F. Doz

Are children born after infertility treatment at increased risk of retinoblastoma

BACKGROUNDnRetinoblastoma (RB) is the most frequent eye tumour in children, with an incidence of 1 in 15-20,000 births. It accounts for 11% of all cancers in the first year of life. Except for the hereditary forms, its causes are not well-known. Studies have recently suggested an increased risk of RB among children born after IVF, but the relevant literature is sparse. We assessed the association between infertility treatment, subfertility and RB.nnnMETHODSnWe included all children living in France diagnosed with RB between 1 January 2000 and 31 December 2006 at the Institut Curie, the national reference centre for RB diagnosis and treatment. We used multiple logistic regression to compare them with a national sample of births in France in 1998 and 2003 (n = 28 170).nnnRESULTSnThe study included 244 non-familial RB cases. The risk of RB increased with maternal age [adjusted odds ratio (adj OR) = 2.07, 95% confidence interval (CI) 1.33-3.22 at 35-39 years compared with younger than 25 years and adj OR = 2.42, 95% CI 1.22-4.81 at 40 years or older], but the associations with IVF (adj OR = 1.37, 95% CI 0.64-2.95) and ovarian stimulation or intrauterine insemination (adj OR = 1.35, 95% CI 0.77-2.38) were not statistically significant after adjustment for maternal age and tobacco use. Among women who had no infertility treatment, the risk of RB was significantly increased when time to pregnancy exceeded 24 months (adj OR = 2.02, 95% CI 1.17-3.48) compared with time to pregnancy ≤ 24 months.nnnCONCLUSIONSnOur study did not observe a significantly increased risk of RB associated with infertility treatment, in particular with IVF. But we did find an increased risk for women for whom time to pregnancy exceeded 24 months.

Familial retinoblastoma: fundus screening schedule impact and guideline proposal. A retrospective study

AimsTo assess if systematic fundus screening according to an ‘intensive’ schedule alters ocular outcome and to propose fundus screening schedule guidelines for children related to a retinoblastoma patient.MethodsFor children with a positive family history of retinoblastoma, we perform fundus exams shortly after birth under general anaesthesia and then at regular intervals according to schedules based on the risk. Familial retinoblastoma cases seen at our institution from January 1995 to December 2004 were retrospectively classified as ‘screened’ or ‘non-screened’ (NS) and, among the ‘screened’ patients, as ‘intensively screened’ (IS) if screening matched our recommendations or ‘non-intensively screened’ (S). Groups were compared by Fisher exact test for categorical variables and Kruskal–Wallis test for continuous variables.ResultsAmong the 547 retinoblastoma patients managed at our institution during this period, 59 were familial cases. In all, 20 were in the NS group, 23 in the S group, and 16 in the IS group. The number of children enucleated was, respectively, 13, 2, and 0 (P<10−4); external beam radiation (EBRT) was required for, respectively, 6, 0, and 2 children (P<0.009). Chemotherapy burden and visual acuity were not significantly different between groups.ConclusionAn ‘intensive’ fundus screening schedule decreased the need for enucleation and EBRT. Therefore, despite the heavy burden of the screening schedule, we recommend physicians and health-care professionals to better inform and refer children with a family history of retinoblastoma for genetic counselling and proper fundus screening in specialized centres.

Diagnostic différentiel du rétinoblastome : étude rétrospective de 486 cas

Differential diagnosis of retinoblastoma: a retrospective study of 486 cases A. Vahedi, L. Lumbroso-Le Rouic, C. Levy Gabriel, F. Doz, I. Aerts, H. Brisse, O. Berges, M.T. Iba Zizen, L. Desjardins Objectives: Detail the most frequent problems encountered in the differential diagnosis of retinoblastoma. Patients and method: We conducted a retrospective study on the children referred to the Curie Institute for suspicion of retinoblastoma between 2000 and 2006. Diagnosis was made by fundus examination using the indirect ophthalmoscope, ultrasonography, and MRI. Results: Of the 486 children seen during this period, 408 had unilateral or bilateral retinoblastoma and 78 (16%) had another lesion: Coats disease (20 children, 25%), congenital malformations (23 children, 30%; coloboma, PHPV, microphthalmia, isolated or associated with retinal dysplasia), other tumors (10 children, 13%; astrocytomas and medulloepithelioma), combined hamartomas (six children, 8%), inflammatory diseases (six children, 8%) ( Toxocara canis , cat scratch eye disease, or toxoplasmosis), and other diseases (13 children, 16%; corneal opacities, congenital cataract, or retinal detachment). Discussion: Compared to previous series, this study shows the proportion of erroneous diagnosis has lowered (16%) compared to earlier studies by Balmer (1986; 30%), and Shields (1991; 42%). No cases of retinopathy of prematurity were seen in our series, demonstrating that screening is good or of a lower frequency in France. The frequency of PHPV has dropped. Coats disease remains a frequent and sometimes difficult diagnosis to make, particularly in advanced stages of the disease.

