. Distant metastases were diagnosed in 51 patients. The median time to metastases was 30.4 months (range 0–68.4 months). Actuarial metastases-free survival rates were 76.5% at 5 years and 69.1% at 10 years. A total of 77 patients died, 46 with distant metastases and 29 from intercurrent diseases. In two patients (without known metastases) the cause of death was unknown. Actuarial overall survival rates were 79.6% at 5 years and 68.2% at 10 years (Fig. 1).
Complications During the course of time, 234 patients developed ocular complications, resulting in a 2-year actuarial survival rate free from complications of 49.7%, and 5-year rate of 27.8%. 194 of these 234 patients had radiation complications such as retinopathy (n = 56), maculopathy (n = 65), or opticopathy (n = 7), and combinations of these (n = 66). Forty patients had various other complications, such as vitreous haemorrhage or retinal detachment. The actuarial rates free of radiation complications were 60.0% at 2 years and 35.0% at 5 years.
0.25
Visual acuity <0.1 0.11–0.32 0.33–0.5 0.51–0.8 >0.8
1 1 10 3 1
2.9 1.9 12.7 2.2 0.8
33 51 69 131 125
97.1 98.1 87.3 97.8 99.2
Proximity to optical nerve Central/juxtapap Peripheral
16 0
6.5 0
232 177
93.5 100
Basal diameter <8 mm 8–11.5 mm 11.5–15 mm >15 mm
0 6 9 1
0 2.8 5.5 10
37 208 155 9
100 97.2 94.5 90.0
Tumour height <3 mm 3–5 mm >5 mm
2 7 7
2.4 3.4 5.1
82 196 131
97.6 96.6 94.9
Dose to apex <100 Gy 100–150 Gy 150–200 Gy >200 Gy
4 9 1 2
4.1 6.9 1.1 1.8
94 121 86 108
95.9 93.1 98.9 98.2
Dose to sclera <400 Gy 400–600 Gy >600 Gy
5 9 2
4.0 4.5 2.0
119 193 97
96.0 95.5 98.0
TTT used No Yes
0 16
0 4.4
59 350
100 95.6
Treatment date 1993–1997 1997–onwards
2 14
2.7 4.0
71 338
97.3 96.0
Functional eye preservation
0.03
0.001
Among the 391 patients with a pre-treatment visual acuity greater than 0.10, 147 had a deterioration of visual acuity in the treated eye to <0.10, thus to legal blindness. Patients with centrally or juxtapapillary located tumours had more often a poor vision before treatment, as well as greater deterioration after treatment. Actuarial rates of preserved vision greater than 0.10 were 66.9% at 2 years and 51.9% at 5 years. Actuarial rates of preserved vision of at least 0.33 among patients with initial visual acuity of >0.32 were 55.1% at 2 years and 36.6% at 5 years.
0.04
Cosmetic eye preservation
0.29
0.12
0.48
0.1
0.61
Note: Statistically significant values are indicated in bold.
Seventeen patients eventually underwent enucleation, resulting in a 5-year actuarial enucleation rate of 4.4%. Most enucleations (76%) were performed within the first 2 years after treatment. Ten patients underwent enucleation for local recurrence and seven for complications. Ocular complications necessitating enucleation were vitreous haemorrhage in three patients, serous detachment in two, neovascularisation in one, and combined vitreous haemorrhage and retinal detachment in one patient.
Prognostic factors Univariate and multivariate analyses of prognostic factors for overall survival, distant metastases, functional visual outcome and complications were done. Significant favourable prognostic factors for survival free of distant metastases were peripheral tumour location (p = 0.02) and smaller basal diameter (p < 0.001). The number of local recurrences was too small to perform multivariate analysis. As shown in Table 3, trends towards lower risk of local recurrence were found for peripheral tumour location, better initial visual acuity and smaller basal diameter.
