Advertisement

Practice changing data and emerging concepts from recent radiation therapy randomised clinical trials

  • Sophie Espenel
    Correspondence
    Corresponding author: Department of Radiation Oncology, Gustave Roussy Cancer Campus, 114 Rue Edouard Vaillant, 94800, Villejuif, France.
    Affiliations
    Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France
    Search for articles by this author
  • Cyrus Chargari
    Affiliations
    Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France

    Institut de Recherche Biomédicale des Armées, F-91220, Brétigny sur Orge, France
    Search for articles by this author
  • Pierre Blanchard
    Affiliations
    Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France

    Université Paris-Saclay, Faculté de Médecine, F-94270, Le Kremlin Bicêtre, France

    Oncostat, Inserm U-1018, F-94805, Villejuif, France
    Search for articles by this author
  • Sophie Bockel
    Affiliations
    Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France
    Search for articles by this author
  • Daphne Morel
    Affiliations
    Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France
    Search for articles by this author
  • Sofia Rivera
    Affiliations
    Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France

    Université Paris-Saclay, Inserm U-1030, Laboratoire de Radiothérapie Moléculaire et d'Innovation Thérapeutique, F-94805, Villejuif, France
    Search for articles by this author
  • Antonin Levy
    Affiliations
    Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France

    Université Paris-Saclay, Faculté de Médecine, F-94270, Le Kremlin Bicêtre, France

    Université Paris-Saclay, Inserm U-1030, Laboratoire de Radiothérapie Moléculaire et d'Innovation Thérapeutique, F-94805, Villejuif, France
    Search for articles by this author
  • Author Footnotes
    1 On behalf of the Radiation Oncology Department.
    Eric Deutsch
    Footnotes
    1 On behalf of the Radiation Oncology Department.
    Affiliations
    Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France

    Université Paris-Saclay, Faculté de Médecine, F-94270, Le Kremlin Bicêtre, France

    Université Paris-Saclay, Inserm U-1030, Laboratoire de Radiothérapie Moléculaire et d'Innovation Thérapeutique, F-94805, Villejuif, France
    Search for articles by this author
  • Author Footnotes
    1 On behalf of the Radiation Oncology Department.

      Highlights

      • Many practice changing data and new concepts emerge from randomised clinical trials.
      • Radioimmunotherapy, pro-apoptotic agents and nanoparticles improve the therapeutic ratio.
      • Stereotactic body radiotherapy allows intensifying treatments and gaining ground.
      • Imaging-based (positron emission tomography–computed tomography, MRI) or biological biomarkers lead to more tailored treatments.
      • Patient satisfaction is a new major end-point, as illustrated by hypofractionated schemes.

      Abstract

      Introduction

      Oncology treatments are constantly and rapidly evolving. We aimed at highlighting the latest radiation therapy practice changing trials and emerging concepts, through an overview of recent randomised clinical trials (RCTs).

      Materials and methods

      Requests were performed in the Medline database to identify all publications reporting radiation therapy RCTs from 2018 to 2021.

      Results

      Recent RCTs sustained the role of newer combinatorial strategies through radioimmunotherapy for early stage or metastatic lung cancer, newer pro-apoptotic agents (e.g. debio 1143 in locoregionally advanced head and neck squamous cell carcinoma) or nanoparticles (e.g. NBTXR3 in locally advanced soft-tissue sarcoma). High-tech radiotherapy allows intensifying treatments and gaining ground in some indications through the development of stereotactic body radiotherapy for example. First randomised evidence on personalised radiation therapy through imaging-based (18FDG positron emission tomography-computed tomography for lung cancer or early stage unfavourable Hodgkin lymphoma, PMSA positron emission tomography-computed tomography or magnetic resonance imaging for high-risk prostate cancer) or biological biomarkers (PSA for prostate cancer, HPV for head and neck cancer, etc) were conducted to more tailored treatments, with more favourable outcomes. Patients' quality of life and satisfaction appeared to be increasing aims. RCTs have validated (ultra)hypofractionated schemes in many indications as for breast, prostate or rectal cancer, resulting in equivalent outcomes and toxicities, more convenient for patients and favouring shared decision making.

      Conclusion

      Radiation therapy is a dynamic field of research, and many RCTs have greatly impacted therapeutic standards over the last years. Investments in radiotherapy research should facilitate the transfer of innovation to clinic.

      Keywords

      1. Introduction

      Cancer treatment represents a dynamic axis of medical research, with many practice changing data and new concepts emerging from randomised clinical trials (RCTs) each year. In the field of radiation oncology, (drug-radiotherapy combinations (e.g. immunoradiotherapy)) and technology developments (stereotactic body radiotherapy [SBRT], image-guided brachytherapy, and in few indications proton therapy) represent ways to improve the therapeutic index ratio [
      • Chargari C.
      • Levy A.
      • Paoletti X.
      • Soria J.-C.
      • Massard C.
      • Weichselbaum R.R.
      • et al.
      Methodological development of combination drug and radiotherapy in basic and clinical research.
      ].
      New major end-points are emerging, focusing on quality of life (QoL) and patient satisfaction. In this context, hypofractionated radiotherapy RCTs have brought particularly interesting data, providing in many cases comparable outcomes to the standard treatment, with several advantages including shorter treatments, higher convenience for patients and decreased costs. Patient preferences and shared decision making are increasingly studied and encouraged.
      Considering that the important number of publications can dilute key messages, we aimed to highlight the main axes of radiation therapy development (Fig. 1), through an overview of practice changing data and emerging concepts from recent radiation therapy RCTs.
      Fig. 1
      Fig. 1Main axes of radiation therapy practice changing trials.