Conservative treatment of retinoblastoma: a prospective phase II randomized trial of neoadjuvant chemotherapy followed by local treatments and chemothermotherapy

PurposeIntraocular retinoblastoma treatments often combine chemotherapy and focal treatments. A first prospective protocol of conservative treatments in our institution showed the efficacy of the use of two courses of chemoreduction with etoposide and carboplatin, followed by chemothermotherapy using carboplatin as a single agent and diode laser. In order to decrease the possible long-term toxicity of chemotherapy due to etoposide, a randomized neoadjuvant phase II protocol was conducted using vincristine–carboplatin vs etoposide–carboplatin.Patients and methodsThe study was proposed when initial tumor characteristics did not allow front-line local treatments. Patients included in this phase II noncomparative randomized study of neoadjuvant chemotherapy received vincristin–carboplatin (new arm) vs etoposide–carboplatin (our reference arm). They were subsequently treated by local treatments and chemothermotherapy. Primary end point was the need for secondary enucleation or external beam radiotherapy (EBRT) not exceeding 40% at 2 years.ResultsA total of 65 eyes in 55 children were included in the study (May 2004 to August 2009). Of these, 32 eyes (27 children) were treated in the arm etoposide–carboplatin and 33 eyes (28 children) in the arm vincristin–carboplatin. At 2 years after treatment, 23/33 (69.7%) eyes were treated and salvaged without EBRT or enucleation in the arm vincristin–carboplatin and 26/32 (81.2%) in the arm etoposide–carboplatin.ConclusionEven if the two treatment arms could be considered as sufficiently active according to the study decision rules, neoadjuvant chemotherapy by two cycles of vincristine–carboplatin followed by chemothermotherapy appear to offer less optimal local control than the etoposide–carboplatin combination.

Treatment of retinoblastoma: The Institut Curie experience on a series of 730 patients (1995 to 2009).

INTRODUCTIONnTo describe the results of retinoblastoma treatment from 1995-2009 in a single institution.nnnMATERIAL AND METHODSnRetrospective review of the charts of patients treated for retinoblastoma. Clinical characteristics at diagnosis, treatments and outcomes in terms of survival and ocular preservation are described.nnnRESULTSnDuring the study period 826 children were referred for retinoblastoma and 730 were managed in our institution. Four hundred and eleven children presented with unilateral retinoblastoma and 319 with bilateral retinoblastoma. Median follow-up is of 93 months. Global survival is 98.5% of children, 10 children presented with second tumors, 11 children died (6 of tumor-related causes). Of the 411 children with unilateral retinoblastoma enucleation was needed at diagnosis for 324 (78.8%). Conservative treatments were attempted for 87 patients (21.2%) and ocular preservation obtained for 65 patients (74% of eyes). Three hundred and nineteen patients presented with bilateral retinoblastoma. Three hundred and ten could be treated conservatively for at least one eye. Initial intravenous chemotherapy was necessary for 75% of them. Ocular preservation without external beam radiation was possible for 221 patients (70%). The use of EBR decreased significantly after 2004 (9.1% of eyes vs 25.1%: P<0.001).nnnDISCUSSIONnManagement and treatment of retinoblastoma are complex, adapted to the extent of the disease. Survival is good. Enucleation is still required for extensive ocular disease, especially for unilateral patients. Intravenous chemotherapy allows good tumor control and eye preservation and decrease the need of EBR.nnnCONCLUSIONSnRetinoblastoma treatment with intravenous chemotherapy and ocular adjuvant therapies is very effective on the local tumor control and eye preservation.

