[Results of treating uveal melanoma with proton beam radiation: 10-year follow-up]. / Résultats du traitement du mélanome malin de l'uvée par faisceau de protons: 10 ans de recul.

PURPOSE: We analyzed the long-term results of uveal melanoma treatment with proton beam irradiation in a series of patients with a follow-up of at least 10 years. PATIENTS AND METHODS: The patients were treated with proton beam radiation between September 1991 and December 1992. They had an initial examination including visual acuity, funduscopy, A and B scan ultrasonography of the eye, fundus photographs and fluorescein angiography. General examination included chest radiography and B scan ultrasonography of the liver. All tumors received a total dose of 60 cobalt-Gray equivalents (applied in four daily fractions) at the Orsay proton therapy center. RESULTS: A total of 167 patients were treated with a median follow-up of 116 months. Their median age was 59 years. Thirteen tumors were anterior to the equator, 76 overlapped the equator and 78 were posterior to the equator. An initial retinal detachment was present in 41 cases. The optic disk was invaded in 10 cases. The median tumor diameter was 12 mm and the median tumor thickness was 5.8 mm. The mean initial acuity was 20/50. The survival rate was 62.93% at 10 years; 72.9% of deaths resulted from metastasis. Statistically significant risk factors for death identified in the multivariate analysis were tumor diameter greater than 12 mm (p=0.0004) and age over 60 years (p=0.0001). The metastasis rate at 10 years was 31%. The liver was affected in 97.8% of these patients. Risk factors for metastasis were the anterior site of the tumor, its volume greater than 0.4 cc and the presence of retinal detachment at diagnosis. The secondary enucleation rate at 10 years was 13.23%, mainly attributable to secondary neovascular glaucoma. The local recurrence rate was 6%. The visual acuity rate in 42.1% of patients was better than 20/100 at 10 years. Visual loss was mainly due to postradiation maculopathy and neuropathy. CONCLUSION: Our study confirms the long-term results found in the literature on proton beam radiation. This therapy allows good tumor control, an excellent eye retention rate, and good final visual acuity for approximately half of the patients.

[Radiotherapy in the treatment of eyelid tumors]. / Place de la radiothérapie dans le traitement des tumeurs des paupières.

We describe the different radiation therapy techniques for malignant tumors of the eyelid, their results in squamous-cell and basal-cell carcinoma, their side effects, and the advantages and disadvantages compared to surgery. The most frequent indications for radiation in the management of these tumors are also reviewed.

[Results of proton beam irradiation for treatment of choroidal melanoma]. / Résultats du traitement du mélanome de la choroïde par faisceau de protons.

PURPOSE: To evaluate the results of proton beam irradiation of choroidal melanomas on a large series of patients. PATIENTS AND METHODS: Retrospective analysis of a series of patients treated with proton beam irradiation between 1991 and December 1998. The data were analyzed to evaluate the local tumor control as well as the general progression and metastatic rate of the patients. Statistical analysis served to isolate risk factors for relapse or metastasis. RESULTS: We treated 1062 patients during the study period, with a median follow-up of 38 months. Local control was obtained for 97.1% of the patients. Tumors anterior to the equator were at risk for relapse. The survival rate was 92% at 2 years and 78% at 5 years. 73.1% of the 1062 patients died from metastasis, 6.1% of living patients presented with metastatic disease. The risk factors for death were the initial diameter, the age of the patient, and large tumor volume at diagnosis. Metastasis were essentially hepatic (94.6%). Risk factors for metastasis were: a large tumor volume, a lesion anterior or straddling the equator and the age of the patient. Ocular complications may induce a visual loss of 0.1 and less in 47% of the patients, due to optic nerve head and macular ischemia. 6% of the patients required secondary enucleation due to local complications (neovascular glaucoma). CONCLUSION: Proton beam irradiation of choroidal melanoma allows good tumor control and eye retention. The survival prognosis is associated with the initial volume of the tumor. The functional results may be improved and new therapeutics are needed to treat metastatic disease.

Intraocular inflammation after proton beam irradiation for uveal melanoma.

