Jean Pierre Caujolle

Association chirurgie-protonthérapie dans le traitement des carcinomes invasifs et récidivants de la conjonctive : technique et résultats préliminaires

INTRODUCTION Invasive squamous cell carcinomas are uncommon neoplasias with high recurrence and mortality rates. The improvement of tumoral control requires additional treatments such as cryotherapy, topical chemotherapy, and radiotherapy. We present the technique and preliminary results of associating treatment with surgery and proton beam therapy for recurrent and invasive squamous cell carcinomas. MATERIALS AND METHODS From June 2001 to September 2008, 15 patients were treated in our ocular oncologic center for squamous cell carcinomas either with recurrences or with invaded resection margins. The treatment combined new surgical resection with protontherapy. Specific improvements in proton beam therapy have been made at the Nice Cyclotron to adapt the treatment to conjunctival tumors. Proton beam carving consists in using a specific device to treat the thickness of the whole lesion site and the adjacent conjunctiva and to spare the surrounding healthy structures. RESULTS Patients were staged according to the TNM classification of malignant tumors in T2: 3; T3: 5; T4: 7. Mean follow-up was 39.1 months (range, 6-90 months). Our 15 patients included 12 males and three females. Left eyes were involved in eight cases. The mean age at first consultation was 63.7 years (range, 46-80 years). In 13 cases (86.8%), the bulbar and limbic conjunctiva was involved, in five of these cases the cornea was invaded, and the anterior chamber was involved in one case. In one case, the tumor was located on bulbar conjunctiva near the caruncle (6.6%) and in one case in the fornix (6.6%). One patient died of another cancer after 48 months of follow-up. We obtained local tumor control for 13 patients (86.8%) and recurrences for two patients (13.2%). One of them has presented with cervical node metastases. These two patients who presented recurring and extensive tumors had had previous repeated surgeries in other centers. Moreover, proton beam therapy was performed more than 6 months after the initial treatment. Exenteration and enucleation had to be performed to treat these recurrences 6 and 24 months after proton beam therapy. The exentered patient has been lost to follow-up. No patients developed recurrences with additional proton beam therapy performed within 6 months after initial surgical resection. As for side effects, seven patients suffered from sicca syndrome, six needed cataract surgeries, three unesthetic dilatations of episclera vessels, two conjunctival postradiation dysplasias, two experienced eyelash loss, one stenosis of the lacrimal duct, and one glaucoma controlled by monotherapy. Conjunctiva and amniotic grafts had to be performed on one of the patients presenting with dysplasia. Due to the rarity and diversity of these cases, it is nearly impossible to carry out prospective and comparative studies. CONCLUSION Traditional adjuvant treatments often failed to control recurring and invasive squamous cell carcinomas. We often ended up performing exenteration to control local recurrences. The preliminary results of the present study suggest that proton beam therapy may be considered as a good alternative to traditional treatments with acceptable side effects.

Treatment of Neovascular Glaucoma after Proton Therapy for Uveal Melanomas with Ranibizumab Injection: Preliminary Results

A last-chance intravitreal injection of ranibizumab was administered alone or in combination with cryotherapy before enucleation for 14 melanomas with neovascular glaucoma (NVG) after proton therapy. These patients were uncontrolled despite medical treatment and experienced pain. All of our patients had a minimum of 4 months of follow-up (ranging from 4 to 22 months). In all of the cases, the neovessels disappeared, and the intra-ocular pressure was normal for 11 out of the 14 patients with or without antiglaucoma drops. No patient experienced pain after the first injection. Tumour regression increased in some patients. However, thus far, the number of cases has been too small to perform any statistical analyses. Although very promising, our results are only preliminary.

Conjunctival melanomas and proton beam therapy.