019 Impact du dépistage systématique dans le rétinoblastome familial : une étude rétrospective

Introduction Le retinoblastome est la tumeur maligne intra oculaire la plus frequente de l’enfant. Dans 10 % des cas il existe un antecedent familial. Il est communement admis que les enfants apparentes a un patient atteint doivent etre depistes regulierement par un examen du fond d’œil des la naissance puis a intervalles reguliers. Le but etant de faire un diagnostic precoce et de traiter par des moyens locaux (thermotherapie, thermo chimiotherapie, cryotherapie, disque radioactif) seuls ou apres chimio reduction, en evitant, si possible, l’enucleation ou la radiotherapie. Neanmoins les donnees sur les resultats de cette recommandation sont tres rares. Materiels et Methodes Il s’agit d’une etude retrospective des dossiers d’enfants atteints de retinoblastome et qui avaient un antecedent familial. Cette etude a compare les donnees cliniques en termes de pronostic oculaire (conservation oculaire, recours a l’irradiation externe et fonction visuelle finale) en fonction du type de depistage applique (pas de depistage, depistage conforme aux recommandations de l’institution dit « intensif » et depistage « intermediaire »). Resultats Entre janvier 1995 et decembre 2004, 547 retinoblastomes ont ete diagnostiques, dont 60 familiaux. Parmi eux, 21 n’avaient pas beneficie de depistage, 23 d’un depistage « intermediaire » et 16 d’un depistage conforme a nos recommandations (« intensif »). L’âge au diagnostic etait respectivement de 10.5 mois, 3.5 mois et 1 mois (pxa0 Discussion Ces donnees portant sur une large cohorte sont comparables a la seule autre etude publiee et confirment l’importance d’un depistage. Conclusion Un depistage « intensif » des enfants apparentes a un patient traite pour retinoblastome permet donc d’ameliorer le pronostic avec une diminution du recours a l’enucleation et a la radiotherapie externe.

338 Traitements conservateurs du rétinoblastome

Objectif Evaluer l’efficacite du traitement conservateur du retinoblastome par des traitements locaux ou la thermo-chimiotherapie (carboplatine intraveineux suivi de thermotherapie sur les tumeurs) precedee d’une phase de chimiotherapie premiere de deux cycles de l’association carboplatine et etoposide. Materiels et Methodes Etude prospective non randomisee concernant des enfants pris en charge a l’Institut Curie entre decembre 1998 et mars 2002 pour un retinoblastome accessible a un traitement conservateur. L’objectif principal est la reduction du recours a l’irradiation externe en raison de ses risques. Resultats 83 enfants ont ete inclus 19 ayant une atteinte unilaterale (22.8 %) et 64 enfants (77.1 %) ayant une atteinte bilaterale soit 147 yeux atteints dont seuls 115 yeux pouvaient beneficier d’une approche conservatrice. 66 enfants ont recu une chimiotherapie neo adjuvante avant les traitements oculaires. Ceux-ci ont consiste en l’association d’un ou plusieurs techniques : thermo-chimiotherapie (65 enfants 86 yeux) avec une moyenne de 3 cycles recus par enfant, thermotherapie seule : 22 enfants (24 yeux), cryo-application : 49 enfants (58 yeux), pose de disque d’iode 125 : 26 enfants (29 yeux). Discussion Au terme de ces traitements un controle tumoral a ete obtenu pour 97 yeux (84 %). Le recours a la radiotherapie externe a ete necessaire pour un total de 9 enfants (11 %) et 13 yeux (12 %) dont 7 enfants (10 yeux) en tant que traitement initial. Une enucleation secondaire a ete necessaire pour 23 yeux (20 %) dont 5 pour complications. Ces resultats, comparables en termes d’efficacite a d’autres series, ont ete obtenus avec des doses cumulatives de chimiotherapie moins importantes laissant esperer une moindre toxicite a moyen et long terme. Conclusion L’association d’une chimiotherapie premiere par deux cycles de carboplatine et etoposide suivie des traitements oculaires dont la thermochimiotherapie permet un controle tumoral satisfaisant et diminue le recours a l’irradiation externe.