      2. Materials and methods

      Requests were performed in the Medline database (via PubMed) to identify all adults publications reporting radiotherapy RCTs since January 2018 (Table S1). The latest update was performed in December 2021, using the following Medical Subject Headings (MeSH) terms: ‘radiotherapy’ AND ‘clinical trial’ AND ‘randomized OR randomised’, as keywords and ‘English’ as language. A total of 1347 results were found, including some protocols, some uncomplete or prematurely closed trials, some supportive care trials, and some negative trials with no impact on standard treatment. Titles and abstracts have been read, as well as manuscripts of the screened papers. Only radiotherapy practice changing or emerging concepts of large randomised phase 2 or 3 clinical trials were selected (n = 110). Primary end-points included overall survival (OS), progression/disease-free survival (PFS/DFS), local control rate, pathological complete response (pCR) or adverse events rate and QoL. Some major RCTs are cited to illustrate the main radiation oncology advances (manuscript, Fig. 1 and Table 1), whereas Table S1 reported all publications matching with the research criteria.
      Table 1Main practice changing and emerging concepts in radiation therapy randomised clinical trials.
      Tumour typeStageContextComparisonMain end-pointStudy namesReferences
      Radiosensitisation
      Chemotherapy or targeted therapyHead and neckLACTRT versus TTRTCDDP > cetuximabOSDe-ESCALaTE HPV, NRG oncology RTOG 1016, TROG 12.01[
      • Mehanna H.
      • Robinson M.
      • Hartley A.
      • Kong A.
      • Foran B.
      • Fulton-Lieuw T.
      • et al.
      Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.
      ,
      • Gillison M.L.
      • Trotti A.M.
      • Harris J.
      • Eisbruch A.
      • Harari P.M.
      • Adelstein D.J.
      • et al.
      Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.
      ,
      • Rischin D.
      • King M.
      • Kenny L.
      • Porceddu S.
      • Wratten C.
      • Macann A.
      • et al.
      Randomized trial of radiation therapy with weekly cisplatin or cetuximab in low-risk HPV-associated oropharyngeal cancer (TROG 12.01) – a trans-Tasman radiation oncology group study.
      ]
      Head and neckLACTRTNedaplatin = CDDPPFS[
      • Tang L.-Q.
      • Chen D.-P.
      • Guo L.
      • Mo H.-Y.
      • Huang Y.
      • Guo S.-S.
      • et al.
      Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised phase 3 trial.
      ]
      OesophagealL + LACTRTCTCR (S-1) > EBRTOSZJCH-E-E[
      • Ji Y.
      • Du X.
      • Zhu W.
      • Yang Y.
      • Ma J.
      • Zhang L.
      • et al.
      Efficacy of concurrent chemoradiotherapy with S-1 vs radiotherapy alone for older patients with esophageal cancer: a multicenter randomized phase 3 clinical trial.
      ]
      UterineLACTRTCTRT + adjuvant CT > EBRTOS, PFSPORTEC-3[
      • de Boer S.M.
      • Powell M.E.
      • Mileshkin L.
      • Katsaros D.
      • Bessette P.
      • Haie-Meder C.
      • et al.
      Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.
      ,
      • Post C.C.B.
      • de Boer S.M.
      • Powell M.E.
      • Mileshkin L.
      • Katsaros D.
      • Bessette P.
      • et al.
      Long-term toxicity and health-related quality of life after adjuvant chemoradiation therapy or radiation therapy alone for high-risk endometrial cancer in the randomized PORTEC-3 trial.
      ]
      New radiosensitisersHead and neckLACTRTDebio > placeboLRCDebio 1143-201[
      • Sun X.-S.
      • Tao Y.
      • Le Tourneau C.
      • Pointreau Y.
      • Sire C.
      • Kaminsky M.-C.
      • et al.
      Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study.
      ]
      SarcomasLAPreop EBRTNBTXR3 > no NBTXR3pCRAct.In.Sarc[
      • Bonvalot S.
      • Rutkowski P.L.
      • Thariat J.
      • Carrère S.
      • Ducassou A.
      • Sunyach M.-P.
      • et al.
      NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.
      ]
      Head and neckLACTRTPlacebo = avelumabPFSJAVELIN head and neck 100[
      • Lee N.Y.
      • Ferris R.L.
      • Psyrri A.
      • Haddad R.I.
      • Tahara M.
      • Bourhis J.
      • et al.
      Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.
      ]
      LungLPreopDurvalumab + SBRT > durvalumabpCR[
      • Altorki N.K.
      • McGraw T.E.
      • Borczuk A.C.
      • Saxena A.
      • Port J.L.
      • Stiles B.M.
      • et al.
      Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.
      ]
      LungMICI naiveSBRT + pembrolizumab > pembrolizumabOSPEMBRO-RT[
      • Theelen W.S.M.E.
      • Peulen H.M.U.
      • Lalezari F.
      • van der Noort V.
      • de Vries J.F.
      • Aerts J.G.J.V.
      • et al.
      Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
      ]
      Treatment intensification
      External beam radiotherapy indicationsHead and neckMAfter induction CTCTRT > CTOSSYSUCC5010[
      • You R.
      • Liu Y.-P.
      • Huang P.-Y.
      • Zou X.
      • Sun R.
      • He Y.-X.
      • et al.
      Efficacy and safety of locoregional radiotherapy with chemotherapy vs chemotherapy alone in de novo metastatic nasopharyngeal carcinoma: a multicenter phase 3 randomized clinical trial.
      ]
      OesophagealLAPreopCTRT > no CTRTOSCROSS, NEOCRTEC5010[
      • Eyck B.M.
      • van Lanschot J.J.B.
      • Hulshof M.C.C.M.
      • van der Wilk B.J.
      • Shapiro J.
      • van Hagen P.
      • et al.
      Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial.
      ,
      • Yang H.
      • Liu H.
      • Chen Y.
      • Zhu C.
      • Fang W.
      • Yu Z.
      • et al.
      Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial.
      ]
      ProstateLAHigh-risk cN0Whole pelvis EBRT > prostate EBRTBDFSPOP-RT[
      • Murthy V.
      • Maitre P.
      • Kannan S.
      • Panigrahi G.
      • Krishnatry R.
      • Bakshi G.
      • et al.
      Prostate-only versus whole-pelvic radiation therapy in high-risk and very high-risk prostate cancer (POP-RT): outcomes from phase III randomized controlled trial.
      ]
      ProstateMSynchronous low volume met(s)Prostate EBRT > noOSSTAMPEDE[
      • Parker C.C.
      • James N.D.
      • Brawley C.D.
      • Clarke N.W.
      • Hoyle A.P.
      • Ali A.
      • et al.
      Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.
      ]
      Dose escalationLungLACTRT60 Gy > 74 GyOSRTOG 0617[
      • Bradley J.D.
      • Hu C.
      • Komaki R.R.
      • Masters G.A.
      • Blumenschein G.R.
      • Schild S.E.
      • et al.
      Long-term results of NRG oncology RTOG 0617: standard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer.
      ]
      OesophagealLACTRT50.4 Gy > 61.6 GyLocal PFSARTDECO[
      • Hulshof M.C.C.M.
      • Geijsen E.D.
      • Rozema T.
      • Oppedijk V.
      • Buijsen J.
      • Neelis K.J.
      • et al.
      Randomized study on dose escalation in definitive chemoradiation for patients with locally advanced esophageal cancer (ARTDECO study).
      ]
      ProstateLInterm and high-risk95 Gy > 77 GyBDFSFLAME[
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • Monninkhof E.M.
      • Smeenk R.J.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME randomized phase III trial.
      ]
      Systemic treatment induction/consolidationHead and neckLAPre-CTRTCDDP-gemcitabine > observationRFS[
      • Zhang Y.
      • Chen L.
      • Hu G.-Q.
      • Zhang N.
      • Zhu X.-D.
      • Yang K.-Y.
      • et al.
      Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma.
      ]
      Head and neckLAPost-CTRTCapecitabine > observationDFSCAN[
      • Chen Y.-P.
      • Liu X.
      • Zhou Q.
      • Yang K.-Y.
      • Jin F.
      • Zhu X.-D.
      • et al.
      Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.
      ]
      LungLAPost-CTRTDurvalumab > placeboOSPACIFIC[
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      ,
      • Faivre-Finn C.
      • Vicente D.
      • Kurata T.
      • Planchard D.
      • Paz-Ares L.
      • Vansteenkiste J.F.
      • et al.
      Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial.
      ]
      OesophagealLAPost-CTRTNivolumab > placeboDFSCheckMate 577[
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • Zander T.
      • Van Cutsem E.
      • Piessen G.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      ]
      RectalLAPreopCT > CTRT > CTRTDFSPRODIGE 23[
      • Conroy T.
      • Bosset J.-F.
      • Etienne P.-L.
      • Rio E.
      • François É.
      • Mesgouez-Nebout N.
      • et al.
      Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.
      ]
      RectalLAPreopRT > CT > CTRT + adjuvant CTDFSRAPIDO[
      • Bahadoer R.R.
      • Dijkstra E.A.
      • van Etten B.
      • Marijnen C.A.M.
      • Putter H.
      • Kranenbarg E.M.-K.
      • et al.
      Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
      ]
      ProstateLAHigh-risk (EBRT)Docetaxel + ADT > ADTOSRG Oncology RTOG 0521[
      • Rosenthal S.A.
      • Hu C.
      • Sartor O.
      • Gomella L.G.
      • Amin M.B.
      • Purdy J.
      • et al.
      Effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer: the randomized phase III NRG oncology RTOG 0521 trial.
      ]
      ProstateLAHigh-risk (EBRT)Abiraterone + ADT > ADTMFSSTAMPEDE[
      • Attard G.
      • Murphy L.
      • Clarke N.W.
      • Cross W.
      • Jones R.J.
      • Parker C.C.
      • et al.
      Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.
      ]
      Local ablative treatments for oligometastasesMixedMMetach met(s)SBRT + SoC > SoCOSSABR-COMET[
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • Louie A.V.
      • Haasbeek C.
      • et al.
      Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
      ]
      ProstateMMetach met(s)SBRT > observationDFSORIOLE[
      • Phillips R.
      • Shi W.Y.
      • Deek M.
      • Radwan N.
      • Lim S.J.
      • Antonarakis E.S.
      • et al.
      Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial.
      ]
      Personalised EBRT
      MRIProstateLAMultiparametric MRI95 Gy > 77 GyBDFSFLAME[
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • Monninkhof E.M.
      • Smeenk R.J.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME randomized phase III trial.
      ]
      Nuclear medicineLungLA18FDG PET-based CTRTIF > ENILRPFSPET-Plan[
      • Nestle U.
      • Schimek-Jasch T.
      • Kremp S.
      • Schaefer-Schuler A.
      • Mix M.
      • Küsters A.
      • et al.
      Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.
      ]
      Hodgkin lymphomaLAPost-CT18FDG PETEBRT = observationPFSGITIL/FIL HD0607[
      • Gallamini A.
      • Rossi A.
      • Patti C.
      • Picardi M.
      • Romano A.
      • Cantonetti M.
      • et al.
      Consolidation radiotherapy could Be safely omitted in advanced Hodgkin lymphoma with large nodal mass in complete metabolic response after ABVD: final analysis of the randomized GITIL/FIL HD0607 trial.
      ]
      Hodgkin lymphomaLPost-CT18FDG PETEBRT = observationPFSGHSG HD17[
      • Borchmann P.
      • Plütschow A.
      • Kobe C.
      • Greil R.
      • Meissner J.
      • Topp M.S.
      • et al.
      PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.
      ]
      BiomarkersBreastLAdjuvant EBRTTGFB1 > no TGFB1Fibrosis[
      • Grossberg A.J.
      • Lei X.
      • Xu T.
      • Shaitelman S.F.
      • Hoffman K.E.
      • Bloom E.S.
      • et al.
      Association of transforming growth factor β polymorphism C-509T with radiation-induced fibrosis among patients with early-stage breast cancer: a secondary analysis of a randomized clinical trial.
      ]
      ProstatePSA+Salvage EBRTADT > observationPFSGETUG-AFU 16[
      • Carrie C.
      • Magné N.
      • Burban-Provost P.
      • Sargos P.
      • Latorzeff I.
      • Lagrange J.-L.
      • et al.
      Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial.
      ]
      Reducing treatment burden, enhancing patients' quality of life and satisfaction
      (Ultra)hypofractionationBreastLAPostop WBRT43.5 Gy/15f = 50 Gy/25fLR[
      • Wang S.-L.
      • Fang H.
      • Song Y.-W.
      • Wang W.-H.
      • Hu C.
      • Liu Y.-P.
      • et al.
      Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.
      ]
      BreastLPostop WBRT26 Gy/5f = 40 Gy/15fIBTRFAST-Forward[
      • Murray Brunt A.
      • Haviland J.S.
      • Wheatley D.A.
      • Sydenham M.A.
      • Alhasso A.
      • Bloomfield D.J.
      • et al.
      Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.
      ]
      BreastLPostop WBRT28.5 Gy/5 once weekly f = 50 Gy/25fNTEFAST[
      • Brunt A.M.
      • Haviland J.S.
      • Sydenham M.
      • Agrawal R.K.
      • Algurafi H.
      • Alhasso A.
      • et al.
      Ten-year results of FAST: a randomized controlled trial of 5-fraction whole-breast radiotherapy for early breast cancer.
      ]
      BreastLPostop APBI30 Gy/5f = 50 Gy/25fIBTRAPBI-IMRT-Florence[
      • Meattini I.
      • Marrazzo L.
      • Saieva C.
      • Desideri I.
      • Scotti V.
      • Simontacchi G.
      • et al.
      Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: long-term results of the randomized phase III APBI-IMRT-Florence trial.
      ]
      ProstateLIntermediate and high-risk42.7 Gy/7f = 78 Gy/39fPFSHYPO-RT-PC[
      • Widmark A.
      • Gunnlaugsson A.
      • Beckman L.
      • Thellenberg-Karlsson C.
      • Hoyer M.
      • Lagerlund M.
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.
      ]
      Refining EBRT indicationLungLAPostop EBRTObservation = postop EBRTDFSLung ART, PORT-C[
      • Le Pechoux C.
      • Pourel N.
      • Barlesi F.
      • Lerouge D.
      • Antoni D.
      • Lamezec B.
      • et al.
      Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial.
      ,
      • Hui Z.
      • Men Y.
      • Hu C.
      • Kang J.
      • Sun X.
      • Bi N.
      • et al.
      Effect of postoperative radiotherapy for patients with pIIIA-N2 non-small cell lung cancer after complete resection and adjuvant chemotherapy: the phase 3 PORT-C randomized clinical trial.
      ]
      BreastLPostop EBRTObservation = postop EBRTIBTRNRG Oncology/RTOG 9804[
      • McCormick B.
      • Winter K.A.
      • Woodward W.
      • Kuerer H.M.
      • Sneige N.
      • Rakovitch E.
      • et al.
      Randomized phase III trial evaluating radiation following surgical excision for good-risk ductal carcinoma in situ: long-term report from NRG oncology/RTOG 9804.
      ]
      Retroperitoneal sarcomasLAPreop EBRTObservation = preop EBRTARFSEORTC-62092, STRASS[
      • Bonvalot S.
      • Gronchi A.
      • Le Péchoux C.
      • Swallow C.J.
      • Strauss D.
      • Meeus P.
      • et al.
      Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial.
      ]
      ProstateLPostop EBRTSalvage > adjuvantEFSGETUG-AFU 17, RTOG 08.03/ANZUP RAVES, RADICALS-RT[
      • Sargos P.
      • Chabaud S.
      • Latorzeff I.
      • Magné N.
      • Benyoucef A.
      • Supiot S.
      • et al.
      Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial.
      ,
      • Kneebone A.
      • Fraser-Browne C.
      • Duchesne G.M.
      • Fisher R.
      • Frydenberg M.
      • Herschtal A.
      • et al.
      Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.
      ,
      • Parker C.C.
      • Clarke N.W.
      • Cook A.D.
      • Kynaston H.G.
      • Petersen P.M.
      • Catton C.
      • et al.
      Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.
      ,
      • Vale C.L.
      • Fisher D.
      • Kneebone A.
      • Parker C.
      • Pearse M.
      • Richaud P.
      • et al.
      Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data.
      ]
      Shared decision makingBreastLAPostop WBRTIM–MS EBRT = no IM–MS EBRTOSEORTC 22922/10925[
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ]
      BreastLPostop EBRT boostAPBI BT = EBRTQoLGEC-ESTRO APBI[
      • Schäfer R.
      • Strnad V.
      • Polgár C.
      • Uter W.
      • Hildebrandt G.
      • Ott O.J.
      • et al.
      Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breast-conserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial.
      ]
      Reducing toxicity with high-tech EBRTUterineLAPostop EBRTIMRT > 3DRTToxicityNRG Oncology-RTOG 1203, PARCER[
      • Yeung A.R.
      • Pugh S.L.
      • Klopp A.H.
      • Gil K.M.
      • Wenzel L.
      • Westin S.N.
      • et al.
      Improvement in patient-reported outcomes with intensity-modulated radiotherapy (RT) compared with standard RT: a report from the NRG oncology RTOG 1203 study.
      ,
      • Chopra S.
      • Gupta S.
      • Kannan S.
      • Dora T.
      • Engineer R.
      • Mangaj A.
      • et al.
      Late toxicity after adjuvant conventional radiation versus image-guided intensity-modulated radiotherapy for cervical cancer (PARCER): a randomized controlled trial.
      ]
      Brain metsMPostop EBRTSRS > WBrRTToxicityJCOG0504[
      • Kayama T.
      • Sato S.
      • Sakurada K.
      • Mizusawa J.
      • Nishikawa R.
      • Narita Y.
      • et al.
      Effects of surgery with salvage stereotactic radiosurgery versus surgery with whole-brain radiation therapy in patients with one to four brain metastases (JCOG0504): a phase III, noninferiority, randomized controlled trial.
      ]
      OesophagealLACTRTPBT > IMRTToxicityNRG-GI006[
      • Lin S.H.
      • Hobbs B.P.
      • Verma V.
      • Tidwell R.S.
      • Smith G.L.
      • Lei X.
      • et al.
      Randomized phase IIB trial of proton beam therapy versus intensity-modulated radiation therapy for locally advanced esophageal cancer.
      ]
      Pain reliefMixedMBone metsSBRT (1f) > 3DRT (10f)Pain reliefNCI-2014-01482[
      • Nguyen Q.-N.
      • Chun S.G.
      • Chow E.
      • Komaki R.
      • Liao Z.
      • Zacharia R.
      • et al.
      Single-fraction stereotactic vs conventional multifraction radiotherapy for pain relief in patients with predominantly nonspine bone metastases: a randomized phase 2 trial.
      ]
      MixedMSpinal metsSBRT (2f) > 3DRT (5f)Pain reliefCCTG SC.24/TROG 17.06[
      • Sahgal A.
      • Myrehaug S.D.
      • Siva S.
      • Masucci L.
      • Foote M.C.
      • Brundage M.
      • et al.
      CCTG SC.24/TROG 17.06: a randomized phase II/III study comparing 24Gy in 2 stereotactic body radiotherapy (SBRT) fractions versus 20Gy in 5 conventional palliative radiotherapy (CRT) fractions for patients with painful spinal metastases.
      ]
      Abbreviations: EBRT: external beam radiotherapy; LA: locally advanced; L: localised; M: metastatic; PSA+: prostate-specific antigen concentration increased from 0.1 ng/mL to between 0.2 ng/mL and 2·0 ng/mL after radical prostatectomy; CTRT: concomitant chemoradiation; TTRT: concomitant target therapy and external beam radiotherapy; preop: preoperative; ICI: immune checkpoint inhibitor; postop: postoperative; LR: locoregional; cN0: clinically node negative; CT: chemotherapy; metach: metachronous; met(s): metastasis(es); WBRT: whole breast radiotherapy; APBI: accelerated partial beast irradiation; CDDP: cisplatin; NBTXR3: high Z hafnium oxide (HfO2) nanoparticle; SBRT: stereotactic body radiotherapy; Gy: gray; SoC: standard of care; IF: involved-field; ENI: elective node irradiation; ADT: androgen deprivation; TGFB1: transforming growth factor beta 1; f: fractions; IM–MS: internal mammary and medial supraclavicular; IMRT: intensity-modulated radiotherapy; 3DRT: three-dimensional conformal radiation therapy; SRS: radiosurgery; WBrRT, whole-brain radiotherapy; PBT: proton beam therapy; OS: overall survival; PFS: progression-free survival; LCR: locoregional control; pCR: pathological complete response; BDFS: biochemical disease-free survival; RFS: recurrence-free survival; MFS: metastasis-free survival; LRPFS: locoregional progression-free survival; LR: locoregional recurrence; IBTR: ipsilateral breast tumour recurrence; NTE: normal tissue effects; ARFS: abdominal recurrence-free survival; EFS: event-free survival; QoL: quality of life.

      3. Result

      3.1 Radiosensitisation

      Radiosensitisation represents a major way to enhance the local therapeutic index and could prevent from distant metastasis. Conventional DNA-targeting chemotherapies have been the standard of care (SoC) in the last 20 years. Within the 2000s, several molecularly targeted therapies have been assessed in association, mostly resulting in higher toxicities and no increased outcomes [
      • Chargari C.
      • Levy A.
      • Paoletti X.
      • Soria J.-C.
      • Massard C.
      • Weichselbaum R.R.
      • et al.
      Methodological development of combination drug and radiotherapy in basic and clinical research.
      ]. Newer radiotherapy combinations with DNA-interfering agents or immune checkpoint blockers are assessed.

      3.2 Chemotherapy and targeted therapies

      HPV-associated oropharyngeal carcinoma displays increased outcomes and better response to treatments, suggesting a possible therapeutic de-escalation. Concurrent cetuximab versus cisplatin was tested in three RCTs, De-ESCALaTE HPV, NRG Oncology RTOG 1016 and TROG 12.01 [
      • Mehanna H.
      • Robinson M.
      • Hartley A.
      • Kong A.
      • Foran B.
      • Fulton-Lieuw T.
      • et al.
      Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.
      ,
      • Gillison M.L.
      • Trotti A.M.
      • Harris J.
      • Eisbruch A.
      • Harari P.M.
      • Adelstein D.J.
      • et al.
      Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.
      ,
      • Rischin D.
      • King M.
      • Kenny L.
      • Porceddu S.
      • Wratten C.
      • Macann A.
      • et al.
      Randomized trial of radiation therapy with weekly cisplatin or cetuximab in low-risk HPV-associated oropharyngeal cancer (TROG 12.01) – a trans-Tasman radiation oncology group study.
      ]. The association of radiotherapy plus cetuximab showed no benefit in terms of reduced toxicity, tumour control, PFS and OS (5-year OS: 77.9% versus 84.6%; non-inferiority p = 0.51), platinum-based radiotherapy remaining the SoC in this setting.
      The best schedule of concurrent chemotherapy remains an open question in locally advanced head and neck squamous cell carcinoma (HNSCC). Once-a-week 30 mg/m2 cisplatin chemoradiation has been compared with once-every-3-weeks 100 mg/m2 [
      • Noronha V.
      • Joshi A.
      • Patil V.M.
      • Agarwal J.
      • Ghosh-Laskar S.
      • Budrukkar A.
      • et al.
      Once-a-Week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: a phase III randomized noninferiority trial.
      ]. High-dose bolus cisplatin resulted in superior locoregional control (73.1% versus 58.5%, p = 0.01), particularly in the adjuvant setting, without survival improvement. This gain in locoregional control must be balanced with increased severe acute toxicities (84.6% versus 71.6%, p = 0.01). However, the weekly dosing was considered suboptimal compared to the more commonly used 40 mg/m2 dose.
      The long-term survival effects of additional chemotherapy over radiotherapy alone continue to be reported. As an example, in high-risk endometrial cancers, the updated analysis of the PORTEC-3 clinical trial has shown improved 5-year OS (81.4% versus 76.1%, p = 0.03) and failure-free survival (76.5% versus 69.1%, p = 0.02) with adjuvant and concurrent chemoradiotherapy versus radiotherapy alone [
      • de Boer S.M.
      • Powell M.E.
      • Mileshkin L.
      • Katsaros D.
      • Bessette P.
      • Haie-Meder C.
      • et al.
      Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.
      ,
      • Post C.C.B.
      • de Boer S.M.
      • Powell M.E.
      • Mileshkin L.
      • Katsaros D.
      • Bessette P.
      • et al.
      Long-term toxicity and health-related quality of life after adjuvant chemoradiation therapy or radiation therapy alone for high-risk endometrial cancer in the randomized PORTEC-3 trial.
      ]. At 5 years, grade ≥ 2 adverse events were reported in 38% of women in the chemoradiotherapy group versus 23% in the radiotherapy-alone group (p < 0.01). The adjunction of chemotherapy was particularly relevant for patients with FIGO stages III and/or serous cancers. However, for stages III or IVA endometrial carcinoma, adjuvant and concurrent chemoradiotherapy was not shown to enhance 5-year relapse-free survival (59% versus 58%) compared to an exclusive chemotherapy consisting of six cycles of chemotherapy doublet (carboplatin and paclitaxel) [
      • Matei D.
      • Filiaci V.
      • Randall M.E.
      • Mutch D.
      • Steinhoff M.M.
      • DiSilvestro P.A.
      • et al.
      Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer.
      ]. Chemoradiotherapy was on the other hand associated with a lower 5-year incidence of vaginal recurrence (2% versus 7%; HR = 0.36; 95% CI = 0.16–0.82) and pelvic and para-aortic lymph node recurrence (11% versus 20%; HR = 0.43; 95% CI = 0.28–0.66) than chemotherapy alone, but distant recurrence was more common (27% versus 21%; HR = 1.36; 95% CI = 1.00–1.86). The benefit of radiotherapy and brachytherapy regarding locoregional control should probably be combined with an intensification of systemic treatment.
      Finally, newer and possibly less toxic chemotherapy could be of interest in frail patients. In the ZJCH-E-E trial, Ji et al. reported that concurrent S-1 (a novel oral fluoropyrimidine derivative) could be effective and tolerable in elder patients with oesophageal cancer. The 2-year OS was increased with radiotherapy and S-1 over irradiation alone (53.2% versus 35.8%, respectively), without increased severe toxicities, except leukopenia [
      • Ji Y.
      • Du X.
      • Zhu W.
      • Yang Y.
      • Ma J.
      • Zhang L.
      • et al.
      Efficacy of concurrent chemoradiotherapy with S-1 vs radiotherapy alone for older patients with esophageal cancer: a multicenter randomized phase 3 clinical trial.
      ]. For patients with locoregionally advanced nasopharyngeal carcinoma, nedaplatin-based concurrent chemoradiotherapy has been compared to cisplatin-based concurrent chemoradiotherapy [
      • Tang L.-Q.
      • Chen D.-P.
      • Guo L.
      • Mo H.-Y.
      • Huang Y.
      • Guo S.-S.
      • et al.
      Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised phase 3 trial.
      ]. The 2-year PFS was 89.9% in the cisplatin group and 88.0% in the nedaplatin group (non-inferiority p < 0.05), with different toxicity profiles (lower frequency of grade 3–4 anorexia, nausea, vomiting, and late auditory toxicities with nedaplatin, but more thrombocytopenia during the treatment). Thus, nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional advanced nasopharyngeal carcinoma.

