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Correlative analyses between tissue-based hypoxia biomarkers and hypoxia PET imaging in head and neck cancer patients during radiochemotherapy—results from a prospective trial

European Journal of Nuclear Medicine and Molecular Imaging volume 47, pages 1046–1055 (2020)Cite this article

Abstract

Purpose

Tumor hypoxia impairs the response of head-and-neck cancer (HNSCC) patients to radiotherapy and can be detected both by tissue biomarkers and PET imaging. However, the value of hypoxia biomarkers and imaging for predicting HNSCC patient outcomes are incompletely understood, and potential correlations between tissue and PET data remain to be elucidated. Here, we performed exploratory analyses of potential correlations between tissue-based hypoxia biomarkers and longitudinal hypoxia imaging in a prospective trial of HNSCC patients.

Methods

Forty-nine patients undergoing chemoradiation for locally advanced HNSCCs were enrolled in this prospective trial. They underwent baseline biopsies and [18F]FDG PET imaging and [18F]FMISO PET at weeks 0, 2, and 5 during treatment. Immunohistochemical analyses for p16, Ki67, CD34, HIF1α, CAIX, Ku80, and CD44 were performed, and HPV status was assessed. Biomarker expression was correlated with biological imaging information and patient outcome data.

Results

High HIF1α tumor levels significantly correlated with increased tumor hypoxia at week 2 as assessed by the difference in the [18F]FMISO tumor-to-background ratios, and high HIF1α and CAIX expressions were both associated with a deferred decrease in hypoxia between weeks 2 and 5. Loco-regional recurrence rates after radiotherapy were significantly higher in patients with high CAIX expression and also increased for high levels of the DNA repair factor Ku80. HPV status did not correlate with any of the tested hypoxia biomarkers, and HPV-positive patients showed higher loco-regional control rates and progression-free survival independent of their hypoxia dynamics.

Conclusion

In this exploratory trial, high expression of the tissue-based hypoxia biomarkers HIF1α and CAIX correlated with adverse hypoxia dynamics in HNSCCs during chemoradiation as assessed by PET imaging, and high CAIX levels were associated with increased loco-regional recurrence rates. Hence, hypoxia biomarkers warrant further investigations as potential predictors of hypoxia dynamics and hypoxia-associated radiation resistance.

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Acknowledgments

We acknowledge Dr. Andrej Bunea, Dr. Hatice Bunea, and Dr. Raluca Stoian for their help with patient recruitment.

Author information

Affiliations

  1. Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany

    Nils H. Nicolay, Nicole Wiedenmann & Anca L. Grosu

  2. German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Nils H. Nicolay, Nicole Wiedenmann, Martin Werner, Anca L. Grosu & Gian Kayser

  3. Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Michael Mix

  4. Department of Nuclear Medicine, Technical University of Munich, Munich, Germany

    Wolfgang A. Weber

  5. Institute of Surgical Pathology, Department of Pathology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Martin Werner & Gian Kayser

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  1. Nils H. Nicolay
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  2. Nicole Wiedenmann
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Correspondence to Nils H. Nicolay.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Independent Ethics Committee of the University of Freiburg, reference no. 479/12) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Nils Nicolay and Nicole Wiedenmann contributed equally to this work. Anca Grosu and Gian Kayser share the senior authorship.

This article is part of the Topical Collection on Oncology – Head and Neck

Electronic supplementary material

Supplementary figure 1:
figure 5

HPV and p16-positive HNSCC patients demonstrate improved loco-regional control rates after chemoradiation. Kaplan-Meier curves demonstrating LRC rates for HPV-positive and negative patients (A) and p16-positive and negative patients (B). P values are derived from logrank test. (PNG 225 kb)

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Supplementary figure 2:
figure 6

HPV-positive HNSCC patients demonstrate improved overall and progression-free survival rates after chemoradiation. Kaplan-Meier curves demonstrating OS and PFS rates for HPV-positive and negative patients. P values are derived from logrank test. (PNG 274 kb)

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Supplementary figure 3:
figure 7

Loco-regional control does not correlate with proliferative and stem cell markers in HNSCC patients. (A) Kaplan-Meier curve showing the LRC rate for the whole cohort. (B) LRC rates for intermediate (G2) and high-grade (G3) HNSCCs. (C) LRC rates for low and high expression of the proliferative marker Ki67. (D) LRC rates for low and high expression of the cancer stem cell marker CD44. P values are derived from logrank test. (PNG 360 kb)

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Supplementary figure 4:
figure 8

Representative images demonstrating the differential dynamics of tumor and hypoxic subvolumes during the course of chemoradiation. Time course of tumor volumes (red contours) and hypoxic tumor subvolumes (purple contours) from week 0 to 5 for a representative patient with early (week 0 to 2, upper panel) or delayed (week 2 to 5, lower panel) resolution of tumor hypoxia. (PNG 626 kb)

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Supplementary figure 5:
figure 9

SUV index values for individual patients. [18F]FMISO SUV index at weeks 0 (blue bars), 2 (red bars) and 5 (green bars) for each patient enrolled in this trial. (PNG 232 kb)

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Supplementary table 1:

Antibodies and protocol specifications used for immunohistochemical analyses (PDF 181 kb)

Supplementary Table 2:

Correlations between tissue-based biomarkers and [18F]FMISO PET imaging parameters. R and p values are derived from Pearson correlation coefficient. *p < 0.05 (PDF 276 kb)

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Nicolay, N.H., Wiedenmann, N., Mix, M. et al. Correlative analyses between tissue-based hypoxia biomarkers and hypoxia PET imaging in head and neck cancer patients during radiochemotherapy—results from a prospective trial. Eur J Nucl Med Mol Imaging 47, 1046–1055 (2020). https://doi.org/10.1007/s00259-019-04598-9

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  • DOI: https://doi.org/10.1007/s00259-019-04598-9

Keywords

  • Head and neck cancer
  • Hypoxia
  • FMISO
  • Carbonic anhydrase 9
  • Radiotherapy
  • Chemoradiation