337 Rétinoblastome et pièges diagnostiques

Introduction Determiner les principaux diagnostics differentiels du retinoblastome. Objectifs et Methodes Revue retrospective des enfants adresses a l’Institut Curie pour suspicion de retinoblastome entre 2000 et 2006. Elements diagnostiques : clinique ; fond d’œil sous anesthesie generale et paracliniques : imagerie oculaire : echographie, IRM, TDM. Resultats 486 enfants ont ete vus pendant cette periode. 408 enfants (84 %) presentaient un retinoblastome et 78 enfants (16 %) presentaient un autre diagnostic dont : Maladie de Coats : 25 % dont 2 cas ayant necessite une confirmation histologique apres enucleation. Pathologies malformatives : 37 % (colobome12 %, persistance du vitre primitif 5 %, microphtalmie 2 %, malformations diverses avec decollement de retine 16 %). Pathologies tumorales : 10 % (5 % d’astrocytome et 5 % de medulo-epitheliome), hamartome : 7 %. Cicatrices post-infectieuses : 7 %. Autres : 14 % (fibres a myeline, cataracte, retinopathie du premature, pigmentation irienne irreguliere, kystes ciliaires et fond d’yeux normaux). Discussion Nous avons donc 16 % d’enfants adresses pour retinoblastome qui presentaient en fait une autre pathologie. Ce taux est inferieur a celui des precedentes etudes (42 % pour Shields en 1991 et 30 % pour Balmer en 1988). Conclusion Le principal diagnostic differentiel du retinoblastome reste la maladie de Coats posant aussi le plus de difficultes diagnostiques, avec 2 cas ayant necessite une confirmation histologique.

Le rétinoblastome@@@Retinoblastoma

Résumé:Le rétinoblastome est la tumeur maligne intraoculaire la plus fréquente de l’enfant. Son incidence est de 1/15000 naissances. Soixante pour cent sont unilatéraux avec un âge médian au diagnostic de deux ans, la plupart étant des formes non héréditaires. Le rétinoblastome est bilate ral dans 40 % des cas, l’âge médian de survenue au diagnostic est alors d’un an. Toutes les formes bilatérales ou unilatérales multifocales sont héréditaires. Le rétinoblastome héréditaire constitue un syndrome de prédisposition génétique au cancer: un sujet porteur d’une mutation constitutionnelle du gène RB1 présente un risque supérieur à 90 % de développer un rétinoblastome et est par ailleurs exposé au risque de tumeur secondaire. Les deux symptômes les plus fréquemment rencontrés sont la leucocorie et le strabisme. L’examen du fond d’oeil permet le diagnostic, l’échographie, le scanner et l’IRM pouvant y contribuer. La prise en charge des patients doit prendre en compte divers facteurs: le potentiel visuel, la possible nature héréditaire de l’affection et le risque vital. Une énucléation est souvent nécessaire en cas de forme unilatérale, un traitement adjuvant étant indiqué en fonction des facteurs de risque histologiques. Un traitement conservateur pour au moins un oeil est possible dans la plupart des formes bilatérales: thermochimiothérapie, cryothérapie, laser (thermothérapie), curiethérapie par disque d’iode. On tente de limiter les indications de radiothérapie externe aux grosses tumeurs avec essaimage vitréen, en raison des effets tardifs dont les sarcomes secondaires. Un suivi à long terme et une information précoce des patients et de leur famille concernant les risques de transmission et de tumeurs secondaires sont nécessaires.Abstract:Retinoblastoma is the most frequent malignant tumour in children with an incidence of 1 in 15,000 live births. Sixty per cent of retinoblastoma cases involve one eye (unilateral):median age at diagnosis is 2 years, and most of these forms are non-hereditary. Forty percent of retinoblastoma cases are bilateral: the median age at diagnosis is 1 year. All bilateral and multifocal unilateral forms are hereditary. Hereditary retinoblastoma is a cancer predisposition syndrome: the presence of a constitutional RB1 gene mutation in patients implies they have a greater than 90% chance of developing retinoblastoma. They also have an increased risk of developing other types of cancer. Leucocoria and strabismus are the most frequent revealing symptoms. Diagnosis is made by fundoscopy. US, MRI and CT scans may contribute to diagnosis. Treatment of patients with retinoblastoma should take into account the various aspects of the disease: the risk to vision, the possible hereditary nature of the disease, the life threatening risk. Enucleation is still often necessary in unilateral disease; adjuvant treatment might be given according to histological risk factors. Conservative treatmentmay be to at least one eye in most of bilateral cases: thermotherapy combined with chemotherapy, cryotherapy and brachytherapy. External beam radiation therapy should be restricted to large ocular tumours and diffuse vitreous seeding ocular because of the risk of late effects, including secondary sarcoma. Long term follow-up of patients with retinoblastoma is important, as well as information given at an early stage to them and their family about the risks of second primary tumours and of transmission to their off springs.