      3.3 Newer radiosensitisers

      In high-risk locoregionally advanced HNSCC, a randomised phase II trial, Debio 1143-201, has highlighted the efficacy of xevinapan (debio 1143), a pro-apoptotic agent (inhibitor of apoptosis proteins antagonist) used for the first time in association with a standard high-dose cisplatin chemoradiotherapy (n = 96) [
      • Sun X.-S.
      • Tao Y.
      • Le Tourneau C.
      • Pointreau Y.
      • Sire C.
      • Kaminsky M.-C.
      • et al.
      Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study.
      ]. Locoregional control at 18 months was achieved in 54% of patients of the experimental arm versus 33% of the standard arm (p = 0.03), with similar toxicity profiles. A phase III trial is ongoing to confirm these results.
      Different type of nanoparticles are currently evaluated with irradiation. A phase II–III clinical trial, Act.In.Sarc, has assessed the safety and efficacy of neoadjuvant intratumoural injection of the high Z hafnium oxide (HfO2) nanoparticle NBTXR3 with radiotherapy (50 Gy/25 fractions) versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (n = 180 patients) [
      • Bonvalot S.
      • Rutkowski P.L.
      • Thariat J.
      • Carrère S.
      • Ducassou A.
      • Sunyach M.-P.
      • et al.
      NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.
      ]. The main objective was the pCR and was reached in 16% of patients in the NBTXR3 group versus 8% of patients in the radiotherapy alone group (p = 0.04).

      3.4 Radioimmunotherapy

      Radiotherapy enhances the antitumour immune response, inducing antigens release and tumour antigen presentation. In the preoperative setting, a first randomised phase II trial showed that concurrent SBRT (24 Gy in 8 fractions) and the anti PD-L1 durvalumab increased major pCR rates (16 [53.3%] versus 2 [6.7%]; p < 0.01) compared to durvalumab alone for patients with early stage lung cancer [
      • Altorki N.K.
      • McGraw T.E.
      • Borczuk A.C.
      • Saxena A.
      • Port J.L.
      • Stiles B.M.
      • et al.
      Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.
      ].
      In locally advanced stages, many concurrent chemoradiotherapy–immunotherapy trials are ongoing [
      • Chargari C.
      • Levy A.
      • Paoletti X.
      • Soria J.-C.
      • Massard C.
      • Weichselbaum R.R.
      • et al.
      Methodological development of combination drug and radiotherapy in basic and clinical research.
      ]. In HNSCC, a large (n = 697 patients) phase III trial, JAVELIN head and neck 100, however, showed disappointing results with the addition of the anti-PD-L1 avelumab to concurrent chemoradiotherapy (median PFS not reached, stratified hazard ratio [HR] = 1.21 [95% CI 0.93–1.57] favouring the placebo group; one-sided p = 0.92) [
      • Lee N.Y.
      • Ferris R.L.
      • Psyrri A.
      • Haddad R.I.
      • Tahara M.
      • Bourhis J.
      • et al.
      Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.
      ].
      In the metastatic setting, radioimmunotherapy trials produced conflicting results in trials evaluating the abscopal effect of radiotherapy when given with immunotherapy. The abscopal effect describes the shrinking or disappearance of the tumour in parts of the body that were not the direct target of local therapy but were destroyed by the immune system. The phase 3 trial CA184-043 has assessed radiotherapy (8 Gy in a single fraction to the bone) + the anti-CTLA4 ipilimumab or placebo in patients with metastatic castrate-resistant prostate cancer[
      • Fizazi K.
      • Drake C.G.
      • Beer T.M.
      • Kwon E.D.
      • Scher H.I.
      • Gerritsen W.R.
      • et al.
      Final analysis of the ipilimumab versus placebo following radiotherapy phase III trial in postdocetaxel metastatic castration-resistant prostate cancer identifies an excess of long-term survivors.
      ]. The primary end-point (OS) was not improved, even if a PFS improvement (HR = 0.70, 95% CI 0.61–0.82; p < 0.01) was observed with ipilimumab. In a phase II randomised trial testing the abscopal effect on 62 patients with metastatic HNSCC, the addition of SBRT to one metastatic lesion to the anti-PD1 nivolumab did not lead to an objective response rate or outcome improvements over nivolumab alone [
      • McBride S.
      • Sherman E.
      • Tsai C.J.
      • Baxi S.
      • Aghalar J.
      • Eng J.
      • et al.
      Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma.
      ]. On the contrary, a pooled analyse of two randomised phase II trials (n = 148) reported improved median PFS (HR = 0.67, p = 0.04) and median OS (HR = 0.67, p < 0.01) in patients with metastatic non-small-cell lung carcinoma (NSCLC) receiving SBRT to a single tumour site (PEMBRO-RT)/lung or liver lesions amenable to RT (MDACC trials) and the anti-PD1 pembrolizumab over pembrolizumab alone [
      • Theelen W.S.M.E.
      • Peulen H.M.U.
      • Lalezari F.
      • van der Noort V.
      • de Vries J.F.
      • Aerts J.G.J.V.
      • et al.
      Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
      ,
      • Welsh J.
      • Menon H.
      • Chen D.
      • Verma V.
      • Tang C.
      • Altan M.
      • et al.
      Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial.
      ,
      • Theelen W.S.M.E.
      • Chen D.
      • Verma V.
      • Hobbs B.P.
      • Peulen H.M.U.
      • Aerts J.G.J.V.
      • et al.
      Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials.
      ]. Only unirradiated lesions were measured for response. Best abscopal response rate was 19.7% with pembrolizumab versus 41.7% with pembrolizumab plus radiotherapy (odds ratio [OR] 2.96, 95% CI = 1.42–6.20; p < 0.01). Confirming phase III (e.g. NCT03774732) is ongoing in this setting.

      4. Treatment intensification

      Newer radiotherapy indication or treatment intensification may lead to an increased proportion of cured patients but at the risk of increased toxicity.

      4.1 Radiotherapy gaining ground

      In hepatocellular carcinoma showing macroscopic vascular invasion, transarterial cisplatin-based-chemoembolisation and normofractionated irradiation was compared to the SoC sorafenib in the AMC IRB 2013-0627 trial [
      • Yoon S.M.
      • Ryoo B.-Y.
      • Lee S.J.
      • Kim J.H.
      • Shin J.H.
      • An J.H.
      • et al.
      Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial.
      ]. The experimental treatment was well tolerated and resulted in an improved OS (13.8 versus 10.8 months, p = 0.04), PFS, objective response rate and time to progression.
      In patients with clinically resectable, locally advanced cancer of the oesophagus or of the oesophagogastric junction, neoadjuvant chemoradiotherapy (consisting of carboplatin plus paclitaxel with concurrent 41.4 Gy radiotherapy) followed by surgery was compared to surgery alone in the CROSS trial [
      • Noordman B.J.
      • Verdam M.G.E.
      • Lagarde S.M.
      • Hulshof M.C.C.M.
      • van Hagen P.
      • van Berge Henegouwen M.I.
      • et al.
      Effect of neoadjuvant chemoradiotherapy on health-related quality of life in esophageal or junctional cancer: results from the randomized CROSS trial.
      ,
      • Eyck B.M.
      • van Lanschot J.J.B.
      • Hulshof M.C.C.M.
      • van der Wilk B.J.
      • Shapiro J.
      • van Hagen P.
      • et al.
      Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial.
      ]. At a long-term follow-up, the absolute 10-year OS benefit was 13% (38% versus 25%) in favour of the neoadjuvant arm [
      • Eyck B.M.
      • van Lanschot J.J.B.
      • Hulshof M.C.C.M.
      • van der Wilk B.J.
      • Shapiro J.
      • van Hagen P.
      • et al.
      Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial.
      ], as confirmed by the NEOCRTEC5010 trial [
      • Yang H.
      • Liu H.
      • Chen Y.
      • Zhu C.
      • Fang W.
      • Yu Z.
      • et al.
      Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial.
      ,
      • Liu S.
      • Wen J.
      • Yang H.
      • Li Q.
      • Chen Y.
      • Zhu C.
      • et al.
      Recurrence patterns after neoadjuvant chemoradiotherapy compared with surgery alone in oesophageal squamous cell carcinoma: results from the multicenter phase III trial NEOCRTEC5010.
      ].
      There is ongoing debate on indications for whole-pelvis rather than prostate only radiation therapy in men with cN0 prostate cancer at a high-risk of nodal involvement. The POP-RT RCT showed that lymph node irradiation improved biochemical control and metastasis-free survival over prostate only radiotherapy, in a population at a high-risk of lymph node involvement (≥20%) [
      • Murthy V.
      • Maitre P.
      • Kannan S.
      • Panigrahi G.
      • Krishnatry R.
      • Bakshi G.
      • et al.
      Prostate-only versus whole-pelvic radiation therapy in high-risk and very high-risk prostate cancer (POP-RT): outcomes from phase III randomized controlled trial.
      ]. The GETUG-AFU 23/PEACE 2 trial (NCT01952223) and RTOG 0524 (NCT01368588), which asked the same question, have since closed accrual with around 800 and 2500 patients, respectively.
      In the metastatic setting, local therapy of the primary tumour is considered with the intent of reducing primary tumour burden, relieving symptoms or propagation of metastases. For patients with de novo metastatic nasopharyngeal carcinoma who had a complete or partial response following three cycles of cisplatin and fluorouracil chemotherapy, the efficacy and safety of chemoradiation (60–70 Gy to GTV, 50–66 Gy to the different PTV/33 fractions) have been compared to exclusive chemotherapy in the SYSUCC5010 trial [
      • You R.
      • Liu Y.-P.
      • Huang P.-Y.
      • Zou X.
      • Sun R.
      • He Y.-X.
      • et al.
      Efficacy and safety of locoregional radiotherapy with chemotherapy vs chemotherapy alone in de novo metastatic nasopharyngeal carcinoma: a multicenter phase 3 randomized clinical trial.
      ]. Radiotherapy added to chemotherapy significantly improved the 24-month OS in this population (76.4% versus 54.5%, p < 0.01). The frequency of late severe (grade ≥ 3) hearing loss and trismus was 5.2% and 3.4%, respectively, in the chemotherapy plus radiotherapy group. Another study, STAMPEDE, demonstrated that prostate radiotherapy improved OS (0.68, p < 0.01) for men with low volume metastatic prostate cancer but not in an unselected population or in patients with high volume metastatic disease [
      • Parker C.C.
      • James N.D.
      • Brawley C.D.
      • Clarke N.W.
      • Hoyle A.P.
      • Ali A.
      • et al.
      Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.
      ].

      4.2 Radiotherapy dose escalation or hyperfractionation

      With modern radiotherapy technologies (intensity-modulated radiotherapy [IMRT], image-guided radiotherapy), some trials hypothesised that additional ionising irradiation doses could be safely delivered. However, several recent RCTs failed to show an advantage of dose escalation. The RTOG 0617 trial compared definitive standard dose (60 Gy) versus high-dose (74 Gy) radiation with concurrent chemotherapy in locally advanced NSCLC. Higher dose resulted in more severe dysphagia and reduced OS compared to 60 Gy, but it should be highlighted that only 47% patients received IMRT in this trial [
      • Bradley J.D.
      • Hu C.
      • Komaki R.R.
      • Masters G.A.
      • Blumenschein G.R.
      • Schild S.E.
      • et al.
      Long-term results of NRG oncology RTOG 0617: standard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer.
      ]. The ARTDECO trial compared concurrent chemoradiotherapy with a 50.4 Gy standard dose to 61.6 Gy in locally advanced oesophageal cancer. No differences were observed in terms of outcome and toxicity in this trial [
      • Hulshof M.C.C.M.
      • Geijsen E.D.
      • Rozema T.
      • Oppedijk V.
      • Buijsen J.
      • Neelis K.J.
      • et al.
      Randomized study on dose escalation in definitive chemoradiation for patients with locally advanced esophageal cancer (ARTDECO study).
      ]. On the other hand, the FLAME trial compared a focal ‘isotoxic’ external beam radiation therapy boost to the prostate (up to 95 Gy versus 77 Gy) based on magnetic resonance imaging (MRI). The addition of the boost resulted in higher biochemical DFS, without observed OS or toxicity differences [
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • Monninkhof E.M.
      • Smeenk R.J.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME randomized phase III trial.
      ].
      Hyperfractionated accelerated (e.g. twice daily) radiotherapy with concomitant chemotherapy (HFCRT) offers the theoretical advantage of the reduction of late radiation injury and the prevention of tumour repopulation in treatment intervals, often at a cost of increased acute side-effects. Twice-daily concurrent chemoradiotherapy is still considered the SoC in localised small cell lung cancer. A recent randomised phase II trial, THORA, suggested that higher HFCRT dose (60 Gy in 40 fractions versus 45 Gy in 30 fractions) could be achievable and improve 2-year OS (OR 3.1; p < 0.01) [
      • Grønberg B.H.
      • Killingberg K.T.
      • Fløtten Ø.
      • Brustugun O.T.
      • Hornslien K.
      • Madebo T.
      • et al.
      High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial.
      ]. In locally advanced HNSCC, a network meta-analysis (MACH-NC) included individual patient data from 28,978 patients in 115 trials showed that HFCRT could offer the best OS compared to conventional chemoradiotherapy [
      • Petit C.
      • Lacas B.
      • Pignon J.-P.
      • Le Q.T.
      • Grégoire V.
      • Grau C.
      • et al.
      Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.
      ]. However, the added cost and logistical challenges of multiple fractions per day have limited the widespread utilisation of these techniques. Induction chemotherapy followed by chemoradiotherapy was the second better intensifying option in this analysis [
      • Petit C.
      • Lacas B.
      • Pignon J.-P.
      • Le Q.T.
      • Grégoire V.
      • Grau C.
      • et al.
      Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.
      ].

