Nicolas Giraud
email: nicolas.giraud@chu-bordeaux.fr

Geoffrey Popinat

Hamza Regaieg

David Tonnelet

Pierre Vera

Positron-emission tomography-guided radiation therapy: ongoing projects and future hopes Radiothérapie guidée par la tomographie par émission de positrons : projets actuels et espoirs futurs

Keywords: Radiation oncology, Clinical oncology, Functional imaging, Image-guided radiation therapy Radiothérapie, Oncologie clinique, Imagerie fonctionnelle, Radiothérapie guidée par l

Radiation therapy has undergone significant advances these last decades, particularly thanks to technical improvements, computer science and a better ability to define the target volumes via morphological and functional imaging breakthroughs. Imaging contributes to all three stages of patient care in radiation oncology: before, during and after treatment. Before the treatment, the choice of optimal imaging type and, if necessary, the adequate functional tracer will allow a better definition of the volume target. During radiation therapy, image-guidance aims at locating the tumour target and tailoring the volume target to anatomical and tumoral variations. Imaging systems are now integrated with conventional accelerators, and newer accelerators have techniques allowing tumour tracking during the irradiation. More recently, MRI-guided systems have been developed, and are already

Résumé

La radiothérapie a connu des avancées significatives ces dernières décennies, liées notamment aux améliorations techniques, à l'informatique et à une meilleure capacité à définir les volumes cibles grâce aux progrès en imagerie morphologique et fonctionnelle. L'imagerie est essentielle aux trois temps du traitement de radiothérapie i.e. avant, pendant et après le traitement du patient. Avant l'irradiation, le choix du bon type d'imagerie ainsi que, le cas échéant, du radiotraceur optimal, permettront une meilleure définition du volume. Au cours de la radiothérapie le guidage par l'image a pour but de localiser la cible tumorale et d'adapter le volume à traiter aux variations anatomiques et tumorales en cours de traitement. Ces systèmes d'imagerie s'intègrent désormais aux accélérateurs classiques, et les nouveaux accélérateurs possèdent des techniques permettant de suivre la tumeur pendant l'irradiation. Plus récemment, des accélérateurs avec IRM embarquée ont été développés, et sont déjà actifs dans quelques centres français. Enfin, après la radiothérapie, l'imagerie joue un rôle majeur dans le suivi de nombreuses pathologies cancéreuses, et doit prendre en compte les spécificités des tissus après irradiation. Dans cette revue, nous nous concentrerons sur les projets actuels de l'imagerie nucléaire en oncologie et la manière dont ils peuvent aider le radiothérapeute à mieux traiter ses patients. Dans cette optique, une revue de la littérature incluant les termes "Radiotherapy", "Radiation Oncology" et "PET-CT" a été réalisée en août 2019 sur Medline et ClinicalTrials.gov.

Nous avons choisi d'aborder successivement ces nouveautés organe par organe, en nous concentrant sur les avancées les plus prometteuses. En conclusion, l'apport de l'imagerie fonctionnelle moderne, via une meilleure définition et le développement de nouveaux traceurs radiopharmaceutiques spécifiques, pourrait permettre des traitements encore plus précis ainsi qu'une surveillance améliorée.

Enfin, elle pourrait fournir des informations déterminantes aux algorithmes d'intelligence artificielle des modèles « -omiques ».

Introduction

Radiation oncology, which uses ionizing radiations to treat cancer, is a mixed discipline on the border between clinical and technical features, and has benefited from the forefront of advances in medical imaging which helped shaping modern radiotherapy.

With the appearance and development of linear accelerators, the notion of dose calculation and treatment planning emerged, leading eventually to computer-based dose calculation rapidly evolving through the last decades. Three-dimensional dose calculation on computerized tomography (CT) scans allowed advanced radiotherapy: more accurate dose distribution, dose optimization, more precise visualization of tumour targets and organs at risk, as well as better patient positioning control. These were the necessary elements that allowed the development of techniques that aim to better conform the irradiation: intensity-modulated radiotherapy (IMRT), volumetric modulated arctherapy, image-guided radiotherapy, etc. [START_REF] De Crevoisier | Radiothérapie guidée par l'image[END_REF]. The availability of ultraprecise imaging is also a mandatory requirement, along with rigorous systems of radiation focalization, for stereotactic body radiotherapy which can deliver very high doses in small volumes.

Currently, radiotherapy planning is completely computerized. The combination of modern conformation techniques and ultra-qualitative imaging modalities allows treatment accuracy of the order of a few millimetres. Improvements can still be made in the definition of target volumes which is sometimes difficult on CT alone, as some specific CT limitations exist, for instance suboptimal tissue contrast and subpar definition for certain areas of the body and lack of functional information. To this end, radiation oncologists often fuse pretherapeutic magnetic resonance imaging (MRI) and positronemission tomography (PET) sequences with the dosimetric scanner to better define the volumes. CT remains compulsory, mainly because it allows physicists to identify mass attenuation or attenuation characteristics which are critical parameters for precise dose calculation.

PET/CT can provide additional information, by allowing the identification of abnormal metabolic areas, guiding delineation and possibly dose escalation to these areas ("dose-painting") [START_REF] Supiot | Dose-painting » : mythe ou réalité ?[END_REF][START_REF] Basu | The scope and potentials of functional radionuclide imaging towards advancing personalized medicine in oncology: emphasis on PET-CT[END_REF]. While ( 18 F)-fluorodeoxyglucose (FDG) remains the most commonly used tracer, new radiopharmaceutical tracers are being evaluated for a range of diseases, aiming to be more informative, sensitive and/or specific.

In this article, we will successively review recent advances and ongoing trials combining PET-CT and radiation therapy, following an organ-after-organ pattern. For each organ we will review the pretherapeutic, pertherapeutic and/or post-therapeutic hopes of future progress in the field of nuclear medicine applied to Radiat Oncol This review was made after an extensive research conducted in August 2019 on Medline and ClinicalTrials.gov. The terms « Radiotherapy », « Radiation Oncology » and « PET-CT » were included. Articles and ongoing trials were then chosen for their relevance to the subject.

Brain malignancies: pretherapeutic imaging

For most brain tumours, radiation treatment is guided by MRI acquisition fused to the dosimetric scan.

FDG PET/CT are rarely useful, because of the vivid physiological glucose metabolism uptake of brain cells. Functional imaging using ( 18 F)-L-dihydroxyphenylalanine ([ 18 F]-dopa) is being tested in a Mayo Clinic pilot study (NCT02104310) to treat gliomas. Indeed, tumour delineation is a difficult task in regions beyond areas of contrast enhancement where infiltrative disease can extend, due to the nonspecific nature of T2 signal abnormalities, which can also include gliosis and peritumoral oedema [START_REF] Villanueva-Meyer | Current clinical brain tumor imaging[END_REF].

( 18 F)-dopa has shown promising results in being able to better distinguish tumour from normal brain tissue, as well as discriminating tumour recurrence and radiation-induced changes. It could also assist the radiation oncologist in identifying the most aggressive regions of the tumour possibly leading to dose escalation of these areas [START_REF] Xiao | Diagnostic and grading accuracy of ( 18 F)-dopa PET and PET/CT in patients with gliomas: a systematic review and meta-analysis[END_REF].

