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Imaging standardisation in metastatic colorectal cancer: A joint EORTC-ESOI-ESGAR expert consensus recommendation

  • Marcus Unterrainer
    Affiliations
    Department of Radiology, University Hospital, LMU Munich, Munich, Germany

    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium
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  • Christophe M. Deroose
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium
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  • Ken Herrmann
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Gastrointestinal Tract Cancer Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Nuclear Medicine, University of Duisburg-Essen, and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany
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  • Markus Moehler
    Affiliations
    Gastrointestinal Tract Cancer Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Medicine, Johannes Gutenberg-University Clinic, University of Mainz, Mainz, Germany
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  • Lennart Blomqvist
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden

    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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  • Roberto Cannella
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    European Society of Gastrointestinal and Abdominal Radiology (ESGAR), Vienna, Austria

    Section of Radiology – Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University Hospital “Paolo Giaccone”, Via Del Vespro 129, Palermo 90127, Italy

    Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Via Del Vespro, 129, 90127 Palermo, Italy
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  • Caroline Caramella
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiology, Groupe Hospitalier Paris Saint-Joseph, Paris, Île-de-France, France
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  • Damiano Caruso
    Affiliations
    European Society of Oncologic Imaging (ESOI), European Society of Radiology, Vienna, Austria

    Department of Medical Surgical Sciences and Translational Medicine, Sapienza – University of Rome, Radiology Unit – Sant'Andrea University Hospital, Italy
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  • Manil D. Chouhan
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Division of Medicine, Centre for Medical Imaging, University College London (UCL), London, UK
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  • Timm Denecke
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Diagnostic and Interventional Radiology, University Hospital Leipzig, Leipzig, Germany
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  • Carolina De la Pinta
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Radiation Oncology Department, Ramón y Cajal Hospital, IRYCIS, Madrid, Spain
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  • Lioe-Fee De Geus-Oei
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands

    Biomedical Photonic Imaging Group, University of Twente, Enschede, the Netherlands
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  • Audrius Dulskas
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Abdominal and General Surgery and Oncology, National Cancer Institute, Vilnius, Lithuania
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  • Michel Eisenblätter
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiology, University Hospital Freiburg, Freiburg, Germany
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  • Kieran G. Foley
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    European Society of Gastrointestinal and Abdominal Radiology (ESGAR), Vienna, Austria

    Division of Cancer & Genetics, School of Medicine, Cardiff University, UK
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  • Sofia Gourtsoyianni
    Affiliations
    European Society of Oncologic Imaging (ESOI), European Society of Radiology, Vienna, Austria

    European Society of Gastrointestinal and Abdominal Radiology (ESGAR), Vienna, Austria

    1st Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Areteion Hospital, Athens, Greece
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  • Frederic E. Lecouvet
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiology, Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium
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  • Egesta Lopci
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Nuclear Medicine, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (MI), Italy
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  • Monique Maas
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • Markus M. Obmann
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    European Society of Gastrointestinal and Abdominal Radiology (ESGAR), Vienna, Austria

    Clinic of Radiology and Nuclear Imaging, University Hospital Basel, Petersgraben 4, 4051 Basel, Switzerland
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  • Daniela E. Oprea-Lager
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center, Amsterdam, the Netherlands
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  • Joost J.C. Verhoeff
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
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  • Ines Santiago
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiology, Champalimaud Foundation, Av. Brasília, 1400-038 Lisbon, Portugal
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  • Sylvain Terraz
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Unit of Interventional Radiology, Division of Radiology, Department of Diagnostics, University Hospitals of Geneva, Geneva, Switzerland
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  • Melvin D'Anastasi
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Medical Imaging Department, Mater Dei Hospital, University of Malta, Msida, Malta
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  • Daniele Regge
    Affiliations
    European Society of Gastrointestinal and Abdominal Radiology (ESGAR), Vienna, Austria

    Department of Surgical Sciences, University of Turin, Turin, 10124, Italy

    Radiology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060, Italy
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  • Andrea Laghi
    Affiliations
    European Society of Oncologic Imaging (ESOI), European Society of Radiology, Vienna, Austria

    European Society of Gastrointestinal and Abdominal Radiology (ESGAR), Vienna, Austria

    Department of Radiology, Groupe Hospitalier Paris Saint-Joseph, Paris, Île-de-France, France
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  • Regina G.H. Beets-Tan
    Affiliations
    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Radiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • Volker Heinemann
    Affiliations
    Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
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  • Florian Lordick
    Affiliations
    Gastrointestinal Tract Cancer Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Medicine II and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany
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  • Elizabeth C. Smyth
    Affiliations
    Gastrointestinal Tract Cancer Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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  • Jens Ricke
    Affiliations
    Department of Radiology, University Hospital, LMU Munich, Munich, Germany

    Gastrointestinal Tract Cancer Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium
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  • Wolfgang G. Kunz
    Correspondence
    Corresponding author: Head of Oncologic Imaging, Research Group PI Oncologic Imaging, EORTC Imaging Group Subcommittee Chair Quality Assurance/Quality Control, Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, 81377 Munich, Germany.
    Affiliations
    Department of Radiology, University Hospital, LMU Munich, Munich, Germany

    Imaging Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    Gastrointestinal Tract Cancer Group, European Organisation of Research and Treatment in Cancer (EORTC), Brussels, Belgium

    European Society of Oncologic Imaging (ESOI), European Society of Radiology, Vienna, Austria
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  • on behalf ofthe European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group@EORTC
  • the European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Group
  • the European Society of Oncologic Imaging (ESOI) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR)
Open AccessPublished:October 20, 2022DOI:https://doi.org/10.1016/j.ejca.2022.09.012

      Highlights

      • Across European cancer centres, imaging protocols show considerable heterogeneity.
      • This European collaboration conducted a consensus finding survey on mCRC imaging.
      • An imaging protocol scorecard is provided to facilitate implementation in trials.

      Abstract

      Background

      Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on reporting and interpretation of imaging findings yet offer no guidance on a standardised imaging protocol tailored to patients with mCRC. Imaging protocol heterogeneity remains a challenge for the reproducibility of conventional imaging end-points and is an obstacle for research on novel imaging end-points.

