Maximizing local tumor control and survival after proton beam radiotherapy of uveal melanoma.

PURPOSE: This study reports local tumor control and survival after proton beam radiotherapy (PBRT) of uveal melanoma. It identifies the risk factors for local tumor-control failure and for ocular tumor-related death. It presents the improvements implemented to increase the rate of local tumor control, and compares the survival rate of patients with locally controlled tumors to those of patients who had to receive a second treatment. PATIENTS AND METHODS: We have treated 2,435 uveal melanomas with PBRT between March 1984 and December 1998. Data were analyzed as of September 1999. Patients' age ranged from 9 to 89 years; there were 1,188 men and 1,247 women. The largest tumor diameter ranged from 4 to 26 mm, and tumor thickness from 0.9 to 15.6 mm. Median follow-up time was 40 months. RESULTS: Local tumor control probability at 5 years was improved from 90.6 +/- 1.7% for patients treated before 1988, to 96.3 +/- 0.6% for patients treated between 1989 and 1993, and became 98.9 +/- 0.6% for patients treated after 1993. Among 2,435 treated patients, 73 (3%) had to receive a second treatment because of tumor regrowth. Cause-specific survival at 10 years was calculated to 72.6 +/- 1.9% for patients with controlled tumors compared to 47.5 +/- 6.5% for those with recurrent tumors. CONCLUSION: Reduced safety margins, large ciliary body tumors, eyelids within the treatment field, inadequate positioning of tantalum clips, and male gender were identified to be the main factors impairing local tumor control. The improvement of local tumor control rate after 1993 is attributed to changes implemented in the treatment procedure. Our data strongly support that the rate of death by metastases is influenced by local tumor control failure: improvement of the local tumor control rate results in a better survival rate.

Adenocarcinoma of the nonpigmented ciliary body epithelium: report of a rare case.

Acquired tumours of the nonpigmented ciliary body epithelium are rare. We present herein a case of low-grade adenocarcinoma in order to stress the problems related to the clinical diagnosis. The tumour in our case was circumscribed, localised on the ciliary body, and nonpigmented. The height of the tumour, measured with ultrasound biomicroscopy, was 3.5 mm. The internal reflectivity of the tumor was homogeneous with low attenuation. The tumour was surgically excised with an uneventful iridocyclectomy. Both clinical presentation and preoperative examinations allowed to circumscribe the correct diagnosis which could be confirmed only with histology.

Proton beam irradiation of choroidal hemangiomas.

PURPOSE: To present a large series of choroidal hemangiomas treated with proton beam irradiation and to describe the treatment outcomes. METHODS: We treated 54 eyes of 53 patients with choroidal hemangioma. The lesions consisted of 48 circumscribed hemangiomas and six diffuse hemangiomas in patients with Sturge-Weber syndrome. The total applied dose was 27.3 Gy in four eyes, 22.7 Gy in three eyes, and 16.4 Gy to 18.2 Gy in 47 eyes. RESULTS: The retina reattached within six months after treatment in all 54 eyes and no recurrence of the secondary retinal detachment occurred within the follow-up period of 6 months to 9 years. Tumors treated with the higher doses regressed faster than tumors treated with the lower doses, but radiation-induced complications of the optic nerve appeared in all four eyes treated with a total dose of 27.3 Gy. Of 31 eyes treated with 16.4 to 18.2 Gy and followed for more than 1 year, 22 had an improvement in their visual acuity, and nine retained the same visual acuity. At the last follow-up examination, the best-corrected visual acuity was 20/20 or better in nine eyes, 20/40 to 20/25 in 13 eyes, 20/100 to 20/50 in six eyes, and 20/200 or less in three eyes. CONCLUSIONS: Proton beam irradiation of choroidal hemangiomas appears to be a valid therapeutic alternative. A total proton dose ranging from 16.4 to 18.2 Gy applied in four daily fractions seems adequate to ensure local control of both tumor and secondary retinal detachment.