Head and neck malignancies

Pretherapeutic imaging

Technological developments, in particular intensity-modulated radiotherapy, have paved the way to innovative therapeutic prospects and functional organs preservation for head and neck malignancies [START_REF] Nutting | Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial[END_REF][START_REF] Braam | Intensity-modulated radiotherapy significantly reduces xerostomia compared with conventional radiotherapy[END_REF][START_REF] Pow | Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled clinical trial[END_REF]. Innovations in nuclear medicine contribute to these therapeutic changes, especially as guidance on metabolic areas available to potential dose escalation. For instance, the RADPAINT trial (NCT03847480) investigates the safety of FDG PET/CT-guided radiotherapy using a volumetric modulated arctherapy simultaneous integrated boost plan with a maximum point dose of 83Gy (73Gy and 78Gy minimum doses to two PET-guided gross tumour volumes inside the conventional 68Gy gross tumour volume). The investigators expect to keep the level of side effects on the normal tissue within the level of conventional radiotherapy. Having the same purpose, UPGRADE-RT (NCT02442375) is a phase III trial that has been opened since June 2016 which questions whether deescalation of radiation doses guided by PET/CT with dose reduction to the elective neck (35Gy versus 45Gy) and 60Gy intermediate dose levels can safely be used for newly diagnosed stage T2-4 N0-2 M0 squamous cell carcinomas of the oropharynx, hypopharynx or larynx without compromising the efficacy [START_REF] Van Den Bosch | Uniform FDG-PET guided gradient dose prescription to reduce late radiation toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma[END_REF]. The RIDPAINT trial (NCT02921581) explores dose-painting methods when reirradiation (relapse or second head and neck cancer) is needed. For concomitant chemoradiotherapy, the ARTFORCE phase III trial (NCT01504815) aims to explore the impact of PET information for adaptive high dose radiotherapy (up to 84Gy maximum in 7 weeks on 50% uptake gross tumour volume) compared to conventional 70Gy in 7 weeks (with concomitant cisplatin in both cases) on locoregional, recurrence-free survival and toxicity for patients with locally advanced HNSCC. This study is estimated to be fulfilled by September 2021 [START_REF] Heukelom | Adaptive and innovative radiation treatment for improving cancer treatment outcome (ARTFORCE); a randomized controlled phase II trial for individualized treatment of head and neck cancer[END_REF]. Finally, TRIMODAL (NCT03897166) is a French trial using a combination of pretherapeutic FDG PET, MRI and CT imaging for 60 patients with head and neck cancers to test a synergistic effect of these modalities to gross tumour volume delineation and to explore anthropometric and radiomic parameters.

Pertherapeutic imaging

Response to radiation therapy depends on a number of biological factors, such as tumour proliferation, number of clonogenic cells or hypoxia [START_REF] Horsman | The impact of hypoxia and its modification of the outcome of radiotherapy[END_REF][START_REF] Wang | Biological effects of radiation on cancer cells[END_REF][START_REF] Torres-Roca | A molecular assay of tumor radiosensitivity: a roadmap towards biology-based personalized radiation therapy[END_REF]. Recently, various markers of hypoxia have been explored. Studies have shown that patients with head and neck squamous cell carcinomas whose tumours are hypoxic after 2 weeks of primary chemoradiotherapy have a significantly lower chance of locoregional control [START_REF] Bredell | Current relevance of hypoxia in head and neck cancer[END_REF]. INDIRA-MISO (NCT03865277) is a new phase II trial evaluating the value of radiation dose escalation based on hypoxia detection by ( 18 F)-misonidazole (F-miso) PET/CT.

Patients with tumours classified as hypoxic with this new radiotracer are randomized after 2 weeks of chemoradiotherapy to completion of standard chemoradiotherapy (70Gy) or chemoradiotherapy with escalated radiation dose (77Gy), in order to evaluate tumour control 2 years after treatment. An additional interventional arm includes a carbon ion boost. Results are expected in 2024. HYPONECK is another ongoing French phase II trial (NCT04031534) using F-miso PET imaging, this time in a preoperative setting for squamous cell carcinomas of the oropharynx. It combines a quasi simultaneous evaluation of preoperative PET/MRI images in order to compare PET and MRI indicators of hypoxia, then combining them to anatomic pathology features to analyse the correlation between hypoxia and one-year recurrence free survival in a second part of the study. This could lead to stimulate research on multimodal imaging-guided radiation dose-escalation to hypoxic tumour areas.

Oesophageal malignancies

Pertherapeutic imaging

PET scan is a major asset in the pre-therapeutic management of oesophageal tumours, and is becoming an early therapeutic evaluation tool, especially for poor early responders. Phase II/III trial SCOPE2 (NCT02741856) will compare the effects of standard dose radiotherapy (50Gy in 25 fractions) to a dose escalation (60Gy in 25 fractions) for patients with oesophageal cancer. Patients are PETreassessed after two weeks of induction chemotherapy consisting of cisplatin and capecitabine.

According to response to this induction chemotherapy, patients will receive standard radiotherapy dose or high dose with standard (cisplatin and capecitabine) or alternative (carboplatin and paclitaxel) regimen of induction chemotherapy. Inclusions have started since November 2016 with estimated primary results in 2021.

Nuclear imaging is also used to guide induction chemotherapy in a phase II study (NCT03791905), aiming to evaluate whether changing the induction chemotherapy regimen during radiation based on PET response to induction chemotherapy (combining oxaliplatin, leucovorin, and 5-fluorouracile or cisplatin and paclitaxel) can improve clinical complete response in patients with unresectable oesophageal squamous cell carcinomas. A second PET is performed on days 36-42 and changes in maximum standard uptake value (SUVmax) compared to baseline are assessed. Using a predefined cutoff value of a 35% decrease in SUVmax, PET responders continue the same induction chemotherapy regimen during radiotherapy, whereas PET non-responders cross over to an alternative regimen. First results are also expected in 2021.

Intermodal research

For locally advanced oesophageal cancer, the standard treatment relies on a neoadjuvant chemoradiotherapy followed by surgery if possible [START_REF] Sjoquist | Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis[END_REF]. The PRIDE trial (NCT03474341), which has been including patients since 2018, hopes to develop a multimodal model that predicts the probability of pathological complete response to neoadjuvant chemoradiotherapy in oesophageal cancer, by integrating diffusion-weighted MRI and dynamic contrast enhanced MRI in conjunction with combined FDG PET/CT scans acquired prior to, during and after administration of neoadjuvant chemoradiotherapy. The underlying ideas are that patients with pathological complete response may not have benefited from surgery, and that an early identification of non-responders would be beneficial to explore other treatments. Finally, the PreSINO trial (NCT03937362) explores the ability of FDG PET/CT to detect residual disease after neoadjuvant chemoradiotherapy. Ultimately, the goal is to offer a possibility of active surveillance instead of esophagectomy in patients with a complete response after neoadjuvant chemoradiotherapy.

Lung malignancies

Pertherapeutic imaging

Chemoradiotherapy is widely used in the treatment strategy of patients with locally advanced lung malignancies. Accurate tumour delineation is crucial for an effective treatment. FDG PET/CT is an interesting tool for delineating the tumour volume [START_REF] Ganem | Delineation of lung cancer with FDG PET/CT during radiation therapy[END_REF], and many trials are being conducted to study the value of PET/CT for dose painting in pre-and pertherapeutic situations. For instance, the French trial entitled "RTEP7" (NCT02473133) aims to study the benefit of personalized radiotherapy dose in patients with locally advanced non-small cell lung cancer. The goal is to investigate the individual tumour heterogeneity on FDG PET during chemoradiotherapy at 42Gy in order to reduce the radiation volume to a biological target that could receive a higher total dose of 74Gy in 6.6 weeks. Therefore, a significant reduction in FDG uptake and/or volume (metabolic response) would suggest that the radiotherapy target volume could be reduced during radiotherapy, possibly improving organs at risk tolerance. Conversely, a lack of metabolic response may justify treatment intensification before the end of radiotherapy. Locoregional control at 15 months (1 year after completion of chemoradiotherapy) is the primary objective. Another trial, entitled "REPAINT" (NCT03481114), is designed to evaluate patient-reported outcomes during and after concurrent chemoradiotherapy for locally advanced non-small cell lung cancer. Patients will be randomized to a standard 6-week radiotherapy course or a 4-week radiotherapy course using dose painting based on pretreatment PET findings (55Gy in 20 fractions for lesions with metabolic tumour volume exceeding 20 cm 3 , 48Gy in 20 fractions otherwise) thus offering the chance for a shorter and more personalized treatment course using PET imaging. Finally, a Danish phase III trial (NCT02354274) aims to investigate a radiation dose escalation (as high as possible taking the tolerance of the normal tissue into consideration) to tumour and lymph nodes based on an inhomogeneous dose distribution based on FDG-PET positive areas, compared to a standard homogeneous dose spread (66Gy in 33 fractions).

Single photon emission computed tomography may also have a role to play in the radiotherapy planning for lung cancer. A pilot study trial (NCT02492867) explores response-driven adaptive radiotherapy for patients with locally advanced non-small cell lung cancer, applying functional imaging, FDG-PET and ventilation/perfusion single photon emission CT, before and during treatment to determine if it helps predict treatment response and pertherapeutic lung function with ventilation/perfusion single photon emission CT, possibly reducing toxicity. Ventilation/perfusion single photon emission CT could also be useful for stereotactic body radiotherapy, helping to avoid critical volumes of functional areas of the lungs in patients with often limited respiratory function [START_REF] Lavrenkov | A potential to reduce pulmonary toxicity: The use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of non-small cell lung cancer[END_REF].