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Brachytherapy for choroidal melanoma
Results for visual outcome are shown in Table 4. Significant favourable prognostic factors for preserved visual acuity of 0.33 or greater were peripheral tumour location (p = 0.02), better initial visual acuity (p < 0.001), and lower apical height (p = 0.04), while dose to sclera or apex did not have prognostic significance. Both lower apical height and better initial visual acuity remained significant when analysed separately for peripherally located tumours, while for central tumours only initial visual acuity was significant. A trend for higher rate of preserved visual acuity >0.32 was found for treatment without TTT (52.1 versus 34.5%, p = 0.06 in univariate analysis). Prognostic factors for risk of radiation complications were younger age (p = 0.03) and use of TTT (p = 0.05), while brachytherapy dose, basal diameter and tumour location were not significantly related to risk of complications (Table 5).
Discussion In this analysis long-term outcomes of Ru-106 brachytherapy with or without TTT were evaluated in a large series of 425 patients with choroidal melanoma. We found excellent local tumour control and eye preservation rates. Five-year actuarial local control and eye preservation were both 96%. These results are comparable to those reported by other groups for small or medium sized tumours. In a series of 270 patients treated with brachytherapy and TTT reported by Shields et al. [14] 5-year local recurrence was 3%, while Damato et al. reported an equally low recurrence rate (2% at 5 and 3% at 7 years) in 458 patients treated with Ru106 brachytherapy, using TTT only in case of uncertain efficacy
[15]. Some authors reported lower 5-year eye preservation rates of 72–82% [7,16,17]. Juxtapapillary choroidal melanomas have inferior outcomes, with lower local control rates (16% recurrence among 25 cases in our series) and higher rates of visual impairment. Sagoo et al. [18] reported 90% local control with I-125 brachytherapy and TTT, but with a 23% enucleation rate; Krema et al. [19] described efficacy of stereotactic radiotherapy with 94% local control, but with significant ocular complications (neovascular glaucoma 42%, cataract 53%, retinopathy 81% and optic neuropathy 64%, and enucleation in 12%). As effective salvage therapies are available, brachytherapy continues to be the preferred treatment option in view of the lower complication rates. Overall and metastases-free survival rates were 79.6% and 76.5%; these rates reflect the fact that this series included patients with small to medium sized melanomas, and again confirm that eye-conserving treatment does not impair survival. Choroidal melanomas are relatively resistant to irradiation, and the brachytherapy doses needed to eradicate these tumours are associated with a substantial risk of radiation damage to the retina and optic nerve. In our analysis the actuarial 2- and 5year rates free of radiation related side effects were 60% and 35%. Especially patients with centrally located tumours experience a gradual decline or loss of visual acuity from retinopathy, maculopathy, opticopathy and other ocular side effects. Radiation induces both an acute transudative and slowly progressive occlusive vasculopathy with neovascularisation and macular oedema, resulting in an deterioration of visual acuity in the affected eye which is ongoing over the years after treatment. In our analysis the probability of retaining visual acuity greater
Table 4 Univariate and multivariate analyses of prognostic factor for visual outcome >0.32 (in patients with initial visual acuity >0.32). Characteristic
N
5-Year rate of vision >0.32
Univariate HR
Age (years) <50 50–70 P70
73 175 91
24.4 42.7 35.5
1 0.7 0.9
Visual acuity 0.33–0.5 0.51–0.8 >0.8
79 134 126
26 31.8 49.9
1 0.5 0.3
Proximity to optical nerve Central/juxtapap Peripheral
184 155
27.5 47.6
1 0.6
Basal diameter <8 mm 8–11.5 mm 11.5–15 mm P15 mm
30 169 133 7
39.2 38.7 32.2 54.6
1 1.3 1.7 1
Tumour height 63 mm 3.01–5 mm >5 mm
74 166 99
40 39.3 32.4
1 1.1 1.7
Dose to apex 6100 Gy 100–150 Gy 150–200 Gy >200 Gy
75 99 69 96
31.1 34.3 29.9 44.4
1 0.8 0.6 0.6
Dose to sclera 6400 Gy 400–600 Gy >600 Gy
104 158 77
38.5 31.3 46.7
1 1.4 1.1
TTT used No Yes
48 291
52.1 34.5
1 1.7
Multivariate 95% CI
p
HR
95% CI
p
0.07 0.5–1.0 0.6–1.3 <0.001
<0.001 1 0.5 0.3
0.3–0.7 0.2–0.4
0.4–0.8 0.2–0.4
0.01
0.02 1 0.7
0.4–0.8
0.5–0.9
0.15 0.7–2.5 0.9–3.3 0.3–3.4 0.02 0.7–1.7 1.1–2.5 0.1 0.5–1.2 0.4–1.0 0.4–0.9 0.09 1.0–2.1 0.7–1.7 0.06
Note: Statistically significant values are indicated in bold.
