Steffen Löck1, Rosalind Perrin2, Annekatrin Seidlitz3, Anna Bandurska-Luque3, Sebastian Zschaeck3, Klaus Zöphel4, Mechthild Krause5, Jörg Steinbach6, Jörg Kotzerke4, Daniel Zips7, Esther G C Troost8, Michael Baumann5. 1. OncoRay - National Center for Radiation Research in Oncology, Biostatistics and Modeling in Radiation Oncology Group, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, Germany. 2. OncoRay - National Center for Radiation Research in Oncology, Biostatistics and Modeling in Radiation Oncology Group, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Center for Proton Therapy, Paul Scherrer Institute, Switzerland. 3. OncoRay - National Center for Radiation Research in Oncology, Biostatistics and Modeling in Radiation Oncology Group, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. 4. Department of Nuclear Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; National Center for Tumor Diseases, partner site Dresden, Germany. 5. OncoRay - National Center for Radiation Research in Oncology, Biostatistics and Modeling in Radiation Oncology Group, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, Germany; National Center for Tumor Diseases, partner site Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology - OncoRay, Germany; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. 6. National Center for Tumor Diseases, partner site Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Germany. 7. Department of Radiation Oncology, Eberhard Karls Universität Tübingen, Germany; German Cancer Consortium (DKTK), partner site Tübingen, Germany. 8. OncoRay - National Center for Radiation Research in Oncology, Biostatistics and Modeling in Radiation Oncology Group, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, Germany; National Center for Tumor Diseases, partner site Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology - OncoRay, Germany. Electronic address: esther.troost@uniklinikum-dresden.de.
Abstract
BACKGROUND: Hypoxia is a well recognised parameter of tumour resistance to radiotherapy, a number of anticancer drugs and potentially immunotherapy. In a previously published exploration cohort of 25 head and neck squamous cell carcinoma (HNSCC) patients on [18F]fluoromisonidazole positron emission tomography (FMISO-PET) we identified residual tumour hypoxia during radiochemotherapy, not before start of treatment, as the driving mechanism of hypoxia-mediated therapy resistance. Several quantitative FMISO-PET parameters were identified as potential prognostic biomarkers. Here we present the results of the prospective validation cohort, and the overall results of the study. METHODS: FMISO-PET/CT images of further 25 HNSCC patients were acquired at four time-points before and during radiochemotherapy (RCHT). Peak standardised uptake value, tumour-to-background ratio, and hypoxic volume were analysed. The impact of the potential prognostic parameters on loco-regional tumour control (LRC) was validated by the concordance index (ci) using univariable and multivariable Cox models based on the exploration cohort. Log-rank tests were employed to compare the endpoint between risk groups. RESULTS: The two cohorts differed significantly in several baseline parameters, e.g., tumour volume, hypoxic volume, HPV status, and intercurrent death. Validation was successful for several FMISO-PET parameters and showed the highest performance (ci=0.77-0.81) after weeks 1 and 2 of treatment. Cut-off values for the FMISO-PET parameters could be validated after week 2 of RCHT. Median values for the residual hypoxic volume, defined as the ratio of the hypoxic volume in week 2 of RCHT and at baseline, stratified patients into groups of significantly different LRC when applied to the respective other cohort. CONCLUSION: Our study validates that residual tumour hypoxia during radiochemotherapy is a major driver of therapy resistance of HNSCC, and that hypoxia after the second week of treatment measured by FMISO-PET may serve as biomarker for selection of patients at high risk of loco-regional recurrence after state-of-the art radiochemotherapy.
BACKGROUND:Hypoxia is a well recognised parameter of tumour resistance to radiotherapy, a number of anticancer drugs and potentially immunotherapy. In a previously published exploration cohort of 25 head and neck squamous cell carcinoma (HNSCC) patients on [18F]fluoromisonidazole positron emission tomography (FMISO-PET) we identified residual tumour hypoxia during radiochemotherapy, not before start of treatment, as the driving mechanism of hypoxia-mediated therapy resistance. Several quantitative FMISO-PET parameters were identified as potential prognostic biomarkers. Here we present the results of the prospective validation cohort, and the overall results of the study. METHODS: FMISO-PET/CT images of further 25 HNSCCpatients were acquired at four time-points before and during radiochemotherapy (RCHT). Peak standardised uptake value, tumour-to-background ratio, and hypoxic volume were analysed. The impact of the potential prognostic parameters on loco-regional tumour control (LRC) was validated by the concordance index (ci) using univariable and multivariable Cox models based on the exploration cohort. Log-rank tests were employed to compare the endpoint between risk groups. RESULTS: The two cohorts differed significantly in several baseline parameters, e.g., tumour volume, hypoxic volume, HPV status, and intercurrent death. Validation was successful for several FMISO-PET parameters and showed the highest performance (ci=0.77-0.81) after weeks 1 and 2 of treatment. Cut-off values for the FMISO-PET parameters could be validated after week 2 of RCHT. Median values for the residual hypoxic volume, defined as the ratio of the hypoxic volume in week 2 of RCHT and at baseline, stratified patients into groups of significantly different LRC when applied to the respective other cohort. CONCLUSION: Our study validates that residual tumour hypoxia during radiochemotherapy is a major driver of therapy resistance of HNSCC, and that hypoxia after the second week of treatment measured by FMISO-PET may serve as biomarker for selection of patients at high risk of loco-regional recurrence after state-of-the art radiochemotherapy.
Authors: Eva-Leonne Göttgens; Christian Ostheimer; Paul N Span; Jan Bussink; Ester M Hammond Journal: Br J Radiol Date: 2018-03-14 Impact factor: 3.039
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Authors: A Sörensen; M Carles; H Bunea; L Majerus; C Stoykow; N H Nicolay; N E Wiedenmann; P Vaupel; P T Meyer; A L Grosu; M Mix Journal: Eur J Nucl Med Mol Imaging Date: 2019-11-26 Impact factor: 9.236
Authors: Constantin Lapa; Ursula Nestle; Nathalie L Albert; Christian Baues; Ambros Beer; Andreas Buck; Volker Budach; Rebecca Bütof; Stephanie E Combs; Thorsten Derlin; Matthias Eiber; Wolfgang P Fendler; Christian Furth; Cihan Gani; Eleni Gkika; Anca-L Grosu; Christoph Henkenberens; Harun Ilhan; Steffen Löck; Simone Marnitz-Schulze; Matthias Miederer; Michael Mix; Nils H Nicolay; Maximilian Niyazi; Christoph Pöttgen; Claus M Rödel; Imke Schatka; Sarah M Schwarzenboeck; Andrei S Todica; Wolfgang Weber; Simone Wegen; Thomas Wiegel; Constantinos Zamboglou; Daniel Zips; Klaus Zöphel; Sebastian Zschaeck; Daniela Thorwarth; Esther G C Troost Journal: Strahlenther Onkol Date: 2021-07-14 Impact factor: 3.621