      Patients and methods

      Acknowledging the recently highlighted potential of radiomics and artificial intelligence tools as decision support for patient care in mCRC, a multidisciplinary, international and expert panel of imaging specialists was formed to find consensus on mCRC imaging protocols using the Delphi method.

      Results

      Under the guidance of the European Organisation for Research and Treatment of Cancer (EORTC) Imaging and Gastrointestinal Tract Cancer Groups, the European Society of Oncologic Imaging (ESOI) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the EORTC-ESOI-ESGAR core imaging protocol was identified.

      Conclusion

      This consensus protocol attempts to promote standardisation and to diminish variations in patient preparation, scan acquisition and scan reconstruction. We anticipate that this standardisation will increase reproducibility of radiomics and artificial intelligence studies and serve as a catalyst for future research on imaging end-points. For ongoing and future mCRC trials, we encourage principal investigators to support the dissemination of these imaging standards across recruiting centres.

      Keywords

      1. Introduction

      The imaging assessment of tumour burden plays a key role in the clinical evaluation and management of almost all solid tumours. A standardised and structured documentation in the change of tumour burden has been pivotal for the implementation of imaging end-points in the scientific evaluation of cancer therapeutics, namely the Response Evaluation Criteria in Solid Tumors (RECIST) published 2009 in the latest version 1.1 [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      ]. Tumour regression as captured by an objective response is routinely used to serve as a measure of drug activity in phase II trials, progression-free survival as an, albeit imperfect, surrogate for overall survival.
      In metastatic colorectal cancer (mCRC), therapy monitoring is routinely performed with computed tomography (CT) imaging [
      • Van Cutsem E.
      • Cervantes A.
      • Adam R.
      • Sobrero A.
      • Van Krieken J.H.
      • Aderka D.
      • et al.
      ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
      ]. It is well documented that intralesional metastatic changes visible to the human eye precede size-based changes during response and progression [
      • Chun Y.S.
      • Vauthey J.N.
      • Boonsirikamchai P.
      • Maru D.M.
      • Kopetz S.
      • Palavecino M.
      • et al.
      Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases.
      ]. Beyond the subjective assessment, new imaging features can be quantified using modern image analysis (termed radiomics). The use of radiomics and artificial intelligence (AI) harbours great potential for early response assessment [
      • Bera K.
      • Braman N.
      • Gupta A.
      • Velcheti V.
      • Madabhushi A.
      Predicting cancer outcomes with radiomics and artificial intelligence in radiology.
      ] and has been extensively studied in mCRC [
      • Dohan A.
      • Gallix B.
      • Guiu B.
      • Le Malicot K.
      • Reinhold C.
      • Soyer P.
      • et al.
      Early evaluation using a radiomic signature of unresectable hepatic metastases to predict outcome in patients with colorectal cancer treated with FOLFIRI and bevacizumab.
      ,
      • Dercle L.
      • Lu L.
      • Schwartz L.H.
      • Qian M.
      • Tejpar S.
      • Eggleton P.
      • et al.
      Radiomics response signature for identification of metastatic colorectal cancer sensitive to therapies targeting EGFR pathway.
      ,
      • Lu L.
      • Dercle L.
      • Zhao B.
      • Schwartz L.H.
      Deep learning for the prediction of early on-treatment response in metastatic colorectal cancer from serial medical imaging.
      ,
      • Giannini V.
      • Pusceddu L.
      • Defeudis A.
      • Nicoletti G.
      • Cappello G.
      • Mazzetti S.
      • et al.
      Delta-radiomics predicts response to first-line oxaliplatin-based chemotherapy in colorectal cancer patients with liver metastases.
      ].
      However, one of the biggest obstacles for applicability in trials and for generalisability towards clinical practice is the intra- and inter-institutional heterogeneity of imaging procedures. This heterogeneity significantly impacts radiomics stability and reproducibility and limits external applications of AI algorithms [
      • Bera K.
      • Braman N.
      • Gupta A.
      • Velcheti V.
      • Madabhushi A.
      Predicting cancer outcomes with radiomics and artificial intelligence in radiology.
      ,
      • Meyer M.
      • Ronald J.
      • Vernuccio F.
      • Nelson R.C.
      • Ramirez-Giraldo J.C.
      • Solomon J.
      • et al.
      Reproducibility of CT radiomic features within the same patient: influence of radiation dose and CT reconstruction settings.
      ]. These issues arise largely from modifiable parameters such as contrast phases, contrast timing, and image reconstruction. These equally affect the CT component of positron emission tomography (PET)/CT examinations [
      • Bijlstra O.D.
      • Boreel M.M.E.
      • van Mossel S.
      • Burgmans M.C.
      • Kapiteijn E.H.W.
      • Oprea-Lager D.E.
      • et al.
      The value of (18)F-FDG-PET-CT imaging in treatment evaluation of colorectal liver metastases: a systematic review.
      ].
      In a European effort across multiple oncology and imaging societies including several national comprehensive cancer centres, we conducted a Delphi consensus finding survey with the goal to standardise the imaging procedures for patients with mCRC.