      4.3 Reinforcing induction/consolidation systemic treatments

      Metastatic relapse is the main pattern of failure in many patients receiving curative-intent radiotherapy, justifying the incorporation of newer and more effective systemic treatments.
      Induction chemotherapy prior to radiotherapy has become SoC in several tumour type including HNSCC (MACH-NC) [
      • Petit C.
      • Lacas B.
      • Pignon J.-P.
      • Le Q.T.
      • Grégoire V.
      • Grau C.
      • et al.
      Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.
      ], nasopharyngeal [
      • Zhang Y.
      • Chen L.
      • Hu G.-Q.
      • Zhang N.
      • Zhu X.-D.
      • Yang K.-Y.
      • et al.
      Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma.
      ] and rectal cancers (PRODIGE 23) [
      • Conroy T.
      • Bosset J.-F.
      • Etienne P.-L.
      • Rio E.
      • François É.
      • Mesgouez-Nebout N.
      • et al.
      Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.
      ]. A recent trial reported an improved 3-year DFS (85.3% in the induction chemotherapy group versus 76.5% in the standard-therapy group, p < 0.01) and 3-years OS (94.6% versus 90.3%) after induction chemotherapy (gemcitabine + cisplatin) before cisplatin-radiotherapy among patients with locoregionally advanced nasopharyngeal carcinoma [
      • Zhang Y.
      • Chen L.
      • Hu G.-Q.
      • Zhang N.
      • Zhu X.-D.
      • Yang K.-Y.
      • et al.
      Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma.
      ]. In two locally advanced rectal cancers phase III trials (PRODIGE23 and RAPIDO), total neoadjuvant oxaliplatin-based chemotherapy before chemoradiotherapy (PRODIGE 23) or after short course radiotherapy (RAPIDO) showed increased response rates and PFS compared to the standard (long-course chemoradiotherapy + adjuvant chemotherapy) groups [
      • Conroy T.
      • Bosset J.-F.
      • Etienne P.-L.
      • Rio E.
      • François É.
      • Mesgouez-Nebout N.
      • et al.
      Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.
      ,
      • Bahadoer R.R.
      • Dijkstra E.A.
      • van Etten B.
      • Marijnen C.A.M.
      • Putter H.
      • Kranenbarg E.M.-K.
      • et al.
      Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
      ].
      For many tumour sites, consolidation systemic treatment in patients who do not progress after frontline chemoradiotherapy was assessed as well to decrease subsequent distant relapse and possibly increase OS. According to the CAN phase III trial, including high-risk nasopharyngeal carcinoma (stage III–IVA, excluding T3–4N0 and T3N1 disease, n = 406) without locoregional disease or distant metastasis after definitive chemoradiotherapy, the addition of oral metronomic capecitabine for a year improved failure-free survival at 3 years (85.3% versus 75.7% in the observation arm; HR = 0.50; p < 0.01) [
      • Chen Y.-P.
      • Liu X.
      • Zhou Q.
      • Yang K.-Y.
      • Jin F.
      • Zhu X.-D.
      • et al.
      Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.
      ]. For patients with high-risk non-metastatic prostate cancer receiving androgen suppression and radiotherapy, the addition of a chemotherapy with docetaxel was shown to be associated with an improved OS (93% versus 89% at 4 years, p = 0.03), an improved DFS and a reduction of distant metastasis, according to the RG Oncology RTOG 0521 trial [
      • Rosenthal S.A.
      • Hu C.
      • Sartor O.
      • Gomella L.G.
      • Amin M.B.
      • Purdy J.
      • et al.
      Effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer: the randomized phase III NRG oncology RTOG 0521 trial.
      ]. In this population, the addition of abiraterone and prednisolone alone or with enzalutamide to androgen-deprivation therapy was also shown to significantly increase the rate of metastasis-free survival compared with androgen-deprivation therapy alone (HR = 0.53, 95% CI = 0.44–0.64, p < 0.01), and the rate of OS (HR = 0.60, 95% CI = 0.48–0.73, p < 0.01) (STAMPEDE trial) [
      • Attard G.
      • Murphy L.
      • Clarke N.W.
      • Cross W.
      • Jones R.J.
      • Parker C.C.
      • et al.
      Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.
      ]. Toxicity profiles were more favourable than reported with docetaxel [
      • Rosenthal S.A.
      • Hu C.
      • Sartor O.
      • Gomella L.G.
      • Amin M.B.
      • Purdy J.
      • et al.
      Effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer: the randomized phase III NRG oncology RTOG 0521 trial.
      ]. There was no evidence of a difference in metastasis-free survival when enzalutamide and abiraterone acetate were administered concurrently, compared with abiraterone acetate alone (interaction HR = 1.02, CI = 0.70–1.50, p = 0.91). Abiraterone acetate with prednisolone should therefore be considered as a new standard treatment for this population.
      Newer compounds are also tested as a consolidation strategy. The LUX-Head & Neck 2 trial reported that EGFR inhibitor afatinib did not show benefit after concurrent chemoradiotherapy in HNSCC [
      • Burtness B.
      • Haddad R.
      • Dinis J.
      • Trigo J.
      • Yokota T.
      • de Souza Viana L.
      • et al.
      Afatinib vs placebo as adjuvant therapy after chemoradiotherapy in squamous cell carcinoma of the head and neck: a randomized clinical trial.
      ]. Adjuvant immunotherapies are showing promising results in some locations. In the PACIFIC trial, the anti-PD-L1 durvalumab delivered after thoracic chemoradiotherapy in locally advanced unresectable NSCLC enhanced OS (at 24-month, 66.3% versus 55.6, p < 0.01) compared to placebo, becoming a SoC in this setting [
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      ,
      • Faivre-Finn C.
      • Vicente D.
      • Kurata T.
      • Planchard D.
      • Paz-Ares L.
      • Vansteenkiste J.F.
      • et al.
      Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial.
      ]. Adjuvant nivolumab (an anti-PD1) compared to placebo (CheckMate 577) also showed increased DFS (HR = 0.69; p < 0.01) among patients with resected oesophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy followed by the surgery [
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • Zander T.
      • Van Cutsem E.
      • Piessen G.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      ]. It should be emphasised that initial 18FDG positron emission tomography–computed tomography (PET-CT) was not mandatory in these trials, possibly enriching the dataset in advanced patients.

      4.4 Local ablative treatments in oligometastatic patients

      The oligometastatic paradigm suggests that some patients with a limited number of metastasis might have a better prognosis, especially after local ablative treatment adjunction. Few RCTs (SABR-COMET, ORIOLE) support the interest of SBRT in oligometastatic case outcomes or its ability to delay systemic treatment [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • Louie A.V.
      • Haasbeek C.
      • et al.
      Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
      ,
      • Phillips R.
      • Shi W.Y.
      • Deek M.
      • Radwan N.
      • Lim S.J.
      • Antonarakis E.S.
      • et al.
      Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial.
      ]. Palma et al. have reported a 13-month increase in OS and a doubling of PFS in patients with a controlled primary tumour and 1–5 metachronous oligometastases, but with 4.5% of patients presenting grade 5 toxicities (radiation pneumonitis, pulmonary abscess and perforated gastric ulcer) [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • Louie A.V.
      • Haasbeek C.
      • et al.
      Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
      ]. Phillips et al. have shown an improved PFS after SBRT for oligometastatic prostate cancer in a randomised phase II trial, without ≥grade 3 adverse events [
      • Phillips R.
      • Shi W.Y.
      • Deek M.
      • Radwan N.
      • Lim S.J.
      • Antonarakis E.S.
      • et al.
      Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial.
      ]. Ost et al., through a randomised phase II trial, reported an increased androgen deprivation therapy-free survival for patients with prostate cancer receiving metastasis-directed therapy (13 months versus 21 months, p = 0.11), with no grade 2–5 toxicity [
      • Ost P.
      • Reynders D.
      • Decaestecker K.
      • Fonteyne V.
      • Lumen N.
      • De Bruycker A.
      • et al.
      Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial.
      ]. Efforts in homogenising oligometastatic definitions/patients selection and generating phase III evidence should be particularly prioritised in this context.

      5. Personalised radiation therapy

      Precision medicine is rapidly moving forward and has demonstrated that molecular or imaging-based subgroups may be deciphered and could avoid the traditional ‘one size fits all’ strategy.

      5.1 Nuclear medicine and MRI integration

      The development of imaging-based biomarkers leads to upgrade cancer staging, prognostic description and predictive data. 18FDG PET-CT leads to a better selection of target volume, allowing chemoradiotherapy volume reduction (involved-fields versus historical elective nodes) in locally advanced NSCLC, without jeopardising outcomes (PET-Plan) [
      • Nestle U.
      • Schimek-Jasch T.
      • Kremp S.
      • Schaefer-Schuler A.
      • Mix M.
      • Küsters A.
      • et al.
      Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.
      ].
      In the pro prostate-specific membrane antigen (PSMA) trial, Hofman et al. have shown that PSMA PET-CT as a first-line investigation was not only superior to conventional CT and bone scan in terms of staging accuracy but also less costly and led to less radiation exposure before curative-intent therapy in men with high-risk prostate cancer [
      • Hofman M.S.
      • Lawrentschuk N.
      • Francis R.J.
      • Tang C.
      • Vela I.
      • Thomas P.
      • et al.
      Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.
      ]. PSMA PET-CT has since become the SoC for prostate cancer staging.
      18FDG PET-CT could also help deciphering best responders to treatments, as highlighted by the GITIL/FIL HD0607 trial [
      • Gallamini A.
      • Rossi A.
      • Patti C.
      • Picardi M.
      • Romano A.
      • Cantonetti M.
      • et al.
      Consolidation radiotherapy could Be safely omitted in advanced Hodgkin lymphoma with large nodal mass in complete metabolic response after ABVD: final analysis of the randomized GITIL/FIL HD0607 trial.
      ]. In the non-inferiority GHSG HD17 trial, consolidation radiotherapy was avoided in patients with PET-negative after chemotherapy for newly diagnosed early-stage unfavourable Hodgkin lymphoma. The difference between-group PFS was 2.2%, demonstrating that omission of consolidation radiotherapy is possible without the loss of efficacy [
      • Borchmann P.
      • Plütschow A.
      • Kobe C.
      • Greil R.
      • Meissner J.
      • Topp M.S.
      • et al.
      PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.
      ].
      The FLAME trial has assessed the benefit of a simultaneous integrated focal boost to the macroscopic prostatic tumour (up to 95 Gy), through a delineation based on a multiparametric MRI, using T2-weighted, diffusion-weighted imaging and dynamic contrast-enhanced sequences [
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • Monninkhof E.M.
      • Smeenk R.J.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME randomized phase III trial.
      ]. With a median follow-up of 72 months, significantly improved 5-year biochemical DFS (from 85% to 92%, p < 0.01) was reported, without significant differences in toxicity. This trial illustrates the concept of dose-painting, using inhomogeneous dose targeted to anatomical, molecular and/or functional imaging, with the aim of focally increasing dose to high-risk volumes, without increasing toxicity rates. This concept is already being used in cervix cancer brachytherapy for more than 15 years, thanks to MRI guided treatment [
      • Haie-Meder C.
      • Pötter R.
      • Van Limbergen E.
      • Briot E.
      • De Brabandere M.
      • Dimopoulos J.
      • et al.
      Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV.
      ]. EBRT RCTs are for example investigating metabolic data and hypoxia-based dose escalation in head and neck cancer (NCT02352792, NCT03865277) or dose escalation using MRI findings for prostate cancer (NCT01411345, NCT02307058).

      5.2 Surrogate biomarkers

      In patients with increasing PSA concentration after radical prostatectomy (from 0.1 ng/mL to between 0.2 ng/mL and 2.0 ng/mL), the 120-month data from the GETUG-AFU 16 trial have shown that salvage radiotherapy (66 Gy/33 fractions) combined with short-term androgen suppression improved outcomes (reduced risks of biochemical or clinical progression and death) compared with salvage radiotherapy alone [
      • Carrie C.
      • Magné N.
      • Burban-Provost P.
      • Sargos P.
      • Latorzeff I.
      • Lagrange J.-L.
      • et al.
      Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial.
      ]. The 120-month PFS was 64% for patients treated with radiotherapy plus short-term androgen suppression and 49% for others (p < 0.01).
      Many biomarkers are currently being tested in clinical trials to guide treatment modalities. Plasma Epstein–Barr Virus DNA in nasopharyngeal cancers (NCT02135042, NCT02363400, NCT02874651 and NCT03544099), HPV DNA in HNSCC [
      • Chera B.S.
      • Kumar S.
      • Shen C.
      • Amdur R.
      • Dagan R.
      • Green R.
      • et al.
      Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer.
      ] or cervical cancers (NCT03739775, NCT02554565), molecular profile (POLE, MSI, NSMP, p53) in endometrial cancers (NCT00411138, NCT03469674), 1p/19q co-deletion in glioblastoma (CeTeG/NOA-09 and trials) [
      • Herrlinger U.
      • Tzaridis T.
      • Mack F.
      • Steinbach J.P.
      • Schlegel U.
      • Sabel M.
      • et al.
      Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial.
      ,
      • van den Bent M.J.
      • Tesileanu C.M.S.
      • Wick W.
      • Sanson M.
      • Brandes A.A.
      • Clement P.M.
      • et al.
      Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.
      ] or EGFR mutations in lung cancers (NCT03521154) are promising markers to personalise the radiation-based treatments. In the phase II trial NRG Oncology HN002 including patients with HPV-associated oropharyngeal cancer, the 2-year PFS after de-escalation (60 Gy IMRT over 6 weeks with concurrent weekly cisplatin) was superior to historical controls, justifying advancement to a phase III study [
      • Yom S.S.
      • Torres-Saavedra P.
      • Caudell J.J.
      • Waldron J.N.
      • Gillison M.L.
      • Xia P.
      • et al.
      Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG oncology HN002).
      ].
      Another way to facilitate a personalised approach to locoregional treatment decisions is to develop biomarkers of toxicities. Grossberg et al. have conducted a cohort study, which was nested in a RCT comparing hypofractionated (42.56 Gy/16 fractions) with conventionally fractionated whole breast irradiation (50 Gy/25 fractions) after breast-conserving surgery [
      • Grossberg A.J.
      • Lei X.
      • Xu T.
      • Shaitelman S.F.
      • Hoffman K.E.
      • Bloom E.S.
      • et al.
      Association of transforming growth factor β polymorphism C-509T with radiation-induced fibrosis among patients with early-stage breast cancer: a secondary analysis of a randomized clinical trial.
      ]. The C-509T allele in TGFB1 was shown to be a candidate genomic marker of radiation breast fibrosis risk. If confirmed, this could possibly facilitate a more personalised approach to locoregional treatment decisions in breast cancer.

