Thibaut Fortané
email: tfortane@chu-grenoble.fr

Emmanuel Beaudouin

Gabriel Lateur

Pedro Giraudo

Gael Kerschbaumer

Mehdi Boudhissa

Jérôme Tonetti

Consolidation des tubérosités dans les prothèses inversées d'épaule en traumatologie : utilisation d'un système modulaire de latéralisation avec greffe osseuse

Keywords: III, cohorte rétrospective fracture humérus proximal, prothèse d'épaule inversée, consolidation des tubérosités, greffe osseuse

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

La prothèse d'épaule inversée (PTEI) est devenue un traitement courant des fractures déplacées de l'humérus proximal (FESH) Neer 3 et 4 chez les patients âgés [START_REF] Boileau | Can surgeons predict what makes a good hemiarthroplasty for fracture?[END_REF]. La raison principale est le résultat décevant des ostéosynthèses qui conduisent à des taux de complications élevés tels que la nécrose de la tête humérale, la pseudarthrose ou lyse tubérositaire, le déplacement du matériel en grande partie à cause de l'ostéoporose [START_REF] Clavert | Pitfalls and complications with locking plate for proximal humerus fracture[END_REF]. De plus, la fonction de l'épaule après reprise chirurgicale par arthroplastie secondaire est améliorée mais reste modeste comparée à l'arthroplastie de première intention [START_REF] Jost | Locking plate fixation of fractures of the proximal humerus: analysis of complications, revision strategies and outcome[END_REF][START_REF] Sebastia-Forcada | Outcomes of Reverse Total Shoulder Arthroplasty for Proximal Humeral Fractures: Primary Arthroplasty Versus Secondary Arthroplasty After Failed Proximal Humeral Locking Plate Fixation[END_REF]. Une autre raison est le résultat inconstant des hémi-arthroplastie principalement en raison de la non consolidation des tubérosités et de l'érosion glénoïdienne [START_REF] Boileau | Can surgeons predict what makes a good hemiarthroplasty for fracture?[END_REF][START_REF] Gallinet | Three or four parts complex proximal humerus fractures: hemiarthroplasty versus reverse prosthesis: a comparative study of 40 cases[END_REF]. Même si l'utilisation de tiges spécifique permet une meilleure consolidation, la non-consolidation des tubérosités est peu prévisible et mène à de mauvais résultats [START_REF] Boileau | Can surgeons predict what makes a good hemiarthroplasty for fracture?[END_REF].

La PTEI permet des résultats bons et constants avec une élévation antérieure possible même sans coiffe des rotateurs ou lyse tubérositaire [START_REF] Gallinet | Three or four parts complex proximal humerus fractures: hemiarthroplasty versus reverse prosthesis: a comparative study of 40 cases[END_REF]. Cependant la lyse des tubérosités conduit à des résultats inférieurs avec augmentation des complications (instabilité, descellement huméral) alors que leur consolidation améliore les amplitudes articulaires actives (AAA) en rotation, en particulier en rotation externe [START_REF] Ohl | How the greater tuberosity affects clinical outcomes after reverse shoulder arthroplasty for proximal humeral fractures[END_REF][START_REF] Gallinet | Improvement in shoulder rotation in complex shoulder fractures treated by reverse shoulder arthroplasty[END_REF][START_REF] Uzer | Does grafting of the tuberosities improve the functional outcomes of proximal humeral fractures treated with reverse shoulder arthroplasty?[END_REF][START_REF] Garofalo | Reverse shoulder arthroplasty for proximal humerus fracture using a dedicated stem: radiological outcomes at a minimum 2 years of follow-up-case series[END_REF][START_REF] Boileau | Reverse shoulder arthroplasty for acute fractures in the elderly: is it worth reattaching the tuberosities?[END_REF]. Il a été démontré que la greffe osseuse et l'utilisation d'une tige spécifique conduisent à une amélioration de la consolidation [START_REF] Garofalo | Reverse shoulder arthroplasty for proximal humerus fracture using a dedicated stem: radiological outcomes at a minimum 2 years of follow-up-case series[END_REF][START_REF] Levy | Reverse shoulder prosthesis for acute four-part fracture: tuberosity fixation using a horseshoe graft[END_REF].

L'hypothèse était que l'utilisation de la greffe osseuse fixée à la prothèse à l'aide d'une cage permettrait une meilleure consolidation des tubérosités, et donc un meilleur résultat fonctionnel.

Nous avons effectué une étude radiologique évaluant la consolidation des tubérosités et une étude clinique évaluant les AAA et les scores fonctionnels. Le critère de jugement principal était le résultat radiologique avec consolidation des tubérosités en fonction de l'utilisation de la cage OMS. Les critères de jugement secondaires étaient les résultats cliniques en fonction de la consolidation tubérositaire (AAA, score de Constant, DASH, SSV, EVA) . Nous avons également évalué les complications radiographiques et cliniques.

MATÉRIEL ET MÉTHODES

Diagramme de flux

Technique chirurgicale et soins postopératoires

La chirurgie a été réalisée en position semi-assise sous anesthésie générale et bloc interscalénique. Tous les chirurgiens ont utilisé la prothèse Humelock Reversed II (figure 1). Une voie d'abord delto-pectorale ou supéro-externe trans-deltoïdienne était utilisée.

La broche guide glénoïdienne était placée 12 mm au-dessus du bord inférieur de la glène et centrée dans le plan antéro-postérieur [START_REF] Kelly | Optimizing glenosphere position and fixation in reverse shoulder arthroplasty, Part One: The twelve-mm rule[END_REF]. L'orientation de la broche était de 90° avec la surface glénoïdienne (tilt de 10° dans la glénosphère). La métaglène était impactée et fixée par deux vis en compression (inférieure et supérieure), puis deux vis verrouillées. Le glénosphère utilisée était de taille 36 ou 40 mm, centré ou excentrée (3 mm) avec un tilt inférieur de 10° selon la morphologie du patient. Sur le versant huméral, la rétroversion était de 20° (alignée avec l'axe de l'avant-bras). La hauteur a été trouvée grâce aux critères de Muraschosky, à la réduction des tubérosités, et au contrôle scopique [START_REF] Murachovsky | Pectoralis major tendon reference (PMT): a new method for accurate restoration of humeral length with hemiarthroplasty for fracture[END_REF]. La tige était cimentée ou verrouillée avec deux vis. Enfin, nous avons utilisé ou non la cage OMS. Le dispositif était vissé sur la métaphyse afin d'améliorer la consolidation anatomique en évitant la lyse, le déplacement secondaire ou la médialisation des tubérosités. Nous avons toujours utilisé une greffe d'os spongieux prélevée au dépend de la tête humérale. L'utilisation du dispositif OMS se faisait à la convenance du chirurgien, de préférence lorsque les tubérosités étaient de mauvaise qualité (comminution, faible épaisseur).

Pour les suites post-opératoires , il était mis en place une simple écharpe pendant 6 semaines. L'utilisation du bras dans les gestes de la vie quotidienne, les mobilités passives et les exercices pendulaires étaient autorisés immédiatement après la chirurgie. La mobilisation active n'était autorisée qu'après 6 semaines. À chaque consultation, nous avons analysé les radiographies avec des incidences de face et de profil de Lamy. Sur les radiographies préopératoires, nous avons utilisé la classification de Neer et recherché une luxation de la tête humérale fracturée [START_REF] Neer | Displaced proximal humeral fractures. I. Classification and evaluation[END_REF]. Sur les radiographies postopératoires immédiates, nous avons analysé la réduction des tubérosités (figure 2). Le tubercule majeur était en position anatomique s'il était visualisé sur l'incidence de face en rotation neutre et non visualisé sur l'incidence de profil comme décrit par Boileau [START_REF] Boileau | Tuberosity malposition and migration: reasons for poor outcomes after hemiarthroplasty for displaced fractures of the proximal humerus[END_REF]. Ensuite, nous avons analysé la consolidation ou la lyse des tubérosités, en position anatomique ou non (figure 3). Nous avons défini la migration des tubérosités comme une position anatomique sur les radiographies postopératoires immédiates et une consolidation non anatomique les radiographies suivantes (figure 4). Nous avons recherché les complications radiologiques tels que le notch décrit par la classification de Sirveaux, le descellement glénoïdien ou huméral et les ossifications [START_REF] Sirveaux | Reverse Prosthesis for Proximal Humerus Fracture, Technique and Results[END_REF].

Évaluation

Analyses statistiques

L'accord de tous les patients inclus était recueilli. Les analyses statistiques ont été réalisées avec le logiciel Excel version 2019. Un test de Fisher non paramétrique a été utilisé pour les variables qualitatives et un test de Student bilatéral pour les variables quantitatives. Le seuil de significativité était fixé à 0,05.

RÉSULTATS (annexe 1)

Nous avons examiné les patients opérés entre novembre 2013 et mai 2018. Nous avons inclus 50 patients dans l'étude, 13 ont été perdus de vue, 3 ont eu des complications telles que : hématome, luxation, sepsis et ablation de la prothèse dans l'année suivant la chirurgie. Nous avons donc pu analyser 34 patients avec PTEI, 27 femmes (79%) et 7 hommes avec un âge moyen de 78±6 ans.

Le suivi moyen était de 18±7,2 mois (extrêmes 12-40). Le mécanisme de la fracture était une simple chute dans 31 cas (91%). Le score ASA moyen était de 2,2±0,5 ; le score de Parker moyen était de 8,4±1,1. Le délai moyen avant la chirurgie était de 6,3±4,5 jours. La fracture était classée Neer 3 dans 10 cas contre 24 Neer 4 (71%) et il existait une luxation de la tête humérale associée dans 7 cas (21%). Nous avons utilisé une approche delto-pectorale dans 22 cas (65%), verrouillé la tige par vis dans 31 cas (91%) et un dispositif OMS a été utilisé dans 26 cas (76%). La réduction anatomique des tubérosités a été obtenue sur 28 (82%) radiographies post-opératoires immédiates. Au dernier recul nous avions 27 (79%) consolidations des tubérosités, mais 19 (56%) en position anatomique avec 4 (17%) migrations. Cliniquement, les AAA moyennes étaient de 117°±24 en EA, 18°±18 en RE et L2 (main-hanche, T7) en RI (cf. Tableau 1). Les scores fonctionnels moyens étaient de 59±13 pour le Constant; 28±17 pour le DASH ; 67±25 pour le SSV. La douleur selon l'EVA a été évaluée respectivement à 0,9±1 et 2,4±2,4 au repos et à l'effort (cf. Tableau 1). Les principales complications que nous avons constatées étaient une lésion du nerf axillaire avec amyotrophie du deltoïde (voie trans-deltoïdienne), une paresthésie isolée ulnaire en cours de récupération au dernier recul et trois ablations de

DISCUSSION

Nous montrons dans cette étude que l'utilisation du dispositif OMS améliore la consolidation des tubérosités autour de la PTEI. Il s'agit de la première étude à analyser spécifiquement la consolidation des tubérosités à l'aide d'un dispositif OMS avec greffe osseuse.