[Value of indocyanine green videoangiography in differential diagnosis of nonpigmented tumors of the choroid]. / Intérêt de l'angiographie numérisée au vert d'indocyanine dans le diagnostic différentiel des tumeurs non pigmentées de la choroïde.

BACKGROUND: Indocyanine green video-angiography (ICG) is a recent examination technique, its possibilities and limitations as far as intraocular tumours are concerned, haven't been fully explored yet. MATERIAL AND METHODS: We have studied 50 cases of non-pigmented choroidal tumours, including 14 cases of choroidal hemangioma's, 11 cases of posterior uveal metastases and 25 cases of non-pigmented melanoma's. RESULTS: Characteristic images were obtained when examining choroidal hemangioma's and, until a certain point, posterior choroidal metastases. Non pigmented melanoma's on the contrary, presented a great variety of different indocyanine green angiographic pictures. CONCLUSION: Indocyanine green video-angiography (ICG) has a definite value in the differential diagnosis of non-pigmented posterior choroidal tumours.

[Contribution of ultrasound biomicroscopy to conservative treatment of anterior uveal melanoma]. / Contribution de la biomicroscopie ultrasonore au traitement conservateur des mélanomes de l'uvée antérieure.

BACKGROUND: Ultrasound Biomicroscopy (UBM) is a new ophthalmological imaging technique essentially designed for the study of the anterior eye segment. Over the last 10 months, we've evaluated its contribution to the conservative treatment of anterior uveal melanoma's by means of accelerated proton beam irradiation. MATERIAL: Using UBM, we have examined 55 cases of uveal melanoma's, whose anterior border was situated at 6 mm or less from the limbus and that were consequently treated by proton beam irradiation. RESULTS: The presumed tumoral origin was the ciliary body's pars plicata in 13 cases and the pars plana or the choroid in 42 cases, 17 of which presented a tumoral invasion of the pars plicata. A pars plana detachment anterior to or surrounding the anterior tumoral border, was present in 22 cases. The height of the tumor could only be measured by UBM if it was less than 2.5 mm. Information gathered using UBM have contributed to an improvement of the therapy plan in 32 cases. CONCLUSION: Because of the strong attenuation of the high frequency ultrasound signal, UBM can only be used for the examination of intra-ocular structures situated in direct neighbourhood to the global wall. Despite this technical limitation, ist contribution to the planning of the conservative treatment of anterior uveal melanoma's by proton beam irradiation has appeared to be considerable.

Cobalt-60 treatment of choroidal hemangiomas.

PURPOSE: We investigated the therapeutic possibilities of gamma brachytherapy to improve the final functional results of eyes with choroidal hemangiomas, which are benign vascular tumors that can induce progressive impairment of visual acuity. METHODS: We treated 41 patients with choroidal hemangioma with cobalt-60 applicators. The lesions consisted of 39 circumscribed hemangiomas and two diffuse hemangiomas in patients with Sturge-Weber syndrome. Before treatment, visual acuity in the affected eye was 20/200 in ten patients, 20/200 to 20/50 in 17 patients, 20/40 to 20/25 in 11 patients, and 20/20 in three patients. All patients were symptomatic. The macula was infiltrated by the tumor in 12 eyes (29.3%). There was retinal detachment in 40 eyes (97.6%), cystoid edema in ten eyes (24.4%), subretinal fibrosis in eight eyes (19.5%), and areolar atrophy in two eyes (4.9%). RESULTS: After treatment, the retina was reattached in all eyes, and the tumor progressively transformed into a flat scar. The postirradiation macular lesions that we identified were pigment migrations in the macular region, subretinal fibrosis, and an areolar atrophic scar. We correlated the functional results at two, five, and ten years after treatment with the initial visual acuity, and with pre-existing and posttreatment macular lesions. CONCLUSIONS: Our results suggest that radiotherapy is a valuable therapeutic modality for choroidal hemangiomas, particularly in hemangiomas that involve the macula, and for tumors associated with bullous retinal detachment.

