1. bookVolume 50 (2016): Issue 1 (March 2016)
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1581-3207
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Prognostic factors of choroidal melanoma in Slovenia, 1986–2008

Published Online: 16 Feb 2016
Volume & Issue: Volume 50 (2016) - Issue 1 (March 2016)
Page range: 104 - 112
Received: 17 Nov 2014
Accepted: 09 Dec 2014
Journal Details
License
Format
Journal
eISSN
1581-3207
First Published
30 Apr 2007
Publication timeframe
4 times per year
Languages
English
Introduction

Uveal melanoma is the most common primary malignancy of the eye.1 Approximately 90% of all uveal melanoma develop in the choroid, 7% in the ciliary body and 3% in the iris.2 The disease is more common in older age, with the highest incidence at about 60 years of age.1,2 For the period 1983–1994, the incidence of uveal melanoma in 16 European countries was analysed by the European Cancer Registry (EUROCARE).3 The incidence in Europe was found ascend from South to North, being 2/million inhabitants in Spain and southern Italy and more than 8/million in Denmark and Norway. In Slovenia, the incidence of choroid melanoma between 1983-2009 was stable, at 7.8 cases/million for men and 7.4/million for women.4

In the majority of patients, the biopsy of tumour is not indicated because the accuracy of clinical diagnosis is reaching 99%.5 However, there is no agreement about the optimal therapy.610 Until development of eye conserving therapies in 1960’s, for more than 100 years, enucleation was the only mode of treatment. The first among eye conserving approaches was the plaque brachytherapy9,1114, followed by proton beam1517 and helium ion radiotherapy1820, stereotactic radiotherapy, transscleral or transretinal local resection10,21,22, and phototherapy brachytherapy23, several types of radioactive plaques with photon emitting isotopes were used, including cobalt-60, iodine-125, and iridium-192. Beta emitting plaques with ruthenium (106Ru/106Ro), however, were introduced in 1964 by Lommatzsch.2426

In Slovenia, treatment of choroidal melanoma by brachytherapy with ruthenium plaques using the Lommatzsch method was introduced in 1985 by the Eye Clinic at the University Clinical Centre Ljubljana in collaboration with the Institute of Oncology Ljubljana.27,28 Before that time, the only available treatment was enucleation of the diseased eye. The aim of this retrospective study was to evaluate these two modalities in the treatment of choroidal melanoma in Slovenia during the period from 1986 to 2008 and to determinate the prognostic factors of survival for choroidal melanoma patients in Slovenia.

Patients and methods
Patients

The database of the Cancer Registry of Slovenia was used for identification of patients with the diagnosis of choroidal melanoma in Slovenia in the years 1986–2008.4 The medical records of identified patients from the Eye Hospital of the University Clinical Centre Ljubljana and from the Department of Ophthalmology of the University Medical Centre Maribor were reviewed for relevant information on clinical characteristics, treatment and outcome. The diagnosis of choroidal melanoma was based on clinical features and full ophthalmologic examination, indirect ophthalmoscopy, fundus photography, ultrasonography and fluorescein angiography. At the time of diagnosis, the patients were evaluated by chest radiography, lymph gland and liver ultrasonography29 and routine blood tests. Genetic testing was not done because it was not available at the time of the study.

The study was approved by the institutional review board and was carried out according the Helsinki Declaration.

Treatment

Applicators manufactured by Bebig (Eckert&Ziegler BEBIG Gmbh, Berlin; later Amersham, GB) were used. The applicators were concave, shell-shaped, with Ru-106/Ro-106 isotope covering the concave surface as a thin, insoluble film and emitting beta rays with the energy of 3.54 MeV and half-life of 373 days. The tumours were localized by transillumination and indirect ophthalmoscopy, and the applicators were sutured to the sclera. The dose at the tumour apex was aimed to be about 120 Gy. The applicator was removed after expiration of appropriate time.

Treatment was selected according to the tumour size: patients with tumours ≤ 16 mm in diameter and ≤ 7.2 mm thick, with useful vision preserved, were treated by brachytherapy, patients with larger tumours had enucleation. The enucleation was performed in general anaesthesia.

First follow-up visits took place one month after the procedure, in 3-month intervals during the first year and once a year thereafter. At each follow up visit, patients underwent ophthalmologic examinations with indirect ophthalmoscopy, fundus photography and ultrasonography.

Statistical methods

For comparative analyses, the Fisher exact test for two proportions as well as t-test and Mann-Whitney test for data of two independent groups were used. Survival estimates were carried out using the Kaplan-Meier method and reported at 5 and 10 years follow up. The difference between the survival curves was evaluated by means of a log-rank comparison. Multivariate survival analysis for study of an independent effect of various parameters that appeared statistically significant on univariate analysis to treatment outcome and survival was performed according to Cox’s proportional hazard models with backward stepwise selection. The end points of survival analysis were locoregional control (LRC, persistent disease or locoregional recurrence considered as an event), disease-free survival (DFS, appearance of loco-regional recurrence or systemic metastases considered as event), disease-specific survival (DSS, melanoma related death considered as event) and overall survival (OS, death from any cause considered as event) which were measured from the first day of therapy. These statistical analyses were performed by using SPSS version 18.0 (SPSS Inc., Chicago, IL) and nonlinear regression Gaussian curve fitting was performed by GraphPad Prism version 5. All tests were two-sided and a P-value of 0.05 was considered statistically significant.

Results

Clinical records of 288 patients with choroidal melanoma treated from January 1986 to December 2008 at the Eye Hospital of the University Clinical Centre Ljubljana and from the Department of Ophthalmology of the University Medical Centre Maribor were reviewed. The follow-up close-out date was December 31, 2013. Median follow-up of all patients was 15 years (range, 4–27 years). In December 2013, 130 patients were alive. The cause of death was melanoma in 107 patients and 51 patients died of melanoma unrelated disease; 20 among them died of other malignant diseases. The characteristics of patients and tumours are shown in Table 1.