      2. Methods

      2.1 Panel composition

      For the abovementioned issue, we established a panel of European experts involved in the management of patients with mCRC. Panelists were actively recruited under auspices of the European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group, the EORTC Gastrointestinal Tract Cancer Group, the European Society of Oncologic Imaging and the European Society of Gastrointestinal and Abdominal Radiology and their chairpersons or presidents, respectively. Panelists were invited based on the clinical expertise, publication records and society guideline involvement with special emphasis on mCRC. Involvement of different European countries was sought. The expert panelists involved in this initiative are presented in Table 1; the country representation is shown in Fig. 1.
      Table 1Participating expert panelists.
      NameAffiliationCityCountry
      Lennart BlomqvistKarolinska InstitutetSolnaSweden
      Roberto CannellaUniversità degli Studi di PalermoPalermoItaly
      Caramella CarolineInstitut de Cancérologie Gustave RoussyVillejuifFrance
      Damiano CarusoSapienza University of RomeRomeItaly
      Manil ChouhanUniversity College London, UCL Centre for Medical ImagingLondonUnited Kingdom
      Melvin D'AnastasiMater Dei Hospital, Department of Medical Imaging, MaltaMsidaMalta
      Timm DeneckeUniversity of LeipzigLeipzigGermany
      Christophe DerooseUniversity Hospitals LeuvenLeuvenBelgium
      Audrius DulskasNational Cancer Institute VilniusVilniusLithuania
      Lioe-Fee De Geus-OeiLeiden University Medical CenterLeidenNetherlands
      Carolina de la PintaHospital Universitario Ramón y CajalMadridSpain
      Michel EisenblätterUniversity of FreiburgFreiburgGermany
      Kieran FoleyCardiff UniversityCardiffUnited Kingdom
      Sofia GourtsoyianniNational and Kapodistrian University of AthensAthensGreece
      Ken HerrmannUniversity of EssenEssenGermany
      Frederic LecouvetCliniques Universitaires Saint Luc, UCLouvainBrusselsBelgium
      Egesta LopciHumanitas Clinical and Research Center, University of MilanMilanItaly
      Monique MaasThe Netherlands Cancer InstituteAmsterdamNetherlands
      Markus ObmannUniversity of BaselBaselSwitzerland
      Daniela Oprea-LagerAmsterdam University Medical Center, Amsterdam (VUmc)AmsterdamNetherlands
      Daniele ReggeUniversità degli Studi di TorinoTorinoItaly
      Jens RickeUniversity Hospital, LMU MunichMunichGermany
      Ines SantiagoChampalimaud Foundation, LisbonLisbonPortugal
      Sylvain TerrazUniversité de GenèveGenevaSwitzerland
      Joost VerhoeffUniversity of UtrechtUtrechtNetherlands
      The panelists are listed in alphabetical order by last name.
      Fig. 1
      Fig. 1Schematic country representation in the panel. Each arrow indicates the location of the participating panelists' affiliations on this schematic.

      2.2 Delphi consensus process

      We conducted a prospective, multistep, modified, non-anonymous Delphi consensus approach to assess imaging properties and specifications regarding mCRC imaging among European mCRC experts [
      • Linstone H.A.
      • Turoff M.
      The Delphi method: techniques and applications.
      ,
      • Jones J.
      • Hunter D.
      Consensus methods for medical and health services research.
      ]. Two local facilitators from LMU Munich (MU & WGK) edited the questionnaires and moderated the consensus finding process. Questionnaires were edited by Google forms (https://www.google.com/forms/about/), and access links were directly forwarded to the expert panelists to initiate every poll. This study received endorsement by the EORTC.
      The first step collected general information regarding local specifications and panelists in order to identify common practice and distinct differences among European centres. In the next two steps, further imaging specification regarding CT and PET/CT imaging in mCRC was assessed. The results of each round were forwarded to the panelists to further foster consensus and to influence opinion-forming among the expert panelists (Supp. Files 1 to 3). The composition of the panel was not anonymous; however, individual answers were not attributable to individual expert panelists. The final aim was to reach consensus regarding a potential mCRC imaging protocol for imaging standardisation. In case of questions with binary answers, an agreement of 70% was considered a consensus. In questions with multiple-choice character, an agreement of at least 50% was considered consensus. A schematic of the applied Delphi process is displayed in Fig. 2.
      Fig. 2
      Fig. 2Schematic of the applied Delphi approach. This figure illustrates the different steps and feedback mechanisms of the applied Delphi approach.

      2.3 Trial registration

      This prospective survey was registered on clinicaltrials.gov (registry number NCT04656782) and can be accessed using this link: https://clinicaltrials.gov/ct2/show/NCT04656782.