In the same way, the study entitled "FLARE radiotherapy" (NCT02773238) is a phase II trial that studies how PET/CT imaging mid-way through treatment of stage IIB-IIIB non-small cell lung cancer could accurately predict treatment efficacy, and single photon emission CT/CT imaging may be able to tell which parts of the lung tissue are healthier than others. Treatment adjustments may then be made to improve survival and decrease toxicity. In this study, patients undergo functional avoidance radiotherapy during weeks 1-3, with FDG PET/CT evaluations at baseline, 3 weeks, and 3 months post treatment, and single photon emission CT/CT at baseline and 3 months postradiation therapy. Patients not responding to treatment at three weeks will receive an escalated dose of radiation. Finally, the "HI-FIVE" study (NCT03569072) is being performed to assess the feasibility of using ventilation/perfusion PET/CT scans to adapt radiotherapy plans using volumetric modulated arctherapy to avoid regions of functional lung and deliver a higher dose to the primary tumour.

Secondarily, this study aims to assess the incidence of acute and late radiotherapy toxicity, to quantify regional ventilation loss and regional perfusion loss on post-treatment ventilation/perfusion PET/CT.

Conventional FDG PET imaging highlights the glucose metabolism of lesions, usually quantified by the SUV from a static acquisition, which is still a controverted way of quantification. Besides the lack of data on the binding kinetics of FDG by tumour cells, some studies have reported significant variation in standard uptake value measures in non-small cell lung cancer lesions for repeated PET examinations in untreated patients [START_REF] Lodge | Repeatability of SUV in Oncologic ( 18 F)-DG PET[END_REF]. This is where the investigators of the PARAPET trial (NCT02821936) suggested a new approach to obtain the parametric information in PET: average percentage of metabolized or unmetabolized FDG and time required to metabolize 80% of FDG. They aim to evaluate the concordance between parametric PET versus standard PET for the one-year prognosis of patients with non-small cell lung cancer treated by chemoradiation. An ancillary study will evaluate the interest of parametric PET imaging during treatment (around 42Gy) to detect local relapse in order to suggest treatment replanification or intensification.

FDG is not the only tracer that may be used in the radiotherapy strategy for lung cancers: new tracers are being studied, such as hypoxia and cell proliferation tracers. A pilot trial (NCT02456246) is investigating the feasibility of using 3'-( 18 F)-deoxy-3'-fluorothymidine (FLT) PET/CT in non-small cell lung cancer treated by stereotactic body radiation for the detection of cancer recurrences compared to regular CT scans. FLT is a thymidine analogue, used to assess the integration of thymidine into DNA as a surrogate of cell proliferation. Conceptually, increased DNA synthesis is correlated to tumour aggressiveness and response to therapy, more so than glucose utilization. Another novel tracer is the ( 18 F)-arabinofuranosylguanine ([araG], NCT04052412) which biodistribution and kinetics are studied in patients with non-small cell lung cancer undergoing immunotherapy with and without adjuvant radiotherapy. One of this study's aims is to correlate the potential change in ( 18 F)-araG uptake within the tumour or draining lymph nodes with clinical and pathologic response in these patients treated with immunotherapy. Finally, hypoxia tracers, like F-miso, are also being studied on non-small cell lung cancer: for instance, an ongoing trial (NCT02016872) is trying to determine if Fmiso can predict treatment response and disease relapse.

Intermodal imaging

Heart sparing is one of the cornerstones of lung cancer radiotherapy. RICT-LUNG (NCT03416972) aims to detect radiation-induced cardiac toxicity after non-small cell lung cancer radiotherapy using hybrid PET/MRI. This non-invasive technique can perform simultaneous metabolic, functional and tissue imaging, avoiding the need of histological biopsy and its complications. The primary objective is to assess acute changes in heart function and to measure inflammation before and six weeks after non-small cell lung cancer radiotherapy. The findings of this study will help designing new studies to reassess dose escalation for locally advanced non-small cell lung cancer while limiting the risk of heart toxicity.

Anorectal malignancies

Pretherapeutic imaging

Radiotherapy is a common component in the strategy of locally advanced rectal cancer treatment. FDG PET/CT is an efficient way to assess treatment response, but the place of other tracers and PET/MR hybrid imaging still remains unexplored. In the RECTOPET trial (NCT03846882), PET/MR is compared with other imaging modalities (PET/CT, CT and MRI) to evaluate its additional staging value for local tumour proliferation, lymph node metastasis and other important prognostic factors (mesorectal fascia involvement, extramuscular vascular involvement). Another primary outcome of this study is to assess tumour regression following CRT in rectal cancer with FDG PET/MR compared to MRI or FDG PET/CT.

Pertherapeutic imaging

AIDA-RE-1 (NCT03479814) is an interventional prospective trial that aims to evaluate the achievement of pathological complete response in high-risk rectal cancer treated with neoadjuvant chemoradiotherapy. 45Gy are delivered to the clinical target volume (rectum and locoregional lymph nodes), and after 2 weeks of treatment, patients are evaluated with a FDG PET/CT allowing the delineation of the additional target volume for a sequential boost of 5Gy (in two fractions).

Intermodal imaging

The clinical trial entitled "TEP ( 64 Cu)-ATSM-Rectum" (NCT03951337) is a French phase II trial that aims to evaluate early and late tumour uptake of a novel radiotracer, ( 64 Cu)-labelled diacetylbis(N4methylthiosemicarbazone (ATSM), in predicting histological response to neoadjuvant chemoradiotherapy treatment in patients with locally advanced rectal cancer. Patients receive pretherapeutic CT scan, pelvic MRI and FDG PET/CT scan within 45 days before enrolment. A ( 64 Cu)-ATSM PET/CT is then achieved before the chemoradiotherapy starts, with two acquisition sequences performed at 1 h and 23 to 25 h after injection in order to evaluate early and late tumour uptake of the tracer. Patients are then treated for 5 weeks by capecitabine combined to a 50Gy radiotherapy. Pelvic MRI is performed 4 weeks after the end of this sequence in order to evaluate the treatment efficacy.

Surgery is scheduled 6 to 8 weeks after chemoradiotherapy.

Anal canal cancer is a relatively rare disease, however the incidence has increased considerably over the past three decades. The standard treatment is an exclusive chemoradiotherapy [START_REF] Bartelink | Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups[END_REF][START_REF] Trial | Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin[END_REF]. Early assessment of the initial extension of the tumour, its therapeutic response and early detection of relapses are determining factors in the management of the disease. The French IFACT trial (NCT02697084) is evaluating whether a post-treatment FDG PET/CT at 2 months could be useful to predict locoregional or metastatic recurrence in patients treated by chemoradiation, distinguishing two groups (low and high risk of 2-year recurrence) of patients based on the metabolic response.

Prostate malignancies: intermodal imaging

The future of nuclear medicine and radiotherapy for prostate cancer will undoubtedly rely on ( 68 Ga)-PSMA-11 PET/CT. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein enzyme which can be up to 1000-fold overexpressed in prostate cancer cells. Because of its high specificity, ( 68 Ga)-PSMA-11 PET/CT could assist physicians in disease localization in case of biochemical recurrence, and also help staging and restaging of the disease [START_REF] Hope | Impact of ( 68 Ga)-PSMA-11 PET on management in patients with biochemically recurrent prostate cancer[END_REF][START_REF] Roach | The impact of ( 68 Ga)-PSMA PET/CT on management intent in prostate cancer: results of an Australian prospective multicenter study[END_REF]. ( 68 Ga)-PSMA-11 PET/CT could select patients for PSMA-targeted molecular radiotherapy, which is being studied in two trials. The first one is the Canadian trial entitled "PSMA-PETgRT" (NCT03525288), expected to end in 2026, where conventional staging-guided radiotherapy is compared to radiotherapy informed by PSMA-PET findings (up to five avid sites distant from the prostate gland can be included in the radiotherapy plan) with 5-year failure free survival or time to failure event being the primary outcome.