The characteristics of patients and tumours by treatment modality

Treatment
BrachytherapyEnucleationTotal
All patients130161291
Excluded3 palliations-3
Treated127161288
Gender
 Man5884142
 Women6977146
Age (median)
 Men58 (29-74)58 (19-86)
 Women60 (22-89)61 (23-92)
T-stage (AJCC)
 138
 269
 38
 No data12
Thickness
 < 3 mm11
 3.1-5.0 mm64
 5.1-7.2 mm49
 > 7.8 mm3
 No data0
Basal diameter
 ≤ 10 mm52
 10,1-12,0 mm38
 > 12 mm25
 No data12
Histology161
 Spindle cell33
 Epithelioid38
 Mixed23
 No data37

AJCC = American Joint Committee on Cancer

Survival

In univariate analysis of all patients, the LRC and DFS were better in enucleation than in brachytherapy group and better in females than in males. Patients < 60 years had better DFS, DSS and OS than older patients. In brachytherapy group, females had statistically better LRC and DFS than males; younger patients had better DSS and OS than older patients. Tumour thickness < 6 mm was associated with better LRC and DFS than thicker tumours, while the base diameter < 11 mm was a good prognostic sign for LRC; DFS, DSS and OS. The treatment time influenced LRC and DFS, while the dose-rate had no influence of the outcome of the treatment. In the enucleation group, age and histology influenced DFS, DSS and OS, while sex had no effect on survival. The detailed data of survival are presented in Tables 2–4.

In multivariate analysis for all patients, gender was independent prognostic factor for LRC, while first treatment and age were independent prognostic factors for DFS, DSS and OS. In the brachytherapy group, gender was independent prognostic factors for LRC; treatment time for LRC and DFS; base diameter for DFS and OS. The age was independent prognostic factor for DFS and OS. In enucleation group, age and histology were independent prognostic factors for DFS and DSS, while on OS influenced only age (Table 5).

Second treatment

In 30 patients treated by brachytherapy, a local recurrence of the tumour occurred. The second application of ruthenium plaque was performed in 13 of these patients, and in 17 patients had enucleation: 12 patients - because of extent of the recurrent tumour and 5 patients - because of the treatment-related side effects (glaucoma, cataract). The eyes were enucleated from 7 months to 18 years (median 24 months) after the first brachytherapy (Figure 1).

Figure 1.

Overall survival of patients treated by brachytherapy after treatment of recurrence.

Univariate analysis of survival: all patients (N = 288)

nLRC (%)DFS (%)DSS (%)OS (%)
5 yrs10 yrsp5 yrs10 yrsp5 yrs10 yrsp5 yrs10 yrsp
All2889088-6550-76586846-
Ruthenium1277875716092798768
0.0000.0140.0000.000
Enucleation161100100604264425431
Men1428582615174616647
0.0260.6730.6470.952
Women1469593694978557046
< 60 years1508986745886688464
0.6480.0020.0000.000
≥ 60 years1389090564065475228

DFS = disease free survival; DSS = disease specific survival; LRC = loco-regional control; n = number of patients; OS = overall survival; yrs = years

Univariate analysis of survival: patients treated by brachytherapy (N = 127)

LRC (%)DFS (%)DSS (%)OS (%)
n5 yrs10 yrsp5 yrs10 yrsp5 yrs10 yrsp5 yrs10 yrsp
Men586660604990768767
0.0030.0390.7030.859
Women698987816993818870
< 60 years687671766698899883
0.3050.1560.0020.000
≥ 60 years598080655184657552
T-stage
 1387979736797849471
 26979740.45172570.35490750.37886720.508
 38604045458686050
Tumour thickness
 2-5.9 mm9783820.00374660.02192790.48986680.724
 6-.2 mm296454643996809670
Base
 < 11 mm6183830.043800.00296840.02496770.002
 ≥ 11 mm547064604587727864
Dose rate Top (Gy/h)
 ≥ 108 Gy5381780.30274660.09995840.28087720.690
 < 108 Gy527468684689728762
Dose- rate base (Gy/h)
 ≥ 5325382740.70874570.80495810.66587690.862
 < 532527471685589758765
Treatment time
 ≤ 96 hours5287840.01580720.00495840.40089740.565
 > 96 hours536862624089718560

DFS = disease free survival; DSS = disease specific survival; LRC = loco-regional control; n = number of patients; OS = overall survival; yrs = years

Distant metastases

Twenty-five of 127 patients treated by brachytherapy and 86 of 161 those treated by enucleation developed systemic metastases. Seventy per cent of all metastases were localized in the liver. The actuarial rates of metastases by treatment modality are depicted in Figure 2. At 5 and 10 years, the incidences were 39% and 57%, respectively, for enucleated patients, and 11% and 21%, respectively, for irradiated patients (P < 0.001).

Figure 2.

Incidence of distant metastases according to the type of treatment.

In patients treated by brachytherapy, half of the metastases developed in 5 years, and in those treated by enucleation in 2.6 years.

Annual melanoma specific mortality rate

The mortality of patients was increased in the first few years after treatment and then slowly returned to pre-treatment values. Melanoma specific mortality rate is displayed in Figure 3.

Figure 3.

Percentage of annual post-treatment melanoma specific mortality according to the type of treatment. *There was no peak in ruthenium treated patients < 60 years.

The peak percentage of annual melanoma specific mortality after treatment was achieved at 3.6 years for patients older than 60 years treated by enucleation and at approximately 6 years for younger enucleated patients and for all patients treated with brachytherapy. The irradiated patients below 60 years contributed little to the peak because of low mortality rate.

No patient from brachytherapy group aged below 40 years died of melanoma. In brachytherapy treated patients the mortality began to increase after the age of 40 and reached 40 % in 70–80 year’s age group. In patients treated by enucleation, the mortality started to increase one decade earlier: the rise started with about 40% and reached about 70 % in patient’s 80–90 years of age (Figure 4).

Figure 4.