      3. Results

      3.1 Panel characteristics

      Twenty-five expert panelists were included to ensure broad representation among European centres. Prerequisites for inclusion were activity in a respective imaging society/oncology-related society and board certification in imaging specialities or oncology-related specialities. Panelists were recruited from 13 European countries with most representatives being from both the Netherlands and Italy (four expert panelists each). In total, 14/25 were radiologists, 5/25 nuclear medicine physicians, 3/25 both radiologists and nuclear medicine physicians, 2/25 radiation oncologists and 1/25 a colorectal surgeon. Most panelists have a clear clinical focus on reporting standard morphological imaging using CT and MRI (19/25, 76%) and 6/25 (24%) have a primary focus on hybrid imaging, e.g., using PET/CT. The panelist responses from the final consensus survey round are listed in Table 2.
      Table 2Panelist responses from the final consensus survey round.
      StatementAnswer option of referenceAgreementConsensus reached
      CT imaging
      In a mCRC consensus protocol, the application of oral contrast in CT scans should NOT be included as mandatory for mCRC staging?Agree92%Yes
      In a mCRC consensus protocol, the application of intravenous contrast in CT scans should be included as mandatory for mCRC?Agree100%Yes
      Which dosage of intravenous contrast (mg per kg bodyweight) should be implemented in a mCRC protocol for CT scans (in case intravenous contrast is applied)?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      1.0–2.0 mg/kg body weight76%Yes
      Which iodine concentration (mg per mL intravenous contrast agent) should be included in a mCRC imaging protocol for CT imaging?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      200–400 mg/mL contrast88%Yes
      Within a core imaging protocol, a dedicated soft tissue kernel should be used for reconstruction?Agree100%Yes
      Within a core imaging protocol, a dedicated lung tissue kernel should be used for reconstruction?Agree88%Yes
      Within a core imaging protocol, a dedicated bone tissue kernel should be used for reconstruction?Yes60%No
      The following slice thickness should be applied for soft tissue reconstructions on CT imaging in mCRC?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      3 mm52%Yes
      The following slice thickness should be applied for lung tissue reconstructions on CT imaging in mCRC?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      1 mm64%Yes
      The following slice thickness should be applied for bone tissue reconstructions on CT imaging in mCRC?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      2 mm60%Yes
      Dual energy or spectral CT imaging in mCRC is NOT a mandatory part of a core mCRC imaging protocol?Agree92%Yes
      Thoracic and abdominal series should be acquired in a monophasic approach?Agree72%Yes
      Neck studies in mCRC CT staging should NOT be included in a core protocol as regular imaging studies?Agree92%Yes
      Thorax studies in mCRC CT staging should be included in a core protocol as regular imaging studies?Agree96%Yes
      Thorax studies in mCRC CT staging should include a venous phase as minimum requirement for a core protocol?Agree64%No
      Thorax studies in mCRC CT staging should include an axial soft-tissue reconstruction as minimum requirement for a core protocol?Agree84%Yes
      Thorax studies in mCRC CT staging should include an axial lung reconstruction as minimum requirement for a core protocol?Agree84%Yes
      Thorax studies in mCRC CT staging should include an axial bone reconstruction as minimum requirement for a core protocol?Agree36%No
      Abdominal studies in mCRC CT staging should be included in a core protocol as regular imaging studies?Agree100%Yes
      Abdominal studies in mCRC CT staging should include a venous phase as minimum requirement for a core protocol?Agree100%Yes
      Abdominal studies in mCRC CT staging should include an axial soft-tissue reconstruction as minimum requirement for a core protocol?Agree96%Yes
      Abdominal studies in mCRC CT staging should include an axial bone reconstruction as minimum requirement for a core protocol?Agree40%No
      PET/CT imaging
      In a mCRC consensus protocol, the application of oral contrast in PET/CT scans should NOT be included as mandatory?Agree100%Yes
      In a mCRC consensus protocol, the application of intravenous contrast in PET/CT scans should be included as mandatory for mCRCAgree48%No
      Which dosage of intravenous contrast (mg per kg bodyweight) should be implemented in a mCRC protocol for CT scans (in case intravenous contrast is applied)?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      1.0–2.0 mg/kg body weight80%Yes
      Which iodine concentration (mg per mL intravenous contrast agent) should be included in a mCRC imaging protocol for PET/CT imaging?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      200–400 mg/mL contrast88%Yes
      The following slice thickness should be applied for soft tissue reconstructions on PET/CT imaging in mCRC?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      3 mm52%Yes
      The following slice thickness should be applied for lung tissue reconstructions on PET/CT imaging in mCRC?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      1 mm56%Yes
      The following slice thickness should be applied for bone tissue reconstructions on PET/CT imaging in mCRC?
      Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.
      2 mm60%Yes
      Neck studies in mCRC PET/CT staging should NOT be included in a core protocol as regular imaging studies?Agree56%No
      Thorax studies in mCRC PET/CT staging should be included in a core protocol as regular imaging studies?Agree96%Yes
      If contrast is applied, thorax studies in mCRC PET/CT staging should include a venous phase as minimum requirement for a core protocol?Agree84%Yes
      Thorax studies in mCRC PET/CT staging should include an axial soft-tissue reconstruction as minimum requirement for a core protocol?Agree84%Yes
      Thorax studies in mCRC PET/CT staging should include an axial lung reconstruction as minimum requirement for a core protocol?Agree84%Yes
      Thorax studies in mCRC PET/CT staging should include an axial bone reconstruction as minimum requirement for a core protocol?Agree32%No
      Abdominal studies in mCRC PET/CT staging should be included in a core protocol as regular imaging studies?Agree100%Yes
      Abdominal studies in mCRC PET/CT staging should include a venous phase as minimum requirement for a core protocol?Agree96%Yes
      Abdominal studies in mCRC PET/CT staging should include an axial soft-tissue reconstruction as minimum requirement for a core protocol?Agree92%Yes
      Abdominal studies in mCRC PET/CT staging should include an axial bone reconstruction as minimum requirement for a core protocol?Agree32%No
      a Multiple-choice statement. The statements indicate questions that have evolved towards the final consensus survey round based on the panelists' feedback. The questions have hence already been adapted to incorporate the general view of the panel.

      3.2 General information and institutional specifications

      Among the panelists' institutions, a broad majority participate in imaging for randomised controlled trials (RCTs) (22/25, 88%), and most institutions currently include patients in RCTs involving mCRC (16/25, 64%); 18/25 panelists experienced the need of imaging protocol adaptations due to the specific requirements of the respective sponsor, even 4/25 (16%) experience imaging protocol changes in at least 50% of clinical trials. Among the participating panelists' institutions, there was a median number of five (range, 1–15) CT scanners and a median number of two (range, 0–4) PET/CTs. Predominant vendors of CT scanners were (multiple answers possible) Siemens Healthineers (56%), Philips Healthcare (48%) and GE Healthcare (48%); predominant vendors of PET/CT scanners were (multiple answers possible) Philips Healthcare (40%), Siemens Healthineers (36%) and GE Healthcare (28%). Regarding PET/CT and CT imaging protocols, only 44% of centres apply a homogenously aligned protocol. Within their own department, 28% of panelists have experienced diverging imaging protocols across CT scanners, e.g., due to diverging slice thickness or diverging reconstruction algorithms. However, 56% of panelists experienced diverging imaging protocols across CT scanners among different institutions; 92% of institutions are experienced with radiomics analyses; here, 72% of panelists have experienced problems during data processing due to diverging protocols across CT scanners.
      Here, 100% of expert panelists reported that imaging harmonisation could be useful for multicentre imaging studies and Europe-wide standardised protocols could facilitate radiomics and AI research. Hence, 24/25 (96%) expert panelists are willing or probably willing to incorporate a potential standardised imaging protocol.

      3.3 CT scan acquisition

      The vast majority of 84% do not give oral contrast for mCRC CT staging purposes, even 88% of expert panelists do not consider oral contrast as essential part of mCRC staging; 92% of included centres give intravenous contrast for CT imaging; here, <5% of scans must be performed without contrast agent due to contraindications (96% of cases), in one centre, 10–15% of cases were performed without contrast agent. In an open question regarding contrast agent dosage, most frequent contrast dosages applied were 1.5 mg/kg for most, 1.0 mg/kg for some cases (24%), 1.5 mg/kg for all cases (16%) and 1.0 mg/kg for most, 1.5 mg/kg for some cases (12%); all values indicate per patient body weight. In an open question regarding contrast agent concentration, most frequent contrast concentrations applied were 300 mg/mL contrast agent (32%) and 350 mg/mL contrast agent (32%).
      mCRC staging does not regularly include neck studies in 96% of centres. If neck studies were included, mostly venous phase (56%) or late arterial phase (36%) was obtained. Thoracic studies were most commonly performed in the venous phase (56%), and the second most common acquisition was in the late arterial phase (36%). Most centres use the venous phase for abdominal CT imaging (88%), whereas late arterial phases were not common (20%) (multiple answers possible in case of multiphase approach). Image acquisition is performed in a monophasic approach in 56% of the included centres.