The second one is the "PSMA-SRT" trial (NCT03582774), which seeks to evaluate the success rate of salvage radiation therapy for recurrence of prostate cancer after prostatectomy with and without planning based on PSMA PET/CT. Indeed, target volume delineations for prostate cancer salvage radiation therapy after radical prostatectomy are usually drawn in the absence of visibly recurrent disease. PSMA PET/CT detects recurrent prostate cancer with superior sensitivity than standard imaging at serum prostate specific antigen (PSA) concentration values low enough to impact routine salvage radiation therapy planning. It could allow finding patients with M1 disease (extr-pelvic disease is seen in at least 13% of patients with [PSA] <1.0 ng/ml) and improving the coverage of recurrent lesions by the pelvic radiation fields (out-of-field pelvic disease is seen in at least 7% of patients) [START_REF] Calais | 68 Ga)-PSMA-11 PET/CT mapping of prostate cancer biochemical recurrence after radical prostatectomy in 270 patients with a[END_REF][START_REF] Calais | Randomized prospective phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning [PSMA-SRT[END_REF].

To conclude, hypoxic markers such as F-miso are also being investigated, for instance in the French trial entitled "HYPOXProstat" (NCT01898065), which recruitment status is complete. This trial uses functional imaging to characterize changes in hypoxia before and during radiotherapy. The aim is to allow dose escalation to radioresistant areas inside the tumour volume.

Lymphomas

Pertherapeutic imaging

Lymphoma is a heterogeneous group of cancers that affect cells of the immune system, primarily those involved in the lymphatic system. PET/CT has become a standard for initial staging and assessment of treatment response for most lymphomas.

A study led by the Memorial Sloan Kettering Cancer Center (NCT03179917) is currently assessing the safety and effectiveness of pembrolizumab followed by involved-site radiotherapy in relapsed or refractory early stage classical Hodgkin lymphoma, to decrease toxicity or further treatments (chemotherapy, stem cell transplant). The patients undergo an initial PET/CT to evaluate the extent of disease, repeated 14 to 21 days after four cycles of pembrolizumab, with involved-site radiotherapy doses guided by PET and CT responses. Also evaluating immunotherapy for lymphomas, the phase I RaDD trial (NCT03610061) hopes to determine the safety profile of concurrent radiotherapy and durvalumab for relapsed diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma.

One of the secondary objectives is to assess the biodistribution of new PET/CT tracers, ( 89 Zr)-labelled durvalumab and ( 89 Zr)-labelled anti-human CD8 probe IAB22M2C.

For Hodgkin lymphomas, EuroNet-PHL-C2 (NCT02684708) is an international, multicentre, randomized trial. It aims to compare an experimental treatment (induction chemotherapy without radiotherapy or restricted radiotherapy) to conventional treatment (induction chemotherapy and radiotherapy) in order to reduce radiotherapy indications. Indeed, patients with a negative PET/CT after two cycles of induction chemotherapy will not receive radiotherapy.

Intermodal imaging

New tracers are being investigated in lymphomas as well. For example, like for lung cancer, FLT imaging is studied as a predictor of treatment response in a secondary objective of a pilot clinical trial (NCT03422731) focusing on bone marrow changes in patients with acute myeloid leukaemia undergoing total body radiotherapy and induction chemotherapy. Eligible patients will receive a FLT PET/CT at baseline, on days 30 and 100, at 1 year, and at the time of relapse.

Sarcomas

Pertherapeutic imaging

An ongoing trial (NCT03076333) is investigating, in patients with high-grade sarcomas, the ability to predict neoadjuvant radiotherapy response combining MRI with tumour functional exploration at the midpoint of radiotherapy. Quantitative measures from PET and MRI will then be computed: PET tumour-mean standard uptake value variation and tumour size as assessed by MRI, from pre-to posttreatment, and from pre-to midtreatment. The image-based quantitative measures will be correlated with the pathology outcomes (completeness of resection and percent of necrosis) to evaluate predictability of the image measures for treatment response.

Intermodal imaging

FDG imaging is a helpful modality in the follow-up of sarcoma patients to evaluate relevant responses, and to provide predictive information for patient outcome. New tracers are nevertheless being evaluated, like ( 18 F)-fluoroazomycin arabinoside (Faza), a hypoxic marker. In a Canadian single centre study (NCT03418818), the use of Faza PET in combination with MRI is being investigated, as hypoxia in sarcoma has been consistently associated with poor treatment outcomes [START_REF] Nordsmark | Hypoxia in human soft tissue sarcomas: Adverse impact on survival and no association with p53 mutations[END_REF]. Parameters such as diffusion, microperfusion, and contrast enhancement (as a surrogate marker for viable tumour tissue) can be simultaneously compared with the Faza-derived pattern. The study is being conducted to measure the volume of hypoxic tumour in high-risk sarcoma patients, using Faza-PET/MRI, before and after neoadjuvant chemoradiotherapy.

Finally, an early phase I American study (NCT03613259) explores the use of FLT PET in patients with intermediate or high grade soft tissue sarcoma. Change in FLT standard uptake value peak/mean values as response to therapy and correlation to mitotic index and MRI enhancement may provide useful information about the tumour's response to treatment and may give early results that would better help to plan the postsurgical therapy.

Conclusion

The future of imaging in radiotherapy planning is promising, with always improving imaging resolutions and development of more sensitive and specific oncological imaging markers. Specifically, higher definition PET/CT and high magnetic field MRI have the ability to improve the visualization of tumours even to the level of microscopic disease extension. Emerging algorithms for automatic imaging fusion will also be more accurate and allow faster fusion process and verification.

Ongoing trials in nuclear medicine applied to oncology focus on three main aspects. Firstly, apart from the historical FDG, new radiotracers are being investigated in order to evaluate their ability to achieve better sensitivity and specificity to identify tumours. As hypoxia plays a major role in the resistance of tumours to oncological treatments especially radiotherapy, hypoxia markers, like FLT, ATSM, and Fmiso, that can better define regions of hypoxia, oxygen metabolism, microscopic disease, and high metabolism inside the tumour are often cited for numerous malignancies [START_REF] Allen | Quo vadis radiotherapy? Technological advances and the rising problems in cancer management[END_REF]. As tumours are often heterogeneous, these new tracers could help mapping the tumour according to each subpart specific properties. Secondly, existing proven radiotracers like FDG have the ability to help radiation therapists better delineate tumour volumes based on functional data, or even influence treatment planning with dose heterogeneity ("dose painting") according to the metabolic activity. Pertherapeutic intermediate PET/CT evaluations could help identifying more aggressive (FDG) or radioresistant (hypoxia markers) areas and residual disease, potentially directing towards radiation boosting of these areas and improved avoidance of organs at risk. Thirdly, new radiotracers could allow more sensitive and specific follow-up, for instance PSMA for prostate malignancies highlighting otherwise undetected early relapses. Ongoing trials in French centres can be found in Table 1.

Finally, this overall improved performance in morphological and functional imaging brings increasing data waiting to be harvested in big data and artificial intelligence algorithms. Indeed, in the race for personalized treatment based on an individual portrait issued from "-omics" (genomics, proteomics, etc.), imaging data ("radiomics") could also bring crucial information [START_REF] Cook | Challenges and promises of PET radiomics[END_REF].

In conclusion, the future of image-guided treatment planning is boundless and its continuous innovations should ultimately lead to higher cure rates and less treatment-associated toxicity.

  resonance imaging; PET: positron-emission tomography; CHU: university hospital.

Table 1 .

 1 Ongoing clinical trials combining positron-emission tomography and radiotherapy in French centres.

Author contributions

Conception or design of the work: NG, GP, HR, DT and PV.

Data collection and drafting the article: NG, GP, HR and DT.

Critical revision of the article: GP, HR, DT and PV.

Final approval of the version to be published: NG, GP, HR, DT and PV.


Marc Igigabel
email: marc.igigabel@cerema.fr

Youssef Diab

Marissa L Yates

Enhancing the resilience of levee systems through methodological developments

INTRODUCTION

Levee managers are confronted with a double problem:

• to maintain levee systems with limited material and human resources, to maintain its performance;

• to adapt the levee system in response to crisis situations or to changes in society and the environment.

The fact that we inherit, generation after generation, even over centuries, the management of levees, naturally leads us to consider primarily the first point, which can result in conservative attitudes, resistance to change, and mainly technical approaches; methodological guides are then considered only as a form of support for the activity.