AIM: To describe the inflammatory reaction that can occur following proton beam irradiation of uveal melanomas based on a large series of patients and to try to determine the risk factors for this reaction. METHODS: Data from a cohort of patients with uveal melanoma treated by proton beam irradiation between 1991 and 1994 were analysed. The presence of inflammation was recorded and evaluated. Kaplan-Meier estimates and statistical analysis of general and tumour related risk factors were performed. RESULTS: 28% of patients treated during this period presented with ocular inflammation (median follow up 62 months). Risks factors were essentially tumour related and were correlated with larger lesions (height > 5 mm, diameter > 12 mm, volume > 0.4 cm(3)). Multivariate analysis identified initial tumour height and irradiation of a large volume of the eye as the two most important risk factors. Ocular inflammation usually consisted of mild anterior uveitis, resolving rapidly after topical steroids and cycloplegics. The incidence of inflammation after proton beam irradiation of melanomas seems higher than previously reported and is related to larger lesions. Evidence of inflammation associated with uveal melanoma has been described and seems to be associated with tumour necrosis (spontaneous or after irradiation). The appearance of transient inflammation during the follow up of these patients may be related to the release of inflammatory cytokines during tumour necrosis. CONCLUSION: Inflammation following proton beam irradiation is not unusual. It is correlated with larger initial tumours and may be related to tumour necrosis.

Osteosarcoma following retinoblastoma: age at onset and latency period.

In order to assess the role of genetic predisposition in the induction of radiation-induced tumors, we performed statistical analysis on data from the literature and from our own Institute with regard to the age at onset and the latency period of osteosarcoma as the second primary tumor for retinoblastoma with or without subsequent radiotherapy. In retinoblastoma survivors who subsequently developed osteosarcoma, the age at onset of retinoblastoma was young (average of 12 months) in both unilateral and bilateral forms. This suggests that all or almost all of the patients were genetically predisposed by a mutation of one allele of the RB1 gene. For retinoblastoma patients, osteosarcomas occurred 1.2 years earlier inside than outside the radiation field. The latency period between radiotherapy and osteosarcoma onset was 1.3 years shorter inside than outside the radiation field. Interestingly, a bimodal distribution of latency periods was observed for osteosarcomas arising inside, but not outside the radiation field: 40% occurred after a short latency, while the latency of the remaining 60% was comparable to that of osteosarcoma occurring outside the radiation field. This suggests that different mechanisms may be involved in radiocarcinogenesis. A radiation-induced mutation of the second RB1 allele may be the cause of osteosarcomas occurring after a short delay, while other genes may be affected in those occurring after a longer delay.

[Neovascular glaucoma following proton-beam therapy. Case report]. / Glaucome néovasculaire compliquant la protonthérapie. A propos d'une observation.

A 52-year-old-male patient was treated for a posterior choroid melanoma of the right eye. When it was diagnosed, it measured 6mm in thickness and 11.9mm for the largest diameter and had a typical mushroom shape. General investigations found no metastatic disease. It was treated with proton-beam irradiation. Seven years later, the patient experienced increased intraocular pressure associated with cataract and pain. The patient finally accepted enucleation, as the vision of this eye was completely lost and the eye had become painful. Histologic analysis of the eye showed changes affecting both the anterior and the posterior segments of the eye, mostly related to the tumor and the consequences of treatment. Neovascular glaucoma is a major complication that very often leads to enucleation.

[Optic neuropathy after proton-beam therapy for malignant choroidal melanoma]. / Neuropathie optique après protonthérapie pour mélanome malin de la choroïde.

Proton-beam irradiation is a conservative therapy commonly used for the treatment of uveal malignant melanomas. Some adverse effects such as optic neuropathy can compromise the visual outcome. We were interested in determining the risk factors for radiation papillopathy. Since there is currently no effective therapy, this is an interesting way to improve prevention of optic neuropathy. Six hundred sixty-two eyes had more than 24 month follow-up after proton-beam irradiation for uveal melanoma. In five hundred twenty-two cases, the clinical examination of the optic nerve head by ophthalmoscopy was possible. One-hundred eleven optic discs were pathologic, whereas 411 remained disease-free. Retrospective study of these two groups allowed to quantify the risk factors for optic neuropathy. The irradiation of more than 2mm of optic nerve at 30 Grays-equivalents appeared to be the major risk factor for optic neuropathy. For a given irradiation dose, the observed pattern of clinical responses was heterogeneous. These results are discussed and compared to the previous published reports. Visual results and life prognosis are also discussed, considering the optic nerve head status. Proton-beam therapy can preserve the optic nerve when the tumor location allows to keep it away from the irradiation-field. Patients must be informed about the risk of optic neuropathy after proton-beam irradiation.