Editor, C onjunctival melanomas get the worst prognosis of all conjunctival malignancies with a 30% death rate at 10 years. Recurrence occurs in more than 50% of the cases with simple surgical excision and increases the risk of metastasis and tumour-related death (Ditta et al. 2011). Since 1992, we have been using cryotherapy and external proton beam irradiation in addition to excisional surgery. For the first treated cases, only bulky melanomas underwent this treatment as an alternative to exenteration (Wuestemeyer et al. 2006). Today, we are extending our indications to tumours over 1.5 mm in thickness, for diffuse and multifocal disease, whenever primary acquired melanosis is present, when the localization involves the fornix or the caruncula and when the margins are involved in histopathological examinations. The first treatment is an excisional surgery. Four tantalium rings are fixed to the sclera to mark the limit of the tumour. A double-freeze cryotherapy is then performed on the excision margins and on the surgical bed. We use new instruments for wound closure to avoid iatrogenic seeding of tumoural cells. For a few months, local chemotherapy with mitomycin C has been added for primary acquired melanosis with atypia. Proton beam irradiation is performed 2 weeks after surgery. A specific device, developed in our department, allows localized radiation of the tumour area, thereby sparing the adjacent healthy structures (Caujolle et al. 2009). A volume in which microscopic disease is expected received 36 grays in 6 fractions. A smaller ‘boost’ volume at high risk is irradiated with additional 16 grays in 2 fractions. Between January 1992 and January 2012, 39 patients with a follow-up of over 6 months have been treated, including eleven with recurrent tumours. Median age was 63 years (33–92 year), and median follow-up was 33 months (6–169 months). According to the 7th TNM classification (Edge et al. 2010), 32 patients were T1N0M0, six were T2N0M0 and one was T3N0M0. Of 39 patients, 11 (28%) were referred to our centre before any surgery, 11 (28%) in the first 3 months following surgery, three patients (8%) between 3 and 6 months following surgery and 14 patients (36%) after 6 months. At 5 years, the rate of overall survival, local-recurrence-free survival and metastasis-free survival was 81% (95% CI: 64–99), 69% (95% CI: 50– 81) and 91% (95% CI: 77–100), respectively. Tumour recurrences occurred in 11 patients (28%) with a mean delay of 40 months (3–114 months). Recurrences were treated with exenteration for five patients and with second proton therapy for six patients. Metastatic spreading was noted in four patients (10%). Two patients (5%) died of melanoma at 4 and 7 years after proton therapy. A total of 22 patients have been treated in the first 3 months after initial surgery. Among them, only 3 (14%) developed recurrences. Neither regional spread nor metastatic spread nor death due to cancer was detected. Among the 17 remaining patients, 8 (47%) developed recurrences. The four patients who developed metastases and the two metastatic deaths belong to this group. Statistical analysis of this cohort is compromised due to the small number of patients and events. Kaplan–Meier curves show a tendency of statistical link between a delay of more than 3 months before referring the patient to our oncological centre and the appearance of recurrence and metastasis. In agreement with Damato & Coupland (2009), we think that the sooner the patient is referred to an oncoophthalmological centre, the better the tumoural control will be. There is no consensus for the treatment for conjunctival melanomas. Yet, the prognosis should be improved by making general ophthalmologists refer their patients to specialists in case of a doubt on a malignant lesion.

528 Lésions pigmentées du fond d’œil : à propos d’un cas de tumeur papillaire pigmentée bilatérale

Introduction Le melanocytome de la papille est rare et plus encore quand il est bilateral. Objectifs et Methodes Nous rapportons le cas d’un patient âge de 36 ans, presentant une lesion papillaire nasale pigmentee de l’œil droit accompagnee d’un decollement sereux retinien inter papillo-maculaire responsable d’une diminution de l’acuite visuelle et de metamorphopsies. Sur l’œil gauche il existe une lesion pigmentee juxta papillaire, avec pigments orange, a type de tumeur melanocytaire a fort potentiel evolutif. La lesion papillaire droite presente les caracteristiques cliniques, echographiques et angiographiques d’un melanocytome. Depuis son suivi dans le service en 2001, cette lesion ne presente aucun signe d’evolutivite. Toutefois, l’analyse de cliches angiographiques anterieurs semble retrouver une periode de modification de taille. Discussion Le melanocytome papillaire est generalement asymptomatique et siege typiquement en temporal inferieur. La transformation maligne est decrite comme exceptionnelle. La difficulte de la prise en charge de ce patient est liee a la fois a la presentation atypique de ce melanocytome avec en particulier la modification de sa taille et son siege nasal mais surtout a la presence d’une lesion pigmentee controlaterale a fort potentiel evolutif. Les effets adverses d’un traitement de cette lesion ne semblent pas se justifier pour le moment dans un tel contexte. Conclusion Deux hypotheses sont envisageables quant a la lesion pigmentee papillaire droite presentee par ce patient. Il s’agit probablement de l’evolution naturelle d’un melanocytome de decouverte initialement fortuite. L’autre hypothese est celle d’une transformation maligne d’un melanocytome. La strategie retenue est une surveillance rapprochee.