Yet in the 21st century, with major disturbances in our environment and profound transformations in society, adaptation should prevail over resistance. Under these conditions, additional effort should be made to define adaptation strategies, without lowering the standards in maintaining levels of protection… In response to current and future trends, this article seeks to define methodologies, which are the backbone of decision-making schemes, that can contribute to the development of better protection against flood risk, either for adaptation or conservation purposes. These reflections make use of the last two decades of major advances in flood risk management and are demonstrated using the example of research relating to the Xynthia storm (2010) 1 .

The article proceeds in two stages.

First, the concepts and strategies that have emerged over the past decades are explored, including those related to resilience, and how methodologies can integrate them to maintain or improve protection.

Second, and in a complementary way, the changes in the methodological procedures are evaluated, in particular with regard to:

• climate change impacts on the biophysical environment;

• more natural intervention modes (related to the ecological transition);

• observation, analysis, and modelling techniques that generate or use ever more diverse data (related to the digital transition).

Through analysis of levee systems, this paper aims to identify ways of developing resilience through a revision of the methodological procedures specifying their design 1 Over the past 10 years, the feedback of this emblematic event contributed significantly to the evolution of protection strategies in France.

and management, to seek a new balance with the natural environment and a transformation of our way of working.

STUDY ORIENTATION

Helping to strengthen the resilience of levee systems through methodological developments requires a clear definition of "resilience". This is not simply to clarify a vague definition, nor yet another attempt to propose an ideal definition for resilience applied to flood risk (Rodina [18] identifies 149 articles published between 1982 and 2017 dealing with this topic), but as a necessity for the remainder of this study. The goal is not to propose a new concept, but to work towards improving its application, by both identifying the most appropriate definition and finding ways of making the best use of it.

In addition, to enrich these reflections, an overview of operational strategies related to this concept will be provided, considering two perspectives: [START_REF]City Resilience Index Brochure[END_REF] flood risk management (an extended point of view compared to our focal point targeting only protection systems); and [START_REF] Cerema | Analyse du fonctionnement hydro-sédimentaire du littoral -Cahier technique[END_REF] the resilience of the urban environment to a variety of hazards (to further expand the range of possible strategies).

These operational strategies and their conceptual basis will be useful for defining the orientations of the study and analyzing the subject: strengthening levee system resilience through methodological developments.

Definition of resilience

The concept of resilience, originally used in physics to designate the energy absorbed by a body during a deformation, has been developed in many disciplines (such as psychology or ecology). In the field of flood risk, many authors have also employed this term, which has led to multiple variants of the definition. Here it is necessary to retain one definition. For this, two selection criteria are applied. The definition must:

• concern a "system", both in the general sense of a "set of interdependent elements that form an isolable whole" and in the practical sense of a "set of material, technical and strategic means aimed at achieving an objective". These two senses, defined in the online philosophical dictionary Dicophilo [START_REF] Dicophilo | dictionnaire philosophique en ligne[END_REF], apply to levee systems; and

• illuminate the multiple facets of the concept and open a wide range of possibilities for protection strategies.

Within the field of climate change adaptation, as discussed in this study, the Intergovernmental Panel on Climate Change (IPCC) defines resilience as:

"the ability of a system and its component parts to anticipate, absorb, accommodate, or recover from the effects of a hazardous event in a timely and efficient FLOODrisk 2020 -4 th European Conference on Flood Risk Management manner, including through ensuring the preservation, restoration, or improvement of its essential basic structures and functions" [14].

This definition fulfils the two conditions described above. It also has a consensual character by construction. Thus, it is retained for the remainder of this work.

Utilization of the concept of resilience

According to the chosen definition, resilience results from several modes of action, assured at the level of a system and its components: "anticipate, absorb, accommodate, or recover". In carrying out these functions, the importance of temporality and efficiency is highlighted. Since the aim of levee systems is to provide better protection, the development of these capacities corresponds to the same goal, and therefore methodological ways of achieving this must be identified. The definition also suggests moving in this direction through "the preservation, restoration, or improvement of its essential basic structures and functions".

"Preservation" and "restoration" contribute to a common objective of stability. In the field of engineering, this objective is achieved:

• first, by structural strength: the objective is achieved if the structures resist deterioration;

• second, when structures have been damaged, by their ability to be repaired, by natural or human actions.

Nevertheless, the search for stability is only meaningful when the evolution of the system occurs slowly. Conversely, with changes in hazards or issues, this objective of preservation or restoration is no longer sufficient and may even be inappropriate: for example, levees that retain water at heights that they were not initially designed for, may lead to increased risk.

The third objective identified in the definition of the IPCC, "improvement", differs from the previous two objectives because it corresponds to the capacity of adaptation. During and after each event, the system can be transformed to protect against dangerous effects with new characteristics. This is particularly valuable in a changing environment such as that caused by climate change. This ability to adapt appears less often in the field of engineering, which may idealize the design of systems and the permanency of their construction (in the form of civil engineering works, with the predominant use of concrete and steel). Conversely, this capacity is more regularly observed in the "living" fields of ecology and sociology.

The IPCC definition is particularly valuable in addressing this problem because it establishes the relationship between a hazard, "the effects of a dangerous event", and an object, "the system", providing guidance for the "modes of reaction" of the object to the hazard. This definition therefore already implies methodological developments: by specifying each of its terms (in a specific context), the essential references for decisionmaking are outlined. However, when applying this approach, the order in which the terms are defined is of great importance. In particular, one must avoid focusing first on modes of action, ignoring the knowledge of the hazard and the identification of the protection system. In the field of risk management, the willingness to act may in fact unconsciously limit the time devoted to acquiring knowledge. Thus, one is reminded that resilience development strategies can be defined only with sufficient knowledge of the hazard and of the object subjected to this hazard.

Flood resilience development strategies

Flood risk management strategies typically include protection measures (to reduce as much as possible the experienced risk) and measures to increase the resilience to the residual risk. In [START_REF] Disse | Exploring the relation between flood risk management and flood resilience[END_REF], the author explores the relationship between these two complementary approaches:

• flood risk assessment and implementation of appropriate protective measures limiting damage; and

• reinforcement of resilience, or the development of the ability to absorb the consequences of a flood.

Flood risk prevention policies have been developed based directly on the concept of resilience, with particular emphasis on protective measures. For example, as of 2009 in the Netherlands, the Four Capacities approach of [10] is based on:

• the threshold capacity (ability to resist floods);

• the coping capacity (ability to reduce damage from floods that exceed the damage threshold);

• the recovery capacity (ability to recover from losses after an event);

• and the adaptive capacity (ability to apply a wide range of adaptive measures). In this approach, the four capacities reproduce nearly word for word the "anticipate, absorb, accommodate, or recover" phrase of the IPCC definition. Only the first capacity differs with its goal to provide protection up to a certain threshold. (In this approach, anticipation can be represented on the four axes.) This approach reflects the fact that beyond the physical consequences of a large-scale extreme natural event, it is necessary to take into account:

• the social impact on the population: isolated people or people who can no longer access certain essential services, deterioration of health conditions, psychological distress; and

• the economic impact: cost of infrastructure restoration, loss of business income, including farms.

Under these conditions, it is clear that building resilience requires more comprehensive, qualitative approaches, involving more scientific disciplines, with ecology and social and economic sciences complementing engineering approaches. The definition of resilience depends on the object to which it applies, as well as the perspective that is taken (engineering, ecology, economy, etc.). Its assessment requires using indicators beyond performance indicators typically used in flood risk management (e.g. mapping of water heights against reference events, etc.). Since evaluation processes are essential for decision-making, methods have been developed to achieve this. To enrich our understanding of flood risk resilience, it is useful to provide an overview of such a method…

Assessing the resilience of urban systems to diverse hazards

The overall evaluation method, called the City Resilience Index, developed by Arup and the Rockefeller Foundation [START_REF]City Resilience Index Brochure[END_REF] under the 100 resilient cities program allows considering several hazards. Figure 1 provides a comprehensive view of the four dimensions to consider in building resilience: health and well-being, economy and society, infrastructure and ecosystems, governance and strategy. Each of these dimensions includes several goals (for a total of 12 goals), each of which may be evaluated according to several indices (for a total of 52 indices). Considering levee systems stricto sensu (as opposed to a system that would integrate both the protection system and all the elements of the territory it protects or with which it interacts), the social and macro-economic views are not considered, and therefore the focus is on the last two dimensions: "infrastructure and ecosystems" and "leadership and strategy". Each indice can be evaluated according to the qualitative resilience-enhancing attributes shown in Figure 2.