Notre étude n'a pas trouvé d'amélioration significative des AAA et des scores cliniques associées à la consolidation des tubérosités, cependant Boileau et Gallinet ont déjà démontrés ces résultats [START_REF] Boileau | Reverse shoulder arthroplasty for acute fractures in the elderly: is it worth reattaching the tuberosities?[END_REF][START_REF] Gallinet | Improvement in shoulder rotation in complex shoulder fractures treated by reverse shoulder arthroplasty[END_REF]. Cela peut être expliqué en raison du faible nombre de patients sans le dispositif OMS. Cependant, l'utilisation de la cage OMS montre une tendance à améliorer les résultats fonctionnels dans notre étude. Un autre avantage de la consolidation des tubérosités est d'éviter les complications après PTEI en traumatologie. Boileau montre que la résection ou lyse tubérositaire entraine un taux élevé de complications , en particulier jusqu'à 40% de luxations [START_REF] Boileau | Reverse shoulder arthroplasty for acute fractures in the elderly: is it worth reattaching the tuberosities?[END_REF]. De la même manière que la réinsertion du subscapulaire dans les PTEI pour omarthrose excentrée conduit à une meilleure rotation interne et à une diminution des complications telles que les luxations, on peut supposer que la consolidation des tubérosités conduit au même résultat en traumatologie [START_REF] Friedman | Comparison of reverse total shoulder arthroplasty outcomes with and without subscapularis repair[END_REF][START_REF] Chalmers | Early dislocation after reverse total shoulder arthroplasty[END_REF][START_REF] Cheung | Instability after reverse total shoulder arthroplasty[END_REF][START_REF] Matthewson | The effect of subscapularis repair on dislocation rates in reverse shoulder arthroplasty: a meta-analysis and systematic review[END_REF].

Les résultats cliniques dans notre étude sont très proches des résultats du symposium de la Sofcot de 2016, qui retrouvent des AAA de 115° en EA, 17° en RE et S1 en RI. Les scores fonctionnels sont également proches avec un Constant à 57 et SSV à 70% dans le symposium [START_REF] Gallinet | Reverse shoulder arthroplasty for recent proximal humerus fractures: Outcomes in 422 cases[END_REF].

Dans notre étude, nous n'observons que peu de notch. Cela peut s'expliquer par le court délai de revu de nos patients. En effet, Cazeneuve [START_REF] Cazeneuve | Delta III reverse shoulder arthroplasty: radiological outcome for acute complex fractures of the proximal humerus in elderly patients[END_REF] montre que le temps moyen d'apparition est de 2 ans pour les encoches de grade 1 et qu'elles sont évolutives dans 50% des cas. Cela peut également s'expliquer par le design de la prothèse et le positionnement bas de la glénosphère déjà tiltée de 10°. Nous utilisons une tige avec un angle cervico-diaphysaire de 145° qui est moins agressif sur le pilier de l'omoplate qu'un angle plus horizontal comme cela a été décrit par Grammont (155°) [START_REF] De Wilde | Prosthetic overhang is the most effective way to prevent scapular conflict in a reverse total shoulder prosthesis[END_REF][START_REF] Erickson | The influence of humeral head inclination in reverse total shoulder arthroplasty: a systematic review[END_REF].

Le descellement huméral est une complication rare [START_REF] Ascione | Long-term humeral complications after Grammont-style reverse shoulder arthroplasty[END_REF]. Notre seul cas de descellement aseptique huméral peut s'expliquer par l'utilisation d'une tige humérale verrouillée alors que la fracture initiale montrait une comminution métaphysaire. Nous pensons qu'il faut utiliser une tige cimentée lorsqu'il existe une telle comminution métaphysaire ou une extension diaphysaire de la fracture. En revanche, en dehors de ces cas particuliers, l'utilisation d'une tige verrouillée peut améliorer la consolidation des tubérosités en évitant l'effet de nécrose osseuse autour du ciment [START_REF] Levy | Avoiding Cement Bone Necrosis Effect on Tuberosity Healing: The "Black-and-Tan" Technique[END_REF]. Un autre avantage à l'utilisation de la tige verrouillée est de faciliter le positionnement en hauteur sous contrôle scopique, qui reste un moment difficile de cette chirurgie en raison de la perte des repères métaphysaires lorsque les tubérosités sont comminutives. Cela rend également la chirurgie de révision moins traumatique lorsque l'implant huméral doit être retiré.

Nous pensons que l'utilisation du dispositif OMS permet aussi d'augmenter l'offset huméral en évitant une consolidation trop médiale des tubérosités. Cela permet une meilleure tension sur les tendons infra-épineux et subscapulaire, en particulier par la possibilité d'utiliser trois tailles différentes de dispositif OMS pour ajuster la latéralisation des tubérosités. Il a été démontré que l'utilisation d'une tige humérale latéralisée augmente la stabilité des PTEI sur omarthrose avec un faible taux de luxation, même sans réinsertion du subscapulaire [START_REF] Friedman | Comparison of reverse total shoulder arthroplasty outcomes with and without subscapularis repair[END_REF]. Il est certain que la consolidation des tubérosités réduit le taux de luxation puisque lors de l'excision des tubérosité, Cazeneuve retrouve un taux de luxation élevé à 11% [START_REF] Cazeneuve | The reverse shoulder prosthesis in the treatment of fractures of the proximal humerus in the elderly[END_REF].

Le taux moyen de consolidation des tubérosités est de 79% dans notre étude et d'environ 70% pour Jain dans sa métanalyse [START_REF] Jain | Tuberosity healing after reverse shoulder arthroplasty for complex proximal humeral fractures in elderly patients-does it improve outcomes? A systematic review and meta-analysis[END_REF].

Nous pouvons expliquer cette amélioration de la consolidation par l'utilisation de la cage, une bonne technique de suture, et le design de l'implant avec verrouillage diaphysaire et métaphyse non encombrante recouverte d' hydroxyapatite bien adaptée à la traumatologie [START_REF] Boileau | Can surgeons predict what makes a good hemiarthroplasty for fracture?[END_REF][START_REF] Frankle | Stability of tuberosity reattachment in proximal humeral hemiarthroplasty[END_REF][START_REF] Krishnan | Shoulder arthroplasty for fracture: does a fracture-specific stem make a difference?[END_REF][START_REF] Li | Hemiarthroplasty for the treatment of complex proximal humeral fractures: does a trabecular metal prosthesis make a difference? A prospective, comparative study with a minimum 3-year follow-up[END_REF]. La conception de cet implant répond aux critères définis par Boileau en traumatologie avec l'avantage d'éviter une consolidation médiale des tubérosités suite à la lyse de la greffe par un excès de pression sur celle-ci. Le dispositif OMS améliore également la stabilité de la greffe et donc sa consolidation.

CONCLUSION

  Design de l'étude L'étude était une cohorte rétrospective bi-centrique. Tous les patients ont été opérés pour une FESH déplacée, Neer 3 ou 4, par mise en place d'une PTEI Humelock II Reversed ™ (Fx Solution, Viriat, France) avec ou sans l'utilisation du système de latéralisation des tubérosité (cage OMS, Offset Modular System) fixée sur la métaphyse prothétique [12]. Les critères d'inclusion étaient : une FESH Neer 3 ou 4 évalué sur une radiographie et un scanner préopératoires et les constatations peropératoires ; l'utilisation d'une PTEI avec ou sans l'OMS ; un suivi minimal d'un an ; une intervention chirurgicale réalisée dans les trois semaines après le traumatisme. Nous avons exclu les patients avec une évaluation clinique impossible (démence ou décès avant 1 an de suivi) ; avec résection des tubérosités pendant l'intervention chirurgicale ; les chirurgies de reprise après échec d'ostéosynthèse, d'hémi-arthroplastie ou de traitement orthopédique.

  Nous avons examiné les patients à 1, 3, 6, 12 mois et chaque année après la chirurgie. Nous avons évalué les amplitudes articulaires passive et active : élévation antérieure (EA), rotation externe et interne (RE, RI) et abduction. Les scores cliniques ont été calculées tous les ans : scores de Constant et Constant ajusté, DASH, EVA et SSV. Les complications cliniques ont été recherchées, en particulier l'atteinte nerveuse axillaire avec amyotrophie du deltoïde, paresthésies des tous les territoires nerveux, hématome, infection, luxation ou fracture.

  prothèse. Dans le premier cas d'ablation de matériel, un surdosage en Coumadine a entrainé un hématome, une reprise chirurgicale pour lavage puis une infection. Les deux autres ont été secondaires à une instabilité dans les deux mois post opératoire suivis d'une reprise chirurgicale et d'une infection. Les deux groupes avec et sans dispositif OMS étaient comparables sur les paramètres suivants : âge, sexe, comorbidités (tabac, pathologies cardiovasculaires, diabète, IMC, score ASA, score Parker), score Neer. La réduction initiale des tubérosités semble être meilleure avec l'utilisation du dispositif OMS. Les tubérosités ont consolidé chez 24 (92 % ) patients avec cage OMS contre 3 (37,5%) sans (p <0,005) . Les résultats sont résumés dans le Tableau 2. Sur l'analyse des résultats cliniques en fonction de la consolidation des tubérosités, nous avons observé une tendance à l'amélioration des AAA en rotation et des scores fonctionnels. Les AAA étaient avec consolidation tubérositaire de 116°, 19°, L2 en EA, RE et RI contre 119°, 14°, L4 avec ostéolyse. De la même manière, les scores cliniques étaient améliorés de façon non significative avec la consolidation des tubérosités. Les résultats sont résumés dans le Tableau 3.