[Current treatment of retinoblastoma. 153 children treated between 1995 and 1998]. / Le traitement actuel du rétinoblastome. 153 enfants traités entre 1995 et 1998.

PURPOSE: Treatment of retinoblastoma has changed significantly over the past few years. There are fewer indications for external beam radiation and a new treatment modality, chemotherapy, has appeared. MATERIAL: and methods: We reviewed a series of 153 children treated for retinoblastoma between 1995 and 1998. There were 67 boys and 86 girls: 76 unilateral and 77 bilateral retinoblastomas. Indications for treatments and outcome were reviewed for 230 eyes and for each tumor. Age at diagnosis varied from 0 to 94 months with a median age of 12 months. A family history of retinoblastoma was found in 24 cases. Three children were seen for treatment of recurrence. RESULTS: Among the 76 cases of unilateral retinoblastoma, 56 were enucleated and 20 were treated conservatively (5 with external beam radiation). Among the 154 eyes with bilateral retinoblastoma, 48 were enucleated and 106 were treated conservatively (49 by external beam radiation). Local treatments included chemothermotherapy, laser alone, cryotherapy, and (125)I plaques. Conservative management other than external beam radiation was used for 81 eyes and was successful in 72 (89%). CONCLUSION: We discuss the indications and results of primary chemotherapy and local treatments. External beam radiation is still often indicated in bilaterally advanced cases. In other forms of retinoblastoma, chemothermotherapy is a very reliable and useful treatment.

Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, P14ARF or cdk4 genes.

In familial cutaneous malignant melanoma (CMM), disruption of the retinoblastoma (pRB) pathway frequently occurs through inactivating mutations in the p16 (p16INK4A/CDKN2A/MTS1) gene or activating mutations in the G1-specific cyclin dependent kinase 4 gene (CDK4). Uveal malignant melanoma (UMM) also occurs in a familial setting, or sometimes in association with familial or sporadic CMM. Molecular studies of sporadic UMM have revealed somatic deletions covering the INK4A-ARF locus (encoding P16INK4A and P14ARF) in a large proportion of tumours. We hypothesized that germline mutations in the p16INK4A, p14ARF or CDK4 genes might contribute to some cases of familial UMM, or to some cases of UMM associated with another melanoma. Out of 155 patients treated at the Institut Curie for UMM between 1994 and 1997, and interviewed about their personal and familial history of melanoma, we identified seven patients with a relative affected with UMM (n = 6) or CMM (n = 1), and two patients who have had, in addition to UMM, a personal history of second melanoma, UMM (n = 1), or CMM (n = 1). We screened by polymerase chain reaction single-strand conformation polymorphism the entire coding sequence of the INK4A-ARF locus (exon 1alpha from p16INK4A, exon 1beta from p14ARF, and exons 2 and 3, common to both genes), as well as the exons 2, 5 and 8 of the CDK4 gene, coding for the functional domains involved in p16 and/or cyclin D1 binding. A previously reported polymorphism in exon 3 of the INK4A-ARF locus was found in one patient affected with bilateral UMM, but no germline mutations were detected, either in the p16INK4A, p14ARF or CDK4 genes. Our data support the involvement of other genes in predisposition to uveal melanoma.

[Complications of hydroxyapatite orbital implants in children: a series of 105 cases]. / Complications des implants orbitaires en hydroxyapatite chez l'enfant. A propos de 105 cas.

PURPOSE: To describe the complications encountered using hydroxyapatite as an orbital implant in the pediatric population after enucleation, and try to define the risk factors for their occurrence. MATERIAL: and methods: Retrospective review of charts of children who underwent enucleation with placement of an hydroxyapatite implant between January 1991 and 1998. Complications and their type (conjunctival, extrusion, eyelids complications) have been specifically looked for. A statistical analysis trying to isolate the risks factors was performed. RESULTS: 105 implants have been used during this period with 26.7% of complications appearing during a median followup of 22 months. Extrusion of the implant was observed in 1.9% of the cases, a chronic conjunctival erosion in 15%, a conjunctival lesion without erosion in 4.75% and no eyelid lesion could be seen. Treatment (medical or surgical) achieved 75% good results. No risk factor could be found. CONCLUSION: Hydroxyapatite orbital implants were initially thought to have no or few complications. More recently, chronic erosions in particular were described. Little data exists on the pediatric population. Our series confirms that complications occur and that they are comparable to the adult population. Nevertheless the hydroxyapatite orbital implant seems better tolerated than other porous or non porous implants and warrants its use.