Conclusion on the study orientation

In order to explore the possibilities of strengthening the resilience of levee systems, methodological developments related to each term of the definition of resilience are examined using a sectoral approach, namely:

• the characterization of the hazard;

• the definition of the protection system; and

• the methods of preserving, restoring or improving the essential structures and functions of this system.

Secondly, through a unified approach, the opportunities to build resilience are explored by returning to methodological fundamentals and asking ourselves what mechanisms need to be implemented to strengthen their effectiveness given current and future global changes. As a follow-up to these considerations, adaptations in governance, expertise and planning are also sought. In accordance with the conclusions, this section is entitled "Seeking unity and consistency".

To illustrate this approach with an application, we will use marine flood protection systems as an example. The same thought process could also be adopted for other issues such as:

• a system designed to protect against other types of hazards; or

• a system that would integrate both the protection system, the vulnerable stakes and all the elements of the territory with which it interacts.

SECTORAL METHODOLOGICAL DEVELOPMENTS

Understanding the hazard and protection system requires a site-specific approach, in particular identifying the geographical, geological and hydraulic characteristics. It is generally observed by studying past events that the link between a protection system and a type of hazard should not be exclusive: for example, if only the coastal hydraulic phenomena are considered, the hazard may occur, in addition to overflowing and overtopping from the sea, by coastal river flooding, runoff, rising water levels… However, the flooding can also generate other phenomena: humid ground or powerful currents may cause mudslides, tree falls, cliff failures, cavity collapses or erosion impacting building foundations or local infrastructure… At the shoreline, marine flooding occurs during the passage of atmospheric depressions, which are often associated with high winds and waves breaking inland of tidal areas. To study the hazard implies first analyzing the different physical components and their possible combinations and sequences. The identification of the protection system and the actions required to ensure its preservation, restoration or improvement must be based in particular on this initial analysis.

Characterisation of the hazard

If coastal inundation alone is considered, the definition of the hazard can be relatively simple:

Coastal inundation occurs during storms that generate energetic sea states and increase the sea level. For a case that is deliberately limited to a single type of hazard, however, the analysis reveals contrasting situations depending on the site, even regarding only the intensity and chronology of the events (these two parameters largely determine the level of danger):

• on tidal coasts, the most unfavorable case is the conjunction of the meteorological surge with the spring tide high water. The peak of the event has a maximum duration of about three hours, but overflows usually occur over an even shorter period around the high water level. Since these overflows can involve very long alongshore distances, water inflows can be very large;

• on coastlines not subject to large tidal variations -in France, the Mediterranean Coast -the rise of water is related only to the meteorological surge and wave breaking. This type of flooding event can last several days depending on the characteristics and duration of the storm.

• in hurricane-prone areas, meteorological and hydrodynamic phenomena may be of greater intensity, causing faster and larger-scale flooding. The duration of the event, from a few hours to several days, depends largely on the cyclone trajectory and kinetics, both of which are difficult to predict. In all cases, breaches in levee systems are likely to deteriorate the situation by accelerating flows and increasing the volume of water entering the system by overflowing or overtopping of structures. Breaches also prolong the duration over which water inflows occur.

By reducing the analysis to a single hazard such as coastal flooding, the "combination of circumstances" is already daunting. For example, during the Xynthia storm, neither the intensity of the winds, nor the astronomical tide, nor the wave heights were exceptional. And yet, this storm, which was common from a strictly meteorological point of view, was exceptional by the conjunction of particular atmospheric and marine factors. Many sites on the French Atlantic coast were inundated, causing the death of 59 people and damages estimated at more than one billion euros. The poor condition of the protective structures, often neglected and without an identified manager, obviously also contributed to this tragedy.

As coastal flooding occurs during storm conditions, the combined effects of wind and marine currents are also difficult to understand when defining and implementing effective control measures. Some measures may thus be ineffective or even counterproductive. For example:

• the implementation of interventions on levees subject to water pressure may be hindered by intense wind gusts; or

• heavy equipment on water-saturated levees can cause settlement or instability.

Potential methodological developments

Hazards often result from a combination of phenomena, but also from particular land configurations or from unfortunate actions or activities. Research about hazards that focuses on developing statistical tools [17] is an appropriate response to assess the exceptional physical conditions (for example, in the case of marine flooding, water levels and wave heights) through the combination of several phenomena. However, in general these insights can only be provided at large spatial scales. They cannot take into account all of the local phenomena resulting from accumulation or cascade effects.

In the future, the objective of strengthening the resilience of systems could therefore involve methodological recommendations encouraging supplementing large-scale analyses with more local analyses taking into account a greater diversity of phenomena.

Definition of the protection system

At a given site, flood risk management is carried out by implementing a coherent set of measures to reduce the risk. These measures may be structural (for example, levee interventions or beach nourishments) or non-structural (for example, increasing population awareness or developing forecasting and alert tools). Considering only structural measures affecting the water propagation, a flood protection system can be defined as: a set of structures or protective elements presenting an overall coherence from a hydraulic point of view to ensure the effective protection of a group of previously identified stakes.

The components of this system can be levees and other civil engineering works (breakwaters, groynes, seawalls, etc.), natural structures (beaches, dunes, shingle bars, etc.), as well as drainage, storage and evacuation systems. These latter devices, positioned inland, must not be neglected, as they ensure the water management, which must complement the defense measures protecting against water inflows (a system is always likely to have water inflows from the land or the sea). Figure 4 shows schematically how these elements can be positioned in a coastal zone.

Potential methodological developments

The restriction of the study subject to relatively static physical objects such as those constituting protection systems allows their definition by a geographical approach based on cartographic plots (which would not be the case if other vulnerable aspects, including humans, were included in the study). However, the definition of protection systems is not simple: the external contours of the system, as well as the delimitation of the subsets constituting the systems (in general, hydraulic cells) remain potentially variable. For example, in the case of marine flood protection systems, the system limits may vary depending on the physical phenomena that are considered, and their intensity. Thus, the methodology to understand the system behaviour proposed following the analysis of the response to the Xynthia storm [11,12] provides a procedure for defining a system during an unexpected marine weather event. However, an adaptation of the system or the occurrence of an event with different characteristics, or the evolution of the environment or of the stakes exposure would be valid reasons to revise the definition of the system. In the future, the objective of strengthening the resilience of systems could therefore involve methodological recommendations offering more adaptability in the definition of protection systems.

Methods of preservation, restoration or improvement

The literature abounds with guides and articles providing general or particular insights into the actions to be carried out throughout structure life cycles (from design to decommissioning, through multiple maintenance, restoration or adaptation operations). The International Levee Handbook [START_REF] Ciria | The International Levee Handbook[END_REF] is a good compendium of the state of the art in this field. However, a single guide cannot address all circumstances. In fact, the coastlines, rivers and torrents -and more specifically estuaries, deltas, lakes and lagoons -have strong singularities. In addition, each region develops its own protection techniques, depending on the hazards and stakes involved, and the resources at its disposal:

• the material resources (soil, sand, rock, concrete, steel, wood, etc.) that depend heavily on the geological context and infrastructure to transport them; and

• the material and financial resources that depend strongly on the economic situation.

For example, after Xynthia, with the primary objective of supporting the restoration of the performance of coastal flood protection systems and adapting these systems in anticipation of future events, methodological frameworks for these coastal territories have been developed to help: • the long-term definition of management and adaptation strategies, including the investment and maintenance costs of the various modes of intervention on levees and other civil engineering works (such as seawalls, groynes, breakwaters, etc.), as well as on beaches and dunes [13] ;

• the supply of materials guaranteeing the safety of the works, and whose production, transportation, and implementation also respect the principles of reasonable resource management and reduction of greenhouse gas emissions [16];

• the consideration of the hydro-sedimentary functioning of the shoreline [START_REF] Cerema | Analyse du fonctionnement hydro-sédimentaire du littoral -Cahier technique[END_REF]. In this example, some issues go well beyond the scope of protection systems:

• additional analyses may be necessary, not at the scale of protection systems, but at the scale of sedimentary cells for coastal zones with significant morphological changes; and

• the supply of materials constituting strategic resources and more broadly the mobilization of the means of intervention (personnel, equipment, etc.) may require taking into account simultaneously several potentially affected protection systems, or even very different activities involving the same resources (for example port works).