      3.3.1 CT scan acquisition consensus round

      In total, 92% of the expert panelists agreed that oral contrast application is not an essential part of a standard mCRC CT imaging protocol. The application of intravenous contrast agent was deemed mandatory by all experts (100%). A majority (76%) agreed that a dosage of 1.0–2.0 mg/kg bodyweight of contrast agent should be applied on CT imaging (followed by <1.0 mg/kg bodyweight (16%)). A majority (88%) argued in favour of an iodine concentration of 200–400 mg/mL contrast agent followed by <200 mg/mL contrast agent (12%) regarding CT imaging. Thoracic and abdominal series should be acquired in a monophasic approach (72% agreement).
      Neck studies are not a mandatory part of mCRC CT imaging (92%), but thoracic studies are a mandatory part of mCRC imaging (96% agreement) and should be performed using a venous phase (64% agreement). Abdominal studies are mandatory (100% agreement) and should be performed using a venous phase (100% agreement).

      3.4 CT scan reconstruction

      Regarding CT reconstruction, 76% of included centres do apply dedicated soft tissue reconstructions and 80% use dedicated lung reconstruction algorithms, whereas a dedicated bone reconstruction algorithm is only used in 40% of the centres. The most applied slice thickness is 3 mm for soft tissue reconstructions (36%) followed by 1 mm (20%). Using dedicated lung reconstructions, 48% used 1 mm slice thickness, followed by 2 mm slice thickness (24%), whereas the most applied slice thickness for bone reconstructions, when applied, was 2 mm (24%) and 1 mm (20%).

      3.4.1 CT scan reconstruction consensus round

      All panelists agreed that a dedicated soft tissue reconstruction should be applied (100%); also, a majority of 84% argued in favour of applying a dedicated lung reconstruction algorithm and 60% in favour of a bone reconstruction algorithm. A majority of 52% voted in favour of 3 mm slice thickness for soft tissue reconstructions, 64% argued for 1 mm slice thickness for lung reconstructions and 56% for 2 mm slice thickness regarding bone reconstructions on CT imaging, if applied. Thoracic studies should include axial soft tissue reconstructions (84% agreement) and axial lung reconstructions (84% agreement), but no axial bone reconstruction (64% agreement). Abdominal imaging should include an axial soft tissue reconstruction (96% agreement). A bone reconstruction was not considered mandatory by the majority of panelists (60% agreement).

      3.5 18F-FDG PET/CT scan acquisition

      The vast majority of panelists (96%) does not apply oral contrast for mCRC CT staging purposes, and 96% of expert panelists do not consider oral contrast as an essential part of mCRC PET/CT imaging; 52% of included centres do apply intravenous contrast for PET/CT imaging; in only 44% of centres, contrast agent is omitted in <5% of cases. In open question regarding contrast agent dosage, most frequent contrast dosages (including ‘not available’) were 1.5 mg/kg for most, 1.0 mg/kg for some cases (12%), 1.5 mg/kg for all cases (8%), 1.0 mg/kg for all cases (8%) and 1.0 mg/kg for most, 1.5 mg/kg for some cases (8%). In an open question regarding contrast agent concentration (including ‘not available’), most frequent contrast concentrations applied were 350 mg/mL contrast agent (28%) and 300 mg/mL contrast agent (16%).
      Contrast agent for PET/CT imaging is mostly provided by Bayer in 28% of centres, by GE Healthcare in 20% of centres and by Bracco Imaging in 16% of included centres. Regarding different phases, most centres (96%) do not apply multiphase imaging on PET/CT for mCRC imaging. Image acquisition on PET/CT is performed in a monophasic approach in 68% of cases.

      3.5.1 PET/CT scan acquisition consensus round

      Here, 100% of the expert panelists agreed that oral contrast application is not essential for standard mCRC CT imaging protocols. No consensus could be reached regarding the application of contrast agents for PET/CT imaging; 52% of the panelists deemed the application of contrast agents not mandatory for PET/CT imaging. A majority of 80% agreed that a dosage of 1.0–2.0 mg/kg bodyweight of contrast agent should be applied on PET/CT imaging (followed by <1.0 mg/kg bodyweight (16%)), in case contrast agent is applied. A majority of 88% argued in favour for an iodine concentration of 200–400 mg/mL contrast agent followed by <200 mg/mL contrast agent (12%) regarding PET/CT imaging. Thoracic and abdominal series should be acquired in a monophasic approach (72% agreement). Neck acquisitions are not a mandatory part of mCRC imaging (92% agreement), but thoracic series are a mandatory part of mCRC imaging (96% agreement) and should be performed using a venous phase (72% agreement), if contrast is applied. Abdominal series are mandatory (100% agreement) and should be performed using a venous phase (96% agreement) if contrast is applied.

      3.6 PET/CT scan reconstruction

      Regarding reconstruction of the CT component on PET/CT imaging, 60% of included centres do apply dedicated soft tissue reconstructions and 52% use dedicated lung reconstruction algorithms, whereas a dedicated bone reconstruction algorithm is only used in 20% of the included centres. The most applied slice thickness is 2 mm and 5 mm for soft tissue reconstructions (20% each) followed by 3 mm (16%). Using dedicated lung reconstructions, 24% used 1 mm and 2 mm slice thickness, respectively, followed by 5 mm slice thickness (16%), whereas the mostly applied slice thickness for bone reconstructions on PET/CT imaging, in case it was applied, was 1 mm and 2 mm (16% each), respectively.

