Recherche clinique en Curiethérapie Cancers du col Cours nationaux de DES de Radiothérapie oncologique Nancy – 2 au 4 février 2012 Dr Claire Brunaud- Centre Alexis Vautrin

Essais en cours Site USA NIH clinical.trials.gov: 560 études cliniques sur le cancer du col, en cours ou terminées 8 centrées sur la curie Légère progression du nombre d’études prospectives avec le temps mais doit devenir la règle pour établir des résultats sur lesquels se baser

High Dose Rate (HDR) Versus Low Dose Rate (LDR) Brachytherapy in Carcinoma Cervix Tata Memorial Hospital (Mumbai); Dr S J Shrivastava Allocation: Randomized Primary Outcome Measures: To asses the feasibility of HDR brachytherapy To compare the early and late reactions of HDR brachytherapy in contrast with LDR brachytherapy. To compare the overall survival and disease free survival in the two regimens. Estimated Enrollment: 750 Study Start Date: May 1996 Estimated Study Completion Date: January 2007

Magnetic Resonance Imaging Guided Gynecologic Brachytherapy Brigham and Women's Hospital (Dr A Viswanathan) Primary Outcome Measures: Insertion of needles into the bladder or rectum Secondary Outcome Measures: Ability of MR imaging to accurately determine tumor, bladder and rectal volumes Assessment of acute skin, genitourinary and gastrointestinal toxicities Assessment of tumor progression or recurrence during a 180 day follow-up period Eligibility: Cervix, Uterine, Vaginal, Vulvar Neoplasms Estimated Enrollment: 15 Study Start Date: March 2003 Estimated Study Completion Date: October 2005

Hyperthermia Combined Brachytherapy in CCU Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Varsovie Eligibility: locally advanced cervical cancer (stage II – III) Allocation: Randomized Interstitial brachytherapy +/- hyperthermia 45 minutes Primary Outcome Measures: Local control Secondary Outcome Measures: Late side effects Early complications of BT procedure ; Reporting the episodes of perforation and bleeding DFS Enrollment: 224 Study Start Date: November 2006 Study Completion Date: March 2009

Optimized Magnetic Resonance Brachytherapy (MR BT) in Cervix Cancer University Health Network, Toronto Primary Outcome Measures: Feasibility of clinical implementation of an effective and safe protocol for optimised MR image guided intra-uterine brachytherapy for cervix cancer. Secondary Outcome Measures: Determine local control,overall survival,acute & late toxicity, & sexual health of patients treated with optimised intra-uterine BT. Evaluate stability of the intra-uterine applicator during BT. Evaluate dose homogeneity of BT for cervix cancer. Estimated Enrollment: 60 Study Start Date: May 2008 Estimated Study Completion Date: May 2011

MRI-Based RT and Cisplatin in Patients With Stage I, II, III, or IV Cervical Cancer Abramson Cancer Center of the University of Pennsylvania Primary Outcome Measures: Feasibility of using MRI for intracavitary brachytherapy treatment planning. Secondary Outcome Measures: Adverse events associated with brachytherapy delivered according to MRI-based treatment planning. Frequency of grade 2 and higher gastrointestinal and genitourinary early event rates as compared to historical series. True pelvis failure, Pelvis Failure, Progression-free survival, Overall survival Toxicity as assessed by NCI CTCAE version 3.0 Estimated Enrollment: 20 Study Start Date: July 2009 Estimated Study Completion Date: July 2011

A Natural History Study of Patients Receiving High-Dose Rate Brachytherapy (NCI) Eligibility: Patients with cancer who could potentially benefit from the use of high dose rate brachytherapy as a component of their treatment. Cervical, Endometrial, Esophageal, Prostate, Biliary Cancer Primary Outcome Measures: To determine the quality of HDR brachytherapy implants An implant will be adequate if 90% of the GTV receives 90% of the dose prescribed and 80% of the prescribed dose. Secondary Outcome Measures: To evaluate local control and late toxicity rates following brachytherapy at NCI ROB Increase the flow of oncology patients requiring brachytherapy Estimated Enrollment: 112 Study Start Date: March 2009 Estimated Study Completion Date: November 2013

Image-Guided Gynecologic Brachytherapy (AMIGO) Dana-Farber Cancer Institute (Dr A Viswanathan) Primary Outcome Measures: Dose determination To determine doses to the rectum, sigmoid and bladder obtained after AMIGO-guided placement compared to standard CT-guided treatment with the anticipation that AMIGO-guided placement will result in lower OAR dosing than standard CT-based imaging. Secondary Outcome Measures: Toxicities To measure toxicities, including gastrointestinal, genitourinary, and skin, from physician-queries using CTCAE 4.0 To assess 90-day gastrointestinal, genitourinary, and skin toxicities and to compare AMIGO results to those obtained in prior CT and Magnetic Resonance Therapy (MRT) units. Estimated Enrollment: 24 Study Start Date: August 2011 Estimated Primary Completion Date: July 2014

Étude Française « STIC PDR » étude prospective, non randomisée 2005-2007 2 groupes de patientes traitées pour cancer du col Curie « classique » 2D Curie « innovante » PDR 3D Données disponibles pour 705 patientes Effets secondaires recueillis selon CTCAEv3.0 Répartition des patientes: 45% groupe 2D, 55% groupe 3D Critères cliniques comparables entre les 2 groupes

Étude Française « STIC PDR » Traitements 3 sous groupes : groupe 1, Curie puis chirurgie (24%) groupe 2, RTH suivie de curie puis de chirurgie (44%) groupe 3, RTH puis curie (32%) RTH Dose médiane 45 Gy/25 fractions, + chimio 80% des cas (cisplatyl hebdo) Curiethérapie Bas débit de dose (LDR ou PDR) Groupe 3D: adaptation des recommandations GYN GEC ESTRO car >80% des dosimétries réalisées sur scanner et non sur IRM