1

 1 Figure 1 Design de la prothèse Humelock Reversed II Fx Solutions™ avec le système OMS de latéralisation des tubérosités.

Figure 2 Figure 3

 23 Figure 2 Radiographies face et profil trois jours et un an après la chirurgie : réduction anatomique postopératoire des tubérosités et ostéolyse après un an (sans le système de latéralisation)

Figure 1

 1 Figure 1Radiographies face et profil un an après la chirurgie : consolidation non anatomique des tubérosités en position postérieure (sans le système de latéralisation).


Dr Paul Sargos
email: p.sargos@bordeaux.unicancer.fr

Sylvie Chabaud

Igor Latorzeff

Nicolas Magné

Ahmed Benyoucef

Stéphane Supiot

Menouar David Pasquier

Samir Abdiche

Olivier Gilliot

Pierre Graff-Cailleaud

Marlon Silva

Philippe Bergerot

Pierre Baumann

Yazid Belkacemi

David Azria

Meryem Brihoum

Prof Michel Soulié

The GETUG-AFU 17 study: a phase III randomised trial comparing adjuvant versus early salvage radiotherapy, combined with short-term androgen deprivation therapy, in men with localised prostate cancer after radical prostatectomy

Keywords: prostate cancer, radical prostatectomy, late toxicity, quality of life

Background Adjuvant radiotherapy (aRT) reduces the risk of biochemical failure in prostate cancer patients following radical prostatectomy (RP). The GETUG-AFU 17 study, compared efficacy and safety of aRT versus early salvage RT (sRT), combined with short-term hormonal

therapy.

Methods This open-label, multicentre, phase III, randomised controlled trial, performed in 46 French centres. Patients, ≥18 years old and Eastern Cooperative Oncology Group performance status ≤1, with pT3-4 and positive margins, pNx or pN0, with post-operative PSA ≤0.1 ng/mL were randomised (by minimisation; 1:1) after RP, to aRT or observation with sRT, combined with 6 months of triptorelin. The primary endpoint was event-free survival (EFS). The incidence of acute and late toxicities were graded using the CTCAE v3.0. This trial is registered with ClinicalTrials.gov number NCT00667069.

Findings Between March 07, 2008, and June 23, 2016, 424 patients were enrolled. We planned to enrol 718 patients. Enrolment was stopped early due to unexpectedly low event rates.

Baseline characteristics were well balanced between arms. Median follow-up was 75•3 months (IQR 50-100). At analysis, 115/212 patients (54%) in the sRT Arm had initiated treatment.

With 58 events, the 5-year EFS was 92% (95% CI 86-95) in the aRT Arm and 90% (95% CI 85-94) in the sRT Arm (HR=0•81 [95% CI 0•48-1•36]; log-rank test p=0•42). Acute grade ≥3 toxicities occurred in 6 patients (3%) in the aRT Arm and in 4 (2%) in the sRT Arm. Late grade ≥2 genitourinary toxicities were reported in 125 patients (59%) in the aRT Arm and in 46 (22%) in the sRT Arm. Late grade ≥2 genitourinary toxicities were worse in the aRT Arm (27% vs 7%; p<0•0001). Grade ≥2 erectile dysfunction was worse in the aRT Arm (p<0•0001).

Interpretation

The GETUG-AFU 17 study, although lacking statistical power, showed no benefit in EFS for aRT compared to sRT. aRT increased the risk of genitourinary toxicity and erectile dysfunction. A policy of early sRT could spare men RT and the associated toxicity.

Introduction

Radical prostatectomy (RP) is a standard treatment for patients with localized prostate cancer, demonstrating excellent long-term outcomes. [START_REF] Hamdy | 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer[END_REF] However, a third of the patients will have pathological high-risk features including extra capsular extension, seminal vesicle involvement and/or positive surgical margins (R1) on the final pathology. These risks factors increase the likelihood of biochemical recurrence, providing a rationale for phase III adjuvant radiotherapy (aRT) trials. [START_REF] Wiegel | Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial[END_REF][START_REF] Thompson | Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: longterm followup of a randomized clinical trial[END_REF][START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)[END_REF] The Southwest Oncology Group (SWOG) S8794, [START_REF] Thompson | Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: longterm followup of a randomized clinical trial[END_REF] the European Organisation for Research and Treatment of Cancer (EORTC) 22911, [START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)[END_REF] and the German Cancer Society ARO 96-02/AUO AP 09/95 2 prospective randomised studies compared aRT, given to the prostate bed, without androgen deprivation therapy, to observation after RP. These studies, which included pathological high-risk patients, reported better long-term biochemical control rate in favour of aRT, and controversial long-term outcomes results. [START_REF] Wiegel | Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial[END_REF][START_REF] Thompson | Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: longterm followup of a randomized clinical trial[END_REF][START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)[END_REF] Moreover, these trials are difficult to interpret, because less than half of patients who recurred in the observation arms received salvage radiotherapy (sRT), a standard in the contemporary era.

In these studies assessing aRT, approximately a third of patients allocated observation did not have disease relapse. Indeed, we risk overtreating patients by proposing aRT to everybody. [START_REF] Van Stam | The Effect of Salvage Radiotherapy and its Timing on the Health-related Quality of Life of Prostate Cancer Patients[END_REF][START_REF] Suardi | Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy[END_REF] The use of aRT, in daily practice, has also been limited by the increased incidence of toxicities and diminished quality of life (QoL) reported. [START_REF] Suardi | Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy[END_REF][START_REF] Sineshaw | Declining Use of Radiotherapy for Adverse Features After Radical Prostatectomy: Results From the National Cancer Data Base[END_REF] In contrast, despite only retrospective evidence supporting efficacy, observation then sRT, proposed at biochemical failure, has increasingly been adopted. [START_REF] Sineshaw | Declining Use of Radiotherapy for Adverse Features After Radical Prostatectomy: Results From the National Cancer Data Base[END_REF] So, the optimal timing of postoperative radiotherapy (RT) remains controversial.

Three large multicentre, open-label trials: RADICALS-RT (NCT00541047), RAVES (NCT00860652), and GETUG-AFU 17 (NCT00667069) were designed to assess whether delayed sRT, given at biochemical relapse, or immediate aRT was more appropriate in this setting. We conducted the GETUG-AFU 17 trial to compare aRT versus early sRT following RP, combined with short-term hormonal therapy, in terms of oncological outcomes and tolerance.

Confidential

Methods

Study design and participants

GETUG-AFU 17 is a randomised, open label, multicentre phase III trial. Men aged ≥18 years and with Eastern Cooperative Oncology Group (ECOG) performance status ≤1, with localised adenocarcinoma of the prostate, treated with RP with or without pelvic lymph node dissection, pathologically-staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection) or pN0 (with negative lymph nodes dissection) and with R1 disease were eligible. The PSA level after RP had to be ≤0.1 ng/mL and confirmed by a second measurement after 4 weeks. Patients who had surgical or chemical castration, or abnormal testosterone level were ineligible. Patients with positive lymph nodes at pathology were not eligible. The delay between RP and enrolment was limited to 6 months. The study was conducted in accordance with the declaration of Helsinki and received regulatory and ethics approvals. All patients provided written informed consent before participation.

Randomisation

Eligible patients were randomly allocated (1:1) to either immediate aRT or delayed sRT at the time of biochemical relapse. Clinicians and patients were not masked to the allocation of study treatment. Furthermore, when the GETUG-AFU 17 study was designed, there was evidence that adding short-term hormonal therapy to RT significantly delayed biochemical relapse in patients with localised prostate cancer. [START_REF] D'amico | 6month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial[END_REF][START_REF] Pilepich | Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate[END_REF] Thus, the investigators decided that postoperative RT was combined with short-term hormonal therapy in both arms. Randomisation, by minimisation, was performed using the web-based, TenAléa software, and stratified by Gleason score (with predominant grade of 4 or not), pT stage (pT3a/pT4a versus pT3b), and by centre.

Procedures

In both arms, combined therapy with RT and concomitant hormonal therapy was planned.

Hormonal therapy was planned to start within the 2 months before RT. Patients allocated aRT initiated treatment between 3 and 6 months after RP. Those randomly allocated to the sRT Arm started when biochemical relapse occurred. [START_REF] Cookson | Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes[END_REF] RT was planned in a supine position, the patient having comfortable full bladder and empty rectum. The clinical target volume (CTV) 1 included the prostate bed and was contoured in a similar way to that used in the RTOG 9601 study. 11 Pelvic lymph nodes could be included in a CTV 2, at the physician's discretion. The planned target volume (PTV) was created with an Confidential anisotropic margins: 5 mm posteriorly and 7-10 mm in all others direction. Both threedimensional conformal RT and intensity-modulated RT were allowed. Three-dimensional conformal RT comprised irradiation in 4 to 6 fields with 6-MV photons. Image-guided RT, in all patients, was based on daily orthogonal kilovoltage radiography or cone-beam computed tomography to verify at least bony alignment. All patients had RT planned for 7 weeks at a dose of 66 Gy in 33 fractions of 2 Gy, 5 days per week. Pelvic lymph nodes could be treated at a dose of 46 Gy in 23 fractions of 2 Gy, 5 days per week.

Hormonal therapy consisted of 6 months of triptorelin (Decapeptyl ® 11•25 SR), administered by intramuscular injection every 3 months.

All patients had weekly study visits during RT. Following randomisation, visits were planned at 3 and 6 months after completing RT, then every 6 months during the first 2•5 years, and then annually, in both treatment arms. During visits, tumour progression/relapse were assessed by PSA assay, and if PSA had increased, with computed tomography and bone scans. Toxicity was assessed throughout the study. Data concerning adverse events that occurred, grade by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, were collected at each study visit. Patients were considered as having discontinued the study if they withdrew consent or died.

Patients completed the QoL questionnaires during study visits: at baseline, then at 2 and 5 years after radiotherapy. Patients were also requested to complete these questionnaires during December 2017, whether or not they had received RT, to analyse the QoL variation from baseline in all patients. The EORTC QLQ-C30 assesses 15 health-related QoL scales: global health status (global health-related QoL), five functional scales (physical, role, emotional, cognitive, and social) and nine symptomatic scales (fatigue, nausea and vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). The QLQ-PR25 assesses five domains: urinary symptoms, bowel symptoms, hormone treatment-related symptoms, sexual activity, and sexual function.