      3.6.1 PET/CT scan reconstruction consensus round

      Regarding dedicated CT reconstruction algorithms please see CT section above. A majority of 52% voted in favour of 3 mm slice thickness for soft tissue reconstructions, 56% argued for 1 mm slice thickness for lung reconstructions and 60% for 2 mm slice thickness regarding bone reconstructions on PET/CT imaging. Thoracic PET/CT series should include axial soft tissue reconstructions (80% agreement) and axial lung reconstructions (84% agreement), but no bone reconstructions (68% agreement). Abdominal PET/CT imaging should include an axial soft tissue reconstruction (92% agreement), but no bone reconstruction (68% agreement).

      3.7 Dual energy or spectral CT imaging

      Dual energy or spectral CT imaging is part of the clinical routine for mCRC imaging in only 32% of the included centres. Also, no expert panelists experienced sponsor requirements towards inclusion of dual energy or spectral CT imaging in RCT imaging protocols.

      3.7.1 Dual energy or spectral CT imaging consensus round

      This is not a mandatory part of a potential core protocol (92% agreement).

      3.8 Core imaging protocol

      3.8.1 CT mCRC core imaging protocol

      Patient preparation and acquisition: No oral contrast. Intravenous contrast dosage: 1.0–2.0 mg/kg bodyweight. Iodine concentration: 200–400 mg/mL. Monophasic acquisition.
      Thorax: Venous phase. Axial soft tissue reconstruction with 3 mm slice thickness. Axial lung reconstruction with 1 mm slice thickness. No bone reconstruction mandatory.
      Abdomen: Venous phase. Axial soft tissue reconstruction with 3 mm slice thickness. No bone reconstruction mandatory.
      Further phases, reconstructions, etc. can be added with emphasis on local specifications and clinical necessities.

      3.8.2 PET/CT mCRC core imaging protocol

      Acquisition: No oral contrast. If intravenous contrast is applied, contrast dosage: 1.0–2.0 mg/kg bodyweight. Iodine concentration: 200–400 mg/mL. Monophasic acquisition.
      Thorax: Unenhanced or venous phase if contrast is applied. Axial soft tissue reconstruction with 3 mm slice thickness. Lung reconstruction with 1 mm slice thickness. No bone reconstruction mandatory.
      Abdomen: Unenhanced or venous phase if contrast is applied. Axial soft tissue reconstruction with 3 mm slice thickness. No bone reconstruction mandatory.
      Further phases, reconstructions etc. can be added with emphasis on local specifications and clinical necessities.

      3.9 Imaging scorecard

      The main components of the consensus core protocol are summarised and illustrated in the Imaging Scorecard as provided in Fig. 3. All questions and responses during the survey process are presented in Supplementary Files 1–3.
      Fig. 3
      Fig. 3Imaging scorecard for implementation of the consensus core protocol. This figure illustrates the core components of this panel's consensus recommendation on imaging in patients with mCRC. The imaging scorecard was developed to facilitate implementation of the standardised protocol in cancer and imaging centres that participate in accrual for RCTs. If PET/CT is the only exam at a certain timepoint, intravenous contrast as would be needed to ensure compatibility with the RECIST1.1 requirements [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      ]; this does not apply if the PET/CT is performed in close temporal proximity of a dedicated CT. §Value refers to per patient body weight. #Oral contrast may be considered if lesion conspicuity in diffuse peritoneal disease is expected to impact response assessment.