Histologically similar, synchronous or metachronous, lacrimal salivary-type and parotid gland tumors: A series of 11 cases.

BACKGROUND: Restricted presentation of malignancy at both lacrimal and parotid salivary glands are unusual occurrences that may pose clinical and diagnostic difficulties. METHODS: We applied certain clinicopathological criteria to distinguish between lacrimal and parotid gland primaries in a series of 11 patients with synchronous and/or metachronous tumors of similar histology at both sites. RESULTS: Of eight patients with primary lacrimal carcinomas, seven had metachronous metastases to parotid glands. All three patients with primary parotid carcinomas had concurrent metastases to lacrimal glands. Patients with primary lacrimal tumors metastasizing to the parotid gland appear to have better clinical outcome in comparison with those with parotid primary with secondary lacrimal metastases. CONCLUSION: Careful examination of parotid glands in the assessment of any lacrimal gland tumor with high-grade adenocarcinoma morphology is recommended to rule out the possibility of a parotid primary.

[Prognostic factors in malignant melanoma of the conjunctiva. An anatomo-clinical study of 56 patients]. / Facteurs pronostiques du mélanome malin de la conjonctive. Etude anatomo-clinique sur 56 patients.

UNLABELLED: We have reviewed a serie of 56 patients treated in our Institute for malignant melanoma of the conjunctiva between 1980 and 1992. We selected cases where histology had been reviewed. PATIENTS AND METHOD: The median follow up is 96 months. The age varies from 13 to 88 years with a mean age of 56 years. There were 22 men and 34 females. In 29 cases (51%) the melanoma appeared de novo, ten cases (17%) it derived from a naevus and in 14 cases (25%) on a precancerous melanosis. The tumour was localized at the limbus and bulbar conjunctiva in 57% of cases. The mean diameter was 6.1 mm and the mean thickness was 2.3 mm. The treatment consisted in surgical excision of the tumour followed by external beam radiothérapy in 49 cases. Histological examination showed invasion of the chorion in 44 cases (78%) and of the sclera in 6 cases (1%). RESULTS: 38 patients are alive and 29 without disease. 2 with disease, 7 lost follow-up. 18 patients died (32%) and among them 14 (25%) died of metastatic disease. 22 patients (39%) have presented local recurrence and among them 10 have had multiple recurrences. The mean delay for recurrence was 56 months. The overall survival was 77% at 5 years and 64% at 10 years. Tumours appeared de novo have a worse prognosis. If we consider the localization tumour located at the limbus or on bulbar conjunctiva have less metastasis. CONCLUSION: Malignant melanoma of conjunctiva is a tumour that can frequently recur. Metastasis are not infrequent and follow up must be prolonged.

[Unilateral retinoblastomas with late bilateralization. Three case reports]. / Rétinoblastomes unilatéraux avec bilatéralisation tardive. A propos de 3 cas.

Three cases of unilateral retinoblastoma with late bilateralization are presented in this study. The rare occurrence of this event underlines the need for prolonged follow-up in the fellow-eye, even in the absence of familial retinoblastoma. In these three cases, the first affected eye was enucleated after a diagnosis made at three months, sixteen months and three years of age. New tumors appeared in the second eye when the children were sixteen years old in one case and five years old in two cases.

A preliminary comparative treatment planning study for radiotherapy of age-related maculopathy.