1.0–2.8
0.04 1 1.1 1.6
0.7–1.7 1.0–2.5
337
K.M.S. Verschueren et al. / Radiotherapy and Oncology 95 (2010) 332–338 Table 5 Univariate and multivariate analyses of prognostic factors for radiation complications. Characteristic
N
5-Year rate free of complic.
Univariate HR
Age (years) <50 50–70 P70
87 207 131
28.1 35.9 33.4
1 0.8 0.6
Visual acuity 60.1 0.11–0.32 0.33–0.5 0.51–0.8 >0.8
34 52 79 134 126
38.9 34.4 38.2 36.1 31.4
1 0.8 0.9 1 1.1
248 177
32.0 37.6
1 0.9
37 214 164 10
21.3 36.6 34.4 49.7
1 0.8 0.8 0.5
Tumour height 63 mm 3.01–5 mm >5 mm
84 203 138
26.9 38.9 37.2
1 1 1
Dose to apex 6100 Gy 100–150 Gy 150–200 Gy >200 Gy
98 130 87 110
37.3 41.0 27.2 33.5
1 0.7 1.1 0.9
Dose to sclera 6400 Gy 400–600 Gy >600 Gy
124 202 99
34.1 33.6 36.0
1 1.2 1.1
TTT used No Yes
59 366
41.2 33.4
1 1.6
Proximity to optical nerve Central/juxtapap Peripheral Basal diameter <8 mm 8–11.5 mm 11.5–15 mm P15 mm
Multivariate 95% CI
p
HR
95% CI
0.02 1 0.8 0.6
0.6–1.1 0.4–0.9
p 0.03
0.6–1.1 0.4–0.9
0.63 0.4–1.8 0.5–1.6 0.6–1.8 0.6–1.9 0.58 0.7–1.2 0.61 0.5–1.3 0.5–1.3 0.1–0.6 0.99 0.7–1.4 0.7–1.5 0.16 0.5–1.1 0.7–1.7 0.6–1.4 0.62 0.8–1.6 0.7–1.6 0.05 1.0–2.6
0.05 1 1.6
1.0–2.6
Note: Statistically significant values are indicated in bold.
