Imaging tumour hypoxia with positron emission tomography

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Abstract

Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers.

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Hydroxylation of HIF-1: oxygen sensing at the molecular level.

Gregg L. Semenza (2004)

The ability to sense and respond to changes in oxygenation represents a fundamental property of all metazoan cells. The discovery of the transcription factor HIF-1 has led to the identification of protein hydroxylation as a mechanism by which changes in PO2 are transduced to effect changes in gene expression.

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Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response.

Peter Vaupel, Louis Benjamin Harrison (2004)

Hypoxia is a characteristic feature of locally advanced solid tumors resulting from an imbalance between oxygen (O(2)) supply and consumption. Major causative factors of tumor hypoxia are abnormal structure and function of the microvessels supplying the tumor, increased diffusion distances between the nutritive blood vessels and the tumor cells, and reduced O(2) transport capacity of the blood due to the presence of disease- or treatment-related anemia. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of radiotherapy, some O(2)-dependent cytotoxic agents, and photodynamic therapy. Tumor hypoxia can also negatively impact therapeutic outcome by inducing changes in the proteome and genome of neoplastic cells that further survival and malignant progression by enabling the cells to overcome nutritive deprivation or to escape their hostile environment. The selection and clonal expansion of these favorably altered cells further aggravate tumor hypoxia and support a vicious circle of increasing hypoxia and malignant progression while concurrently promoting the development of more treatment-resistant disease. This pattern of malignant progression, coupled with the demonstration of a relationship between falling hemoglobin level and worsening tumor oxygenation, highlights the need for effective treatment of anemia as one approach for correcting anemic hypoxia in tumors, and in so doing, possibly improving therapeutic response.

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Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis.

Jens Overgaard (2011)

The importance of tumour hypoxia for the outcome of radiotherapy has been under investigation for decades. Numerous clinical trials modifying the hypoxic radioresistance in squamous cell carcinoma of the head and neck (HNSCC) have been conducted, but most have been inconclusive, partly due to a small number of patients in the individual trial. The present meta-analysis was, therefore, performed utilising the results from all clinical trials addressing the specific question of hypoxic modification in HNSCC undergoing curative intended primary radiotherapy alone. A systematic review of published and unpublished data identified 4805 patients with HNSCC treated in 32 randomized clinical trials, applying, normobaric oxygen or carbogen breathing (5 trials); hyperbaric oxygen (HBO) (9 trials); hypoxic radiosensitizers (17 trials) and HBO and radiosensitizer (1 trial). The trials were analysed with regard to the following endpoints: loco-regional control (32 trials), disease specific survival (30 trials), overall survival (29 trials), distant metastases (12 trials) and complications to radiotherapy (23 trials). Overall hypoxic modification of radiotherapy in head and neck cancer did result in a significant improved therapeutic benefit. This was most dominantly observed when using the direct endpoint of loco-regional control with an odds ratio (OR) of 0.71, 95% cf.l. 0.63-0.80; p<0.001), but this was almost mirrored in the disease specific survival (OR: 0.73, 95% cf.l. 0.64-0.82; p<0.001), and to a lesser extent in the overall survival (OR: 0.87, 95% cf.l. 0.77-0.98; p=0.03). The risk of distant metastases was not significantly influenced although it appears to be less in the tumours treated with hypoxic modification (OR: 0.87, 95% cf.l. 0.69-1.09; p=0.22), whereas the radiation related late complications were not influenced by the overall use of hypoxic modifications (OR: 1.00, 95% cf.l. 0.82-1.23; p=0.96). The improvement in loco-regional control was found to be independent of the type of hypoxic modification. The trials have used different fractionation schedules, including large doses per fraction, which may result in relatively more hypoxia and greater benefit. However, analysis of HNSCC trials using conventional fractionation only, showed that the significant effect of hypoxic modification was maintained. The meta-analysis thus demonstrates that there is level 1a evidence in favour of adding hypoxic modification to radiotherapy of squamous cell carcinomas of the head and neck. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Print): 20 January 2015

Publication date (Electronic): 16 December 2014

Volume: 112

Issue: 2

Pages: 238-250

Affiliations

[1 ]Aberdeen Biomedical Imaging Centre , Lilian Sutton Building, Foresterhill, Aberdeen AB25 2ZD, UK

[2 ]Department of Radiology, School of Clinical Medicine, University of Cambridge , Box 218-Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK

[3 ]Division of Imaging Sciences and Biomedical Engineering, St Thomas' Hospital, King's College London , 4th Floor, Lambeth Wing, London SE1 7EH, UK

[4 ]Manchester Academic Health Science Centre, Institute of Cancer Sciences, University of Manchester , Wilmslow Road, Manchester M20 4BX, UK

[5 ]Manchester Pharmacy School, Faculty of Medical and Human Sciences, University Manchester , Stopford Building, Oxford Road, Manchester M13 9PT, UK

[6 ]EPSRC and CRUK Cancer Imaging Centre in Cambridge and Manchester , Cambridge, UK

[7 ]Molecular Oncology Laboratories, University Department of Medical Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital , Headington, Oxford OX3 9DS, UK

[8 ]Centre for Cardiovascular and Metabolic Research, Respiratory Medicine, Hull-York Medical School, University of Hull , Hull HU16 5JQ, UK

Author notes

[* ]E-mail: fjg28@ 123456medschl.cam.ac.uk

Article

Publisher Item ID: bjc2014610

DOI: 10.1038/bjc.2014.610

PMC ID: 4453462

PubMed ID: 25514380

SO-VID: d5c56cfc-bb22-4c0d-adac-40b647f5c85f

License:

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

History

Date received : 18 August 2014

Date revision received : 30 September 2014

Date accepted : 10 November 2014

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Most cited references 79

Hydroxylation of HIF-1: oxygen sensing at the molecular level.

Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response.

Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis.

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