Linear regression analysis of melanoma related mortality per age decades, according to the type of treatment. Points represent percent mortality rate for the elapsed decade. No patient less than 40 years who was treated with Ru-106 died of melanoma.

Complications

Because of retrospective character of the study, acute complications were not systematically recorded. For chronic complications patients were reviewed annually. Post-radiation retinopathy started to appear after two years and was documented in 18 patients (12 mild, 6 severe), neovascular glaucoma in 5 patients and cataract in 6 patients. None of the patients had optic neuropathy.

Vision after treatment

After brachytherapy, the eye was retained in all patients and the vision was assessed in 112 patients. Compared to pre-treatment status, 22 (19.6%) patients had better visual acuity; in 12 (10.7%) patients the vision was unchanged while in 78 (69.6%) patients the acuity of vision was worse. The majority of brachyradiotherapy patients retained vision which was better than counting fingers.

Discussion

Our retrospective study reports results of the treatment of patients with choroidal melanoma in Slovenia from 1986 to 2008. In our study, the overall and specific mortality rate in patients treated by enucleation was higher mainly because larger tumours were selected for enucleation as compared to those treated by brachytherapy. Brachytherapy could be used only for selected tumours, depending on their size, location and shape of applicators, for which a satisfactory dose distribution of dose can be achieved. Because no data about the dimensions of the enucleated tumours was available, comparison of results between the two treatment modalities by tumour stage could not be made.

The randomized as well as nonrandomized studies reported no difference in survival rates in patients treated either by enucleation or brachy-therapy when matched by the stage, age and other prognostic parameters.68,11,12,3033 The largest of these studies was the COMS, which included 1317 patients and prospectively compared on randomized fashion enucleation and brachytherapy. There was no statistical difference in 5- and 10-year OS between the two treatment groups.30 In the matched pairs study of Guthoff et al. melanoma specific survival at 12 years of follow-up was 77.9% in irradiated patients and 78.6% in enucleated patients (P > 0.05).31 When the OS at 10 years of our patients treated by brachytherapy was compared with that from COMS study, no difference could be observed: 32% vs. 35%; similarly, the DSS at 10 years in our series was 79% and was comparable with DSS reported by Guthoff.

There are several prognostic factors for outcome of the choroidal melanoma, including age3033, gender33, basal tumour diameter34, tumour thickness3337, T-stage35, cell morphology1,7,33,38 and various genetic changes of the tumour, especially monosomy of chromosome 3.33,3941 Some of them appeared statistically significant also in the present study, although the strength of our results should be interpreted with caution. Namely, we only had complete information on age and gender of the patients, histology of the enucleated tumours, and data of tumour diameter, thickness, irradiation dose on the base and top of the tumour and the treatment time for brachytherapy patients, but not also on some other highly relevant prognosticators (e.g. genetic alterations), which limits the strength of statistical analysis.

In both treatment groups, the post-treatment annual mortality related to melanoma at first increased, as expected due to systemic metastases, but few years later it decreased to a few or zero percent. In patients of 60 years or more who were treated by enucleation, mortality reached its peak of 18% at 3.7 years after treatment, while in patients younger than 60 years the peak was reached at six years after treatment and was 7%. Patients treated by brachytherapy fared better: regardless of age, six years after treatment completion the peak mortality was 3%. However, the mortality of irradiated patients aged ≥ 60 years reached the peak of 7% at 6 years post-treatment, while no increase in mortality was noticed among younger patients, probably due to the small number of deaths.

Univariate analysis of survival: patients treated by enucleation (N = 161)

None of enucleated patients had local recurrence; DFS = disease free survival; DSS = disease specific survival; n = number of patients; OS = overall survival; yrs = years

DFS (%)DSS (%)OS (%)
n5 yrs10 yrsp5y10 yrsp5 yrs10 yrsp
Men8462510.154635153340.775
Women77593365340,2755627
< 60 years8273520.001765274510.000
≥ 60 years79493050300.0003410
Spindle cell33747081726649
epithelioid3856360.05061330.02955240.026
Mixed cell23622867245215

Multivariate analysis of survival of all patients (N = 288)

HR95% CIP
lowerupper
All patientsLRCFirst treatment40.8425.565299.7170.000
Gender2.6581.2455.6780.012
DFSFirst treatment1.6281.1442.3160.007
Age < 60 years vs. ≥ 60 years1.8001.2752.5400.001
DSSFirst treatment3.9372.5096.1780.000
Age < 60 years vs. ≥ 60 years2.5341.7143.7470.000
OSFirst treatment3.1532.2184.4800.000
Age < 60 years vs. ≥ 60 years3.8182.7105.3770.000
Gender2.3061.0135.2510.047
RutheniumLRC
Treatment time (≤ 96 h vs. > 96 h)2.8411.2206.6230.015
Treatment time (≤ 96 h vs. > 96 h)2.6741.2765.5870.009
DFSBase (< 11 mm vs. ≥ 11 mm)2.5191.0156.2500.046
T-stage2.3201.0025.3760.050
DSSAge (< 60 years vs. ≥ 60 years)4.7621.70913.3330.003
OSBase (< 11 mm vs v11 mm)3.6101.3919.4340.008
Age (< 60 years vs. ≥ 60 years)5.6502.53812.6580.000
NucleationLRC-----
DFSAge (< 60 years vs. ≥ 60 years)2.1321.1493.9680.016
Histology S VS E VS M1.4671.0002.1510.050
DSSAge (< 60 years vs. ≥ 60 years)2.3261.2294.4030.009
Histology S vs. E vs. M1.5551.0522.2980.027
OSAge (< 60 years vs. ≥ 60 years)3.8762.2226.7570.000
Histology (S vs. E vs. M)1.4441.0511.9830.023

CI = confident interval; DFS = disease free survival; DSS = disease specific survival; E = epitheloid; HR = hazard ratio; LRC = loco-regional control; M = mixed cell; n = number of patients; OS = overall survival; S = spindle cell