      6. Reducing treatment burden, enhancing patients QoL and satisfaction with similar survival outcomes

      With longer-term survivors, more attention has been given to sequelae of treatments. Technological improvements allowed to better spare critical organs and possibly reduce overall treatment time.

      6.1 (Ultra)hypofractionated radiotherapy

      Hypofractionation (increasing dose per fraction above 2 Gy, leading possibly to acceleration i.e. decrease the total duration of treatment) is one of the main ways to enhance value-based health care in radiotherapy, if non-inferiority of survival outcomes is proven, without increased toxicities. Hypofractionation and acceleration are relevant for the health care systems (e.g. more patients treated in a shorter period), particularly in the context of an ageing/frail population [
      • Iyengar P.
      • Zhang-Velten E.
      • Court L.
      • Westover K.
      • Yan Y.
      • Lin M.-H.
      • et al.
      Accelerated hypofractionated image-guided vs conventional radiotherapy for patients with stage II/III non-small cell lung cancer and poor performance status: a randomized clinical trial.
      ], with limited health care resources and with the emergence of pandemics.
      In patients with early stage breast cancer, the DBCG HYPO trial confirmed that adjuvant whole breast radiotherapy schedule delivering 40 Gy/15 fractions offers locoregional tumour control and rates of late toxicities at least as good as the accepted international standard of 50 Gy/25 fractions [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jakobsen E.H.
      • Nielsen M.H.
      • Krause M.
      • et al.
      Hypofractionated versus standard fractionated radiotherapy in patients with early breast cancer or ductal carcinoma in situ in a randomized phase III trial: the DBCG HYPO trial.
      ,
      • Schmeel L.C.
      • Koch D.
      • Schmeel F.C.
      • Röhner F.
      • Schoroth F.
      • Bücheler B.M.
      • et al.
      Acute radiation-induced skin toxicity in hypofractionated vs. conventional whole-breast irradiation: an objective, randomized multicenter assessment using spectrophotometry.
      ]. According to a recent randomised trial, hypofractionated adjuvant radiotherapy delivered to the breast and lymph nodes seems to be similarly relevant for higher risk breast cancer (tumour stage T3–T4 and/or positive lymph nodes) [
      • Wang S.-L.
      • Fang H.
      • Song Y.-W.
      • Wang W.-H.
      • Hu C.
      • Liu Y.-P.
      • et al.
      Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.
      ]. Further trials comparing moderate hypofractionated to conventional lymph node radiotherapy are ongoing (NCT03127995, NCT02690636, NCT03829553, NCT04025164, NCT02912312 and NCT04228991).
      More hypofractionated whole breast or accelerated partial breast irradiation (APBI) schedules have been reported with or without acceleration. The FAST-Forward trial has shown that a more hypofractionated adjuvant whole breast scheme, with 26 Gy/5 fractions over one week, is as effective and safe as the 40 Gy/15 fractions regimen [
      • Murray Brunt A.
      • Haviland J.S.
      • Wheatley D.A.
      • Sydenham M.A.
      • Alhasso A.
      • Bloomfield D.J.
      • et al.
      Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.
      ]. With a median follow-up of 71.5 months and 4110 enrolled patients with invasive carcinoma of the breast (pT1–3, pN0–1, M0), the 5-year incidence of ipsilateral breast tumour relapse was non-inferior after 26 Gy (1.4%) than after 40 Gy (2.1%; p < 0.01), without increased toxicities. Not only the incidence of locoregional relapses but also distant relapses, DFS and OS were not different. The FAST trial has also assessed highly hypofractionated adjuvant whole breast treatment (30 or 28.5 Gy/5 fractions), delivered with once weekly fraction, for women ≥50 years of age with low-risk invasive breast carcinoma (pT1-2 pN0) [
      • Brunt A.M.
      • Haviland J.S.
      • Sydenham M.
      • Agrawal R.K.
      • Algurafi H.
      • Alhasso A.
      • et al.
      Ten-year results of FAST: a randomized controlled trial of 5-fraction whole-breast radiotherapy for early breast cancer.
      ]. At 10 years, normal tissue effects were not different after 28.5 Gy/5 once weekly fractions than after 50 Gy/25 fractions, as well as breast cancer-related events or deaths, offering a particularly interesting scheme for frail patients with a low-risk breast cancer. Regarding APBI, the APBI-IMRT-Florence trial showed that APBI (30 Gy/5 daily-fractions over one week) resulted in similar 10-year ipsilateral breast tumour recurrence (3.7% versus 2.5%, respectively, p = 0.40), OS (91.9% versus 91.9%) and breast cancer-specific survival (97.8% versus 96.7%, p = 0.45) than conventionally fractionated whole breast irradiation (50 Gy/25 fractions) [
      • Meattini I.
      • Marrazzo L.
      • Saieva C.
      • Desideri I.
      • Scotti V.
      • Simontacchi G.
      • et al.
      Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: long-term results of the randomized phase III APBI-IMRT-Florence trial.
      ]. APBI was associated with less acute (p < 0.01) and late adverse events (p < 0.01) and improved late cosmetic outcomes as evaluated by both physicians (p < 0.01) and patients (p < 0.01). At the contrary, twice-daily APBI resulted in higher late side-effects [
      • Whelan T.J.
      • Julian J.A.
      • Berrang T.S.
      • Kim D.-H.
      • Germain I.
      • Nichol A.M.
      • et al.
      External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.
      ] and possibly higher ipsilateral breast-tumour recurrence [
      • Vicini F.A.
      • Cecchini R.S.
      • White J.R.
      • Arthur D.W.
      • Julian T.B.
      • Rabinovitch R.A.
      • et al.
      Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial.
      ] than whole breast irradiation according to two large phase III trials, the RAPID and the NSABP B-39/RTOG 0413.
      Moderate hypofractionation has also become SoC in localised prostate cancer [
      • Avkshtol V.
      • Ruth K.J.
      • Ross E.A.
      • Hallman M.A.
      • Greenberg R.E.
      • Price R.A.
      • et al.
      Ten-year update of a randomized, prospective trial of conventional fractionated versus moderate hypofractionated radiation therapy for localized prostate cancer.
      ]. The interest of ultrahypofractionation SBRT, defined as fraction sizes of at least 5 Gy, has also been assessed. The HYPO-RT-PC trial has compared conventionally fractionated radiotherapy (78 Gy/39 fractions) with ultrahypofractionated treatment (42.7 Gy/7 fractions) in intermediate or high-risk prostate cancer [
      • Widmark A.
      • Gunnlaugsson A.
      • Beckman L.
      • Thellenberg-Karlsson C.
      • Hoyer M.
      • Lagerlund M.
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.
      ]. The 5-year PFS rates were 84% in both arms. Late toxicities were similar, except for an increase in urinary toxicity at 1-year follow-up in the ultrahypofractionation group (6% versus 2%). The recently published clinical trial PACE-B suggests that substantially shortening treatment courses with SBRT does not increase either gastrointestinal or genitourinary acute toxicity [
      • Brand D.H.
      • Tree A.C.
      • Ostler P.
      • van der Voet H.
      • Loblaw A.
      • Chu W.
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      ]. Late side-effects also seem to be comparable after ultrahypofractionated, compared to conventionally fractionated radiation therapy [
      • Widmark A.
      • Gunnlaugsson A.
      • Beckman L.
      • Thellenberg-Karlsson C.
      • Hoyer M.
      • Lagerlund M.
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.
      ,
      • Rasmusson E.
      • Gunnlaugsson A.
      • Wieslander E.
      • Höglund P.
      • Widmark A.
      • Fransson P.
      • et al.
      Erectile dysfunction and absorbed dose to penile base structures in a randomized trial comparing ultrahypofractionated and conventionally fractionated radiation therapy for prostate cancer.
      ,
      • Fransson P.
      • Nilsson P.
      • Gunnlaugsson A.
      • Beckman L.
      • Tavelin B.
      • Norman D.
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
      ].

      6.2 Refining radiotherapy indications, timing and dose

      The timing, dose and indications of radiotherapy are continuously challenged. The interest of a radiotherapy dose reduction (24 Gy in 12 fractions versus 4 Gy in 2 fractions) was assessed in indolent follicular and marginal zone lymphoma, in the FoRT trial. The 2- and 5-year local progression-free rates were decreased in the lower dose group, showing that 24 Gy in 12 fractions remains the optimal schedule [
      • Hoskin P.
      • Popova B.
      • Schofield O.
      • Brammer C.
      • Robinson M.
      • Brunt A.M.
      • et al.
      4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial.
      ]. Considering that many recurrences occur in vaginal cuff or distant sites, Randall et al. have addressed the question of the superiority of vaginal cuff brachytherapy and chemotherapy compared with pelvic EBRT alone, in a population of patients with stage I endometrioid histology with high-intermediate–risk, stage II disease or stage I to II serous or clear cell tumours (GOG-0249) [
      • Randall M.E.
      • Filiaci V.
      • McMeekin D.S.
      • von Gruenigen V.
      • Huang H.
      • Yashar C.M.
      • et al.
      Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer.
      ]. No difference was shown in terms of 5-year recurrences-free survival, OS or late toxicity rate, but acute toxicities were increased. In prostate cancer, the question of early salvage radiotherapy role has been addressed. The GETUG-AFU 17 and the RTOG 08.03/ANZUP RAVES trials have compared adjuvant radiotherapy (66 Gy) versus early salvage radiotherapy (64 Gy) following radical prostatectomy, with or without concomitant short-term hormonotherapy, respectively [
      • Sargos P.
      • Chabaud S.
      • Latorzeff I.
      • Magné N.
      • Benyoucef A.
      • Supiot S.
      • et al.
      Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial.
      ,
      • Kneebone A.
      • Fraser-Browne C.
      • Duchesne G.M.
      • Fisher R.
      • Frydenberg M.
      • Herschtal A.
      • et al.
      Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.
      ]. Patients had pathologically-staged pT3a–pT4a (bladder), positive surgical margins, pNx or pN0 disease and PSA ≤ 0.1 ng/mL. No benefit was retrieved for event-free survival in patients assigned to adjuvant compared to salvage radiotherapy, and the risk of genitourinary toxicity and erectile dysfunction was increased. The RADICALS-RT trial and a meta-analysis have also reported consistent data [
      • Parker C.C.
      • Clarke N.W.
      • Cook A.D.
      • Kynaston H.G.
      • Petersen P.M.
      • Catton C.
      • et al.
      Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.
      ,
      • Vale C.L.
      • Fisher D.
      • Kneebone A.
      • Parker C.
      • Pearse M.
      • Richaud P.
      • et al.
      Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data.
      ]. Thus, delaying salvage radiotherapy could spare men from overtreatment.
      Some trials failed to show a benefit of radiotherapy. For patients with resectable, locally recurrent nasopharyngeal carcinoma who have previously received radiotherapy, endoscopic surgery significantly improved OS compared with IMRT (20% of grade 5 toxicities in the radiotherapy arm), according to the ChiCTR-TRC-11001573 trial [
      • Liu Y.-P.
      • Wen Y.-H.
      • Tang J.
      • Wei Y.
      • You R.
      • Zhu X.-L.
      • et al.
      Endoscopic surgery compared with intensity-modulated radiotherapy in resectable locally recurrent nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.
      ]. In retroperitoneal sarcoma, preoperative radiotherapy (50.4 Gy/28 fractions) did not reduce the median abdominal recurrence-free survival, and increased toxicity rates compared to observation (EORTC-62092, STRASS) [
      • Bonvalot S.
      • Gronchi A.
      • Le Péchoux C.
      • Swallow C.J.
      • Strauss D.
      • Meeus P.
      • et al.
      Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial.
      ]. In two phase III trials (Lung ART and PORT-C) assessing the role of postoperative radiotherapy for resected pIIIA N2 NSCLC who received (neo)adjuvant chemotherapy, DFS was not different compared to the observation arm [
      • Le Pechoux C.
      • Pourel N.
      • Barlesi F.
      • Lerouge D.
      • Antoni D.
      • Lamezec B.
      • et al.
      Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial.
      ,
      • Hui Z.
      • Men Y.
      • Hu C.
      • Kang J.
      • Sun X.
      • Bi N.
      • et al.
      Effect of postoperative radiotherapy for patients with pIIIA-N2 non-small cell lung cancer after complete resection and adjuvant chemotherapy: the phase 3 PORT-C randomized clinical trial.
      ]. Subsequent analyses will evaluate the role of adjuvant radiotherapy in high-risk subgroups. For patients with locally advanced NSCLC, prophylactic cranial irradiation (PCI, mainly with 30 Gy/15 fractions, 30 Gy/12 fractions or 30 Gy/10 fractions) has been compared to observation in two phase III RCTs, the NRG Oncology/RTOG 0214 and NVALT-11/DLCRG-02 [
      • Sun A.
      • Hu C.
      • Wong S.J.
      • Gore E.
      • Videtic G.
      • Dutta S.
      • et al.
      Prophylactic cranial irradiation vs observation in patients with locally advanced non-small cell lung cancer: a long-term update of the NRG oncology/RTOG 0214 phase 3 randomized clinical trial.
      ,
      • De Ruysscher D.
      • Dingemans A.-M.C.
      • Praag J.
      • Belderbos J.
      • Tissing-Tan C.
      • Herder J.
      • et al.
      Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: a randomized phase III NVALT-11/DLCRG-02 study.
      ]. PCI decreased the 5- and 10-year rate of brain metastasis and improved the 5- and 10-year DFS, but did not improve OS (the primary end-point of the NRG Oncology/RTOG 0214 trial). Grade 3 and 4 acute toxic events occurred in 4% and 1% of cases in the PCI arm. Grade 3 late toxicities were reported in 3% of cases in the PCI arm, and grade 1–2 memory impairment and cognitive disturbance were increased.