PURPOSE: We present a comparative planning of different approaches for external radiotherapy in age-related maculopathies. MATERIALS AND METHODS: Calculated dose distributions and dose-volume histograms for (a) bilateral irradiation with 6 MV photons, (b) a single lateral-oblique beam using either photons, electrons or protons and (c) an anterior circular proton beam. RESULTS: For lateral photon or electron beams the dose to the lens is usually lower than 10% of the dose to the macula. The entrance doses for bilateral photon beams are about 50% which increase up to 100% at the orbital bone. About 5 mm of optic nerves are irradiated at the maximal dose while the optic chiasma is spared. A single photon beam gives 50% of the dose to the fellow eye. The electron beam spares the fellow eye but gives a rather inhomogeneous dose to the target volume. For a lateral proton beam, 4 mm of optic nerve receives 90% of the dose, the skin dose is at least 70% of the dose to the macula and the lens and the fellow eye are spared. An anterior proton beam gives 90% of the dose to 1 mm of optic nerve and the 50% isodose approaches the periphery of the lens. CONCLUSION: Doses to the critical structures can be dramatically diminished for all the techniques by reducing the beam size, but only if very precise set-up techniques are used. Proton beams are an attractive solution, but the impact of such a choice on the use of proton facilities and on the national health system should be carefully evaluated, as well as the risk of radio-induced secondary neoplasias.

Treatment of liver metastases from uveal melanoma by combined surgery-chemotherapy.

AIMS: To investigate sporadic results demonstrating prolonged survival after surgical resection and/or intraarterial chemotherapy (IACH) for liver metastases from uveal melanoma. METHODS: From December 1992 to March 1997 every patient with liver metastases from uveal melanoma was enrolled in a prospective study including: (1) aggressive surgical approach removing as much liver disease as possible; (2) implantation of an intraaterial catheter; (3) intraarterial chemotherapy for 6 months. 75 patients were enrolled: 38 men, 37 women, mean age 51 years (range: 18-72), mean time from initial diagnosis of uveal melanoma to liver metastases 37 months (ranged: 1-168). RESULTS: Disseminated disease in both lobes was present in all but one patient. Macroscopically curative surgery was possible in 27.5%. Significant tumour reduction was performed in 49.3% and a simple biopsy was possible in 23.2%. Eight patients did not receive chemotherapy and died soon after. IACH included Fotemustine and/or DTIC-Platinum for 4-9 cycles. Overall median survival was 9 months; very similar to non-operated historical controls. In the 61 patients receiving complete treatment surgery plus chemotherapy, median survival improved to 10 months. When curative resection was possible, survival increased to 22 months (P < 0.001). CONCLUSIONS: Aggressive surgical resection, when possible, appears to be the best method of improving survival of liver metastases from uveal melanoma. New drug combinations are also required to improve survival.

Role of chemotherapy alone or in combination with hyperthermia in the primary treatment of intraocular retinoblastoma: preliminary results.

BACKGROUND: The efficacy of the etoposide-carboplatin combination in extraocular retinoblastoma is well known. This drug combination is therefore used in intraocular retinoblastoma, as primary reduction chemotherapy, before local treatment. The use of carboplatin in combination with diode laser hyperthermia as local treatment (thermochemotherapy) has been recently described as a conservative approach avoiding external beam radiotherapy in posterior pole tumours. METHODS: All patients were reviewed, who were treated for retinoblastoma at the Institut Curie between June 1994 and October 1995, in whom treatment included either reduction chemotherapy or thermochemotherapy or both modalities successively. 23 patients presenting with unilateral (three) or bilateral (20) intraocular retinoblastoma received neoadjuvant chemotherapy consisting of two courses of etoposide 150 mg/m2/day and carboplatin 200 mg/m2/day for 3 days. 15 patients (17 eyes), eight of whom had already received neoadjuvant chemotherapy, were treated by thermochemotherapy. RESULTS: Neoadjuvant chemotherapy: overall, seven eyes in seven patients could be treated conservatively, avoiding external beam irradiation, with a median follow up of 14 months. Thermochemotherapy: external beam irradiation was avoided for 14 of the 17 eyes treated. CONCLUSION: Integration of neoadjuvant chemotherapy and combined treatment with carboplatin and diode laser, into the therapeutic armamentarium for retinoblastoma allows use of more aggressive treatments such as enucleation and external beam radiation.

[Initial results of proton therapy in choroidal melanoma at the d'Orsey Center for Proton Therapy; the first 464 cases]. / Résultats préliminaires de la protonthérapie du mélanome de la choroïde au centre de protonthérapie d'Orsay (CPO): les 464 premiers cas.