The increase in annual mortality following enucleation was first observed by Zimmermann.42,43 He re-analysed the data of Paul et al.38 who monitored 2652 patients for 40 years and found a steep increase in mortality following enucleation. In this study, the peak of 8% was reached at 2 years after enucleation, slowly diminishing during the next few years to the “normal” 1%.43,44 Similarly, Seddon et al. reported the increase in mortality to 6.5 % in the first 2–3 years after treatment and slowly return to “normal” 1% during the next 7 years.45

The post-treatment increase in melanoma related mortality can be attributed to the loss of antiangiogenic activity of the primary tumour after its removal or destruction. Uveal melanoma cells produce angiostatin, growth inhibitor of metastatic foci46,47, which was found to be present in the circulation only up to five days after the removal of the primary tumour.48,49

Damato et al.33 found that the probability of metastases was greater in older patients as their tumours grew longer and had more time for accumulation of chromosome instabilities, making the tumour more malignant and more prone to metastasize. Accordingly, the younger patients should have smaller and perhaps less malignant tumours, and the appearance of metastases is less likely. It is assumed that following primary tumour removal, metastases in younger patients reach the lethal tumour mass at a later time. The peak in melanoma-related mortality in younger enucleated patients from our series appeared 2.5 years later than in older counterpart, confirming this assumption. However, not all patients from advanced age group have advanced primary tumour and metastases. In our series, 59 patients ≥ 60 years had primary tumours small enough to be treated by brachytherapy. The annual melanoma related mortality curve suggests that the burden of their metastases was also smaller, and reached the lethal mass at a later time. The synchronous peaks of enucleated patients < 60 years and of irradiated patients ≥ 6o years suggests that the burden of metastases in enucleated group, was similar in these two groups (Figure 3).

There is no good scientific evidence that treatment can prolong patients’ life.33 The increase in annual post-treatment mortality rate implies that the life of some patients might be shortened due to the therapy, particularly of older ones. This observation and the fact that some tumours and their metastases grow very slowly raise the question when the treatment of uveal melanoma can be withheld. The COMS study showed that the estimated risk of death at 5 years of follow-up in 42 untreated patients was 50%, and risk of 1317 patients treated by a standard method, was 18%.50 It seems that treatment in older patients without eyesight problems, in spite of evident metastases, could be postponed until the problems eventually ensue. On the other hand, it may be assumed that some of the younger patients are without micrometastases at the time of therapy and can be cured by the early treatment. Indeed, in our study, none of the patients younger than 40 years from brachytherapy group died of metastases, while death of metastases in older patients steeply increased with age (Figure 4).

To conclude, treatment-specific and age-dependent pattern of -related mortality was confirmed in our study, confirming observation of other authors. For quality of life reasons we believe that preference should be given to eyesight preserving brachytherapy or other eye preserving treatments of choroidal melanoma over enucleation, if the size and location are suitable even though the definite opinion on the best treatment differed in the literature.51,52

Figure 1.

Overall survival of patients treated by brachytherapy after treatment of recurrence.
Overall survival of patients treated by brachytherapy after treatment of recurrence.

Figure 2.

Incidence of distant metastases according to the type of treatment.
Incidence of distant metastases according to the type of treatment.

Figure 3.

Percentage of annual post-treatment melanoma specific mortality according to the type of treatment. *There was no peak in ruthenium treated patients < 60 years.
Percentage of annual post-treatment melanoma specific mortality according to the type of treatment. *There was no peak in ruthenium treated patients < 60 years.

Figure 4.

Linear regression analysis of melanoma related mortality per age decades, according to the type of treatment. Points represent percent mortality rate for the elapsed decade. No patient less than 40 years who was treated with Ru-106 died of melanoma.
Linear regression analysis of melanoma related mortality per age decades, according to the type of treatment. Points represent percent mortality rate for the elapsed decade. No patient less than 40 years who was treated with Ru-106 died of melanoma.

Univariate analysis of survival: all patients (N = 288)

nLRC (%)DFS (%)DSS (%)OS (%)
5 yrs10 yrsp5 yrs10 yrsp5 yrs10 yrsp5 yrs10 yrsp
All2889088-6550-76586846-
Ruthenium1277875716092798768
0.0000.0140.0000.000
Enucleation161100100604264425431
Men1428582615174616647
0.0260.6730.6470.952
Women1469593694978557046
< 60 years1508986745886688464
0.6480.0020.0000.000
≥ 60 years1389090564065475228

The characteristics of patients and tumours by treatment modality

Treatment
BrachytherapyEnucleationTotal
All patients130161291
Excluded3 palliations-3
Treated127161288
Gender
 Man5884142
 Women6977146
Age (median)
 Men58 (29-74)58 (19-86)
 Women60 (22-89)61 (23-92)
T-stage (AJCC)
 138
 269
 38
 No data12
Thickness
 < 3 mm11
 3.1-5.0 mm64
 5.1-7.2 mm49
 > 7.8 mm3
 No data0
Basal diameter
 ≤ 10 mm52
 10,1-12,0 mm38
 > 12 mm25
 No data12
Histology161
 Spindle cell33
 Epithelioid38
 Mixed23
 No data37

Multivariate analysis of survival of all patients (N = 288)