Potential methodological developments

Depending on the case study and the proposed actions, the spatial scales of the analysis may be unique or multiple (country, region, protection system, structure), and the disciplines applied should also be clearly identified. Regarding this last point, before the Xynthia storm, the recommendations for the design, adaptation, maintenance, and management of coastal works did not address the economic aspects explicitly enough, since they did not provide assistance in assessing their overall cost. However, at the scale of protection structures, and a fortiori at the scale of a levee system, without economic analyses, it is not possible to evaluate quantitatively the structure life cycle and the long-term project management.

In the future, the objective of strengthening the resilience of protection systems could therefore involve some adjustments to the methodological recommendations relating to the definition of conservation, restoration, or improvement actions. The first step would be to mobilize more disciplines: both engineering sciences, such as hydraulics and geotechnics, to understand the physical behaviour of works, but also geography, history and economics to put into perspective, in space and time, the functional objectives of these works. This requires exploring interactions between these disciplines, as well as between the various actors involved in the decision-making or implementation of operational actions, and producing specific recommendations about this subject.

Conclusions of sectoral methodological developments

Methodological recommendations should support reaching the objectives set out in the definition of resilience, namely the preservation, restoration or improvement of the essential structures and functions of protection systems. In practice, the methodological recommendations are mainly defined by considering only one type of hazard, according to a segmented « sourcepathway-receptor-consequence » approach [START_REF] Gouldby | Language of Risk -Project definitions[END_REF], resulting in successive treatment of :

• the hazard;

• the behavior of the system subject to this hazard; and

• the reaction of the vulnérable stakes to the residual risk.

The plurality of hazards and the interdependent relationships at the level of the protection system and at the level of the elements within the system require complementary approaches. Depending on the various environmental, economic, or social developments, redefining the extent and structures of a system should be considered more frequently. In this sense, the design of systems must already provide for more adaptability.

The study of resilience development strategies also encourages us to pay more attention to the issue of resources, including material, technical, financial, or intellectual resources within the range of utilized disciplines.

Ultimately, integrating the principles associated with resilience requires two actions:

• expanding the approaches used for hazard characterization, the definition of the protection system, and the development of intervention strategies;

• a de-compartmentalization of methodologies, both in the way they are developed and in the way they are applied.

SEEKING UNITY AND CONSISTENCY

The development of a methodological approach promoting the development of the protection system resilience involves going beyond the framework of sectoral approaches. This finding leads to examining the extent to which the fundamental objectives assigned to methodologies are compatible with the "new principles" stemming from the concept of resilience, where the ecological transition and digital revolution also impose their own rules. This reflection leads to formulating recommendations for the adaptation of methodologies and, as a corollary, for the adaptation (necessary for the effective implementation of methodologies) of leadership, expertise, and planning modes.

Fundamental methodological objectives

Since methodological developments are primarily designed to improve decision-making on the ground, they must reconcile four fundamental objectives:

• contributing to protection system quality control through continuous improvements;

• integrating site-specific characteristics;

• providing time indications for actions;

• accelerating decision making.

Contributing to continuous system improvement

The management and adaptation of levee systems must be consistent with continuous improvement. The proposed methodologies must assist the stakeholders in this process, by both:

• encouraging site-specific actions ; and • capitalizing on experiences from multiple sites for the benefit of others (through the production of guides, but also by highlighting exemplary territories). Methodological developments and progress on the ground must therefore be mutually enriching. The development of the methodological framework must itself be part of a process of continuous improvement. According to these principles, after the Xynthia storm impacted a multitude of sites, the methodologies previously presented benefited from the observation of the projects in progress.

Integrating site-specific characteristics

Methodologies are designed to help each actor in charge in the field to define actions that take into account both the characteristics of the environment, as well as the level of expertise and the material and financial resources available. This subject has already been discussed at length in this article, by dealing successively with the characterization of hazards, and the definition of systems and actions. As an illustration, four months after the Xynthia storm, the Minister of State, Jean-Louis Borloo, emphasized the imperative need to respect the sitespecific characteristics by stating:

"In this period of trauma, using the same words, the same process and the same calendar for two significantly different geographic situations was probably an error. I think that's where most of our challenges come from." [15].

Providing time indications for action

Methodologies should help to plan the timing of diverse actions and to take into account specific circumstances to optimize the overall efficiency and effectiveness. Methodological recommendations should therefore include indications as to when analyses or actions should be carried out. In particular, this information should be provided for the establishment of diagnoses, the revision of flood response plans, and the definition of adaptation projects (in particular by integrating an economic component for calculating the overall cost). References to the life cycles of structures are particularly useful in this regard.

Accelerating decision making

As responsiveness is an essential parameter for ensuring protective functions, methodologies should assist in accelerating decision-making, while ensuring that the decisions taken remain relevant. This is achieved by shedding light on the appropriate concepts, exposing the necessary knowledge, and providing recommendations for observation and analysis techniques.

Adapting methodologies to the concept of resilience

In the previous section, the fundamental objectives of the methodologies largely overlap with those of resilience since they emerge from the definition of the IPCC: The integration of the specificity of the sites, the provision of time indications and the acceleration of decision-making are reflected in the need to act « in a timely and efficient manner ». In addition, in flood protection, continuous improvement, advocated by the methodological process, can be achieved in the development of this capacity to « anticipate, absorb, accommodate, or recover ». It therefore appears that methodological objectives are closely linked to the development of capacities that characterize resilience. This proximity is so great that it could even be assumed that methodological developments, through the capitalization of knowledge and the resources they offer in the preparation of actions, are intrinsically (i.e., regardless of the development of the resilience concept) the first step in resilience development.

More generally, in the history of flood risk management, methodologies have adapted well to the emergence of new concepts that have been a kind of fuel to move them forward. Thus, in flood risk management, the principles of analysis based on the lifecycle of the structures, their failure modes and organization in protection systems, and the "source -pathway -receptor -consequence" model have led to real progress… The emergence of the concept of resilience, by suddenly opening up a range of additional modes of analysis provides a good opportunity to redefine a more relevant framework. The difficulties in adapting the methodological corpus are therefore probably not so much due to the appearance of this new concept as to the major changes in the period when it appeared: the effects of climate change, the ecological transition and the information technology revolution. Therefore, it is necessary, first, to achieve the "fundamental objectives of methodologies" set out above and, second, more broadly, to respect the principles of resilience in an evolving context.

Adaptation of methodologies to global changes

Since methodologies evolve in parallel with actions carried out in the field and over time with feedback, they must have virtually the same qualities as protection systems, particularly with regard to global changes. By using the list of qualities developed for the evaluation of indices in the approach of [START_REF]City Resilience Index Brochure[END_REF], one seeks to attribute these qualities to the methodologies such that they themselves become integrated, inclusive, reflective, resourceful, robust, flexible and even, when necessary, redundant.

Considering the digital revolution on one hand and environmental disturbances on the other, the possibilities offered by new information technologies can help to adapt to current and future changes (by ensuring naturally that these technologies are used in an environmentally friendly manner) including:

• the necessary adaptation of information management; and • the development of tools that can be used in all circumstances.

Adaptation of information management

The management of flood protection systems involves, in crisis situations and in restoration or adaptation phases, decisions based on numerous and heterogeneous data. This leads to various and potentially highly elaborate information processing. In addition, the requirements of risk protection and environmental preservation, both of which are enshrined in laws and regulations, can give decision-makers, particularly in crisis situations, the impression of being subject to contradictory injunctions. Stakeholder interests that may also result in opposition and slowdowns or blockages may occur. Consequently, decision-making often takes longer, if not much longer, than the implementation of the measures.