Outcomes

The primary outcome was the event-free survival (EFS): the time interval from randomisation to first documented event, either disease relapse (loco-regional or metastatic), biochemical progression, or death. Biochemical progression was defined as either a PSA level ≥0•4 ng/mL at least 6 months after completing aRT or sRT, confirmed after 4 weeks, or a PSA level ≥1 ng/mL at any time after randomisation, or clinical progression or death from any cause.

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Biochemical relapse before initiating sRT, not considered as an event, was defined as a PSA level >0•2 ng/mL confirmed after 4 weeks. [START_REF] Cookson | Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes[END_REF] The date of the initial increased PSA level was considered the date of biochemical progression.

Secondary efficacy outcomes were overall survival (OS) and metastasis-free survival (MFS).

MFS was defined as time interval from randomisation to the first documented metastasis or death from any cause. OS was defined as the time interval from randomisation to death from any cause. Secondary safety outcomes included the incidence of acute and late toxicities (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0), QoL evolution from baseline until December 2017 (QLQ-C30 and QLQ-PR25 instruments), and functional dependence in patients older than 75 years (Instrument Activities of Daily Living scale [IADL]). Acute toxicities were those reported during RT up until 3 months after completing RT. All toxicities reported after this time, up until 5 years after RT, were considered as late toxicities. The QoL and IADL instruments were to be completed at enrolment and then at 2 and 5 years after treatment. In addition, patients complete these instruments in December 2017 to allow for the analysis of acute and late toxicities, as well as QoL, reported here.

Statistical analysis

The efficacy and safety analyses were to be performed in the intent-to-treat (ITT) population: all randomised patients according to treatment arm. QoL was analysed in patients with available data. Qualitative data were to be reported as frequency and percentages. Quantitative data were to be reported with mean and associated standard deviation (SD) and median with interquartile range (IQR).

In time-to-event analyses, the date of randomisation would be considered as the date of reference. Patients without events were censored at the last date known to be alive. The median follow-up was to be estimated using the reverse Kaplan-Meier method. EFS, MFS, and OS were to be analysed in each study arm using the Kaplan-Meier method. The survival in the study arms were to be compared using the bilateral logrank test, with the statistical significance level set at 5%. The results were to be presented as rates at various time points with their associated 95% confidence intervals (CI). To assess potential bias resulting from the 3 to 6 months delay between RP and randomisation (3-6 months), a post-hoc sensitivity analysis for EFS and OS using the date of RP as reference date for survival were performed.

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Acute toxicities (those reported from the start of radiotherapy until 3 months after the last dose) and late toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Statistical comparisons of the incidence of adverse events are exploratory.

The global quality of life scores, as well as each scale/domain of the QLQ-C30 and QLQ-PR25 were calculated according to the scoring manual. Missing data was not replaced. Absolute individual variations from baseline were calculated and median changes from baseline until December 2017 were compared between arms using a non-parametric Kruskal-Wallis test.

The study was designed to show a 10% increase in the 5-year EFS rate, from 60% with early sRT to 70% with aRT (HR=0•70). The α-risk was fixed at 5% and the power at 80%. Under these hypotheses, 242 EFS events were needed at final analysis. Enrolment was planned for 5 years with a final analysis planned 2•5 year after the last patient enrolled. Consequently, the study planned to enrol 718 patients, 359 in each arm. An interim analysis for efficacy and safety was planned after 121 events had occurred. The Peto method for α-adjustment was planned, i.e. a conservative α-threshold of 0•001 at interim analysis to maintain a 5% α-level at final analysis. P-values <0•05 were considered as statistically significant for all outcomes. The study was overseen by a trial steering committee and an independent data monitoring committee (IDMC).

Statistical analyses were performed using the SAS software v9.4. This trial is registered at EudraCT (2007-002495-34) and at ClinicalTrials.gov (NCT00667069).

Role of the funding source

Unicancer, the study sponsor, was responsible for study design, as well as the collection, analysis, and interpretation of the data. In addition, Unicancer was responsible for writing the report and for the decision to submit this article. PS and PR had access to all of the data and made the final decision to submit this article for publication. Ipsen provided financial support for the study, and conducted a courtesy review of the draft manuscript, but was not involved in study design, data collection, data analysis, data interpretation, or writing of the report.

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Results

Between March 07, 2008, and June 23, 2016, 424 patients were enrolled from 46 French centres (see appendix p 2-3). The protocol planned to enrol 718 patients, 359 in each study arm.

However, on May 20, 2016, an IDMC, recommended early termination of enrolment. At that time, only 12 of the 242 events awaited for the primary outcome analysis had been reported.

Consequently, the planned analysis would still require years. Finally, as the GETUG-AFU group was contacted by the RADICALS team to participate in the ARTISTIC meta-analysis it was decided to use the meta-analysis as the time point for our study analysis. When enrolment was stopped, 424 patients had been randomly allocated: 212 to the aRT Arm and 212 to the sRT Arm. Figure 1 presents the study flow chart. Baseline characteristics (table 1) were well balanced between arms except for hypertension that was more frequent in the aRT Arm. In the study population (n=424), 389 patients (94%) were ECOG performance status 0, with a median age at randomisation of 63•8 years (interquartile range [IQR]: 59•7-67•9). The majority of patients had pT3a (326 patients, 77%), pN0 (304, 72%), and a Gleason score of 7 (340, 80%).

Hypertension was observed in 164 patients (40%).

(figure 1)

(table 1)
At database lock, on December 19, 2019, median follow-up from randomisation was 75 months (IQR 50-100): 74 (IQR 47-100) in the aRT Arm and 78 (IQR 52-101) in the sRT Arm. In the aRT Arm, 205/212 patients (97%) had started treatment: 200 with RT combined with hormonal therapy, 3 with RT alone, and 2 with only hormonal therapy. Five patients withdrew their consent, one patient was excluded due to intercurrent event (inguinal surgery), and another had missing data. In the sRT Arm, 115/212 patients (54%) had initiated study treatment related to biochemical relapse: 107 with RT combined with hormonal therapy, 7 with RT alone, 1 with only hormonal therapy. Also, 8 patients never started treatment due to consent withdrawal (n=3), investigator decision (n=1), patient decision (n=1), and non-neoplastic death (n=3). Furthermore, 7 patients were lost to follow-up and 82 were still monitored. The median PSA level was 0.24 ng/mL (IQR 0.22-0.29) when sRT was started. The median delay between randomisation and RT was 1•1 months in the aRT Arm and 23 months in the sRT Arm. In the aRT Arm, for patients receiving RT, 61 (30%) had intensity-modulated RT and 141 (70%) 3Dconformal RT; data was missing for 1 patient. Similarly, in the sRT Arm, 54 (48%) had intensity-modulated RT; data was missing for 1 patient. All treated patients received RT to the Confidential prostate bed. Pelvic lymph nodes were irradiated in 36 of 203 (18%) patients in the aRT Arm and in 27 of the 114 treated patients (24%) in the sRT Arm.

The median irradiation dose delivered to the prostate bed was 66 Gy (IQR 66-66) and to the pelvic lymph nodes was 46 Gy (IQR 46-46). The median duration of RT was 7 weeks (IQR 6•6-7•3): 7 weeks (IQR 6•7-7•3) in both arms. The duration of RT was longer than 8 weeks for 6 patients (5%) with sRT and for 7 (3%) with aRT. The extended duration of RT was due to acute toxicities in all except 2 patients with intercurrent diseases: shingles and bowel obstruction.

We analysed efficacy in the 424 patients in the ITT population: 212 patients in both the aRT and sRT Arms. For the primary outcome analysis, 58 events were reported: 25 in the aRT Arm (7 with biochemical progression alone, 6 biochemical progression associated with disease progression, 1 disease progression without biochemical progression, and 11 with death as first event) and 33 in the sRT Arm (13 with biochemical progression alone, 9 biochemical progression associated to disease progression, 4 disease progression without biochemical progression and 7 with death as first event). The 5-year EFS rate was 92% (95% CI 86-95) in the aRT Arm and 90% (95% CI 85-94) in the sRT Arm (HR=0•81 [95% CI 0•48-1•36]; logrank test p=0•42; figure 2A).

At analysis, only the first progressive events were recorded. MFS was not sufficiently mature for comparison of randomised arms. Eleven metastatic progressions were observed, 3 in aRT Arm versus 8 in sRT Arm.

Deaths were observed in 24 patients (6%): 14 (7%) in the aRT Arm and 10 (5%) in the sRT Arm. Four of them were due to prostate cancer, 2 in each arm. In addition, 7 patients died from second cancers, 3 from cardiovascular problems, 1 from an infection, 1 from a trauma after falling, and 8 patients with cause of death unknown. The 5-year OS rate was 96% (95% CI 92-98) in the aRT Arm and 99% (95% CI 96-100) in the sRT Arm (HR=1•60 [95% CI 0•71-3•60]; p=0•25; figure 2B). Similar results were observed using prostatectomy date as reference date for survival calculation (appendix p 1). At analysis, in the ITT population (n=424), acute toxicities were reported in 184 patients (87%) in the aRT Arm (n=212) and 93 (44%) in the sRT Arm (n=212). Of these, 10 reported AEs of grade ≥3 including 3 reported serious adverse events (a urinary retention, a bowel obstruction, and an insulin-dependent diabetes). The most frequently acute toxicities are detailed in the table Confidential 2. Acute AEs, potentially related to hormonal treatment, were hot flushes, asthenia, and hyperhidrosis. Acute genitourinary AEs of grade ≥2 were noted in 37 patients (17%) in the aRT Arm and in 9 (4%) in the sRT Arm (p<0•0001). Acute gastrointestinal AEs of grade ≥2 were noted in 23 patients (11%) in the aRT Arm and in 9 (4%) in the sRT Arm (p=0•010).

(table 2)

Late toxicities were reported in 196 patients (92%) in the aRT Arm and in 90 (42%) in the sRT Arm. These were of grade ≥2 in 125 patients (59%) in the aRT Arm and in 46 (22%) in the sRT Arm. The most frequently occurring late toxicities are detailed in table 3.