HR95% CIP
lowerupper
All patientsLRCFirst treatment40.8425.565299.7170.000
Gender2.6581.2455.6780.012
DFSFirst treatment1.6281.1442.3160.007
Age < 60 years vs. ≥ 60 years1.8001.2752.5400.001
DSSFirst treatment3.9372.5096.1780.000
Age < 60 years vs. ≥ 60 years2.5341.7143.7470.000
OSFirst treatment3.1532.2184.4800.000
Age < 60 years vs. ≥ 60 years3.8182.7105.3770.000
Gender2.3061.0135.2510.047
RutheniumLRC
Treatment time (≤ 96 h vs. > 96 h)2.8411.2206.6230.015
Treatment time (≤ 96 h vs. > 96 h)2.6741.2765.5870.009
DFSBase (< 11 mm vs. ≥ 11 mm)2.5191.0156.2500.046
T-stage2.3201.0025.3760.050
DSSAge (< 60 years vs. ≥ 60 years)4.7621.70913.3330.003
OSBase (< 11 mm vs v11 mm)3.6101.3919.4340.008
Age (< 60 years vs. ≥ 60 years)5.6502.53812.6580.000
NucleationLRC-----
DFSAge (< 60 years vs. ≥ 60 years)2.1321.1493.9680.016
Histology S VS E VS M1.4671.0002.1510.050
DSSAge (< 60 years vs. ≥ 60 years)2.3261.2294.4030.009
Histology S vs. E vs. M1.5551.0522.2980.027
OSAge (< 60 years vs. ≥ 60 years)3.8762.2226.7570.000
Histology (S vs. E vs. M)1.4441.0511.9830.023

Univariate analysis of survival: patients treated by brachytherapy (N = 127)

LRC (%)DFS (%)DSS (%)OS (%)
n5 yrs10 yrsp5 yrs10 yrsp5 yrs10 yrsp5 yrs10 yrsp
Men586660604990768767
0.0030.0390.7030.859
Women698987816993818870
< 60 years687671766698899883
0.3050.1560.0020.000
≥ 60 years598080655184657552
T-stage
 1387979736797849471
 26979740.45172570.35490750.37886720.508
 38604045458686050
Tumour thickness
 2-5.9 mm9783820.00374660.02192790.48986680.724
 6-.2 mm296454643996809670
Base
 < 11 mm6183830.043800.00296840.02496770.002
 ≥ 11 mm547064604587727864
Dose rate Top (Gy/h)
 ≥ 108 Gy5381780.30274660.09995840.28087720.690
 < 108 Gy527468684689728762
Dose- rate base (Gy/h)
 ≥ 5325382740.70874570.80495810.66587690.862
 < 532527471685589758765
Treatment time
 ≤ 96 hours5287840.01580720.00495840.40089740.565
 > 96 hours536862624089718560

Univariate analysis of survival: patients treated by enucleation (N = 161)None of enucleated patients had local recurrence; DFS = disease free survival; DSS = disease specific survival; n = number of patients; OS = overall survival; yrs = years

DFS (%)DSS (%)OS (%)
n5 yrs10 yrsp5y10 yrsp5 yrs10 yrsp
Men8462510.154635153340.775
Women77593365340,2755627
< 60 years8273520.001765274510.000
≥ 60 years79493050300.0003410
Spindle cell33747081726649
epithelioid3856360.05061330.02955240.026
Mixed cell23622867245215

Singh AD, Bergman L, Seregard S. Uveal melanoma: epidemiological aspects. Ophthalmol Clin North Am 2005;18: 75–84.SinghADBergmanLSeregardSUveal melanoma: epidemiological aspectsOphthalmol Clin North Am200518758410.1016/j.ohc.2004.07.002Search in Google Scholar

Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment and survival. Ophthalmology. 2011; 118: 1881–5.SinghADTurellMETophamAKUveal melanoma: trends in incidence, treatment and survivalOphthalmology20111181881510.1016/j.ophtha.2011.01.040Search in Google Scholar

Virgili D, Gatta G, Ciccolallo L, Capoccacia R, Biggeri A. Incidence of uveal melanoma in Europe. Ophthalmology 2007; 114: 2309–15.VirgiliDGattaGCiccolalloLCapoccaciaRBiggeriAIncidence of uveal melanoma in EuropeOphthalmology200711423091510.1016/j.ophtha.2007.01.032Search in Google Scholar

Cancer incidence in Slovenia 1983–2009. Ljubljana: Institute of Oncology Ljubljana, Cancer Registry of Republic of Slovenia, 1987–2012.Cancer incidence in Slovenia 1983-2009. Ljubljana: Institute of Oncology Ljubljana, Cancer Registry of Republic of Slovenia19872012Search in Google Scholar

Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. COMS report No1. Arch Ophthalmol 1990; 108: 1268–73.Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. COMS report No1Arch Ophthalmol199010812687310.1001/archopht.1990.01070110084030Search in Google Scholar

Shields JA, Shields CL. Current management of posterior uveal melanoma. Mayo Clin Proc 1993; 68: 1196–200.ShieldsJAShieldsCLCurrent management of posterior uveal melanomaMayo Clin Proc199368119620010.1016/S0025-6196(12)60072-XSearch in Google Scholar

Shields JA, Shields CL, De Potter P, Singh AD. Diagnosis and treatment of uveal melanoma. Semin Oncol 1996; 23: 763–7.ShieldsJAShieldsCLDe PotterPSinghADDiagnosis and treatment of uveal melanomaSemin Oncol1996237637Search in Google Scholar

Hungerford JL. Management of ocular melanoma. British Medical Bulletin 1995; 51: 694–716.HungerfordJLManagement of ocular melanomaBritish Medical Bulletin19955169471610.1093/oxfordjournals.bmb.a072987Search in Google Scholar

Albert DM. The ocular melanoma story, Edward Jackson memorial lecture: Part II. Am J Ophthalmol 1997; 123: 729–41.AlbertDMThe ocular melanoma story, Edward Jackson memorial lecture: Part IIAm J Ophthalmol19971237294110.1016/S0002-9394(14)71119-5Search in Google Scholar

Kertes PJ, Johnson JC, Peyman GA. Internal resection of posterior uveal melanomas. B J Ophthalmol 1998; 82: 1147–53.KertesPJJohnsonJCPeymanGAInternal resection of posterior uveal melanomasB J Ophthalmol19988211475310.1136/bjo.82.10.1147Search in Google Scholar

Packer S, Stoller S, Lesser ML, Mandel FS, Finger PT. Long-term results of iodine 125 irradiation of uveal melanoma. Ophthalmology 1992; 99: 767–73.PackerSStollerSLesserMLMandelFSFingerPTLong-term results of iodine 125 irradiation of uveal melanomaOphthalmology1992997677310.1016/S0161-6420(92)31899-8Search in Google Scholar