Étude Française « STIC PDR » Résultats Cliniques groupe 1 groupe 2 groupe 3 p 2D 76 3D 89 142 163 118 117 CL RLR DFS 91.9% 87.9% 86.5% 100% 96.1% 89.7% 84.7% 77.2% 73% 93% 88.6% 77.1% 73.9% 61.2% 55.2% 78.5% 69.6% 60.3% 0.003 0.001 0.086 Toxicité grade 3-4 Urinaire Digestive Gynécologique Globale 5.8% 6.8% 5.7% 14.6% 1.3% 1.2% 7.5% 8.9% 7.6% 0.9% 6.4% 12.5% 5.5% 4.8% 2.8% 8.8% 9.2% 9% 15.4% 22.7% 0% 1.4% 2.6% 0.02 0.17 0.01 0.002

Étude Française « STIC PDR » Conclusions Une dosimétrie 3D est faisable pour toutes les patientes traitées par curiethérapie pour cancer du col Les taux de complications tardives sont moins élevées dans le groupe 3D avec un contrôle loco régional amélioré Une augmentation de dose est possible dans des cas sélectionnés dose totale délivrée aux OARs en dessous des maximales admises Amélioration du dessin des volumes cibles si IRM dosimétrique Décision de poursuite par étude d’escalade de dose: PHRC Tridicol

Protocole Tridicol Optimisation de la distribution de dose en 3 dimensions de la curiethérapie utéro-vaginale à débit pulsé des cancers du col localement avancés Méthodologie : Étude prospective multicentrique de phase II, non randomisée Nombre de centres impliqués: 9 Nombre de patientes prévues: 48 Débutée en octobre 2011, durée inclusion prévue: 2 ans Objectifs principaux augmenter la dose délivrée aux volumes cibles (CTV-HR et CTV-RI) augmenter le taux de contrôle local à deux ans de 71,0% à 86,7% Objectifs secondaires maintenir le taux de complications de grade 3 et 4 en dessous de 6,5% étudier les relations entre les doses aux CTV et le contrôle local d’une part, et entre les doses aux organes critiques et taux de complications survenant au cours du temps de grade 3 et 4 d’autre part. Indication: Stades IB2 à III Patientes traitées par radiochimio curie exclusive Dosi 3D basée sur IRM, calcul des doses en EQD2

Embrace : A European study on MRI-guided brachytherapy in locally advanced cervical cancer Objectives: To introduce MRI based 3D-4D BT in locally advanced cervical cancer in a multicenter setting within the frame of a prospective observational study. To establish a bench-mark for clinical outcome with image based BT in a large patient population with respect to local control, survival, morbidity and QoL To establish a reference material with regard to image based DVH parameters according tothe guidelines from the GEC ESTRO working group. To correlate image based DVH parameters for CTV and for OAR with outcome To develop prognostic and predictive statistical models for clinical outcome including volumetric, dosimetric, clinical and biological risk factors To establish radiobiological parameter estimates that will allow a precise risk estimation in individual patients and aid in the development of new treatment protocols

« retro Embrace » Data collection will be done in a retrospective manner under the title Retro EMBRACE. A CRF similar to the EMBRACE CRF, but much shorter for easier collection, All patients can and should be included into RetroEMBRACE, namely those diagnosed with cervical cancer and treated with curative intend by way of IGBT (including MRI, CT, (US) or combination of these) before EMBRACE started accrual at your centre, irrespective of the follow up time. Central data base similar to the EMBRACE one The aim of this data collection is to gather information on the existing experience with IGBT in cervical cancer until EMBRACE data matures.

Embrace Critères d’inclusion: cancers du col prouvés dont le traitement va comporter radio (chimio)thérapie suivie de curiethérapie guidée par l’IRM au moins pour la 1ere application. Recrutement prévu: 600 patients, 3 ans d’inclusion, 3 ans de suivi environ 25 centres Recommandations précises RTE: doses/ volumes/ étalement Chimio Curiethérapie: contourage, reconstruction des cathéters, optimisation, données dosimétriques à recueillir, calcul des doses en EQD2..

Embrace Prudence pour les recommandations de dose sur les volumes cibles: « Within the clinical experience collected in the GYN GEC ESTRO network, the following doses were reported for the target volume: For the HR-CTV D90 doses of 75-96 Gy are reported depending on tradition, technique,tumour volume and response (Leuven, Aarhus, Vienna, Paris IGR). For the IR CTV D90 doses of 60-75 Gy are reported dependent on tradition, technique,tumour volume and response (Paris, IGR; Nancy, Aarhus, Vienna). »

Embrace Prudence également pour les recommandations de dose sur les organes à risque: « The following dose volume constraints for OAR are applied at present within the GYN GEC ESTRO network based on institutional experience and clinical tradition derived from point assessment. However, there is very limited clinical data to support these values. The following dose-volume constraints therefore have to be taken with much caution. If applied, they have to be checked and controlled continuously. The total dose values are based on the expected cumulative dose of EBRT and BT and are expressed in EQD2 using an a/b value of 3 and T½=1.5 hours: Rectum D2cc < 70-75 Gy Sigmoid colon D2cc < 75 Gy Bladder D2cc < 90 Gy

Conclusion Études prospectives concernant la curiethérapie des cancers du col encore rares Une étude française basée sur le scanner a montré la supériorité de la curie 3D Grande étude européenne en cours basée sur l’IRM corrélations doses/volume sur CTV et OARs attendues