Late genitourinary adverse events, of all grades, were reported by 155 patients (73%) in the aRT Arm and by 62 (29%) in the sRT Arm. Those of grade ≥2 in 58 patients (27%) in the aRT Arm versus 14 (7%) in the sRT Arm (p<0•0001): mainly urinary incontinence, urinary frequency, and haematuria. Late genitourinary toxicities of grade ≥3 were reported in 12 patients (6%) in the aRT Arm and in 3 (1%) in the sRT Arm (p=0•018).

Late gastrointestinal adverse events, all grades were reported in 94 patients (44%) in the aRT Arm and in 42 (20%) in the sRT Arm. These late gastrointestinal toxicities were mainly grade 1-2 rectal haemorrhage, diarrhoea and proctitis in both treatment arms. Late gastrointestinal toxicities (grade ≥2) were noted in 17 patients (8%) in the aRT Arm and in 11 (5%) in the sRT Arm (p=0•24). Furthermore, late gastrointestinal AEs of grade ≥3 were reported in 8 patients (4%) in the aRT Arm and in 1 patients (<1%) in the sRT Arm (p=0•044).

The late erectile dysfunction of all grades were reported in 77 patients (36%) in the aRT Arm and in 27 (13%) in the sRT Arm (p<0•0001). Among these, erectile dysfunction was of grade ≥2 in 60 patients (28%) in the aRT Arm and in 17 (8%) in the sRT Arm (p<0•0001); and of grade ≥3 in 9 (4%) and 3 (1%), respectively (p=0•079).

(table 3)

The evolution of QoL was evaluated in patients with data, see figure 1. QoL results for QLQ-C30 and QLQ-PR25 are available in the appendix p 4-7. The functional dependence in the elderly was not analysed since only 3 patients completed the IADL scale at baseline. The change in global health status from enrolment until the QLQ-C30 completed after RT and before December 2017 were similar in the treatments arms (p=0•11). Similarly, the changes in the other domains of the QLQ-C30 were similar with aRT and sRT. The functional scales of the QLQ-PR25 remained stable with time.

Confidential Discussion

In the GETUG-AFU 17 multicentre, open label, phase III randomised study comparing aRT to sRT after RP, EFS was not significantly prolonged with aRT. The rate of events in our study was unexpectedly low. Moreover, patients exposed to aRT had significantly more acute and late grade ≥2 genitourinary toxicity and more grade ≥2 erectile dysfunction. The change in global health status were similar in the arms (p=0•11). Our results suggest that observation after RP, with early sRT when biochemical relapse occurs, could spare approximately half of the men from RT, and the related toxicity. At 5 years, more than 90% of patients in the aRT arm were free of progression. In the adjuvant setting, three randomised trials assessing postoperative RT have been completed. Firstly, the EORTC 22911 trial randomised 1005 patients (pT2 R1or pT3N0) to either aRT, within 4 months of RP, or a wait-and-see strategy. After a median follow-up of 5 years, the biochemical progression-free survival was significantly extended with aRT (74•0%, 98% CI 68•7-79•3) compared to the wait-and-see strategy (52•6%, 98% CI 46•6-58•5, p=0•0001). [START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911)[END_REF] Secondly, the ARO 96-02 trial randomised 307 men, with pT3N0 disease at RP, to aRT or observation.

Biochemical progression-free survival after 5 years was significantly extended with aRT (72% [95% CI 65-81] vs 54% [95% CI 45-63]; HR=0•53 [95% CI 0•37-0•79]; p=0•0015). This benefit was confirmed after a median follow-up of 110 months, the probability of patients being without biochemical progression was 20% higher with aRT compared to observation. [START_REF] Wiegel | Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial[END_REF] Finally, the SWOG S8794 trial randomised 431 patients, with pT3N0 prostate cancer, to aRT or initial observation. [START_REF] Thompson | Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: longterm followup of a randomized clinical trial[END_REF] After a median follow-up of 10•2 years, aRT had a reduced 10-year risk of biochemical treatment failure (42% vs 72%), local failure (7% vs 20%), and distant failure (4% vs 12%) compared with observation. Nevertheless, the results are difficult to interpret due to the lack of timely sRT in the control arms from these trials. The low rate of events in the GETUG-AFU 17 trial, compared to the aRT arm from the "old-fashioned" studies [START_REF] Thompson | Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: longterm followup of a randomized clinical trial[END_REF][START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911)[END_REF][START_REF] Wiegel | Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95[END_REF] , could be related to differences in populations, heterogeneity in radiation techniques and the prescribed dose given to the prostate bed. [START_REF] Ost | Adjuvant high-dose intensity-modulated radiotherapy after radical prostatectomy for prostate cancer: clinical results in 104 patients[END_REF] Furthermore, in localised prostate cancer, adding hormonal therapy to RT reduces biochemical relapse, compared to RT alone. [START_REF] Bolla | External irradiation with or without longterm androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study[END_REF][START_REF] Roach | Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610[END_REF][START_REF] Pilepich | Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31[END_REF] In the adjuvant setting, hormonal therapy is not a standard of care, possibly improving our EFS rates. [START_REF] Ost | High-dose adjuvant radiotherapy after radical prostatectomy with or without androgen deprivation therapy[END_REF] The RADICALS HD trial randomised patients to RT alone (early or deferred) or RT with 6 months of hormonal treatment or RT with 24 months of hormonal treatment. The primary outcome is the disease-specific mortality. This trial will

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probably provide an answer concerning the place of postoperative hormonal therapy in this setting.

Early sRT can be curative for patients with biochemical relapse after RP. Whether sRT should be administered alone or combined with hormonal therapy remains controversial. In the last decade, three randomised studies have evaluated hormonal therapy in men receiving sRT after RP. The RTOG 9601, a phase III randomised control trial demonstrated that 24 months of bicalutamide extended survival with a HR=0.77 (95% CI 0.59-0.99). 11 The GETUG-AFU 16 study showed that 5-year progression-free survival was prolonged with sRT plus 6 months of goserelin compared to sRT alone (80% [95% CI 75-84] vs 62% [95% CI 57-67]; HR=0•50, 95% CI 0•38-0•66; p<0•0001). [START_REF] Carrie | Salvage radiotherapy with or without shortterm hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial[END_REF] These results were confirmed with a 120-month metastasisfree survival rate in favour of the combined arm. [START_REF] Carrie | Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial[END_REF] The NRG Oncology/RTOG 0534 SPPORT trial randomised 1,736 patients to either (i) sRT to the prostate bed, (ii) sRT to the prostate bed with short-term hormonal therapy, or (iii) sRT to the prostate bed and the pelvic lymph nodes with short-term hormonal therapy. SPPORT's population 5-year freedom from progression improved from 71% to 87% when adding both short-term hormonal therapy and pelvic lymph nodes to prostate bed RT (HR=0•45, 95% CI 0•34-0•61). [START_REF] Pollack | Short Term Androgen Deprivation Therapy Without or With Pelvic Lymph Node Treatment Added to Prostate Bed Only Salvage Radiotherapy: The NRG Oncology/RTOG 0534 SPPORT Trial[END_REF] Similar to the good results in the combined arms from these three trials, we observed a 5-year EFS rate of 90% (95% CI 85-94) in our sRT Arm. 11, [START_REF] Carrie | Salvage radiotherapy with or without shortterm hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial[END_REF][START_REF] Pollack | Short Term Androgen Deprivation Therapy Without or With Pelvic Lymph Node Treatment Added to Prostate Bed Only Salvage Radiotherapy: The NRG Oncology/RTOG 0534 SPPORT Trial[END_REF] The PSA level before sRT may predict who will most benefit from sRT and whether hormonal therapy should be added, in terms of PSA-driven and long-terms outcomes. The GETUG-AFU 16 multivariate analysis showed that adding goserelin to sRT was beneficial, even in the most favourable group. [START_REF] Carrie | Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial[END_REF] However, in a new analysis from the RTOG 9601, examining a subset of patients relapsing after RP with PSA levels ≤0.6 ng/mL (n=389), closer to today's standard for early sRT, patients were nearly twice as likely to die from non-cancer causes when bicalutamide was added (HR=1.94; p=0.009). Patients with the lowest PSA levels (0.2-0.3 ng/mL) (n=148) had the greatest risk of death (HR=4•14; 95% CI 1•57-10•89). [START_REF] Spratt | Two years of anti-androgen treatment increases other-cause mortality in men receiving early salvage radiotherapy: a secondary analysis of the NRG Oncology/RTOG 9601 randomized phase III trial[END_REF] In our study, the median PSA level triggering sRT and short duration hormonal treatment was 0.24 ng/mL, lower than that reported in the Spratt et al. analysis. So the added value of hormonal treatment in our early sRT arm is debatable.

We have shown that aRT increased the risk of genitourinary and sexual morbidity compared to sRT. Our results accord with those from the three studies comparing aRT to observation: patients allocated aRT reported increased genitourinary toxicities of grade ≥2. [START_REF] Wiegel | Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial[END_REF][START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)[END_REF][START_REF] Moinpour | Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy[END_REF] Our incidences of late grade ≥2 genitourinary toxicities are in accordance with those reported in the Confidential we observed. Similar to the genitourinary toxicity analysis, the use of intensity-modulated RT [START_REF] Ost | A matched control analysis of adjuvant and salvage high-dose postoperative intensity-modulated radiotherapy for prostate cancer[END_REF] and the toxicity scales used may also influence the interpretation of our results compared to others trials. [START_REF] Wiegel | Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial[END_REF][START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)[END_REF] We observed that grade ≥2 erectile dysfunction was significantly worse in the aRT Arm (p<0•0001).Only the SWOG S8794 trial reported data on sexual function. [START_REF] Moinpour | Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy[END_REF] Van Stam et. al.

showed that men receiving postoperative RT, more than 6 months after RP, experienced better sexual satisfaction compared with those treated within 6 months following surgery, confirming the relation between timing of postoperative RT and sexual tolerance. [START_REF] Van Stam | The Effect of Salvage Radiotherapy and its Timing on the Health-related Quality of Life of Prostate Cancer Patients[END_REF] Overall, we can expect an increased rate in both acute and late AEs of all grades, and a decreased of QoL, in GETUG-AFU 17 compared to studies without hormonal therapy, owing to the 6-months of hormonal therapy initially delivered concurrent with RT. [START_REF] Wiegel | Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial[END_REF][START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)[END_REF][START_REF] Moinpour | Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy[END_REF][START_REF] Hackman | Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension[END_REF] Our analysis of the QLQ-C30 and QLQ-PR25 data found no significant differences between arms, in accordance to the SWOG S8794 trial reporting no differences in intermediate-term QoL between men receiving aRT or with initial observation. [START_REF] Moinpour | Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy[END_REF] Akhtar et al. reported favourable long-term QoL and late toxicity following postoperative RT. Patients' QoL were assessed in men treated with post-RP intensity-modulated RT, using the Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire. 29 The GETUG-AFU 17 trial has some limitations. Our analysis is limited by the patient accrual not reaching the target, giving a lack of statistical power to strongly conclude on efficacy. In addition, the trial was not powered to study long-term outcomes such as OS and MFS, even with longer follow-up. It is well known that EFS, particularly when PSA driven, is not a surrogate for longer-term outcomes. 30 Looking at the older trials of aRT versus observation, they showed large improvements in biochemical progression with RT without showing clear benefit in long-term outcomes. Therefore, from our study, it is very unlikely that results will change consistently in favour of aRT with more follow-up. Finally, regarding the relevance of androgen deprivation added to postoperative RT from the recent literature, our results could be questionable, highlighting potential overtreatment in both arms.