      4. Discussion

      In this European collaboration across multiple societies, we conducted a successful consensus finding survey on mCRC imaging applying the Delphi process. The survey included imaging specialists with a focus on mCRC from cancer centres across Europe as panelists. The first rounds during the survey illustrated the existing heterogeneity of CT imaging protocols. During the Delphi process, the imaging panelists agreed on standardisations for the imaging of patients with mCRC. This standardisation covers patient preparation, scan acquisition and scan reconstruction; all of which are known factors that limit data reproducibility. Examples of imaging protocol heterogeneity in an mCRC trial are illustrated in Fig. 4.
      Fig. 4
      Fig. 4Examples of imaging protocol heterogeneity in a randomised controlled trial. Illustration of imaging protocol heterogeneity in patients with mCRC included in the FIRE-3 RCT [
      • Heinemann V.
      • von Weikersthal L.F.
      • Decker T.
      • Kiani A.
      • Vehling-Kaiser U.
      • Al-Batran S.E.
      • et al.
      FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.
      ]. ST refers to soft tissue, i.e., the windowing settings to evaluate mediastinal and visceral organs. The first and second column portray the available ST kernel reconstructions and the third column shows lung kernel reconstructions if available. The last column indicates conformity with the core imaging protocol according to this panel's consensus recommendation (green: compliant; red: non-compliant). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article).
      This consortium supports the use of a standardised core imaging protocol that will build the backbone for the imaging data in mCRC trials. This concept was introduced to facilitate the implementation of new imaging standards as institutional and individual preferences could affect their acceptance. This approach will give institutions the choice to fully switch to this proposed protocol or to keep existing protocols by adding the required image reconstructions. Notably, all imaging panelists indicated that their institutions are either committed or likely willing to implement this core imaging protocol. Notably, spectral imaging was not deemed mandatory among the participating experts.
      The heterogeneity of imaging protocols remains a significant challenge for reproducibility of conventional as well as novel imaging end-points [
      • Bera K.
      • Braman N.
      • Gupta A.
      • Velcheti V.
      • Madabhushi A.
      Predicting cancer outcomes with radiomics and artificial intelligence in radiology.
      ]. As examples for the size-based RECIST1.1 criteria, CT acquisition and reconstruction parameters affect reproducibility of lymph node [
      • Onuma Y.
      • Tsuruta C.
      • Okita K.
      • Hamabe A.
      • Ogura K.
      • Takemasa I.
      • et al.
      CT reconstruction with thick slices not only underestimates lymph node size but also reduces data reproducibility in colorectal cancer.
      ] and liver lesion size assessments [
      • Li Q.
      • Liang Y.
      • Huang Q.
      • Zong M.
      • Berman B.
      • Gavrielides M.A.
      • et al.
      Volumetry of low-contrast liver lesions with CT: investigation of estimation uncertainties in a phantom study.
      ]. Efforts by the International Biomarker Standardisation Initiative have standardised the image post-processing and analysis [
      • Zwanenburg A.
      • Vallieres M.
      • Abdalah M.A.
      • Aerts H.
      • Andrearczyk V.
      • Apte A.
      • et al.
      The image biomarker standardization initiative: standardized quantitative radiomics for high-throughput image-based phenotyping.
      ] yet not addressed heterogeneity arising from imaging protocols. Regarding novel imaging end-points, however, differences in CT acquisition and reconstruction parameters have been repeatedly shown to affect radiomics feature reproducibility [
      • Meyer M.
      • Ronald J.
      • Vernuccio F.
      • Nelson R.C.
      • Ramirez-Giraldo J.C.
      • Solomon J.
      • et al.
      Reproducibility of CT radiomic features within the same patient: influence of radiation dose and CT reconstruction settings.
      ,
      • Berenguer R.
      • Pastor-Juan M.D.R.
      • Canales-Vazquez J.
      • Castro-Garcia M.
      • Villas M.V.
      • Mansilla Legorburo F.
      • et al.
      Radiomics of CT features may be nonreproducible and redundant: influence of CT acquisition parameters.
      ].
      With this core imaging protocol, which reached consensus by the participating oncology and imaging societies, we expect to reduce protocol heterogeneity and pave the way for future research on modern imaging end-points. The use of radiomics data has significant potential in treatment monitoring of mCRC [
      • Staal F.C.R.
      • van der Reijd D.J.
      • Taghavi M.
      • Lambregts D.M.J.
      • Beets-Tan R.G.H.
      • Maas M.
      Radiomics for the prediction of treatment outcome and survival in patients with colorectal cancer: a systematic review.
      ]. Basic radiomics features of liver metastases predict a poor outcome at 2 months with the same performance as RECIST1.1 evaluation at 6 months in first-line mCRC treatment [
      • Dohan A.
      • Gallix B.
      • Guiu B.
      • Le Malicot K.
      • Reinhold C.
      • Soyer P.
      • et al.
      Early evaluation using a radiomic signature of unresectable hepatic metastases to predict outcome in patients with colorectal cancer treated with FOLFIRI and bevacizumab.
      ]. In another application, a radiomics signature outperformed existing biomarkers (KRAS-mutational status, tumour shrinkage) in predicting survival as well as in the detection of treatment sensitivity to cetuximab [
      • Dercle L.
      • Lu L.
      • Schwartz L.H.
      • Qian M.
      • Tejpar S.
      • Eggleton P.
      • et al.
      Radiomics response signature for identification of metastatic colorectal cancer sensitive to therapies targeting EGFR pathway.
      ].
      The application of AI has significant potential for even further improvement in early response assessment. Deep learning methods enabled prediction of early on-treatment response using conventional CT imaging in patients with mCRC [
      • Lu L.
      • Dercle L.
      • Zhao B.
      • Schwartz L.H.
      Deep learning for the prediction of early on-treatment response in metastatic colorectal cancer from serial medical imaging.
      ]. The quantitative characterisation of tumour morphological changes from pretreatment to follow-up CT scans significantly strengthened the association with patient survival and may be used for early on-treatment decision-making. Notably, all these radiomics and AI studies excluded trial patients based on imaging protocol deviations (which were avoidable, i.e., not due to medical contraindications).
      For patients with mCRC, robust assessment of such novel imaging end-points will open avenues towards new trial designs. In the field of mCRC, there are no imaging response-adapted trial designs. The pioneering effort of response-adapted treatment guidance has been made in the management of Hodgkin's lymphoma, using positron-emission tomography for decisions on additive radiation [
      • Engert A.
      • Haverkamp H.
      • Kobe C.
      • Markova J.
      • Renner C.
      • Ho A.
      • et al.
      Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial.
      ] or treatment de-escalation [
      • Johnson P.
      • Federico M.
      • Kirkwood A.
      • Fossa A.
      • Berkahn L.
      • Carella A.
      • et al.
      Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma.
      ]. In solid malignancies, response-adapted treatment de-escalation of immunotherapy has been successfully tested in a phase II trial in metastatic melanoma [
      • Postow M.A.
      Adaptive dosing of nivolumab 1 ipilimumab immunotherapy based upon early, interim radiographic assessment in advanced melanoma (the ADAPT-IT study).
      ]. Similar trial designs could pave the way for personalised treatment of mCRC patients based on reliable and robust imaging end-points.
      International efforts for standardisation of imaging procedures in oncology have significantly increased over the past few years, and consensus recommendations were either achieved with or without the use of dedicated methods (e.g. the Delphi process). Imaging recommendations are often part of guidelines that cover acquisition, interpretation and reporting. Protocol recommendations with high adherence in clinical trials exist for prostate cancer screening [
      • Turkbey B.
      • Rosenkrantz A.B.
      • Haider M.A.
      • Padhani A.R.
      • Villeirs G.
      • Macura K.J.
      • et al.
      Prostate Imaging Reporting and Data System version 2.1: 2019 update of Prostate Imaging Reporting and Data System version 2.
      ], metastatic prostate cancer [
      • Padhani A.R.
      • Lecouvet F.E.
      • Tunariu N.
      • Koh D.M.
      • De Keyzer F.
      • Collins D.J.
      • et al.
      METastasis reporting and data system for prostate cancer: practical guidelines for acquisition, interpretation, and reporting of whole-body magnetic resonance imaging-based evaluations of multiorgan involvement in advanced prostate cancer.
      ], breast cancer [
      • Baltzer P.
      • Mann R.M.
      • Iima M.
      • Sigmund E.E.
      • Clauser P.
      • Gilbert F.J.
      • et al.
      Diffusion-weighted imaging of the breast-a consensus and mission statement from the EUSOBI International Breast Diffusion-Weighted Imaging working group.
      ], endometrial cancer [
      • Nougaret S.
      • Horta M.
      • Sala E.
      • Lakhman Y.
      • Thomassin-Naggara I.
      • Kido A.
      • et al.
      Endometrial cancer MRI staging: updated guidelines of the European Society of Urogenital Radiology.
      ], multiple myeloma [
      • Messiou C.
      • Hillengass J.
      • Delorme S.
      • Lecouvet F.E.
      • Moulopoulos L.A.
      • Collins D.J.
      • et al.
      Guidelines for acquisition, interpretation, and reporting of whole-body MRI in myeloma: Myeloma Response Assessment and Diagnosis System (MY-RADS).
      ] and lung cancer [
      • Chen D.L.
      • Ballout S.
      • Chen L.
      • Cheriyan J.
      • Choudhury G.
      • Denis-Bacelar A.M.
      • et al.
      Consensus recommendations on the use of (18)F-FDG PET/CT in lung disease.
      ].
      Interpretation and reporting of mCRC imaging studies are covered by the RECIST1.1 criteria [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      ]. Yet there are no consensus recommendations available to standardise imaging protocols for patients with mCRC. Dedicated recommendations for imaging protocol standardisation have been previously published for primary brain tumours [
      • Ellingson B.M.
      • Bendszus M.
      • Boxerman J.
      • Barboriak D.
      • Erickson B.J.
      • Smits M.
      • et al.
      Consensus recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials.
      ] and for brain metastases [
      • Kaufmann T.J.
      • Smits M.
      • Boxerman J.
      • Huang R.
      • Barboriak D.P.
      • Weller M.
      • et al.
      Consensus recommendations for a standardized brain tumor imaging protocol for clinical trials in brain metastases.
      ], which have been instrumental for successful AI applications [
      • Kickingereder P.
      • Isensee F.
      • Tursunova I.
      • Petersen J.
      • Neuberger U.
      • Bonekamp D.
      • et al.
      Automated quantitative tumour response assessment of MRI in neuro-oncology with artificial neural networks: a multicentre, retrospective study.
      ]. Our protocol recommendations could thereby serve as a catalyst to accelerate such research efforts in mCRC.
      Strengths of our study are the participation of leading oncology and imaging societies and adherence to the Delphi process. We thereby ensure that our recommendations represent the collective position of all key opinion leaders without individual overrepresentation. Our and other protocol recommendations cannot elude lack of inter-vendor standardisation, yet this limitation represents a subordinate impact on radiomics feature assessment [
      • Zwanenburg A.
      • Vallieres M.
      • Abdalah M.A.
      • Aerts H.
      • Andrearczyk V.
      • Apte A.
      • et al.
      The image biomarker standardization initiative: standardized quantitative radiomics for high-throughput image-based phenotyping.
      ]. The time delays between contrast administration and different phase acquisitions could not be standardised as panelist responses were mostly given in ranges or as rough estimates. We did not include magnetic resonance imaging due to the technical complexity and very strong dependence on vendor-specific sequences. Among the panelists, there may be differences in technical proficiency regarding CT and/or PET/CT imaging based on training. Overall, a Delphi process was considered a suitable approach for consensus finding in a set of European experts, as this approach enables an inclusion of a wide range of expertise among panelists. These can express their own opinion on questions more individually compared to the dynamic of a group discussion; however, certain limitations have to be listed, e.g. such as a potentially dominant influence of the facilitators or a high consumption of time and resources. Moreover, the process depends on expertise and motivation of the panelists [
      • Linstone H.A.
      • Turoff M.
      The Delphi method: techniques and applications.
      ,
      • Jones J.
      • Hunter D.
      Consensus methods for medical and health services research.
      ,
      • Vernon W.
      The Delphi technique: a review.
      ,
      • Thangaratinam S.
      • Redman C.W.
      The Delphi technique.
      ].
      In conclusion, this group of imaging experts reached consensus through a Delphi survey on a standardised CT imaging protocol with easy-to-implement core components for patients with mCRC. We anticipate that this standardisation will increase reproducibility of radiomics and AI studies and serve as a catalyst for future research on imaging end-points. For ongoing and future mCRC trials, we encourage principal investigators to support the dissemination of these imaging standards across recruiting centres.