025 Résultats préliminaires du traitement par injection intra-vitréenne d’anti-VEGF dans les glaucomes néovasculaires compliquant une protonthérapie pour mélanome uvéal postérieur

Introduction La protontherapie oculaire dans la prise en charge des melanomes malins de l’uvee posterieure est un traitement conservateur permettant un taux eleve de controle tumoral local avec espoir de conservation de la fonction visuelle. Les succes carcinologiques et fonctionnels sont regulierement aneantis par la survenue d’un glaucome neovasculaire conduisant dans un certain nombre de cas a une enucleation de deuxieme intention. Materiels et Methodes Nous avons traite nos premiers patients par injection intra-vitreenne d’anti VEGF lorsqu’un glaucome neovasculaire refractaire au traitement medical maximal associe a un large decollement de retine exsudatif venait compliquer les suites d’une protontherapie oculaire alors que le controle tumoral etait bon. Resultats A un mois, on objective chez tous les patients une normalisation tensionnelle, une reduction de la rubeose et une replication au moins partielle de la retine. Discussion Les traitements par injections intra-vitreennes d’anti-VEGF semblent prometteurs pour le sauvetage de globes oculaires prealablement soumis a un traitement carcinologique conservateur en evitant parfois d’avoir un recours force a l’enucleation d’« yeux douloureux non voyant ». Conclusion L’analyse des premiers resultats va nous conduire a elargir nos indications afin de parfaire la prise en charge des melanomes apres protontherapie.

278 Analyse rétrospective de 1 000 cas de mélanomes malins de la choroïde et du corps ciliaire reçus depuis l’acquisition en juin 1991 d’un cyclotron pour protonthérapie

Objectif Les melanomes malins de l’uvee sont les tumeurs intra-oculaires primitives les plus frequentes et justifient d’evaluer et de parfaire regulierement leur protocole de prise en charge et nos pratiques. Leur relative faible incidence incite a repertorier « tous » les melanomes afin d’y parvenir. L’objectif de notre travail est ainsi de participer a l’effort de creation des bases de donnees nationales qui serviront ce but. Materiels et Methodes Dans cette etude retrospective, 1 000 patients porteurs de melanomes de l’uvee posterieure ont ete admis entre juin 1991 et novembre 2007 afin, pour leur majeure partie, d’etre adresses a notre centre de radiotherapie pour une protontherapie en faisceaux qui reste, apres 17 ans d’usage, l’actuel traitement de reference. Pour chaque patient, nous repertorions son statut anatomique et fonctionnel, ses caracteristiques tumorales, ses particularites de traitement et son devenir avec un suivi de 17 ans a 3 mois. Discussion Nous appuierons notre presentation sur les resultats obtenus chez nos 1 000 patients en termes de survie, de survie sans complication de la maladie ou du traitement, de statut anatomique et fonctionnel des yeux conserves. Nous situerons nos resultats par rapport a nos etudes anterieures et aux donnees de la litterature. Nous degagerons les facteurs pronostiques pour la survenue de metastases ou de complications du traitement et pour le bon resultat fonctionnel d’un traitement conservateur. Conclusion Ce travail initiera la base de donnees de tous les melanomes de l’uvee posterieure deja traites, pour une meilleure lecture de l’enregistrement prospectif national des futurs patients.

780 Traitement des tumeurs malignes conjonctivales par protonthérapie : technique et résultats

Introduction Les tumeurs malignes de la conjonctive sont des tumeurs rares et potentiellement letales necessitant un traitement adjuvant a l’exerese chirurgicale. La protontherapie fait partie des outils therapeutiques a notre disposition. Objectifs et Methodes Nous nous proposons de presenter les specificites techniques imaginees et appliquees dans notre Centre de radiotherapie afin d’adapter la protontherapie, dont l’efficacite a deja ete etablie pour les melanomes choroidiens, au traitement des tumeurs conjonctivales. Le protocole mis en place demande une cooperation etroite entre ophtalmologiste et radiotherapeute. Un reperage par clips scleraux est realise en premier lieu par le chirurgien ; puis l’adaptation d’un compensateur personnalise et un schema d’irradiation fractionne permettent de traiter au mieux la conjonctive bulbaire et palpebrale ainsi que la sclere sur une epaisseur de 2 mm. Resultats Nous appuierons notre presentation sur les resultats obtenus chez les patients presentant un melanome malin – 33 patients dont 12 melanomes primitifs et 21 melanomes recidivant — ou un carcinome invasif – 11 patients dont 4 carcinomes primitifs et 7 carcinomes recidivants- et qui ont beneficie de cette strategie therapeutique depuis 1992. Discussion Notre protocole de protontherapie semble apporter une amelioration dans le traitement des tumeurs malignes de la conjonctive. Les resultats sont neanmoins dependants du type de tumeur et des possibilites d’intervention des la premiere exerese chirurgicale. Conclusion La protontherapie, deja utilisee pour de nombreuses tumeurs malignes oculaires, peut, grâce a notre technique, etre adaptee a la prise en charge des tumeurs malignes de la conjonctive avec une amelioration notable du pronostic, surtout lorsqu’elle est prescrite en premiere intention.