      6.3 Shared decision making

      Some clinical trials with different treatment modalities highlighted equivalent outcomes and different toxicity profiles. They offer other therapeutic options that should be proposed to patients and permit favouring patients choices and preferences. It can also be a way to enhance patients compliance with the planned treatment, which is an important parameter, as compliance correlated with important oncologic outcomes (e.g. locoregional failure-free survival, PFS and OS) in rectal and anal cancers (CAO/ARO/AIO-04 and ACT II trials) [
      • Diefenhardt M.
      • Ludmir E.B.
      • Hofheinz R.-D.
      • Ghadimi M.
      • Minsky B.D.
      • Rödel C.
      • et al.
      Association of treatment adherence with oncologic outcomes for patients with rectal cancer: a post hoc analysis of the CAO/ARO/AIO-04 phase 3 randomized clinical trial.
      ,
      • Glynne-Jones R.
      • Meadows H.M.
      • Lopes A.
      • Muirhead R.
      • Sebag-Montefiore D.
      • Adams R.
      • et al.
      Impact of compliance to chemoradiation on long-term outcomes in squamous cell carcinoma of the anus: results of a post hoc analysis from the randomised phase III ACT II trial.
      ]. Thus, shared decision making is possible in many cases that are increasingly frequent and could results in more relevant treatment decisions.
      For early breast cancers, the GEC-ESTRO APBI trial has shown that APBI using multicatheter brachytherapy after breast-conserving surgery was non-inferior to whole breast irradiation (50 Gy/25 fractions followed by a boost) in terms of local control and OS and was not associated with worse QoL compared with whole breast irradiation [
      • Schäfer R.
      • Strnad V.
      • Polgár C.
      • Uter W.
      • Hildebrandt G.
      • Ott O.J.
      • et al.
      Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breast-conserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial.
      ]. The total treatment time for patients in the APBI group was 4–5 days. These findings support APBI using brachytherapy as an alternative treatment after breast-conserving surgery for patients with early breast cancer, which could be safely offered in this population.
      Concerning good-risk ductal carcinoma in situ, EBRT was shown to significantly reduce the 15-year cumulative incidence of ipsilateral breast recurrence (7.1% versus 15.1%; p < 0.01), compared to observation (NRG Oncology/RTOG 9804) [
      • McCormick B.
      • Winter K.A.
      • Woodward W.
      • Kuerer H.M.
      • Sneige N.
      • Rakovitch E.
      • et al.
      Randomized phase III trial evaluating radiation following surgical excision for good-risk ductal carcinoma in situ: long-term report from NRG oncology/RTOG 9804.
      ]. However, it was associated to 1% of reported late grade 3 toxicities. The authors concluded that these results are not an absolute indication for RT but rather should inform shared patient–physician treatment decisions.

      6.4 Reducing side-effects with high-tech radiotherapy

      Technologic development could upgrade not only oncologic outcomes but also patient-reported adverse events and QoL.
      The implementation of IMRT had reduced the volumes receiving high doses while creating a low dose bath and was shown to improve radiotherapy tolerance in many indications, mainly head, neck and pelvic areas (NRG Oncology-RTOG 1203, PARCER) [
      • Klopp A.H.
      • Yeung A.R.
      • Deshmukh S.
      • Gil K.M.
      • Wenzel L.
      • Westin S.N.
      • et al.
      Patient-reported toxicity during pelvic intensity-modulated radiation therapy: NRG oncology-RTOG 1203.
      ,
      • Yeung A.R.
      • Pugh S.L.
      • Klopp A.H.
      • Gil K.M.
      • Wenzel L.
      • Westin S.N.
      • et al.
      Improvement in patient-reported outcomes with intensity-modulated radiotherapy (RT) compared with standard RT: a report from the NRG oncology RTOG 1203 study.
      ,
      • Chopra S.
      • Gupta S.
      • Kannan S.
      • Dora T.
      • Engineer R.
      • Mangaj A.
      • et al.
      Late toxicity after adjuvant conventional radiation versus image-guided intensity-modulated radiotherapy for cervical cancer (PARCER): a randomized controlled trial.
      ]. The role of hippocampal-avoidance brain radiotherapy is currently assessed. Some reports, as the PREMER and the NRG Oncology CC001 trials, suggest a benefit in terms of neurocognitive preservation [
      • Rodríguez de Dios N.
      • Couñago F.
      • Murcia-Mejía M.
      • Rico-Oses M.
      • Calvo-Crespo P.
      • Samper P.
      • et al.
      Randomized phase III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small-cell lung cancer (PREMER): a GICOR-GOECP-SEOR study.
      ,
      • Brown P.D.
      • Gondi V.
      • Pugh S.
      • Tome W.A.
      • Wefel J.S.
      • Armstrong T.S.
      • et al.
      Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: phase III trial NRG oncology CC001.
      ], but not all (NCT01780675) [
      • Belderbos J.S.A.
      • De Ruysscher D.K.M.
      • De Jaeger K.
      • Koppe F.
      • Lambrecht M.L.F.
      • Lievens Y.N.
      • et al.
      Phase 3 randomized trial of prophylactic cranial irradiation with or without hippocampus avoidance in SCLC (NCT01780675).
      ]. No difference in intracranial PFS and OS is reported in these trials.
      Local relapse after brain metastases surgery may be reduced with adjuvant stereotactic radiosurgery. The JCOG0504 trial has compared, after brain surgery, adjuvant whole-brain radiation therapy (standard arm) versus adjuvant stereotactic radiosurgery in patients with 1–4 brain metastases [
      • Kayama T.
      • Sato S.
      • Sakurada K.
      • Mizusawa J.
      • Nishikawa R.
      • Narita Y.
      • et al.
      Effects of surgery with salvage stereotactic radiosurgery versus surgery with whole-brain radiation therapy in patients with one to four brain metastases (JCOG0504): a phase III, noninferiority, randomized controlled trial.
      ]. The median OS was 15.6 months in both arms, with a longer median intracranial PFS in the standard arm (10.4 months versus 4.0 months in the experimental arm). However, 16.4% of patients in the whole-brain radiotherapy arm and 7.7% in the SBRT arm experienced grade 2–4 cognitive dysfunction.
      The 15-year analysis of the EORTC 22922/10925 trial has reported a non-improved OS (73.1% in the experimental group versus 70.9%, p = 0.36) after internal mammary and medial supraclavicular lymph node chain irradiation in stage I–III breast cancers (50 Gy/25 fractions) [
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ]. However, it could be balanced with a significant reduction of breast cancer mortality, of any breast cancer recurrences, and it should be interpreted taking into account the technical advances of radiotherapy and staging from the beginning of the study (1996). The implementation of IMRT in this situation could modify the therapeutic ratio of this treatment.
      The dosimetric advantages of proton beam therapy (PBT) results in a highly accurate treatment. However, PBT is less accessible and more expansive than photon beam therapy, and dosimetric advantages are insufficient to justify its use. Some clinical trials have assessed if PBT could translate into improved clinical outcomes compared with IMRT. Lin et al. have shown that for locally advanced oesophageal cancer, PBT can reduce the risk and severity of adverse events measured using the total toxicity burden compared with IMRT, while maintaining similar PFS (NRG-GI006 trial) [
      • Lin S.H.
      • Hobbs B.P.
      • Verma V.
      • Tidwell R.S.
      • Smith G.L.
      • Lei X.
      • et al.
      Randomized phase IIB trial of proton beam therapy versus intensity-modulated radiation therapy for locally advanced esophageal cancer.
      ]. Concerning locally advanced NSCLC, a first clinical trial did not show local failure or severer radiation pneumonitis decrease with passive scattering PBT compared with IMRT [
      • Liao Z.
      • Lee J.J.
      • Komaki R.
      • Gomez D.R.
      • O'Reilly M.S.
      • Fossella F.V.
      • et al.
      Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer.
      ]. A newer trial comparing concurrent chemotherapy and intensity-modulated PBT versus IMRT is ongoing (NCT01993810).

      6.5 Palliative radiotherapy

      With higher access, SBRT could also be used to relief pain in metastatic patients and to improve local control. High-dose single-fraction SBRT (12 or 16 Gy, respectively, for ≥4 cm or < 4 cm lesions) was shown to improve pain response rates compared with conventional multifraction radiotherapy (30 Gy/10 fractions) for non-spinal metastases (NCI-2014-01482 trial) [
      • Nguyen Q.-N.
      • Chun S.G.
      • Chow E.
      • Komaki R.
      • Liao Z.
      • Zacharia R.
      • et al.
      Single-fraction stereotactic vs conventional multifraction radiotherapy for pain relief in patients with predominantly nonspine bone metastases: a randomized phase 2 trial.
      ]. For spinal metastases, SBRT (24 Gy/2 fractions) was compared to conventional external beam radiotherapy (20 Gy/5 fractions) in the CCTG SC.24/TROG 17.06 trial [
      • Sahgal A.
      • Myrehaug S.D.
      • Siva S.
      • Masucci L.
      • Foote M.C.
      • Brundage M.
      • et al.
      CCTG SC.24/TROG 17.06: a randomized phase II/III study comparing 24Gy in 2 stereotactic body radiotherapy (SBRT) fractions versus 20Gy in 5 conventional palliative radiotherapy (CRT) fractions for patients with painful spinal metastases.
      ]. Among 229 included patients, complete response for pain at 3 months was higher in the SBRT versus conventional group (35% versus 14%, respectively; risk ratio 1.33, 95% CI = 1.14–1.55; p < 0.01). No toxicity difference, including vertebral fracture or myelopathy, was observed.

      7. Discussion

      The abovementioned data demonstrate a great dynamism of radiation oncology research in most primary tumour types (Fig. 1, Fig. 2). A permanent update is needed, as suggested by the important number of high-level publications available each year. New major end-points are emerging, focusing on QoL, patient satisfaction and shared decision making. Most of enrolled patients reported the perception that trial participation would result in better treatment and more medical attention than off trials [
      • Shumway D.A.
      • Motomura A.
      • Griffith K.A.
      • Hayman J.A.
      • Pierce L.J.
      • Jagsi R.
      Patient perceptions in a nonblinded randomized trial of radiation therapy technologies: a novel survey study exploring therapeutic misconception.
      ]. Despite these elements, and although most patients with cancer receive radiotherapy, the worldwide budget for radiotherapy research is limited. Compared to medical oncologic research, which is often supported by pharmaceutical companies, radiation oncology clinical trials receive mostly public funding. Thus, academic research centres have a key role in assessing innovative treatments or new treatment strategies to develop and promote effective, QoL preserving, and cost efficient treatments. Investments in radiotherapy research through public funds and national governments would have a crucial impact and could facilitate the transfer of innovation to standard care.
      Fig. 2
      Fig. 2Main radiotherapy randomised clinical trials depending on the primary location. EBRT: external beam radiotherapy; CDDP: cisplatin; CTRT: concomitant chemoradiation; preop: preoperative; SBRT: stereotactic body radiotherapy; 18FDG PET: 18FDG positron emission tomography – computed tomography; IF: involved-fields; ENI: elective node irradiation; ADT: androgen-deprivation therapy; SRS: stereotactic radiosurgery; WBRT: whole-brain radiotherapy; APBI: accelerated partial breast irradiation; IMRT: intensity-modulated radiotherapy.
      To demonstrate the superiority of a new treatment over the current standard, properly conducted trials in radiation oncology are required. Prospective quality control becomes a standard in EBRT and brachytherapy, as in surgery. Thus, accreditations, dummy run, data monitoring, quality assurance and continuous education of physicians, physicists and research technicians are increasing. Such items are the subject of publications since they determine the reliability of the results of study [
      • Jaccard M.
      • Zilli T.
      • Dubouloz A.
      • Escude L.
      • Jorcano S.
      • Linthout N.
      • et al.
      Urethra-sparing stereotactic body radiation therapy for prostate cancer: quality assurance of a randomized phase 2 trial.
      ,
      • Giraud P.
      • Racadot S.
      • Vernerey D.
      • Goldstein D.
      • Glimelius B.
      • Van Houtte P.
      • et al.
      Investigation of relation of radiation therapy quality with toxicity and survival in LAP07 phase 3 trial for locally advanced pancreatic carcinoma.
      ,
      • Cho W.K.
      • Kim H.
      • Park W.
      • Kim S.-W.
      • Kim J.
      • Lee K.K.
      • et al.
      A dummy-run evaluation of postoperative hypofractionated intensity-modulated radiation therapy (POHIM-RT) trials for cervical cancer.
      ,
      • Giaddui T.
      • Geng H.
      • Chen Q.
      • Linnemann N.
      • Radden M.
      • Lee N.Y.
      • et al.
      Offline quality assurance for intensity modulated radiation therapy treatment plans for NRG-HN001 head and neck clinical trial using knowledge-based planning.
      ,
      • Hildebrandt G.
      • Stachs A.
      • Gerber B.
      • Potenberg J.
      • Krug D.
      • Wolter K.
      • et al.
      Central review of radiation therapy planning among patients with breast-conserving surgery: results from a quality assurance process integrated into the INSEMA trial.
      ,
      • Khalladi N.
      • Dejean C.
      • Bosset M.
      • Pointreau Y.
      • Kinj R.
      • Racadot S.
      • et al.
      A priori quality assurance using a benchmark case of the randomized phase 2 GORTEC 2014-14 in oligometastatic head and neck cancer patients.
      ]. High-tech radiotherapy studies require particularly high quality control. Protocol deviations, with a potential impact on tumour control or toxicities, have, for example, been reported in 31% of patients in a prospective clinical trial assessing urethra-sparing SBRT [
      • Jaccard M.
      • Zilli T.
      • Dubouloz A.
      • Escude L.
      • Jorcano S.
      • Linthout N.
      • et al.
      Urethra-sparing stereotactic body radiation therapy for prostate cancer: quality assurance of a randomized phase 2 trial.
      ]. In the LAP 07 trial, assessing chemoradiation versus chemotherapy in patients with locally advanced pancreatic cancer, minor deviations were reported in 60% of cases, and major deviations in 14%, with a trend for worst survival (17.0 months versus 13.4 months, respectively, p = 0.055) [
      • Giraud P.
      • Racadot S.
      • Vernerey D.
      • Goldstein D.
      • Glimelius B.
      • Van Houtte P.
      • et al.
      Investigation of relation of radiation therapy quality with toxicity and survival in LAP07 phase 3 trial for locally advanced pancreatic carcinoma.
      ].
      In the context of international public health emergency related to the COVID-19 outbreak, radiotherapy adapted quickly in order to ensure treatment the continuity for patients and safety of caregivers. In this context, hypofractionated radiotherapy RCTs have brought particularly interesting data, providing in many cases comparable outcomes to the standard treatment, with several advantages including shorter treatments limiting the risk of COVID-19 transmission, higher convenience for patients and decreased costs and healthcare resources consumption.
      Many other aspects are in developments within the scope of radiation oncology and will hopefully soon be tested within well-designed RCTs (Fig. 3). Newer DNA interfering agents (PARP, ATR, ATM inhibitors) will be assessed in combination with ionising radiation. Various newer predictive signatures (gut microbiota, circulating biomarkers) are tested and could promote individualised radiotherapy. Liquid biopsy (including DNA repair genomic signature) and imaging-based artificial intelligence (radiomics, connected tools) clinical implementation is fastly moving forward and needs to be prospectively authenticated. Newer technologies (nano-technologies, protons, plasma laser, photobiomodulation) will hopefully decrease side-effects in longer-term cancer survivors. Finally, newer concepts such as lymph node sparing radiotherapy or radiation therapy used as an in situ vaccine are being developed. The individual prediction of the best therapeutic index combined with the integration of new technologies will ideally allow the RCTs validation of highly personalised radiation therapy.
      Fig. 3
      Fig. 3Landscape of radiotherapy development. MRI: magnetic resonance imaging.

      Financial support

      None.