than 0.1 (not being legally blind) was 52% at 5 years, comparable to other large series [20,21]. It is important to note that visual acuity as reported here is only a measure of central vision of the affected eye. Peripheral visual acuity remains at least partly preserved, which is essential for binocular vision and orientation in space. Some authors have investigated the impact of treatment factors such as total dose and dose rate on visual acuity [21–23]. Increased dose and dose rate (exceeding 90–100 cGy/h) to the macula and optic disc, and small distance of the tumour to these structures, were associated with increased toxicity and poor visual outcome [22,24]. In our analysis, central location of the tumour was a significant prognostic factor for loss of visual acuity, but we could not demonstrate dose–response relationships between dose to the sclera or to the tumour apex and poor visual outcome. Recent data suggest that treatment of radiation retinopathy with intravitreal anti-vascular endothelial growth factors such as bevacizumab (Avastin) may decrease neovascularisation, vascular permeability and retinal edema, resulting in stabilization or improvement of visual acuity [25]. In our centre most patients have been treated with Ru-106 brachytherapy in combination with transpupillary thermotherapy (TTT) [9–11]. With TTT necrosis is induced to a depth of 3 mm. The combined use of TTT and brachytherapy was expected to have additive effects, as with TTT the apex of the tumour is treated up to 3 mm, while with brachytherapy the highest dose is given to the tumour base. Combining both treatments would enable treatment of patients with tumour prominences exceeding 5 mm, which was
traditionally regarded as the maximum height suitable for Ru-106 brachytherapy. Furthermore, it was expected that with lower radiation doses the risk of complications would be reduced. We did, however, not find reduced complication rates, nor better visual outcomes with the use of lower brachytherapy doses in conjunction with TTT. A possible explanation could be that the doses used, ranging from 400 to 800 Gy at the scleral surface, are well above the levels with potential dose–effect relationships. In addition, TTT causes deterioration of visual acuity which occurs immediately after treatment, while the effect of brachytherapy on visual outcome slowly increases over time. A trend for higher rates of preserved visual acuity >0.32 was found for treatment without TTT, but this might be related to the peripheral location of these tumours, where treatment has less impact on central visual acuity. At multivariate analysis, however, the use of TTT was associated with increased rates of radiation related complications. Although this analysis was not done to evaluate the efficacy of TTT used in conjunction with brachytherapy, we could not demonstrate any trend towards increased efficacy. Peripheral tumours (most treated without TTT) had better survival rates and a trend for lower relapse rates. It is, however, not possible to draw definite conclusions as peripheral tumour location is by itself a favourable prognostic factor, and the number of patients treated without TTT was small. It should be noted that the apex doses which resulted from dose prescription at the scleral surface in our patients were relatively high (46% had apex doses exceeding 150 Gy). We could not demonstrate a dose–effect relationship for dose to the scleral surface, nor
338
Brachytherapy for choroidal melanoma
for dose to the tumour apex. Most authors [4,5,14–17] have used dose levels of 100–120 Gy specified to the tumour apex, often with a maximum of 1000 Gy to the scleral surface. In our analysis 100 Gy at the tumour apex was also found to be an efficacious dose level, but using combination treatment with TTT, even lower apex doses (<100 Gy) did not result in reduced treatment efficacy. Dose specification at the apex has the advantage of giving lower doses to the sclera and retina in patients with smaller tumours, which might reduce complication rates. Apex doses of 100 Gy and greater are effective. Use of TTT in conjunction with adequate apex doses does not seem to improve outcome; on the contrary, TTT seems to increase the risk of ocular complications and, depending on tumour location, results in an immediate deterioration of vision. Therefore, TTT should be reserved for cases with insufficient apex dose or for salvage treatment in case of insufficient tumour regression or a local recurrence after treatment [15]. For treatment of small to medium sized melanoma, we prefer Ru-106 brachytherapy to other radiation modalities, such as charged particle irradiation or stereotactic radiation. Although these methods seem to be equally effective with regard to the risk of metastases and survival, brachytherapy is associated with fewer and less severe local complications [19,26–28]. For larger melanomas, however, these radiation modalities should be considered as effective eye-conserving treatment alternatives. In conclusion, we have confirmed the efficacy of Ruthenium106 brachytherapy for eye-conserving treatment for patients with choroidal melanoma, with excellent rates of local control and eye preservation. Melanomas up to 16 mm diameter and 8 mm prominence can safely be treated. Dose specification at the tumour apex, with TTT reserved for cases with insufficient apex dose and/or insufficient tumour regression, are preferable to reduce the risk of complications and poor visual outcome. Further research should be directed towards strategies to reduce the progressive effects of radiation retinopathy and use of lower brachytherapy doses.
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