      Author contribution

      M.U., C.M.D., J.R. and W.G.K. contributed to the conception, design and planning of the study. M.U., C.M.D., M.M., A.L., R.B.-T., F.L., E.C.S., J.R. and W.G.K. contributed to conduct of the data. C.M.D., K.H., L.B., R.C., D.C., M.D.C., T.D., C.D.L.P., L.-F.D.G.-O., A.D., M.E., K.G.F., S.G., F.L., E.L., M.M., M.O., D.E.O.-L., J.J.C.V., I.S., S.T., M.D., D.R. and J.R. participated in the acquisition of the survey data. M.U., C.M.D., M.M., L.-F.D.G.-O., F.L., D.E.O.-L., A.L., R.B.-T., V.H., F.L., E.C.S., J.R. and W.G.K. contributed to the interpretation of the results. M.U. and W.G.K. drafted the manuscript. All authors critically reviewed or revised the manuscript for important intellectual content and approved the final version to be submitted. This final manuscript received endorsement by the EORTC.

      Funding

      The authors received no specific funding for this work.

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.H. reports personal fees from Bayer , personal fees and other from Sofie Biosciences , personal fees from SIRTEX , non-financial support from ABX, personal fees from Adacap , personal fees from Curium , personal fees from Endocyte , grants and personal fees from BTG , personal fees from IPSEN , personal fees from Siemens Healthineers , personal fees from GE Healthcare , personal fees from Amgen , personal fees from Novartis , personal fees from Y-mAbs , all outside the submitted work. L.B. is a cofounder of Collective Minds Radiology. R.C. reports travel support by Bracco Imaging . T.D. reports honorary fees and travel support by Siemens, Canon , Bayer, b.e. imaging and research grants by Siemens Healthineers, Bayer, Guerbet  and b.e. imaging. E.L. reports receiving research grants from AIRC and from the Italian Ministry of Health , and faculty remuneration from ESMIT (European School of Multimodality Imaging and Therapy) and MI&T Congressi. D.E.O.-L. received expert remuneration from EAU for participating in PET PSMA Consensus Meeting in January 2022. The remaining authors declare that they have no conflict of interest related to this study. W.G.K. reports personal fees from Bristol-Myers Squibb.

      Appendix A. Supplementary data

      The following are the supplementary data to this article:

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