      Conflict of interest statement

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

      Acknowledgement

      Tina Marie Zaarour.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Chargari C.
        • Levy A.
        • Paoletti X.
        • Soria J.-C.
        • Massard C.
        • Weichselbaum R.R.
        • et al.
        Methodological development of combination drug and radiotherapy in basic and clinical research.
        Clin Cancer Res. 2020; 26: 4723-4736
        • Mehanna H.
        • Robinson M.
        • Hartley A.
        • Kong A.
        • Foran B.
        • Fulton-Lieuw T.
        • et al.
        Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.
        Lancet. 2019; 393: 51-60
        • Gillison M.L.
        • Trotti A.M.
        • Harris J.
        • Eisbruch A.
        • Harari P.M.
        • Adelstein D.J.
        • et al.
        Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.
        Lancet. 2019; 393: 40-50
        • Rischin D.
        • King M.
        • Kenny L.
        • Porceddu S.
        • Wratten C.
        • Macann A.
        • et al.
        Randomized trial of radiation therapy with weekly cisplatin or cetuximab in low-risk HPV-associated oropharyngeal cancer (TROG 12.01) – a trans-Tasman radiation oncology group study.
        Int J Radiat Oncol Biol Phys. 2021; 111: 876-886
        • Noronha V.
        • Joshi A.
        • Patil V.M.
        • Agarwal J.
        • Ghosh-Laskar S.
        • Budrukkar A.
        • et al.
        Once-a-Week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: a phase III randomized noninferiority trial.
        J Clin Oncol. 2018; 36: 1064-1072
        • de Boer S.M.
        • Powell M.E.
        • Mileshkin L.
        • Katsaros D.
        • Bessette P.
        • Haie-Meder C.
        • et al.
        Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.
        Lancet Oncol. 2019; 20: 1273-1285
        • Post C.C.B.
        • de Boer S.M.
        • Powell M.E.
        • Mileshkin L.
        • Katsaros D.
        • Bessette P.
        • et al.
        Long-term toxicity and health-related quality of life after adjuvant chemoradiation therapy or radiation therapy alone for high-risk endometrial cancer in the randomized PORTEC-3 trial.
        Int J Radiat Oncol Biol Phys. 2021; 109: 975-986
        • Matei D.
        • Filiaci V.
        • Randall M.E.
        • Mutch D.
        • Steinhoff M.M.
        • DiSilvestro P.A.
        • et al.
        Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer.
        N Engl J Med. 2019; 380: 2317-2326
        • Ji Y.
        • Du X.
        • Zhu W.
        • Yang Y.
        • Ma J.
        • Zhang L.
        • et al.
        Efficacy of concurrent chemoradiotherapy with S-1 vs radiotherapy alone for older patients with esophageal cancer: a multicenter randomized phase 3 clinical trial.
        JAMA Oncol. 2021; 7: 1459-1466
        • Tang L.-Q.
        • Chen D.-P.
        • Guo L.
        • Mo H.-Y.
        • Huang Y.
        • Guo S.-S.
        • et al.
        Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised phase 3 trial.
        Lancet Oncol. 2018; 19: 461-473
        • Sun X.-S.
        • Tao Y.
        • Le Tourneau C.
        • Pointreau Y.
        • Sire C.
        • Kaminsky M.-C.
        • et al.
        Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study.
        Lancet Oncol. 2020; 21: 1173-1187
        • Bonvalot S.
        • Rutkowski P.L.
        • Thariat J.
        • Carrère S.
        • Ducassou A.
        • Sunyach M.-P.
        • et al.
        NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.
        Lancet Oncol. 2019; 20: 1148-1159
        • Altorki N.K.
        • McGraw T.E.
        • Borczuk A.C.
        • Saxena A.
        • Port J.L.
        • Stiles B.M.
        • et al.
        Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.
        Lancet Oncol. 2021; 22: 824-835
        • Lee N.Y.
        • Ferris R.L.
        • Psyrri A.
        • Haddad R.I.
        • Tahara M.
        • Bourhis J.
        • et al.
        Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.
        Lancet Oncol. 2021; 22: 450-462
        • Fizazi K.
        • Drake C.G.
        • Beer T.M.
        • Kwon E.D.
        • Scher H.I.
        • Gerritsen W.R.
        • et al.
        Final analysis of the ipilimumab versus placebo following radiotherapy phase III trial in postdocetaxel metastatic castration-resistant prostate cancer identifies an excess of long-term survivors.
        Eur Urol. 2020; 78: 822-830
        • McBride S.
        • Sherman E.
        • Tsai C.J.
        • Baxi S.
        • Aghalar J.
        • Eng J.
        • et al.
        Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma.
        J Clin Oncol. 2021; 39: 30-37
        • Theelen W.S.M.E.
        • Peulen H.M.U.
        • Lalezari F.
        • van der Noort V.
        • de Vries J.F.
        • Aerts J.G.J.V.
        • et al.
        Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
        JAMA Oncol. 2019; 5: 1276-1282
        • Welsh J.
        • Menon H.
        • Chen D.
        • Verma V.
        • Tang C.
        • Altan M.
        • et al.
        Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial.
        J Immunother Cancer. 2020; 8e001001
        • Theelen W.S.M.E.
        • Chen D.
        • Verma V.
        • Hobbs B.P.
        • Peulen H.M.U.
        • Aerts J.G.J.V.
        • et al.
        Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials.
        Lancet Respir Med. 2021; 9: 467-475
        • Yoon S.M.
        • Ryoo B.-Y.
        • Lee S.J.
        • Kim J.H.
        • Shin J.H.
        • An J.H.
        • et al.
        Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial.
        JAMA Oncol. 2018; 4: 661-669
        • Noordman B.J.
        • Verdam M.G.E.
        • Lagarde S.M.
        • Hulshof M.C.C.M.
        • van Hagen P.
        • van Berge Henegouwen M.I.
        • et al.
        Effect of neoadjuvant chemoradiotherapy on health-related quality of life in esophageal or junctional cancer: results from the randomized CROSS trial.
        J Clin Oncol. 2018; 36: 268-275
        • Eyck B.M.
        • van Lanschot J.J.B.
        • Hulshof M.C.C.M.
        • van der Wilk B.J.
        • Shapiro J.
        • van Hagen P.
        • et al.
        Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial.
        J Clin Oncol. 2021; 39: 1995-2004
        • Yang H.
        • Liu H.
        • Chen Y.
        • Zhu C.
        • Fang W.
        • Yu Z.
        • et al.
        Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial.
        J Clin Oncol. 2018; 36: 2796-2803
        • Liu S.
        • Wen J.
        • Yang H.
        • Li Q.
        • Chen Y.
        • Zhu C.
        • et al.
        Recurrence patterns after neoadjuvant chemoradiotherapy compared with surgery alone in oesophageal squamous cell carcinoma: results from the multicenter phase III trial NEOCRTEC5010.
        Eur J Cancer. 2020; 138: 113-121
        • Murthy V.
        • Maitre P.
        • Kannan S.
        • Panigrahi G.
        • Krishnatry R.
        • Bakshi G.
        • et al.
        Prostate-only versus whole-pelvic radiation therapy in high-risk and very high-risk prostate cancer (POP-RT): outcomes from phase III randomized controlled trial.
        J Clin Oncol. 2021; 39: 1234-1242
        • You R.
        • Liu Y.-P.
        • Huang P.-Y.
        • Zou X.
        • Sun R.
        • He Y.-X.
        • et al.
        Efficacy and safety of locoregional radiotherapy with chemotherapy vs chemotherapy alone in de novo metastatic nasopharyngeal carcinoma: a multicenter phase 3 randomized clinical trial.
        JAMA Oncol. 2020; 6: 1345-1352
        • Parker C.C.
        • James N.D.
        • Brawley C.D.
        • Clarke N.W.
        • Hoyle A.P.
        • Ali A.
        • et al.
        Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.
        Lancet. 2018; 392: 2353-2366
        • Bradley J.D.
        • Hu C.
        • Komaki R.R.
        • Masters G.A.
        • Blumenschein G.R.
        • Schild S.E.
        • et al.
        Long-term results of NRG oncology RTOG 0617: standard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer.
        J Clin Oncol. 2020; 38: 706-714
        • Hulshof M.C.C.M.
        • Geijsen E.D.
        • Rozema T.
        • Oppedijk V.
        • Buijsen J.
        • Neelis K.J.
        • et al.
        Randomized study on dose escalation in definitive chemoradiation for patients with locally advanced esophageal cancer (ARTDECO study).
        J Clin Oncol. 2021; 39: 2816-2824
        • Kerkmeijer L.G.W.
        • Groen V.H.
        • Pos F.J.
        • Haustermans K.
        • Monninkhof E.M.
        • Smeenk R.J.
        • et al.
        Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME randomized phase III trial.
        J Clin Oncol. 2021; 39: 787-796
        • Grønberg B.H.
        • Killingberg K.T.
        • Fløtten Ø.
        • Brustugun O.T.
        • Hornslien K.
        • Madebo T.
        • et al.
        High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial.
        Lancet Oncol. 2021; 22: 321-331
        • Petit C.
        • Lacas B.
        • Pignon J.-P.
        • Le Q.T.
        • Grégoire V.
        • Grau C.
        • et al.
        Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.
        Lancet Oncol. 2021; 22: 727-736
        • Zhang Y.
        • Chen L.
        • Hu G.-Q.
        • Zhang N.
        • Zhu X.-D.
        • Yang K.-Y.
        • et al.
        Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma.
        N Engl J Med. 2019; 381: 1124-1135
        • Conroy T.
        • Bosset J.-F.
        • Etienne P.-L.
        • Rio E.
        • François É.
        • Mesgouez-Nebout N.
        • et al.
        Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.
        Lancet Oncol. 2021; 22: 702-715
        • Bahadoer R.R.
        • Dijkstra E.A.
        • van Etten B.
        • Marijnen C.A.M.
        • Putter H.
        • Kranenbarg E.M.-K.
        • et al.
        Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
        Lancet Oncol. 2021; 22: 29-42
        • Chen Y.-P.
        • Liu X.
        • Zhou Q.
        • Yang K.-Y.
        • Jin F.
        • Zhu X.-D.
        • et al.
        Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.
        Lancet. 2021; 398: 303-313
        • Rosenthal S.A.
        • Hu C.
        • Sartor O.
        • Gomella L.G.
        • Amin M.B.
        • Purdy J.
        • et al.
        Effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer: the randomized phase III NRG oncology RTOG 0521 trial.
        J Clin Oncol. 2019; 37: 1159-1168
        • Attard G.
        • Murphy L.
        • Clarke N.W.
        • Cross W.
        • Jones R.J.
        • Parker C.C.
        • et al.
        Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.
        Lancet. 2021; (S0140-6736(21)2437-5)
        • Burtness B.
        • Haddad R.
        • Dinis J.
        • Trigo J.
        • Yokota T.
        • de Souza Viana L.
        • et al.
        Afatinib vs placebo as adjuvant therapy after chemoradiotherapy in squamous cell carcinoma of the head and neck: a randomized clinical trial.
        JAMA Oncol. 2019; 5: 1170-1180
        • Antonia S.J.
        • Villegas A.
        • Daniel D.
        • Vicente D.
        • Murakami S.
        • Hui R.
        • et al.
        Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
        N Engl J Med. 2018; 379: 2342-2350
        • Faivre-Finn C.
        • Vicente D.
        • Kurata T.
        • Planchard D.
        • Paz-Ares L.
        • Vansteenkiste J.F.
        • et al.
        Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial.
        J Thorac Oncol. 2021; 16: 860-867
        • Kelly R.J.
        • Ajani J.A.
        • Kuzdzal J.
        • Zander T.
        • Van Cutsem E.
        • Piessen G.
        • et al.
        Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
        N Engl J Med. 2021; 384: 1191-1203
        • Palma D.A.
        • Olson R.
        • Harrow S.
        • Gaede S.
        • Louie A.V.
        • Haasbeek C.
        • et al.
        Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
        Lancet. 2019; 393: 2051-2058
        • Phillips R.
        • Shi W.Y.
        • Deek M.
        • Radwan N.
        • Lim S.J.
        • Antonarakis E.S.
        • et al.
        Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial.
        JAMA Oncol. 2020; 6: 650-659
        • Ost P.
        • Reynders D.
        • Decaestecker K.
        • Fonteyne V.
        • Lumen N.
        • De Bruycker A.
        • et al.
        Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial.
        J Clin Oncol. 2018; 36: 446-453
        • Nestle U.
        • Schimek-Jasch T.
        • Kremp S.
        • Schaefer-Schuler A.
        • Mix M.
        • Küsters A.
        • et al.
        Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.
        Lancet Oncol. 2020; 21: 581-592
        • Hofman M.S.
        • Lawrentschuk N.
        • Francis R.J.
        • Tang C.
        • Vela I.
        • Thomas P.
        • et al.
        Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.
        Lancet. 2020; 395: 1208-1216
        • Gallamini A.
        • Rossi A.
        • Patti C.
        • Picardi M.
        • Romano A.
        • Cantonetti M.
        • et al.
        Consolidation radiotherapy could Be safely omitted in advanced Hodgkin lymphoma with large nodal mass in complete metabolic response after ABVD: final analysis of the randomized GITIL/FIL HD0607 trial.
        J Clin Oncol. 2020; 38: 3905-3913
        • Borchmann P.
        • Plütschow A.
        • Kobe C.
        • Greil R.
        • Meissner J.
        • Topp M.S.
        • et al.
        PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.
        Lancet Oncol. 2021; 22: 223-234
        • Haie-Meder C.
        • Pötter R.
        • Van Limbergen E.
        • Briot E.
        • De Brabandere M.
        • Dimopoulos J.
        • et al.
        Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV.
        Radiother Oncol. 2005; 74: 235-245
        • Carrie C.
        • Magné N.
        • Burban-Provost P.
        • Sargos P.
        • Latorzeff I.
        • Lagrange J.-L.
        • et al.
        Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial.
        Lancet Oncol. 2019; 20: 1740-1749
        • Chera B.S.
        • Kumar S.
        • Shen C.
        • Amdur R.
        • Dagan R.
        • Green R.
        • et al.
        Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer.
        J Clin Oncol. 2020; 38: 1050-1058
        • Herrlinger U.
        • Tzaridis T.
        • Mack F.
        • Steinbach J.P.
        • Schlegel U.
        • Sabel M.
        • et al.
        Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial.
        Lancet. 2019; 393: 678-688
        • van den Bent M.J.
        • Tesileanu C.M.S.
        • Wick W.
        • Sanson M.
        • Brandes A.A.
        • Clement P.M.
        • et al.
        Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.
        Lancet Oncol. 2021; 22: 813-823
        • Yom S.S.
        • Torres-Saavedra P.
        • Caudell J.J.
        • Waldron J.N.
        • Gillison M.L.
        • Xia P.
        • et al.
        Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG oncology HN002).
        J Clin Oncol. 2021; 39: 956-965
        • Grossberg A.J.
        • Lei X.
        • Xu T.
        • Shaitelman S.F.
        • Hoffman K.E.
        • Bloom E.S.
        • et al.