[Familial uveal melanoma]. / Les mélanomes familiaux de l'uvée.

BACKGROUND: Familial uveal melanoma are rare and a few number of cases has been described in literature until now. An autosomal dominant inheritance was proposed. MATERIAL AND METHOD: From the 2169 patients examined and/or treated in the Jules Gonin Hospital for an uveal melanoma from 1969, we identified 11 patients from 9 families in which at least two members were affected. We compared the clinical data of the familial melanoma with those of the sporadic cases of our collective with the Kruskal-Wallis Tests. The following parameters were studied: age and sex of patients, largest and smallest tumor diameter, height and volume of tumor, distance between tumor and optic nerve and macula, distance of tumor to the equator. Age and sex were also compared with literature. RESULTS: Among the 11 patients, nine were treated with an accelerated proton beam, one with Cobalt60 applicator and one has been enucleated. The median age was 58 years among the probands and 54.6 years among the sporadic cases of the collective. Sex ratio is superposable between both groups: male 45.5%, female 54.5% among the probands and male 48.6%, female 51.4% among the sporadic cases. The comparison between both groups with the Kruskal-Wallis Tests did not show any significant statistical difference. CONCLUSION: An uveal melanoma occurring at least in two members of the same family is not due to chance alone. Genetic factors associated to external factors are probably responsable.

Study of the blood-aqueous barrier in choroidal melanoma.

AIMS: Aqueous flare was used to determine the frequency and amount of blood-aqueous barrier breakdown and correlate it with tumour variables. METHODS: Aqueous flare was analysed prospectively by laser flare photometry in 139 consecutive patients seen in the oncology unit for choroidal melanoma. Both eyes of patients were examined with a laser flare cell meter in a standard fashion. RESULTS: Mean flare difference between healthy and tumour eyes was 3.01 (SD 2.5) photons per millisecond (ph/ms) in 32 cases of small melanomas (p < 0.0001), 10.74 (13.9) ph/ms in 92 cases of medium and large melanomas (p < 0.0001), and 19.23 (11.8) ph/ms in 15 cases of very large melanomas (p < 0.0001). This mean differential flare was significantly higher in medium and large than in small melanomas (p < 0.002) and in very large melanomas than in medium and large melanomas (p < 0.028). A difference of > or = 7 ph/ms between affected and healthy eyes was noted in 70 of 139 melanomas (50.4%). It was found in 3/32 small melanomas (9.4%), in 53/92 medium and large melanomas (57.6%), and in 14/15 very large melanomas (93.3%). CONCLUSION: Multiple linear regression analysis showed that flare was most strongly correlated with tumour volume (r = 0.43; p < 0.0001) and tumour height (r = 0.41; p < 0.0008).

[Metastases to the uvea: statistical study of 133 cases]. / Les métastases de l'uvée: étude statistique de 133 cas.

133 cases of uveal metastasis were reviewed. The study included 97 women and 36 men, aged 10 to 80 (mean 53.1). Breast carcinoma in women and lung carcinoma in men were the primary malignancies, which most frequently led to uveal metastasis. Metastasis from lung carcinoma were often diagnosed before the primary tumor. Survival from ocular diagnosis to death depends on the histological type of the primary tumor.

[Combined surgery, cryocoagulation and radiotherapy for treatment of melanoma of the conjunctiva]. / Chirurgie, cryocoagulation et radiothérapie combinée pour le traitement des mélanomes de la conjonctive.

