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Research ArticleOncology

Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer: Results from a Prospective Imaging Trial

Nils H. Nicolay, Alexander Rühle, Nicole Wiedenmann, Gabriele Niedermann, Michael Mix, Wolfgang A. Weber, Dimos Baltas, Martin Werner, Gian Kayser and Anca-L. Grosu
Journal of Nuclear Medicine April 2021, 62 (4) 471-478; DOI: https://doi.org/10.2967/jnumed.120.248633
Nils H. Nicolay
1Department of Radiation Oncology, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
2German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany
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Alexander Rühle
1Department of Radiation Oncology, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
2German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany
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Nicole Wiedenmann
1Department of Radiation Oncology, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
2German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany
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Gabriele Niedermann
1Department of Radiation Oncology, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
2German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany
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Michael Mix
3Department of Nuclear Medicine, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
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Wolfgang A. Weber
4Department of Nuclear Medicine, Technical University of Munich, Munich, Germany; and
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Dimos Baltas
1Department of Radiation Oncology, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
2German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany
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Martin Werner
2German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany
5Institute of Surgical Pathology, Department of Pathology, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
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Gian Kayser
2German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany
5Institute of Surgical Pathology, Department of Pathology, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
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Anca-L. Grosu
1Department of Radiation Oncology, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, Freiburg, Germany
2German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany
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Abstract

Tumor hypoxia in head-and-neck squamous cell carcinoma (HNSCC) leads to an immunosuppressive microenvironment and reduces the response to radiotherapy. In this prospective imaging trial, we investigated potential interactions between functional hypoxia imaging and infiltrating lymphocyte levels as a potential predictor for treatment response in HNSCC patients. Methods: In total, 49 patients receiving definitive chemoradiation for locally advanced HNSCCs underwent pretherapeutic biopsies and peritherapeutic hypoxia imaging using 18F-misonidazole PET at weeks 0, 2, and 5 during chemoradiation. Hematoxylin–eosin and immunohistochemical stainings for tumor-infiltrating lymphocytes, tissue-based hypoxia, and microvascular markers were analyzed and correlated with the longitudinal hypoxia dynamics and patient outcomes. Results: High levels of tumor-infiltrating total lymphocytes correlated with superior locoregional control (LRC) (hazard ratio [HR], 0.279; P = 0.011) and progression-free survival (PFS) (HR, 0.276; P = 0.006). Similarly, early resolution of 18F-misonidazole PET–detected tumor hypoxia quantified by 18F-misonidazole dynamics between weeks 0 and 2 of chemoradiation was associated with improved LRC (HR, 0.321; P = 0.015) and PFS (HR, 0.402; P = 0.043). Outcomes in the favorable early hypoxia resolution subgroup significantly depended on infiltrating lymphocyte counts, with patients who showed both an early hypoxia response and high lymphocyte infiltration levels exhibiting significantly improved LRC (HR, 0.259; P = 0.036) and PFS (HR, 0.242; P = 0.017) compared with patients with an early hypoxia response but low lymphocyte counts. These patients exhibited oncologic results comparable to those of patients with no hypoxia response within the first 2 wk of chemoradiation. Conclusion: This analysis established a clinical hypoxia-immune score that predicted treatment responses and outcomes in HNSCC patients undergoing chemoradiation and may help to devise novel concepts for biology-driven personalization of chemoradiation.

  • head-and-neck cancer
  • hypoxia
  • FMISO PET
  • chemoradiation
  • immune system

Footnotes

  • Published online Aug. 28, 2020.

  • © 2021 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 62 (4)
Journal of Nuclear Medicine
Vol. 62, Issue 4
April 1, 2021
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Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer: Results from a Prospective Imaging Trial
Nils H. Nicolay, Alexander Rühle, Nicole Wiedenmann, Gabriele Niedermann, Michael Mix, Wolfgang A. Weber, Dimos Baltas, Martin Werner, Gian Kayser, Anca-L. Grosu
Journal of Nuclear Medicine Apr 2021, 62 (4) 471-478; DOI: 10.2967/jnumed.120.248633

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Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer: Results from a Prospective Imaging Trial
Nils H. Nicolay, Alexander Rühle, Nicole Wiedenmann, Gabriele Niedermann, Michael Mix, Wolfgang A. Weber, Dimos Baltas, Martin Werner, Gian Kayser, Anca-L. Grosu
Journal of Nuclear Medicine Apr 2021, 62 (4) 471-478; DOI: 10.2967/jnumed.120.248633
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Keywords

  • head-and-neck cancer
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  • FMISO PET
  • chemoradiation
  • Immune system
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