        Association of transforming growth factor β polymorphism C-509T with radiation-induced fibrosis among patients with early-stage breast cancer: a secondary analysis of a randomized clinical trial.
        JAMA Oncol. 2018; 4: 1751-1757
        • Iyengar P.
        • Zhang-Velten E.
        • Court L.
        • Westover K.
        • Yan Y.
        • Lin M.-H.
        • et al.
        Accelerated hypofractionated image-guided vs conventional radiotherapy for patients with stage II/III non-small cell lung cancer and poor performance status: a randomized clinical trial.
        JAMA Oncol. 2021; 7: 1497-1505
        • Offersen B.V.
        • Alsner J.
        • Nielsen H.M.
        • Jakobsen E.H.
        • Nielsen M.H.
        • Krause M.
        • et al.
        Hypofractionated versus standard fractionated radiotherapy in patients with early breast cancer or ductal carcinoma in situ in a randomized phase III trial: the DBCG HYPO trial.
        J Clin Oncol. 2020; 38: 3615-3625
        • Schmeel L.C.
        • Koch D.
        • Schmeel F.C.
        • Röhner F.
        • Schoroth F.
        • Bücheler B.M.
        • et al.
        Acute radiation-induced skin toxicity in hypofractionated vs. conventional whole-breast irradiation: an objective, randomized multicenter assessment using spectrophotometry.
        Radiother Oncol. 2020; 146: 172-179
        • Wang S.-L.
        • Fang H.
        • Song Y.-W.
        • Wang W.-H.
        • Hu C.
        • Liu Y.-P.
        • et al.
        Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.
        Lancet Oncol. 2019; 20: 352-360
        • Murray Brunt A.
        • Haviland J.S.
        • Wheatley D.A.
        • Sydenham M.A.
        • Alhasso A.
        • Bloomfield D.J.
        • et al.
        Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.
        Lancet. 2020; 395: 1613-1626
        • Brunt A.M.
        • Haviland J.S.
        • Sydenham M.
        • Agrawal R.K.
        • Algurafi H.
        • Alhasso A.
        • et al.
        Ten-year results of FAST: a randomized controlled trial of 5-fraction whole-breast radiotherapy for early breast cancer.
        J Clin Oncol. 2020; 38: 3261-3272
        • Meattini I.
        • Marrazzo L.
        • Saieva C.
        • Desideri I.
        • Scotti V.
        • Simontacchi G.
        • et al.
        Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: long-term results of the randomized phase III APBI-IMRT-Florence trial.
        J Clin Oncol. 2020; 38: 4175-4183
        • Whelan T.J.
        • Julian J.A.
        • Berrang T.S.
        • Kim D.-H.
        • Germain I.
        • Nichol A.M.
        • et al.
        External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.
        Lancet. 2019; 394: 2165-2172
        • Vicini F.A.
        • Cecchini R.S.
        • White J.R.
        • Arthur D.W.
        • Julian T.B.
        • Rabinovitch R.A.
        • et al.
        Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial.
        Lancet. 2019; 394: 2155-2164
        • Avkshtol V.
        • Ruth K.J.
        • Ross E.A.
        • Hallman M.A.
        • Greenberg R.E.
        • Price R.A.
        • et al.
        Ten-year update of a randomized, prospective trial of conventional fractionated versus moderate hypofractionated radiation therapy for localized prostate cancer.
        J Clin Oncol. 2020; 38: 1676-1684
        • Widmark A.
        • Gunnlaugsson A.
        • Beckman L.
        • Thellenberg-Karlsson C.
        • Hoyer M.
        • Lagerlund M.
        • et al.
        Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.
        Lancet. 2019; 394: 385-395
        • Brand D.H.
        • Tree A.C.
        • Ostler P.
        • van der Voet H.
        • Loblaw A.
        • Chu W.
        • et al.
        Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
        Lancet Oncol. 2019; 20: 1531-1543
        • Rasmusson E.
        • Gunnlaugsson A.
        • Wieslander E.
        • Höglund P.
        • Widmark A.
        • Fransson P.
        • et al.
        Erectile dysfunction and absorbed dose to penile base structures in a randomized trial comparing ultrahypofractionated and conventionally fractionated radiation therapy for prostate cancer.
        Int J Radiat Oncol Biol Phys. 2020; 107: 143-151
        • Fransson P.
        • Nilsson P.
        • Gunnlaugsson A.
        • Beckman L.
        • Tavelin B.
        • Norman D.
        • et al.
        Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
        Lancet Oncol. 2021; 22: 235-245
        • Hoskin P.
        • Popova B.
        • Schofield O.
        • Brammer C.
        • Robinson M.
        • Brunt A.M.
        • et al.
        4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial.
        Lancet Oncol. 2021; 22: 332-340
        • Randall M.E.
        • Filiaci V.
        • McMeekin D.S.
        • von Gruenigen V.
        • Huang H.
        • Yashar C.M.
        • et al.
        Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer.
        J Clin Oncol. 2019; 37: 1810-1818
        • Sargos P.
        • Chabaud S.
        • Latorzeff I.
        • Magné N.
        • Benyoucef A.
        • Supiot S.
        • et al.
        Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial.
        Lancet Oncol. 2020; 21: 1341-1352
        • Kneebone A.
        • Fraser-Browne C.
        • Duchesne G.M.
        • Fisher R.
        • Frydenberg M.
        • Herschtal A.
        • et al.
        Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.
        Lancet Oncol. 2020; 21: 1331-1340
        • Parker C.C.
        • Clarke N.W.
        • Cook A.D.
        • Kynaston H.G.
        • Petersen P.M.
        • Catton C.
        • et al.
        Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.
        Lancet. 2020; 396: 1413-1421
        • Vale C.L.
        • Fisher D.
        • Kneebone A.
        • Parker C.
        • Pearse M.
        • Richaud P.
        • et al.
        Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data.
        Lancet. 2020; 396: 1422-1431
        • Liu Y.-P.
        • Wen Y.-H.
        • Tang J.
        • Wei Y.
        • You R.
        • Zhu X.-L.
        • et al.
        Endoscopic surgery compared with intensity-modulated radiotherapy in resectable locally recurrent nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.
        Lancet Oncol. 2021; 22: 381-390
        • Bonvalot S.
        • Gronchi A.
        • Le Péchoux C.
        • Swallow C.J.
        • Strauss D.
        • Meeus P.
        • et al.
        Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial.
        Lancet Oncol. 2020; 21: 1366-1377
        • Le Pechoux C.
        • Pourel N.
        • Barlesi F.
        • Lerouge D.
        • Antoni D.
        • Lamezec B.
        • et al.
        Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial.
        Lancet Oncol. 2021; (S1470-2045(21)606-609)
        • Hui Z.
        • Men Y.
        • Hu C.
        • Kang J.
        • Sun X.
        • Bi N.
        • et al.
        Effect of postoperative radiotherapy for patients with pIIIA-N2 non-small cell lung cancer after complete resection and adjuvant chemotherapy: the phase 3 PORT-C randomized clinical trial.
        JAMA Oncol. 2021; 7: 1178-1185
        • Sun A.
        • Hu C.
        • Wong S.J.
        • Gore E.
        • Videtic G.
        • Dutta S.
        • et al.
        Prophylactic cranial irradiation vs observation in patients with locally advanced non-small cell lung cancer: a long-term update of the NRG oncology/RTOG 0214 phase 3 randomized clinical trial.
        JAMA Oncol. 2019; 5: 847-855
        • De Ruysscher D.
        • Dingemans A.-M.C.
        • Praag J.
        • Belderbos J.
        • Tissing-Tan C.
        • Herder J.
        • et al.
        Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: a randomized phase III NVALT-11/DLCRG-02 study.
        J Clin Oncol. 2018; 36: 2366-2377
        • Diefenhardt M.
        • Ludmir E.B.
        • Hofheinz R.-D.
        • Ghadimi M.
        • Minsky B.D.
        • Rödel C.
        • et al.
        Association of treatment adherence with oncologic outcomes for patients with rectal cancer: a post hoc analysis of the CAO/ARO/AIO-04 phase 3 randomized clinical trial.
        JAMA Oncol. 2020; 6: 1416-1421
        • Glynne-Jones R.
        • Meadows H.M.
        • Lopes A.
        • Muirhead R.
        • Sebag-Montefiore D.
        • Adams R.
        • et al.
        Impact of compliance to chemoradiation on long-term outcomes in squamous cell carcinoma of the anus: results of a post hoc analysis from the randomised phase III ACT II trial.
        Ann Oncol. 2020; 31: 1376-1385
        • Schäfer R.
        • Strnad V.
        • Polgár C.
        • Uter W.
        • Hildebrandt G.
        • Ott O.J.
        • et al.
        Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breast-conserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial.
        Lancet Oncol. 2018; 19: 834-844
        • McCormick B.
        • Winter K.A.
        • Woodward W.
        • Kuerer H.M.
        • Sneige N.
        • Rakovitch E.
        • et al.
        Randomized phase III trial evaluating radiation following surgical excision for good-risk ductal carcinoma in situ: long-term report from NRG oncology/RTOG 9804.
        J Clin Oncol. 2021; 39: 3574-3582
        • Klopp A.H.
        • Yeung A.R.
        • Deshmukh S.
        • Gil K.M.
        • Wenzel L.
        • Westin S.N.
        • et al.
        Patient-reported toxicity during pelvic intensity-modulated radiation therapy: NRG oncology-RTOG 1203.
        J Clin Oncol. 2018; 36: 2538-2544
        • Yeung A.R.
        • Pugh S.L.
        • Klopp A.H.
        • Gil K.M.
        • Wenzel L.
        • Westin S.N.
        • et al.
        Improvement in patient-reported outcomes with intensity-modulated radiotherapy (RT) compared with standard RT: a report from the NRG oncology RTOG 1203 study.
        J Clin Oncol. 2020; 38: 1685-1692
        • Chopra S.
        • Gupta S.
        • Kannan S.
        • Dora T.
        • Engineer R.
        • Mangaj A.
        • et al.
        Late toxicity after adjuvant conventional radiation versus image-guided intensity-modulated radiotherapy for cervical cancer (PARCER): a randomized controlled trial.
        J Clin Oncol. 2021; : JCO2002530
        • Rodríguez de Dios N.
        • Couñago F.
        • Murcia-Mejía M.
        • Rico-Oses M.
        • Calvo-Crespo P.
        • Samper P.
        • et al.
        Randomized phase III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small-cell lung cancer (PREMER): a GICOR-GOECP-SEOR study.
        J Clin Oncol. 2021; 39: 3118-3127
        • Brown P.D.
        • Gondi V.
        • Pugh S.
        • Tome W.A.
        • Wefel J.S.
        • Armstrong T.S.
        • et al.
        Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: phase III trial NRG oncology CC001.
        J Clin Oncol. 2020; 38: 1019-1029
        • Belderbos J.S.A.
        • De Ruysscher D.K.M.
        • De Jaeger K.
        • Koppe F.
        • Lambrecht M.L.F.
        • Lievens Y.N.
        • et al.
        Phase 3 randomized trial of prophylactic cranial irradiation with or without hippocampus avoidance in SCLC (NCT01780675).
        J Thorac Oncol. 2021; 16: 840-849
        • Kayama T.
        • Sato S.
        • Sakurada K.
        • Mizusawa J.
        • Nishikawa R.
        • Narita Y.
        • et al.
        Effects of surgery with salvage stereotactic radiosurgery versus surgery with whole-brain radiation therapy in patients with one to four brain metastases (JCOG0504): a phase III, noninferiority, randomized controlled trial.
        J Clin Oncol. 2018; 2018786186
        • Poortmans P.M.
        • Weltens C.
        • Fortpied C.
        • Kirkove C.
        • Peignaux-Casasnovas K.
        • Budach V.
        • et al.
        Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
        Lancet Oncol. 2020; 21: 1602-1610
        • Lin S.H.
        • Hobbs B.P.
        • Verma V.
        • Tidwell R.S.
        • Smith G.L.
        • Lei X.
        • et al.
        Randomized phase IIB trial of proton beam therapy versus intensity-modulated radiation therapy for locally advanced esophageal cancer.
        J Clin Oncol. 2020; 38: 1569-1579
        • Liao Z.
        • Lee J.J.
        • Komaki R.
        • Gomez D.R.
        • O'Reilly M.S.
        • Fossella F.V.
        • et al.
        Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer.
        J Clin Oncol. 2018; 36: 1813-1822
        • Nguyen Q.-N.
        • Chun S.G.
        • Chow E.
        • Komaki R.
        • Liao Z.
        • Zacharia R.
        • et al.
        Single-fraction stereotactic vs conventional multifraction radiotherapy for pain relief in patients with predominantly nonspine bone metastases: a randomized phase 2 trial.
        JAMA Oncol. 2019; 5: 872-878
        • Sahgal A.
        • Myrehaug S.D.
        • Siva S.
        • Masucci L.
        • Foote M.C.
        • Brundage M.
        • et al.
        CCTG SC.24/TROG 17.06: a randomized phase II/III study comparing 24Gy in 2 stereotactic body radiotherapy (SBRT) fractions versus 20Gy in 5 conventional palliative radiotherapy (CRT) fractions for patients with painful spinal metastases.
        Int J Radiat Oncol Biol Phys. 2020; 108: 1397-1398
        • Shumway D.A.
        • Motomura A.
        • Griffith K.A.
        • Hayman J.A.
        • Pierce L.J.
        • Jagsi R.
        Patient perceptions in a nonblinded randomized trial of radiation therapy technologies: a novel survey study exploring therapeutic misconception.
        Int J Radiat Oncol Biol Phys. 2020; 108: 867-875
        • Jaccard M.
        • Zilli T.
        • Dubouloz A.
        • Escude L.
        • Jorcano S.
        • Linthout N.
        • et al.
        Urethra-sparing stereotactic body radiation therapy for prostate cancer: quality assurance of a randomized phase 2 trial.
        Int J Radiat Oncol Biol Phys. 2020; 108: 1047-1054
        • Giraud P.
        • Racadot S.
        • Vernerey D.
        • Goldstein D.
        • Glimelius B.
        • Van Houtte P.
        • et al.
        Investigation of relation of radiation therapy quality with toxicity and survival in LAP07 phase 3 trial for locally advanced pancreatic carcinoma.
        Int J Radiat Oncol Biol Phys. 2021; 110: 993-1002
        • Cho W.K.
        • Kim H.
        • Park W.
        • Kim S.-W.
        • Kim J.
        • Lee K.K.
        • et al.
        A dummy-run evaluation of postoperative hypofractionated intensity-modulated radiation therapy (POHIM-RT) trials for cervical cancer.
        J Radiat Res. 2021; 62: 149-154
        • Giaddui T.
        • Geng H.
        • Chen Q.
        • Linnemann N.
        • Radden M.
        • Lee N.Y.
        • et al.
        Offline quality assurance for intensity modulated radiation therapy treatment plans for NRG-HN001 head and neck clinical trial using knowledge-based planning.
        Adv Radiat Oncol. 2020; 5: 1342-1349
        • Hildebrandt G.
        • Stachs A.
        • Gerber B.
        • Potenberg J.
        • Krug D.
        • Wolter K.
        • et al.
        Central review of radiation therapy planning among patients with breast-conserving surgery: results from a quality assurance process integrated into the INSEMA trial.
        Int J Radiat Oncol Biol Phys. 2020; 107: 683-693
        • Khalladi N.
        • Dejean C.
        • Bosset M.
        • Pointreau Y.
        • Kinj R.
        • Racadot S.
        • et al.
        A priori quality assurance using a benchmark case of the randomized phase 2 GORTEC 2014-14 in oligometastatic head and neck cancer patients.
        Cancer Radiother. 2021; 25: 755-762