In conclusion, from the GETUG-AFU 17 trial, no difference in EFS rate was shown between aRT and sRT, although the analysis lacked statistical power. Our results show that sRT could spare men from receiving RT and its toxicity. Thus the questions about the best postoperative policy to propose after RP and which patient could still benefit from aRT, are still valid. The publication of the prospective ARTISTIC meta-analysis, including RAVES, RADICALS-RT, and GETUG-AFU 17 trials, will assess the impact of aRT vs early sRT on early, but also long-

FiguresFigure 1 :

 1 Figures

Acknowledgements

We would like to thank Ipsen and the French Health Ministry for funding this study. In addition, we thank all of the investigators who recruited patients; the patients who participated in the study, the clinical and research staff at all trial sites of the French GETUG-AFU group, the GETUG team at Unicancer, the data management team from the Institut Bergonié, Bordeaux, and the statistical team from the Centre Léon Bérard, Lyon. We would like to thank Trevor Stanbury (Unicancer) for medical writing assistance.

Funding French Health Ministry (PHRC

Funding

The sponsor of the trial was the Unicancer consortium of French Comprehensive Cancer Centres. The trial was supported financially by Ipsen. The trial was selected by the PHRC-Cancer call for proposals and funded through a grant from the French Health Ministry (PHRC-K-2006-04-11).

Confidential

genitourinary toxicity, and grade ≥2 erectile dysfunction compared to sRT. QoL was similar in the arms. Thus, sRT could spare men from RT and its toxicity. The sRT approach should be considered as standard if aRT is not superior to sRT in terms of efficacy.

Confidential Confidential

During the study, 7 patients reported second cancers: 4 in the aRT Arm and 3 in the sRT Arm.

In the aRT Arm, patients reported a muscle invasive bladder cancer, an anal canal cancer, a cancer of the larynx, and a transitional cell carcinoma. In the sRT Arm, patients reported a colorectal cancer, a kidney cancer, and a myelodysplastic syndrome. The time intervals to second cancers were 58, 66, 86, and 87 months after initiating RT in the aRT Arm and 21, 28, and 56 months in the sRT Arm.

Confidential

aRT arm of the EORTC 22911 study: genitourinary toxicities of grade ≥2 were significantly higher with aRT compared to observation (21•3% vs 13•5%; p=0•003). [START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)[END_REF] The EORTC 22911 study assessed acute toxicity using the WHO scale and late toxicities with the Late Morbidity Scoring Scheme (RTOG/EORTC), making the comparison with our study difficult. In contrast, the ARO 96-02/AUO AP 09/95 study reported that late genitourinary toxicities (by RTOG scale) were scarce, although more frequent with aRT. [START_REF] Wiegel | Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial[END_REF] However, urinary incontinence, frequently observed in our study, is not included in the RTOG/EORTC scoring scheme. The Finnish randomised trial also reported high rates of toxicity with aRT compared to RP alone. [START_REF] Hackman | Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension[END_REF] The LENT SOMA Scale, used for grading genitourinary toxicity in this trial, tends to higher grades compared to the CTCAE used in our study. [START_REF] Hackman | Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension[END_REF] For the safety analysis, we need to consider the total dose of RT administered in these studies.

We delivered more than the 60 Gy given in the EORTC 22911 and SWOG S8794 trials. This increased dose of RT, has been associated with higher rates of genitourinary toxicity. [START_REF] Ohri | Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling[END_REF] It is also important to highlight the RT techniques used when analysing these results. Indeed, in the SWOG S8794 trial, performed more than 25 years ago, details concerning RT were not reported. [START_REF] Thompson | Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: longterm followup of a randomized clinical trial[END_REF] The EORTC 22911 study used linear accelerators (5-25 MV), using an isocentric technique with non-3-D planning. [START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911)[END_REF] The ARO 96-02/AUO AP 09/95 study was the first, in this postoperative setting, to propose a 3-D RT approach. [START_REF] Wiegel | Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95[END_REF] The use of intensity-modulated RT in approximately 40% of our patients could explain our acceptable grade ≥2 genitourinary toxicity rate despite the increased RT dose given. [START_REF] Ost | Adjuvant high-dose intensity-modulated radiotherapy after radical prostatectomy for prostate cancer: clinical results in 104 patients[END_REF][START_REF] Cozzarini | Clinical factors predicting late severe urinary toxicity after postoperative radiotherapy for prostate carcinoma: a single-institute analysis of 742 patients[END_REF] It is noteworthy that since RT was delayed with sRT, more patients in the sRT arm benefited from intensity-modulated RT, as this technique became more available in France. [START_REF] Marchal | Intensity modulated radiotherapy (IMRT) in France: The boost of the national funding for the new expensive innovative technologies (STIC 2001 and 2002)[END_REF] As we showed in our results, in the literature, the delay between RP and postoperative RT is supposed to influence the risk of long-term AEs.

Interestingly, the recovery from urinary incontinence, after RP, occurs at a lower rate in patients after aRT compared to sRT. [START_REF] Van Stam | The Effect of Salvage Radiotherapy and its Timing on the Health-related Quality of Life of Prostate Cancer Patients[END_REF][START_REF] Suardi | Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy[END_REF] Our data are also concordant with the GETUG-AFU 16 results, showing late genitourinary adverse events of grade ≥3 in 7% of the patients in the combined sRT Arm. [START_REF] Carrie | Salvage radiotherapy with or without shortterm hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial[END_REF] Only 4 patients (1.9%) in our sRT arm experienced grade ≥3 genitourinary adverse events confirming the good tolerance of the delayed RT approach.

Regarding, the gastrointestinal toxicities reported, they were predominantly of grade 1-2, without significant difference between arms. Likewise, the EORTC 22911 study found around 5% of 10-year grade 3 gastrointestinal toxicities with aRT. [START_REF] Bolla | Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)[END_REF] In the GETUG-AFU 16 study, in the sRT combined with hormonal therapy treatment arm, similar to that used in our sRT arm, grade ≥3 gastrointestinal events rates were low (2%). [START_REF] Carrie | Salvage radiotherapy with or without shortterm hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial[END_REF] These rates are comparable with those Confidential term, outcomes in this patient group. Because of the limited power in these trials taken individually, ARTISTIC is a unique opportunity to evaluate the impact of RT timing across patient subgroups.

Confidential

Contributers

PR was the principal investigators for the study. SC and PR contributed to the design of the trial. PS, SC, IL, NM, AB, SS, DP, MSA, OG, PGC, MSi, PBe, PBa, YB, DA, MSo, and PR all contributed to the acquisition, analysis, and interpretation of the data. MB and SC were responsible for trial management, as well as the acquisition and analysis of data. The manuscript was drafted by PS, SC, and PR, all of the other authors critically reviewed and revised the manuscript. All authors have approved the final version of the manuscript prior to submission.

Declaration of interests

PS and IL declares receiving honoraria, providing medical advice, and participating on boards for Astellas, Bayer, Bouchara, Ferring, Ipsen, Janssen, Sanofi, and Takeda. SS declares to have received funding from Jansen,Astra-Zeneca, and Astellas, as well as personal fees and nonfinancial support from Jansen, Astellas, Ipsen, Takeda, Bouchara-recordati, and Sanofi. DA received honoraria from NovaGray. All other authors declare no conflicts of interest.

Data sharing statement

Unicancer will share de-identified individual data that underlie the results reported in this article under the following conditions: the data shared will be limit to that required for independent Confidential mandated verification of the published results, the reviewer will need authorisation from Unicancer for personal access, and data will only be transferred after signing of a data access agreement. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan, will be examined upon request. Unicancer will consider access to study data upon written detailed request, from 6 months until 5 years after the publication of this article. Lithiasis 1 (<1%) 1 (<1%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)

Confidential

Infections and infestations

Injury, poisoning, and procedural complications

Cystitis radiation 1 (<1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Investigations 44 (21%) 43 (20%) 0 (0%) 0 (0%) 0 (0%) 14 (7%) 13 (6%) 1 (<1%) 0 (0%) 0 (0%)

Weight decrease 41 (19%) 41 (19%) 0 (0%) 0 (0%) 0 (0%) 14 (7%) 13 (6%) 1 (<1%) 0 (0%) 0 (0%) Blood creatinine increased 1 (<1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Aortic dissection 1 (<1%) 0 (0%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)

Musculoskeletal and connective tissue disorders

Peripheral arterial occlusive disease 1 (<1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Table 3: Late toxicities of grade 1 or 2 reported in ≥10% of patients and all grade 3-5 reported in any arm, by system organ class and type of toxicity graded using the CTCAE v3.0.


Alexane Tournier
email: alexane.tournier2@gmail.com

Elodie Clouqueur

Elodie Drumez

Céline Petit

Marion Guckert

Véronique Houfflin-Debarge

PhD Damien Subtil

PhD Charles Garabedian

Ms Alexane Tournier

MD ; Ms Elodie Drumez

MD Ms Marion Guckert

Can we induce labor by mechanical methods following preterm premature rupture of membranes?