BACKGROUND: Conjunctival melanomas are malignant tumors with a high local recurrence rate after simple surgical excision. The rate of recurrence is particularly high in cases of large size tumor, of widespread tumors and with PAM associated lesions. Tumor recurrences have a bad long-term prognostic significance and often necessitate exenteration. PATIENTS AND METHODS: A method of therapy combining total surgical excision with proton-beam irradiation, cobalt plaque irradiation and cryotherapy is described. This technique is used in particular unfavorable cases with the aim of lowering the rate of recurrences. It was practiced in 19 cases in Lausanne, 10 of which were recurrent tumors. The melanoma invaded 3 quadrants of the bulbar conjunctiva in 8 cases and 4 quadrants in 11 cases. At least one neighbouring tarsal conjunctiva was invaded in 11 cases and both in 7 cases. The skin of the eyelid was infiltrated in 6 cases and the caruncle in 9 cases. Tumor thickness was 1 to 2 mm in 8 cases, 3 to 4 mm in 4 cases and 5 to 10 mm in 7 cases. RESULTS: PAM was present in 16 cases. Follow-up period was less than 1 year in 2 cases, between 1 to 2 years in 5 cases, between 2 to 3 years in 5 cases and more than 3 years in 7 cases. 5 patients had lymph node metastases, 3 died of metastatic disease and 2 had a local recurrence. One of these recurrences was small-sized and was excised, the other was widespread and the patient died soon with metastatic disease. No exenteration was performed. CONCLUSION: The method of therapy that is here described appears to be a valuable alternative to exenteration of the orbit for the treatment of diffuse or large-size conjunctival melanomas which have a high risk of local recurrence.

[Treatment of eye tumors by accelerated proton beams. 7 years experience]. / Le traitement des tumeurs oculaires par faisceau de protons accélérés. 7 ans d'expérience.

The therapeutic results of 1070 cases of intraocular tumors treated with an accelerated proton beam at the University Eye Clinic of Lausanne and at the Paul Scherrer Institute of Villigen are analysed. This total is composed of 981 cases of uveal melanomas treated by proton beam as first treatment modality, 42 cases of recurrent choroidal melanomas, 16 cases of conjunctival melanomas, 8 cases of choroidal hemangiomas, 18 cases of uveal metastases and of 5 other ocular tumors. The mortality rate at 5 years for tumors treated with an accelerated proton beam as first treatment modality was 13%, and the mortality rate of recurrent melanomas was 23%. The risk factor for life expectancy analysed with the Cox model pointed out that the largest tumor diameter, the width of the tumor, the presence of an extrocular extension and the age of the patient were the most significant parameters. The conclusions of this study are compared with those found in available literature.

[Treatment of exterior extension of choroid melanomas by accelerated proton beams]. / Le traitement des mélanomes exteriorisés de la choroide par faisceau de protons accelerés.

Among the 934 patients with a choroidal melanoma treated in first intention with an accelerated proton beam since 1984, 41 (4.4%) presented an extrascleral extension, of which 11 were located anteriorly and 30 posteriorly. For these 30 cases, the diagnosis was made by B ultrasonography only when the volume of the extension was important, between 20 and 2280 mm3. The Cox model multi-variant analysis was used to study the statistically significant parameters in the development of an extrascleral extension. It appears that the maximal diameter of the intraocular tumor (p = 0.0012), the localisation of the anterior margin (p = 0.0304) and the age of the patients (p = 0.0097) are statistically meaningful. The 4 years' survival, studied with the Kaplan-Meier curves, is estimated at 60% for the patients with extrascleral extension and at 85% for the patients without. These results are similar to those of literature, whatever treatment is chosen (enucleation and radiotherapy, exenteration).

[Uveal melanomas in patients less than 20 years of age]. / Les mélanomes de l'uvée chez les patients de 20 ans et moins.

During the past 15 years we observed 21 uveal tumors in patients aged 20 years and younger. Four of them were younger than 10 years, 4 were 11 to 15 years' old, 4 ranged from 16-17 years and 9 from 18-20 years. An accelerated beam irradiation was applied in 11 cases, a surgical excision was carried out in 4 cases, and a 60 CO-applicator used for 3 patients. Three enucleations were carried out straight away. In this study we present the clinical characteristics of melanomas of young people, the therapy used, as well as the systematic analysis of the vital prognosis of the patients and of the functional prognosis of the eyes under treatment.

