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Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging

  • Author Footnotes
    1 Shared first authorship.
    Steffen Löck
    Footnotes
    1 Shared first authorship.
    Affiliations
    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
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  • Author Footnotes
    1 Shared first authorship.
    Rosalind Perrin
    Footnotes
    1 Shared first authorship.
    Affiliations
    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
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  • Annekatrin Seidlitz
    Affiliations
    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
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  • Anna Bandurska-Luque
    Affiliations
    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
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  • Author Footnotes
    3 Current address: Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.
    Sebastian Zschaeck
    Footnotes
    3 Current address: Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.
    Affiliations
    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
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  • Klaus Zöphel
    Affiliations
    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
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  • Mechthild Krause
    Affiliations
    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
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  • Jörg Steinbach
    Affiliations
    National Center for Tumor Diseases, partner site Dresden, Germany

    Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Germany
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  • Jörg Kotzerke
    Affiliations
    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
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  • Daniel Zips
    Affiliations
    Department of Radiation Oncology, Eberhard Karls Universität Tübingen, Germany

    German Cancer Consortium (DKTK), partner site Tübingen, Germany
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  • Author Footnotes
    2 Shared last authorship.
    Esther G.C. Troost
    Correspondence
    Corresponding author at: OncoRay – National Center for Radiation Research in Oncology, Fetscherstrasse 74, 01307 Dresden, Germany.
    Footnotes
    2 Shared last authorship.
    Affiliations
    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
    Search for articles by this author
  • Author Footnotes
    2 Shared last authorship.
    Michael Baumann
    Footnotes
    2 Shared last authorship.
    Affiliations
    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
    Search for articles by this author
  • Author Footnotes
    1 Shared first authorship.
    2 Shared last authorship.
    3 Current address: Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.

      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.

      Keywords

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