Keywords: preterm premature rupture of membranes, induction, balloon catheter, prostaglandins, intrauterine infection

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Preterm premature rupture of membranes (PPROM) complicates 3% of pregnancies. [START_REF] Lorthe | Impact of Latency Duration on the Prognosis of Preterm Infants after Preterm Premature Rupture of Membranes at 24 to 32 Weeks' Gestation: A National Population-Based Cohort Study[END_REF] The primary risk from PPROM is exposure to intrauterine infection (IUI), with incidence estimated from 15% to 25%. [START_REF] Kuba | ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes[END_REF] Management of PPROM is mainly based on prevention until 34 weeks' gestation and then induction is considered between weeks 34 and 37, based on varying national guidelines. [START_REF] Kuba | ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes[END_REF][START_REF] Schmitz | Preterm premature rupture of membranes: CNGOF Guidelines for clinical practice -Short version[END_REF][START_REF] Delorme | Modalities of birth in case of uncomplicated preterm premature rupture of membranes: CNGOF Preterm Premature Rupture of Membranes Guidelines[END_REF] Cervical ripening and labor induction can be performed by oxytocin, prostaglandins, or mechanical approaches (i.e., single or double balloon catheter). The balloon catheter technique is efficacious compared with other methods, with the advantage of reducing uterine hyperstimulation, which is primarily responsible for causing abnormal fetal heart rates. [START_REF] Penfield | Labor Induction Techniques: Which Is the Best?[END_REF][START_REF] Alfirevic | Methods to induce labour: a systematic review, network metaanalysis and cost-effectiveness analysis[END_REF][START_REF] Wang | Controlled-release dinoprostone insert versus Foley catheter for labor induction: a meta-analysis[END_REF] Despite this, one concern with using mechanical methods is infection risk. While the efficacy and safety -including IUI risk-of intracervical balloons has been confirmed for use with intact membranes, [START_REF] Mcmaster | Evaluation of a Transcervical Foley Catheter as a Source of Infection: A Systematic Review and Meta-analysis[END_REF] few studies have examined balloon-related IUI in premature rupture of membranes (PROM). [START_REF] Kruit | Foley Catheter or Oral Misoprostol for Induction of Labor in Women with Term Premature Rupture of Membranes: A Randomized Multicenter Trial[END_REF][START_REF] Cabrera | Use of intracervical balloons and chorioamnionitis in term premature rupture of membranes[END_REF][START_REF] Amorosa | A randomized trial of Foley Bulb for Labor Induction in Premature Rupture of Membranes in Nulliparas (FLIP)[END_REF][START_REF] Mackeen | Foley Plus Oxytocin Compared With Oxytocin for Induction After Membrane Rupture: A Randomized Controlled Trial[END_REF] Whether its effect is reduced in PPROM due to the absence of any effect on the membrane -and thus on endogenous prostaglandin secretion-is unknown.

Thus, the study objective was to evaluate effectiveness of the balloon catheter for induction in PPROM and determine whether balloon catheter for cervical ripening increases the Ceasarean section rate, compared with locally applied prostaglandins. The secondary objective was to assess the safety of the balloon catheter and mainly IUI rate in PPROM.

MATERIALS AND METHODS

This was a monocentric, retrospective cohort study in Lille (tertiary care hospital), France, examining patient records kept from 2002 to 2017. Patients were included if they had a singleton pregnancy with PPROM before term (<35 weeks) and were induced, after more than a week of management, by either locally applied (vaginal) prostaglandins or intracervical balloon. Patients were excluded in the case of intrauterine fetal death, if they were induced for suspicion of IUI, and if they did not need cervical ripening (Bishop > 6).

PPROM was clinically defined as fluid loss or ultrasound showing oligoamnios (maximum vertical pocket <2 cm). It was confirmed with positive Actim Prom test (Medix Biochemica), detecting the insulinlike growth factor binding protein-1 (IGFBP-1). Following current standard of care, PPROM-diagnosed patients received antenatal corticosteroids and prophylactic antibiotics (seven days of Amoxicillin), as soon as they were diagnosed. PPROM management during the study period, prior to implementation of homecare management, was conventional hospitalization. [START_REF] Petit | Preterm premature rupture of membranes : which criteria contraindicate home care management ?[END_REF] Labor induction occurred between 34 and 37 weeks, as recommended by the American College of Obstetrics and Gynecology. [START_REF] Kuba | ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes[END_REF] Patients in the study had an unfavorable cervix (Bishop score ≤ 6) and required cervical ripening, by either prostaglandin E2 or balloon catheter. There were two periods : the primary mode of cervical ripening was prostaglandins (gel or intravaginal device) until 2013, after which the intracervical balloon became the method of reference and was systematically used, whatever the bishop score, the fetal heart rate or the fetal presentation. Balloon catheter remained in situ 12 hours. The double balloon type (Cook Cervical Ripening Balloon reference J-CRBS-184000) was used initially, followed in 2015 by the single 50 mL inflated balloon (Cook Universa Foley catheter Fr 16 reference 028518-CE), which has the same efficacy and a lower cost. [START_REF] Pez | Cervical ripening and labor induction: Evaluation of single balloon catheter compared to double balloon catheter and dinoprostone insert[END_REF][START_REF] Lajusticia | Single versus double-balloon catheters for the induction of labor of singleton pregnancies: a meta-analysis of randomized and quasi-randomized controlled trials[END_REF] After the first ripening method, vaginal prostaglandins could be used as second induction agent if cervix was still unfavorable. Oxytocin was only used after the balloon catheter or the prostaglandins, if contractions or cervical dilation was insufficient. During labor, antibiotic prophylaxis with amoxicillin was systematic.

Management was the same in patients with a previous Cesarean delivery.

The primary study outcome balloon catheter efficiency evaluated by Cesarean section rate.

Secondary outcomes were: and interval from induction to delivery, labor duration (latent phase, active phase i.e. dilation > 5 cm and second stage), oxytocin use, IUI rate, maternal complications (i.e., postpartum hemorrhage and endometritis), and neonatal complications (respiratory distress, hyaline membrane disease, neonatal infection, intraventricular hemorrhage, necrotizing enterocolitis, neonatal death). IUI was defined according to the criteria set by Higgins et al.: temperature >38°C on two occasions, or >39°C with fetal tachycardia (>160 beats per minute for >30 minutes), purulent cervical discharge, or maternal leukocytosis (>15,000 cells/µL). [START_REF] Higgins | Evaluation and Management of Women and Newborns With a Maternal Diagnosis of Chorioamnionitis: Summary of a Workshop[END_REF][START_REF] Peng | Intrauterine inflammation, infection, or both (Triple I): A new concept for chorioamnionitis[END_REF] Endometritis was defined as a temperature >38°C associated with uterine pain or purulent cervical discharge, and with no other source of hyperthermia.

Statistical analyses

Data are presented as value (percentage) for categorical variables and mean ± standard deviation (SD) or median interquartile range (IQR) for continuous variables. Normality of distribution was checked graphically and using the Shapiro-Wilk test. Between-groups comparisons were made using the Chi-square test for categorical variables or Student's t-tests (or Mann-Whitney tests for non-Gaussian distribution) for continuous variables.

Statistical analyses used a two-tailed α, with p < 0.05 considered statistically significant. Data were analyzed using SAS software (version 9.4; SAS Institute Inc., Cary, NC).

Ethics

The study was approved by the Comité local de la Commission Nationale Informatique et Libertés (CNIL) (reference DEC16-210).

RESULTS

Over 211 patients induced for PPROM, 120 patients had an unfavorable cervix and were induced between 34 and 37 weeks (Figure 1). 91 patients had a bishop > 6 and were induced by oxytocin alone. Two patients were induced for suspicion of IIU and were excluded from the study. Therefore, 118 patients (55.9%) were included : 60 in the vaginal prostaglandin group (50.8%) and 58 in the balloon catheter group (49.2%). Among the latter, 42 were induced by double balloon and 16 with single balloon. Twenty-nine (50%) patients induced by balloon catheter required a second line of induction with prostaglandins. Demographics and pregnancy characteristics were similar between the groups except for induction term and neonatal weight (Table 1 and3); induction term differed between the groups, which was 35 weeks, 6 days (range: 35 weeks, 2 days to 36 weeks, 3 days) for patients induced by prostaglandins vs 36 weeks, 2 days (range: 36 weeks, 1 day to 36 weeks, 6 days) for patients induced by balloon catheter (p < 0.001). Neonatal weight also differed with 2580 grams for prostaglandins vs 2700 grams for balloons (p = 0.017). Bishop score at induction was comparable between the two groups: 3 (range: 2 to 4) for prostaglandins alone vs 3 (range: 2 to 4) for balloon catheter (p = 0.87).

There was not a significant difference between-groups in delivery mode (20.0% cesarean for prostaglandins group vs 10.3% for balloon catheter group p = 0.14; Table 2). The time from induction onset to birth did not differ significantly between the prostaglandin (29 hours) and balloon catheter (28 hours) groups (p = 0.32).

Among the secondary outcomes, there was not a significant difference in occurrence of IUI (11.7% for vaginal prostaglandins vs 12.1% for balloon catheter; p = 0.95). Labor duration among patients induced by prostaglandins alone was shorter compared with that of patients induced by balloon catheter (275 vs 283 minutes, respectively; p = 0.006); this result was found for each labor stage. Regarding labor characteristics, there was not a significant between-groups difference in rate of oxytocin use, although a higher total dose was observed for patients induced by balloon catheter (1.3 IU vs 0.6 IU for the prostaglandin group; p = 0.005).

Table 3 shows neonatal outcomes based on induction method. In the prostaglandin group, there were more transfers to intensive care (22% vs 5.2% in the balloon catheter group; p = 0.008) and more respiratory distress (16.7% vs 1.7% in the balloon catheter group; p = 0.005).

Among the 11 cases of intrauterine infection, 5 bacteria were found during the antenatal period using vaginal swab and 6 bacteria during the postpartum period. Among these cases, two patients had both antenatal and postnatal bacteria, and this bacterium was the same in one case. All patients had antibiotics during labor. Among the intrauterine infection cases, two presented maternal infection and one neonatal infection.