In analyzing this situation in a pragmatic way, it appears that climate change and the ecological transition require more data to be taken into account in management and adaptation actions: not only those related to risk management, but also those associated with the preservation of the environment. The digital transition also means that we have more and more data (characterization of meteorological and hydrodynamic phenomena, condition and behavior of structures, characterization of strategic materials resources, etc.). Observational tools have progressed and generate this mass of information. In parallel, analysis tools often exploit this information through models or geographic information systems. This way of understanding reality can be extremely effective in describing the functioning of protection systems, in predicting their behavior and in organizing operational interventions. Nevertheless, the data must be accessible and organized in such a way that the mass of information does not become paralyzing for decision-making. Otherwise, the risk of being drowned in the information flow is not only virtual: the consequences can be very real.

With regard to the fundamental objectives of the methodologies, the development of information technology can improve taking into account the sitespecific characteristics. Modelling and geolocation tools can contribute to the continuous improvement of the protection system by integrating more data in time. However, the use of high-tech tools exploiting a large amount of information can undermine the objective of accelerating decision-making if decision-making patterns are not adapted to this technological environment.

A necessary condition for achieving the fundamental objectives of the methodologies is to design databases that are adapted to the developed methodologies (and vice versa). Adaptation to the effects of climate change and other environmental disturbances certainly requires an ability to make this combination of databases and methodologies evolve and to supplement the databases at a frequency sufficient to monitor developments. This can be done, for example, by updating the cost study of coastal protection [START_REF] Cerema | Interventions d'urgence sur les dispositifs de protection contre les submersions marines[END_REF], the Inventory of armourstone [4], or flood response plans.

Development of tools that can be used in all circumstances

The regulatory framework requires the establishment of emergency response plans to deal with crisis situations and to restore the normal functioning of the protection system… These emergency plans define the operational organization of the response and technical arrangements as well as the staff preparedness to deal with degraded situations. These plans are naturally an essential part of crisis management. Although it is necessary to provide an emergency management system that is distinct from the normal one, certain methodological developments designed for these two situations would often benefit from being considered as a whole. In particular:

• economic studies should consider the entire life cycle of the project to optimize the overall cost and the expected service throughout the period considered. Note that this analysis goes beyond the strict framework of the protection system: the optimum overall cost (according to different hypotheses) can be defined only by a costbenefit analysis of the whole system and the stakes it protects;

• methodological frameworks for the diagnosis of systems should encourage the installation of devices for observing their behavior in crisis situations;

• the methodological framework for project management should include provisions facilitating emergency repairs;

• the methodological framework for the supply of materials should anticipate the stresses resulting from crisis situations. This global approach is all the more justified since constant changes in levee systems under the influence of multiple natural and anthropogenic actions should never be neglected: management strategies in normal time (resistance to slow disturbances) should accompany crisis management strategies (resistance to shocks). Within this framework, nature-based solutions often appear to be the most relevant to build resilience, while limiting expenses and environmental impacts.

If current and future changes require making additional efforts to define adaptation strategies, it is necessary to continue monitoring the structures and to ensure that their performance is maintained… It appears that these two aspects should never be dissociated because the resilience of systems can also be enhanced by strengthening the links between them, particularly in the establishment of the decision-making. The methodologies should be defined in accordance with this principle. The production of the International Levee Handbook [START_REF] Ciria | The International Levee Handbook[END_REF], covering all these topics, has fostered synergies. This effort should be maintained in future developments.

Adaptation of governance, expertise and planning modes

By analogy with the development of the methodological corpus, the concept of resilience is an aid in defining the modes of governance, expertise and planning to address the constraints imposed by global changes.

Adaptation of governance modes

By looking at the evolution of governance modes relative to flood risk protection in France, it is particularly clear that:

• Decree 2015-1826 of 12 May 2015 (levee Decree), basing the authorizations on the concept of « levee system » and not on isolated levees, marked a turning point in the management of flood risk. This new framework required a single manager per levee system and the production of a specific hazard study for the system;

• Law No. 2014-58 of 27 January 2014, giving municipalities a targeted and compulsory power on the management of aquatic environments and flood prevention gave them the means to jointly address the problems of « water security » and « environmental protection ».

Concerning this last subject, it should be noted that the power is given to public institutions for intercommunal cooperation with a proper tax system. This means that the manager is able to mobilize funds to carry out all the actions accompanying the lifecycle of the structures. A levee system with no financial resources would have very little or no resilience. Identifying managers with the capacity to raise funds is therefore crucial to strengthening the resilience of the system.

Through this example, it is clear that methodological developments would be useless without legislative and regulatory support, and without legitimate institutions to raise funds and design and implement action programs.

Adaptation of expertise and development modes

An essential mission of expertise is to guide the development of protective systems towards resilient solutions. One criterion is that these developments facilitate decision-making. There are two ways to do this:

• the project is designed in such a way that it manages itself: the adoption of nature-based solutions meets this criterion; or

• the project has characteristics that make it possible to manage it serenely: well identified and available means, sustainable exploitation of resources… Resilience-building approaches can also be beneficial in mitigating the effects of slow disturbances. For example, designing robust and redundant levee systems will give more time to react to degradation of levees that may be generated by tree roots or burrowing animals. This type of design will allow levee managers to take a more serene stance in comparison to a design that is dimensioned to optimize performance relative to a single reference event.

The utilization of several disciplines in the development of methodologies is also a means that is difficult to substitute when it comes to forge links between the actors involved in expertise activities. Similarly, if a material recovery stream is created, the links between the stakeholders in that stream will improve crisis management.

Findings on the search for unity and consistency

In conclusion, it appears that methodological production relating to the links between resilience and protective works is an activity whose intrinsic characteristics can improve the management of the structures with a richer and more integrative approach. In an age marked by profound changes in the environment and by a technological revolution, methodological production has become essential for the societal adaptation, provided that it encourages the utilization of various disciplines and strengthens the solidarity between the different actors. The links between disciplines and actors must be woven over time, under normal circumstances, in order to be able to be applied rapidly in crisis situations. Urban Engineering, « set of disciplines to enable life in urban areas », is likely to meet this need for multidisciplinarity: urban engineering is indeed based on a holistic vision of complex realities in reaction to the analytical approach of its component techniques.

Finally, it should be noted that progress in the field of applied research does not trigger automatically effective application in the field. It is therefore essential to carry out actions to disseminate knowledge and to take ownership of the developed methodologies. Governance arrangements can also be revised to encourage increasing the expertise shared with levee managers.

Conclusion

History has largely shown that levee systems cannot protect a site against any type of event, if only because of changes in the environment and limited financial and material resources. Their rapid restoration is a prerequisite for the restoration of normal living conditions within the levee system. Adapting the system to the uncertain conditions created by climate change is FLOODrisk 2020 -4 th European on Flood Risk Management another challenge for levee managers. Methodological developments, coupled with actions to disseminate knowledge, represent an essential pathway to strengthen the resilience of systems, a concept that integrates both recovery and adaptation capacity.

Methodological developments in hazard knowledge, protection system definition, and interventions on structures must continue. Nevertheless, it seems possible in a search for unity and coherence, to adopt a more transversal approach, because these methodological developments are based on the same principles and their implementation draws on the same data sources. Methodological development programs will therefore always require real coordination to respond optimally, in the short, medium or long term, to developments, whether global (linked for example to climate change) or more local (related for example to land use).

In recent years, changes in governance modes and in project options have led, more than in the past, to considering jointly the issues of protection against risks and preservation of the natural environment. These developments are very positive for building resilience over the long term.

Ultimately, the development of methodologies and operational tools must be designed to serve in all circumstances, within the framework of a global, integrated and cohesive approach.

Figure 1 .

 1 Figure 1. An example of the City Resilience Index[START_REF]City Resilience Index Brochure[END_REF], where the filled inner rings assess performance. The darkest color represents "very poor" and lightest color represents "excellent."

Figure 2 .

 2 Figure 2.Qualitative attributes of a resilient system[START_REF]City Resilience Index Brochure[END_REF]

Figure 3

 3 Figure3shows the contributions to « static » and « instantaneous » water levels at the shoreline, as caused by meteorological and hydrodynamic phenomena.

Figure 3 .

 3 Figure 3. Forcings acting during a marine flood (Courtesy : Nicolae-Lerma)

Figure 4 .

 4 Figure 4. Schematic representation of a coastal flood protection system (Courtesy : Reinhard Pohl)

•

  emergency response preparation, both in terms of general organization (strategy, preparation, training) and specific operations (materials, training and exercises, monitoring, interventions on structures) [5];

10. de Graaf R., van