PURPOSE: Retrospective analysis of the treatment of choroidal melanoma with protontherapy at the Centre de protonthérapie d'Orsay, France. PATIENTS AND METHODS: Between September 1991 and September 1995, 612 patients presenting with choroidal melanoma were treated by protontherapy in Orsay. Following initial management of the first 464 patients, results were analyzed, as were results after a 1-year follow-up for 305 patients, a 2-year follow-up for 169 patients, and a 3-year follow-up for 59 patients. RESULTS: Univariate analysis showed that the actuarial local recurrence rate was 5%, the 3-year survival rate 88%, and the overall metastasic rate 5%. The initial tumor volume was the most significant predictive factor for visual results and metastases. Multivariate analysis revealed that visual results were significantly related to the initial tumor volume, initial retinal detachment, and total dose delivered to the optic nerve and macula. CONCLUSION: Protontherapy of choroidal melanoma allows in most cases conservation of the eye without modification of survival. Visual results mainly depend on the site and size of the tumor.

Histopathologic risk factors in retinoblastoma: a retrospective study of 172 patients treated in a single institution.

BACKGROUND: Microscopic extrascleral involvement and involvement of optic nerve resection line are accepted risk factors for orbital and/or metastatic disease from retinoblastoma. Conversely, choroidal and retrolaminar optic nerve involvement are questionable risk factors. The aim of this retrospective study was to define the histopathologic risk factors for orbital and/or metastatic disease in patients treated by first-line enucleation. METHODS: Histopathologic review of 172 evaluable patients treated at Institut Curie between 1977 and 1990 determined the degree of choroidal (minimal or massive), scleral (intra- or extrascleral), optic nerve (prelaminar, retrolaminar with or without resection line involvement), and anterior chamber invasion. The degree of differentiation was also analyzed. The log rank test was used for univariate analysis and the Cox regression model was used for multivariate analysis. RESULTS. Eighty-seven percent of the 172 patients were disease free at 3 years. Twenty-three patients developed retinoblastoma recurrence. The disease-free survival was significantly different among the five subgroups of choroidal or scleral invasion (P = 3 x 10(-3). The differences among the four subgroups of optic nerve invasion were also significant (P = 10(-4)). Classical factors were confirmed in our series (extrascleral involvement and involvement of optic nerve resection line). Multivariate analysis of the 149 patients without these classical risk factors revealed two factors that increase the risk of orbital and/or metastatic disease: massive choroidal invasion and postlaminar optic nerve involvement. CONCLUSIONS: In our experience, retrolaminar optic nerve involvement, with free resection line, and massive choroidal invasion significantly increase the risk for orbital and/or metastatic disease.

External radiotherapy for carcinoma of the eyelid: report of 850 cases treated.

PURPOSE: We report a retrospective series of 850 patients treated by external irradiation for carcinoma of the eyelid at Institut Curie and we compare our results with other techniques: brachytherapy and surgery. METHODS AND MATERIALS: Eight hundred fifty patients were treated by external radiotherapy for carcinoma of the eyelid. None of these patients have been previously treated. All the patients were classified according to the TNM classification of (UICC). We distinguished five histological types and five clinical groups according to the site of the skin tumor. Three modalities of external radiotherapy were used: contact therapy, conventional radiotherapy, and electrontherapy. We reviewed the clinical files of the 850 patients who went regularly at follow-up visits. RESULTS: We report the 5-year survival results--alive with no evidence of disease: 72%; alive with progression: 2%; died from tumor progression: 0.5%; died from intercurrent disease: 19.5%; and lost to follow-up: 5%. The 5-year local control rate was 97.5%. We observed 45 failures--lymph node, metastatic, and local--and emphasize this last group by presenting the results of treatment of these local failures. We studied the complications of treatment: 2.3% of corneal complications, 2% of cataracts, and 1.4% of serious ocular complications. CONCLUSIONS: Our results concerning local failures and loss of the eye are comparable to those reported for other techniques involving brachytherapy or surgery. Overall, external radiotherapy is a safe and effective treatment, as it ensures a high local control rate and provides perfectly satisfactory functional and esthetic results. It seemed particularly useful to report this series in that few publications are available on this subject that, nevertheless, constitutes a topical issue.