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Published Online: 11 September 2014

The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

Publication: Antioxidants & Redox Signaling
Volume 21, Issue Number 10

Abstract

Tumor hypoxia is a well-established biological phenomenon that affects the curability of solid tumors, regardless of treatment modality. Especially for head and neck cancer patients, tumor hypoxia is linked to poor patient outcomes. Given the biological problems associated with tumor hypoxia, the goal for clinicians has been to identify moderately to severely hypoxic tumors for differential treatment strategies. The “gold standard” for detecting and characterizing of tumor hypoxia are the invasive polarographic electrodes. Several less invasive hypoxia assessment techniques have also shown promise for hypoxia assessment. The widespread incorporation of hypoxia information in clinical tumor assessment is severely impeded by several factors, including regulatory hurdles and unclear correlation with potential treatment decisions. There is now an acute need for approved diagnostic technologies for determining the hypoxia status of cancer lesions, as it would enable clinical development of personalized, hypoxia-based therapies, which will ultimately improve outcomes. A number of different techniques for assessing tumor hypoxia have evolved to replace polarographic pO2 measurements for assessing tumor hypoxia. Several of these modalities, either individually or in combination with other imaging techniques, provide functional and physiological information of tumor hypoxia that can significantly improve the course of treatment. The assessment of tumor hypoxia will be valuable to radiation oncologists, surgeons, and biotechnology and pharmaceutical companies who are engaged in developing hypoxia-based therapies or treatment strategies. Antioxid. Redox Signal. 21, 1516–1554.

Abstract

I. Introduction
II. The Clinical Importance of Tumor Hypoxia
A. Pathophysiology of hypoxia
B. Hypoxia's negative impact on the effectiveness of curative treatment
1. Hypoxic tumors accumulate and propagate cancer stem cells
2. Hypoxia reduces the effectiveness of radiotherapy
3. Hypoxia increases metastasis risk and reduces the effectiveness of surgery
4. Hypoxic tumors are resistant to the effects of chemotherapy and chemoradiation
C. Hypoxia is prognostic for poor patient outcomes
III. Diagnosis of Tumor Hypoxia
A. Direct methods
1. Oxygen electrode—direct pO2 measurement most used in cancer research
2. Phosphorescence quenching—alternative direct pO2 measurement
3. Electron paramagnetic resonance
4. 19F-magnetic resonance spectroscopy
5. Overhauser-enhanced MRI
B. Endogenous markers of hypoxia
1. Hypoxia-inducible factor-1α
2. Carbonic anhydrase IX
3. Glucose transporter 1
4. Osteopontin
5. A combined IHC panel of protein markers for hypoxia
6. Comet assay
C. Physiologic methods
1. Near-infrared spectroscopy/tomography—widely used for pulse oximetry
2. Photoacoustic tomography
3. Contrast-enhanced color duplex sonography
4. MRI-based measurements
5. Blood oxygen level-dependent MRI
6. Pimonidazole
7. EF5 (pentafluorinated etanidazole)
8. Hypoxia PET imaging—physiologic hypoxia measurement providing tomographic information
a. 18F-fluoromisonidazole
b. 18F-fluoroazomycinarabinofuranoside
c. 18F-EF5 (pentafluorinated etanidazole)
d. 18F-flortanidazole
e. Copper (II) (diacetyl-bis (N4-methylthiosemicarbazone))
f. 18F-FDG imaging of hypoxia
IV. Modifying Hypoxia to Improve Therapeutic Outcomes
A. Use of hypoxia information in radiation therapy planning
B. Use of hypoxia assessment for selection of patients responsive to nimorazole
C. Use of hypoxia assessment for selection of patients responsive to tirapazamine
D. Use of hypoxia assessment for selection of patients responsive to oxygen delivery therapies
V. Concluding Remarks

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cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 21Issue Number 10October 1, 2014
Pages: 1516 - 1554
PubMed: 24512032

History

Published in print: October 1, 2014
Published online: 11 September 2014
Published ahead of print: 9 May 2014
Published ahead of production: 10 February 2014
Accepted: 8 February 2014
Revision received: 30 January 2014
Received: 16 April 2013

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Joseph C. Walsh
Siemens Molecular Imaging, Inc., Culver City, California.
Artem Lebedev
Siemens Molecular Imaging, Inc., Culver City, California.
Edward Aten
Certus International, Inc., Bedford, New Hampshire.
Kathleen Madsen
Certus International, Inc., Chesterfield, Missouri.
Liane Marciano
Certus International, Inc., Bedford, New Hampshire.
Hartmuth C. Kolb
Siemens Molecular Imaging, Inc., Culver City, California.

Notes

Reviewing Editors: Claudine Kieda, Periannan Kuppusamy, Ken-Ichiro Matsumoto, Suzanne Monte, Des Richardson, Matteo A. Russo, Gregg Semenza, Chandan K. Sen, Jolanta Tarasuik, Michel Toledano, Laura Vera-Ramirez
Address correspondence to:Dr. Hartmuth C. KolbSiemens Molecular Imaging, Inc.6140 Bristol ParkwayCulver City, CA 90230E-mail: [email protected]

Author Disclosure Statement

Joseph C. Walsh is an employee of Siemens MI, a company that developed PET biomarkers for imaging hypoxia. Artem Lebedev and Hartmuth C. Kolb are former employees of Siemens MI. Kathleen Madsen is a consultant statistician to Siemens Molecular Imaging, with compensation based on fair market value and not tied to outcomes. Edward Aten is acting as Interim Medical Director to Siemens Molecular Imaging, with compensation based on fair market value and not tied to outcomes. Liane Marciano is a consultant to Siemens Molecular Imaging, with compensation based on fair market value and not tied to outcomes.

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