Vrabec TR, Augsburger JJ, Gamel JW, Brady LW, Hernandez C, Woodleigh R. Impact of local tumor relapse on patient survival after cobalt 60 plaque radiotherapy. Ophthalmology 1991; 89: 984–8.VrabecTRAugsburgerJJGamelJWBradyLWHernandezCWoodleighRImpact of local tumor relapse on patient survival after cobalt 60 plaque radiotherapyOphthalmology199189984810.1016/S0161-6420(91)32193-6Search in Google Scholar

Augsburger JJ, Mullen D, Kleineidam M. Planned combined I 125 plaque irradiation and indirect ophthalmoscope laser therapy for choroidal malignant melanoma. Ophthalmic Surgery 1993; 24: 76–81.AugsburgerJJMullenDKleineidamMPlanned combined I 125 plaque irradiation and indirect ophthalmoscope laser therapy for choroidal malignant melanomaOphthalmic Surgery199324768110.3928/1542-8877-19930201-03Search in Google Scholar

Papageorgiou KI, Cohen VML, Bunce C, Kinsella M, Hungerford JL. Predicting local control of choroidal melanomas following 106 Ru plaque brachy-therapy. Br J Ophthalmol 2011; 95: 166–70.PapageorgiouKICohenVMLBunceCKinsellaMHungerfordJLPredicting local control of choroidal melanomas following 106 Ru plaque brachy-therapyBr J Ophthalmol2011951667010.1136/bjo.2009.176198Search in Google Scholar

Bercher L, Zografos L, Egger E, Chamot L, Uffer S, Gaillaud C. [Treatment of exterior extension of choroid melanomas by accelerated proton beams]. [French]. Klin Monbl Augenheilkd 1992; 200: 440–3.BercherLZografosLEggerEChamotLUfferSGaillaudC[Treatment of exterior extension of choroid melanomas by accelerated proton beams]. [French]Klin Monbl Augenheilkd1992200440310.1055/s-2008-1045787Search in Google Scholar

Zografos L, Bercher L, Egger E. [Treatment of eye tumors by accelerated proton beams. 7 years experience]. [French]. Klin Monbl Augenheilkd 1992; 200: 431–5.ZografosLBercherLEggerE[Treatment of eye tumors by accelerated proton beams. 7 years experience]. [French]Klin Monbl Augenheilkd1992200431510.1055/s-2008-1045785Search in Google Scholar

Saornil MJ, Egan KM, Gragoudas ES, Seddon JM, Walsh SM, Albert DM. Histopathology of proton beam-irradiated vs. enucleated uveal melanomas. Arch Ophthalmol 1992; 110: 1112–8.SaornilMJEganKMGragoudasESSeddonJMWalshSMAlbertDMHistopathology of proton beam-irradiated vs. enucleated uveal melanomasArch Ophthalmol19921101112810.1001/archopht.1992.01080200092031Search in Google Scholar

Char DH, Castro JR, Kroll SM, Irvine AR, Quivery JM, Stone RD. Five-year follow-up of helium ion therapy for uveal melanoma. Arch Ophthalmol 1990; 108: 209–14.CharDHCastroJRKrollSMIrvineARQuiveryJMStoneRDFive-year follow-up of helium ion therapy for uveal melanomaArch Ophthalmol19901082091410.1001/archopht.1990.01070040061031Search in Google Scholar

Char DH, Quivery JM, Castro JR, Kroll SK, Phillips T. Helium ions versus iodine 125 brachytherapy in the management of uveal melanoma. Ophthalmology 1993; 100: 1547–54.CharDHQuiveryJMCastroJRKrollSKPhillipsTHelium ions versus iodine 125 brachytherapy in the management of uveal melanomaOphthalmology199310015475410.1016/S0161-6420(93)31446-6Search in Google Scholar

Char CH, Kroll SM, Castro J. Ten-year follow-up of helium ion therapy for uveal mela-noma. Am J Ophthalmol 1998; 25: 81–9.CharCHKrollSMCastroJTen-year follow-up of helium ion therapy for uveal mela-nomaAm J Ophthalmol19982581910.1016/S0002-9394(99)80238-4Search in Google Scholar

Damato BE, Paul J, Foulds WS. Risk factors for residual and recurrent uveal melanoma after trans-scleral local resection. Br J Ophthalmol 1996; 80: 102–8.DamatoBEPaulJFouldsWSRisk factors for residual and recurrent uveal melanoma after trans-scleral local resectionBr J Ophthalmol199680102810.1136/bjo.80.2.1025053998814738Search in Google Scholar

Char DH. Clinical ocular oncology. 2nd edition. Philadelphia: Lippincott-Raven Publishers; 1997. p. 114–60.CharDHClinical ocular oncology2nd editionPhiladelphiaLippincott-Raven Publishers199711460Search in Google Scholar

Oosterhuis JA, Journee-de Korver HG, Kakebeeke-Kemme HM, Bleeker JC. Transpupillary thermotherapy in choroidal melanomas. Arch Ophthalmol 1995; 113: 315–21.OosterhuisJAJournee-de KorverHGKakebeeke-KemmeHMBleekerJCTranspupillary thermotherapy in choroidal melanomasArch Ophthalmol19951133152110.1001/archopht.1995.011000300710247887845Search in Google Scholar

Lommatzsch PK. Results after beta-irradiation (106Ru/106Rh) of choroidal melanomas: 20 years experience. Br J Ophthalmol 1986; 70: 844–51.LommatzschPKResults after beta-irradiation (106Ru/106Rh) of choroidal melanomas: 20 years experienceBr J Ophthalmol1986708445110.1136/bjo.70.11.84410408403790487Search in Google Scholar