[Ocular melanocytosis, oculodermal melanocytosis and choroid melanomas]. / Mélanocytose oculaire, mélanocytose oculodermique et mélanomes de la choroïde.

Among 837 cases of choroidal melanomas treated conservatively, 22 cases (2.69%) presented an ocular or oculodermal melanocytosis. This incidence is compared with the data of the literature. The role of melanocytosis on tumors' parameters and vital prognosis is studied.

[Melanoma of the conjunctiva and its treatment]. / Les mélanomes de la conjonctive et leur traitement.

37 cases of conjunctival melanomas treated in the University Eye Clinic of Lausanne are analysed. This total is made of 20 men and 17 women aged between 19 and 81 years with a mean age of 54.7 years. Tumors were localized in the bulbar conjunctival in 27 cases, in the palpebral conjunctival in 2 cases and were diffuse in 8 cases. Cornea was infiltrated in 19 cases. In 21 cases, the first treatment was made in our service and 16 cases were recurrences following a treatment made elsewhere. The mortality rate to 5 years was 20%. In a multivariant analysis using the COX Model, the height of the tumor was the only significant parameter (p = 0.035) for life expectancy. Recurrence of the tumor (p = 0.060) and presence of a PAM (p = 0.652) were not significant parameters. Benefits of cryocoagulation and indications for a proton beam irradiation are discussed.

[Evaluation of tolerance, efficacy and safety of 3-year simvastatin use in the treatment of primary hypercholesterolemia]. / Evaluation de la tolérance, de l'efficacité et de la sécurité d'emploi de la simvastatine dans le traitement des hypercholestérolémies primaires pendant 3 ans.

Simvastatin (synvinolin MK-733) is a potent inhibitor of 3-HMG-CoA-reductase, the key enzyme for cholesterol biosynthesis. To investigate the efficiency and safety of this new drug on a long term basis, simvastatin was administered for 3 years to ten patients with type II hyperlipoproteinemia. Daily dosages were 20 or 40 mg. The drug therapy produced a significant reduction in serum levels of total cholesterol (19-34%), LDL-cholesterol (26-44%) and Apo B (19-33%). Triglycerides decreased moderately (2-23%) while HDL-cholesterol and Apo A1 changed only slightly (-3 to 6% and 5-13% respectively). Simvastatin was well tolerated. No consistent adverse clinical or biochemical effects were observed during the three-year therapy. The results indicate that simvastatin is a promising new therapy for high risk hypocholesterolemic patients.

[Irradiation treatment of choroidal hemangiomas]. / Le traitement des hémangiomes de la choroïde par radiothérapie.

Therapeutic results obtained following the treatment of 24 cases of choroidal hemangiomas (21 solitary and 3 in a Sturge-Weber syndrome) treated with 60Co applicators or an accelerated proton beam were analyzed. The observation period was less than 2 years for 4 cases, 2 to 5 years for 10 cases, 5 to 10 years for 7 cases and more than 10 years for 3 cases. Reabsorption of retinal detachment without any recurrency was obtained for all the cases. The V.A. was increased in 16 cases, did not change in 4 cases and decreased in 4 other cases. Final V.A. was 6/7.5 or more in 9 cases (37.5%), 6/60 à 6/7.5 in 6 cases (25%), and 6/60 or less in 9 cases (37.5%). None of the cases we treated presented complications induced by radiotherapy (actinic papillitis, circulatory disturbances in the macular area, or neovascular glaucoma). The comparison of the results we obtained with cases treated by photocoagulation or external radiotherapy demonstrated a slight advantage in favour of the focalized radiotherapy, which is not statistically significant because of the small number of cases included in the studies. Meanwhile, contact radiotherapy and irradiation with an accelerated proton beam seems to be a substantial alternative for the treatment of large hemangiomas and tumors invading the macula.