DISCUSSION

PPROM management includes induction between 34 and 37 weeks' gestation [START_REF] Kuba | ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes[END_REF] and the primary complication of PPROM is IUI risk. According to our study, induction by balloon catheter is not associated with an increase of this risk compared with induction by vaginal prostaglandins. Nor did we find a difference in delivery mode or time from onset of induction to birth. However, labor duration was shorter, and total dose of oxytocin lower, for patients induced by prostaglandins alone, whereas superior neonatal outcome was observed in the balloon catheter group.

Few studies have investigated induction methods in patients with rupture of membranes prior to 37 weeks' gestation; among these, most have focused on the optimal gestational age for birth, comparing expectative management to immediate delivery between 34 and 37 weeks. [START_REF] Van Der Ham | Induction of labor versus expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks: a randomized controlled trial[END_REF][START_REF] Van Der Ham | Management of late-preterm premature rupture of membranes: the PPROMEXIL-2 trial[END_REF][START_REF] Morris | Immediate delivery compared with expectant management after preterm pre-labour rupture of the membranes close to term (PPROMT trial): a randomised controlled trial[END_REF] In those studies, induction mode was either oxytocin or prostaglandins. Various national guidelines do not recommend one induction method over another. Rather, they draw conclusions based on the efficacy and acceptability of oxytocin and prostaglandins, and on the relative lack of data on balloon catheter. [START_REF] Kuba | ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes[END_REF][START_REF] Schmitz | Preterm premature rupture of membranes: CNGOF Guidelines for clinical practice -Short version[END_REF][START_REF] Delorme | Modalities of birth in case of uncomplicated preterm premature rupture of membranes: CNGOF Preterm Premature Rupture of Membranes Guidelines[END_REF][START_REF]ACOG Committee on Practice Bulletins --Obstetrics. ACOG Practice Bulletin No. 107: Induction of labor[END_REF] Mechanical induction by single or double balloon catheter has been primarily discussed in the contexts of infection risk and mechanism of action. The main concern is a theoretical risk of infection due to the presence of a foreign body in the cervix, particular when the membranes have ruptured. [START_REF] Packard | Labor induction in the patient with preterm premature rupture of membranes[END_REF] McMaster et al. conducted a meta-analysis of 26 randomized trials with 5,563 patients with intact membranes, finding a similar rate of infection between Foley and prostaglandin groups; each had approximately 7.2% IUI, 3.5% endometritis, and 3.5% neonatal infections. [START_REF] Mcmaster | Evaluation of a Transcervical Foley Catheter as a Source of Infection: A Systematic Review and Meta-analysis[END_REF] Amorosa et al. compared use of a Foley catheter with oxytocin vs oxytocin alone in a randomized trial of 128 patients with premature rupture of membranes (PROM) after 34 weeks' gestation. [START_REF] Amorosa | A randomized trial of Foley Bulb for Labor Induction in Premature Rupture of Membranes in Nulliparas (FLIP)[END_REF] These authors found no difference in delivery mode nor in induction-to-delivery time between the groups, with no significant difference in IUI rate (10% in the Foley group vs 5% in the oxytocin alone group; p = 0.31).

Conversely, in a randomized trial of 201 patients with PROM after 34 weeks' gestation, Mackeen et al. found an increased IUI rate in the oxytocin + Foley group compared with oxytocin alone (8% vs 0%, respectively; p < 0.01). The Cesarean section rate (27% vs 19% respectively, p=0.35) and the induction-delivery delay was similar between groups in that study. [START_REF] Mackeen | Foley Plus Oxytocin Compared With Oxytocin for Induction After Membrane Rupture: A Randomized Controlled Trial[END_REF] After 37 weeks' gestation, Cabrera et al. retrospectively evaluated 42 patients induced by Foley, compared with 82 induced by oxytocin alone. [START_REF] Cabrera | Use of intracervical balloons and chorioamnionitis in term premature rupture of membranes[END_REF] Using logistic regression, that group found the occurrence of IUI to be associated with nulliparity and use of internal tocometry, rather than use of balloon catheter. In a randomized trial of 202 patients, Kruit et al. compared induction following PROM after 37 weeks by Foley vs prostaglandins and did not find any difference in either rate of cesarean delivery rates (23.6 vs. 18.2% respectively ; p = 0.36), time from induction to birth (1,311 vs. 1,435 minutes; p = 0.31) or rate of IUI (2.2 vs 2%, respectively; p = 1.00). [START_REF] Kruit | Foley Catheter or Oral Misoprostol for Induction of Labor in Women with Term Premature Rupture of Membranes: A Randomized Multicenter Trial[END_REF] The second concern with balloon catheter in PPROM is its efficacy when the membranes are ruptured. Indeed, rupture of membranes is associated with local secretion of prostaglandins, facilitating spontaneous labor.

However, the balloon catheter also aids secretion of local prostaglandins, via membrane stripping. Due to the mechanism of rupture, it is possible that the optimal physiological amount of prostaglandins has already been reached. The effect of the balloon would therefore be limited. In our analyses, we observed balloon catheter induction to have the same efficacy as prostaglandins. Labor lasted 8 minutes longer in the balloon catheter group, which is clinically negligible. Consistent with Wang et al., we observed a decrease in the use of oxytocin in prostaglandin induction compared with a mechanical method. [START_REF] Wang | Controlled-release dinoprostone insert versus Foley catheter for labor induction: a meta-analysis[END_REF] This study is original since other authors studied induction with balloon catheter in term PROM and never in PPROM, to our knowledge. It is all the more interesting as risk of IUI increase with length of latency. Although our novel study revealed valuable findings on the safety and efficacy of balloon catheter induction in the management of PPROM, it was not without several limitations. First, the two groups were not strictly comparable because their induction terms differed by 3 days (although this difference is not clinically meaningful) and the neonatal weight also differed. It might be the reason of the statistical difference in neonatal outcomes. Second, our sample size was relatively small, [START_REF] Cabrera | Use of intracervical balloons and chorioamnionitis in term premature rupture of membranes[END_REF][START_REF] Amorosa | A randomized trial of Foley Bulb for Labor Induction in Premature Rupture of Membranes in Nulliparas (FLIP)[END_REF] and thus did not allow analysis of rare events (e.g., endometritis, neonatal infections). A larger number of patients may have revealed a significant difference on outcomes such as delivery mode . In fact, there were twice as many Cesarean deliveries in the prostaglandin group (20%) than in the balloon group (10%; p = 0.14). The sample size for the outcomes are not of sufficient number to rule out a type II error for the small differences in the variables measured. Third, there is a classification bias given that 50% of the balloon group received prostaglandins. A subgroup analysis was not statistically relevant considering our sample size. Forth, we cannot rule out the possibility of an IUI classification bias in the prostaglandin group; indeed, hyperthermia is a known side effect of dinoprostone. [START_REF] Penfield | Labor Induction Techniques: Which Is the Best?[END_REF] Moreover, the assessment of the IUI was not blinded so views of the clinicians could affect the diagnosis of IUI. Nevertheless, we used a standardized IUI definition, based on the criteria by Higgins et al. and objective data. [START_REF] Higgins | Evaluation and Management of Women and Newborns With a Maternal Diagnosis of Chorioamnionitis: Summary of a Workshop[END_REF] Finally, a mid-study change in standard practice within our center, implementation of homecare management, may have affected our patients' microbial ecology.

CONCLUSION

Compared with locally applied prostaglandins, induction by intracervical balloon is not associated with a significantly higher risk of Cesarean section. Thus, balloon catheter appears to be an option for PPROM management. These results should be confirmed in a randomized study with a larger sample.

Table 1 .

 1 Sample characteristics based on cervical ripening method.

	Variable	Prostaglandin group	Balloon group	P value
		n = 60	n = 58
	Age (years)	25.5 (21.0-31.0)	28.0 (24.0-34.0)	0.094
	Prepregnancy BMI (kg/m2)	22.0 (19.0-26.0)	22.0 (20.0-25.0)	0.37
	Smoking	13 (21.7)	9 (15.5)	0.39
	Nulliparous	25 (41.7)	32 (55.2)	0.14
	Prior Cesarean delivery	2 (3.3)	3 (5.2)	NA
	IUGR	5 (8.3)	4 (6.9)	1.00
	Obstetrical pathology	14 (23.3)	9 (15.5)	0.28
	Premature labour,	6 (10.0)	2 (3.4)	NA
	Gestational diabetes,	5 (8.3)	5 (8,6)	NA
	Obstetric cholestasis	1 (1.7)	0	NA
	Gestational age at PPROM* (weeks)	31.9 (27.1-32.8)	29.2 (25.1-32.6)	0.22
	Positive bacteriological culture on	5 (8.5)	4 (7.0)	1.00
	vaginal swab at PPROM
	Oligoamnios at PPROM	9 (15.0)	5 (8.6)	0,28
	Gestational age at induction*	35.9 (35.4-36.3)	36.3 (36.1-37.0)	<0.001
	(weeks)
	IUGR = intrauterine growth restriction
	Data expressed as n (%) or median* (interquartile range)

Table 2 .

 2 Induction characteristics in PPROM patients based on cervical ripening method.

	Variable	Prostaglandin group	Balloon group	P value
		n = 60	n = 58
	Bishop score*	3.0 (2.0-4.0)	3.0 (2.0-4.0)	0.87
	Need for a second line of induction	24 (40.0)	29 (50.0)	0.27
	Number of prostaglandins*	1.00 (1.00-2.00)	1.00 (0.00-2.00)	<0.001
	Time from onset of induction to	24.0 (8.2-38.8)	21.8 (14.8-39.5)	0.48
	delivery room* (hours)
	Time from induction to delivery*	29.0 (13.3-48.9)	28.0 (20.9-46.7)	0.32
	(hours)
	Oxytocin use	33 (57.9)	41 (71.9)	0.12
	Total dose of oxytocin*	0.6 (0.3; 2.0)	1.3 (0.8; 2.

Table 3 .

 3 Neonatal outcomes in PPROM patients based on cervical ripening method.

	027
	0.026
	0.006

COMPLIANCE WITH ETHICAL STANDARDS

Funding details : Funding was not obtained for this study Conflict of interest : The authors report no conflict of interest.