Lommatzsch PK. Radiotherapie der intraokularen Tumoren, insbesondere bei Aderhautmelanom. [Experience in treatment of retinoblastoma in the German Democratic Republic]. [German]. Klin Monbl Augenheilkd 1979; 174: 948–58.LommatzschPKRadiotherapie der intraokularen Tumoren, insbesondere bei Aderhautmelanom. [Experience in treatment of retinoblastoma in the German Democratic Republic]. [German]Klin Monbl Augenheilkd197917494858Search in Google Scholar

Lommatzsch PK, Werschnik C, Schuster E. Long-term follow-up of Ru-106/ Rh-106 brachytherapy for posterior uveal melanoma. Graefe’s Arch Clin Exp Ophthalmol 2000; 238: 129–37.LommatzschPKWerschnikCSchusterELong-term follow-up of Ru-106/ Rh-106 brachytherapy for posterior uveal melanomaGraefe’s Arch Clin Exp Ophthalmol20002381293710.1007/PL00007880Search in Google Scholar

Jančar B. [Choroidal melanoma]. [Slovenian]. Zdrav Vestn 1992; 61: 439–41.JančarB[Choroidal melanoma]. [Slovenian]Zdrav Vestn19926143941Search in Google Scholar

Novak-Andrejčič K, Logar P, Brovet-Zupančič I, Jančar B. [Treatment of choroidal melanoma with Ru-106 brachytherapy - 14-year experience]. [Slovenian]. Zdrav Vestn 2002; 71(Suppl II): 67–70.Novak-AndrejčičKLogarPBrovet-ZupančičIJančarB[Treatment of choroidal melanoma with Ru-106 brachytherapy - 14-year experience]. [Slovenian]Zdrav Vestn200271(Suppl II)6770Search in Google Scholar

Solivetti FM, Elia F, Santaguida MG, Guerrisi A, Visca P, Cercato MC, et al. The role of ultrasound and ultrasound-guided fine needle aspiration biopsy of lymph nodes in patients with skin tumours. Radiol Oncol 2014; 48: 29–34.SolivettiFMEliaFSantaguidaMGGuerrisiAViscaPCercatoMCThe role of ultrasound and ultrasound-guided fine needle aspiration biopsy of lymph nodes in patients with skin tumoursRadiol Oncol201448293410.2478/raon-2013-0084390884424587776Search in Google Scholar

The COMS randomized trial of Iodine125 brachytherapy for choroidal melanoma. COMS report No. 28. Arch Ophthalmol 2006; 124: 1684–93.The COMS randomized trial of Iodine125 brachytherapy for choroidal melanoma. COMS report No. 28Arch Ophthalmol200612416849310.1001/archopht.124.12.168417159027Search in Google Scholar

Guthoff R, Frischmuth J, Jensen OA. [Choroid melanoma. A retrospective randomized comparative study of ruthenium irradiation vs enucleation]. [German]. Klin Monbl Augenheilkd 1992; 200: 257–61.GuthoffRFrischmuthJJensenOA[Choroid melanoma. A retrospective randomized comparative study of ruthenium irradiation vs enucleation]. [German]Klin Monbl Augenheilkd19922002576110.1055/s-2008-10457481614086Search in Google Scholar

Rouberol F, Roy P, Kodjikian L, Gerard JP, Jean-Louis B. Survival, anatomic and functional long-term results in choroidal and ciliary body melanoma after ruthenium brachytherapy. Am J Ophthalmol 2004; 137: 893–900.RouberolFRoyPKodjikianLGerardJPJean-Louis B. Survival, anatomic and functional long-term results in choroidal and ciliary body melanoma after ruthenium brachytherapyAm J Ophthalmol200413789390010.1016/j.ajo.2003.12.03215126155Search in Google Scholar

Damato BE, Heimann H, Kalirai H, Coupland SE. Age, survival predictors, and metastatic death in patients with choroidal melanoma: tentative evidence of a therapeutic effect on survival. JAMA Ophthalmol 2014; 132: 605–13.DamatoBEHeimannHKaliraiHCouplandSEAge, survival predictors, and metastatic death in patients with choroidal melanoma: tentative evidence of a therapeutic effect on survivalJAMA Ophthalmol20141326051310.1001/jamaophthalmol.2014.7724626610Search in Google Scholar

Damato B, Coupland SE. A reappraisal of the significance of largest basal diameter of posterior uveal melanoma. Eye (Lond) 2009; 23: 2152–60.DamatoBCouplandSEA reappraisal of the significance of largest basal diameter of posterior uveal melanomaEye (Lond)20092321526010.1038/eye.2009.23519876071Search in Google Scholar

Kujala E, Damato B, Coupland SE, Desjardins L, Bechrakis NE, Kivela T. Staging of ciliary body and choroidal melanomas based on anatomic extent. J Clin Oncol 2013: 31: 2825–31.KujalaEDamatoBCouplandSEDesjardinsLBechrakisNEKivelaTStaging of ciliary body and choroidal melanomas based on anatomic extentJ Clin Oncol20133128253110.1200/JCO.2012.45.277123816968Search in Google Scholar

Shields CL, Furuta M, Thangappan A, Nagori S. Metastasis of uveal melanoma milimeter by milimeter in 8033 consecutive eyes. Arch Ophthalmol 2009; 127: 898–98.ShieldsCLFurutaMThangappanANagoriSMetastasis of uveal melanoma milimeter by milimeter in 8033 consecutive eyesArch Ophthalmol20091278989810.1001/archophthalmol.2009.20819667335Search in Google Scholar

Damato B. Progress in the management of patients with uveal melanoma. Eye (Lond) 2012; 26: 1157–72.DamatoBProgress in the management of patients with uveal melanomaEye (Lond)20122611577210.1038/eye.2012.126Search in Google Scholar

Paul EU, Paunell BL, Braker M. Prognostic factors in malignant melanoma of the choroid and ciliary body. Int J Ophthalmol Clin 1962; 2: 387–402.PaulEUPaunellBLBrakerMPrognostic factors in malignant melanoma of the choroid and ciliary bodyInt J Ophthalmol Clin19622:38740210.1097/00004397-196206000-00007Search in Google Scholar

Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jöckel KH, Becher R. Prognostic implications of monosomy in uveal melanoma. Lancet 1996; 347: 1222–5.PrescherGBornfeldNHircheHHorsthemkeBJöckelKHBecherRPrognostic implications of monosomy in uveal melanomaLancet19963471222510.1016/S0140-6736(96)90736-9Search in Google Scholar

Onken MD, Worley LA, Person E, Char DH, Bowcock AM, Harbour JW. Loss of heterozygosity of chromosome 3 detected with single nucleotide polymorphisms is superior to monosomy 3 for predicting metastasis in uveal melanoma. Clin Cancer Res 2007; 13: 2923–7.OnkenMDWorleyLAPersonECharDHBowcockAMHarbourJWLoss of heterozygosity of chromosome 3 detected with single nucleotide polymorphisms is superior to monosomy 3 for predicting metastasis in uveal melanomaClin Cancer Res2007132923710.1158/1078-0432.CCR-06-2383Search in Google Scholar

Tschentscher F, Prescher G, Zeschnigk M, Horsthemke B, Lohmann DR. Identification of chromosomes 3, 6, and 8 aberrrations in uveal melanoma by microsatellite analysis in comparison to comparative genomic hybridization. Cancer Genet Cytogenet 2000; 122: 13–7.TschentscherFPrescherGZeschnigkMHorsthemkeBLohmannDRIdentification of chromosomes 3, 6, and 8 aberrrations in uveal melanoma by microsatellite analysis in comparison to comparative genomic hybridizationCancer Genet Cytogenet200012213710.1016/S0165-4608(00)00266-1Search in Google Scholar

Mossbock G, Rauscher T, Winkler P, Kapp KS, Langman G. Impact of dose rate on clinical course in uveal melanoma after brachytherapy with ruthenium-106. Strahlenther Onkol 2007; 10: 571–5.MossbockGRauscherTWinklerPKappKSLangmanGImpact of dose rate on clinical course in uveal melanoma after brachytherapy with ruthenium-106Strahlenther Onkol200710571510.1007/s00066-007-1734-xSearch in Google Scholar

Zimmerman L, McLean IW, Foster WD. Does enucleation of the eye containing malignant a melanoma prevent or accelerate the dissemination of malignant cells. Br J Ophthalmol 1978; 62: 420–5.ZimmermanLMcLeanIWFosterWDDoes enucleation of the eye containing malignant a melanoma prevent or accelerate the dissemination of malignant cellsBr J Ophthalmol197862420510.1136/bjo.62.6.420Search in Google Scholar

Zimmerman L, McLean IW. An evaluation of the enucleation in the management of uveal melanoma. Am J Ophthalmol 1979; 87: 741–60.ZimmermanLMcLeanIWAn evaluation of the enucleation in the management of uveal melanomaAm J Ophthalmol1979877416010.1016/0002-9394(79)90348-9Search in Google Scholar

Seddon JM, Gragoudas ES, Egan KM, Polivogianis L. Relative survival rates after alternative therapies for uveal melanoma. Ophthalmology 1990; 97: 769–77.SeddonJMGragoudasESEganKMPolivogianisLRelative survival rates after alternative therapies for uveal melanomaOphthalmology1990977697710.1016/S0161-6420(90)32512-5Search in Google Scholar

Westphal JR, Hullenaar RV, Geurts-Moespot A, Sweep FC, Verheijen JH, Bussemakers MM. Angiostatin generation by human tumor cell lines. Int J Cancer 2000; 86: 760–7.WestphalJRHullenaarRVGeurts-MoespotASweepFCVerheijenJHBussemakersMMAngiostatin generation by human tumor cell linesInt J Cancer200086760710.1002/(SICI)1097-0215(20000615)86:6<760::AID-IJC2>3.0.CO;2-4Search in Google Scholar

Apte RS, Niederkorn JY, Mayhew E, Alizadeh H. Angiostatin produced by certain primary uveal melanoma cell lines impedes the development of liver metastases. Arch Ophthalmol 2001; 119: 1805–9.ApteRSNiederkornJYMayhewEAlizadehHAngiostatin produced by certain primary uveal melanoma cell lines impedes the development of liver metastasesArch Ophthalmol20011191805910.1001/archopht.119.12.1805Search in Google Scholar

Grossniklaus HE. Progression of ocular melanoma metastasis to the liver JAMA Ophthalmol 2013; 131: 462–9.GrossniklausHEProgression of ocular melanoma metastasis to the liverJAMA Ophthalmol2013131462910.1001/jamaophthalmol.2013.2547Search in Google Scholar

Kauffman EC, Robinson VL, Stadler WM, Sokoloff MH, Rinker-Schaeffer CW. Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site. J Urol 2003; 169: 1122–33.KauffmanECRobinsonVLStadlerWMSokoloffMHRinker-Schaeffer CW. Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary siteJ Urol200316911223310.1097/01.ju.0000051580.89109.4bSearch in Google Scholar

Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No.26. Arch Ophthalmol 2005; 123: 1639–43.Diener-WestMReynoldsSMAgugliaroDJCaldwellRCummingKEarleJDDevelopment of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No.26Arch Ophthalmol200512316394310.1001/archopht.123.12.1639Search in Google Scholar

Straatsma BR, Diener-West M, Caldwell R, Engstrom RE. Mortality after deferral of treatment or no treatment for choroidal melanoma. Am J Ophthalmol 2003; 136: 47–54.StraatsmaBRDiener-WestMCaldwellREngstromREMortality after deferral of treatment or no treatment for choroidal melanomaAm J Ophthalmol2003136475410.1016/S0002-9394(02)02270-5Search in Google Scholar

Damato B. Does ocular treatment of uveal melanoma influence survival. Br J Cancer 2010; 103: 285–90.DamatoBDoes ocular treatment of uveal melanoma influence survivalBr J Cancer20101032859010.1038/sj.bjc.6605765292001920661247Search in Google Scholar

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