Hypoxia imaging with PET: which tracers and why? Kazumi Chia a , Ian N. Fleming b and Philip J. Blower a Nuclear Medicine Communications 2012, 33:217–222 a King’s College London, Division of Imaging Sciences and Biomedical Engineering, St Thomas’ Hospital, London and b Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK Correspondence to Dr Kazumi Chia, MBBS, King’s College London, Division of Imaging Sciences and Biomedical Engineering Rayne Institute, St Thomas’ Hospital, London SE1 7EH, UK Tel: + 44 20 718 88366; fax: + 44 20 718 85442; e-mail: kazumi.chia@kcl.ac.uk Received 21 October 2011 Revised 15 November 2011 Accepted 29 October 2011 Introduction As efficient energy production through the respiratory chain in oxidative phosphorylation depends on maintain- ing O 2 concentrations within a narrow range [1], it is not surprising that reduced oxygen concentration (hypoxia) plays a key role in many human pathological processes such as ischaemic heart disease, stroke, pulmonary hypertension, inflammation and cancer [2–5]. Noninva- sive methods to map oxygen deficiency in tumours and the whole body have been extensively sought and PET has been prominent in this endeavour. The purpose of this editorial is to identify key questions that need to be discussed or researched further to enable PET imaging of hypoxia to be widely adopted in the clinic for the benefit of cancer patients. Hypoxia and oncology The anatomical basis of hypoxia in solid tumours was first described in 1955 [6] but the link between low oxygen concentration and radioresistance was known since 1923 [7]. Tumour hypoxia may be categorized as acute or chronic. Chronic hypoxia is experienced by cells located beyond the diffusion distance of O 2 (150 mm) from capillaries [8], whereas acute hypoxia is caused by fluctuations in blood flow through the abnormal capil- laries such that even cells adjacent to the capillary may become hypoxic for a time ranging from minutes, hours and even days [9]. Scores of studies have demonstrated hypoxia to be a feature of many solid tumours [10]. According to the ‘oxygen fixation hypothesis’, cellular damage by ionizing radiation is mediated by free radicals produced either directly in the target DNA or indirectly by free radicals created by ionization of water mole- cules [5]. In the presence of oxygen, the DNA free radical reacts to form an organic peroxide radical (DNA-OO K ), a nonrestorable form of DNA damage. Thus, oxygen is said to ‘fix’ the DNA damage caused by ionizing radiation. In the absence of oxygen, the DNA radical can be reduced and thereby undergo repair. Critical cellular oxygen concentration thresholds at which radiation sensitivity is reduced are well established. The action of certain chemotherapeutic agents is also oxygen dependent but the critical oxygen thresholds for some of these drugs have yet to be determined [11]. The discovery of hypoxia-inducible factor 1, a key transcription factor in hypoxia, showed how the impact of hypoxia in oncology reaches beyond treatment resistance to influence meta- bolic pathways, angiogenesis, metastatic potential, DNA replication and protein synthesis [5]. Role of hypoxia measurement in tumours There is no established routine clinical role for hypoxia measurement in cancer at present. However, in light of knowledge of the role of hypoxia in both cancer progression and treatment resistance, a noninvasive method of locating and quantifying tumour hypoxia is expected to be a clinically valuable tool in oncology. An important role of hypoxia imaging is to increase our basic understanding of cancer biology and the role that hypoxia plays in tumour progression, metastasis and resistance to treatment. Although hypoxia is not the only determinant of response to radiotherapy [12], through hypoxia imaging, we may be able to identify the relative contribution that hypoxia makes towards radiotherapy treatment failures. Recent reports indicating that a hypoxic microenvironment is crucial for the maintenance and function of cancer stem cells [13] further emphasize the importance of being able to map and target tumour hypoxia. Clinically, one can conceive several settings in which hypoxia mapping and measurement might lead to improved patient management, especially around radio- therapy. At the simplest level, the ability to predict which tumours will respond to radiotherapy, on the basis of an index of hypoxia, would inform the risk–benefit analysis associated with decisions about radiotherapy. The ability to map hypoxia within a tumour may inform radiotherapy planning so that doses to tumour regions could be tuned to relate to hypoxia distribution. Radiotherapy has witnessed significant technical advances recently, en- abling the delivery of geometrically conformed radiation doses to tumours. Moreover, new technologies such as intensity-modulated radiation therapy allow very precise doses of radiation to be delivered to different parts of the tumour (dose painting). Now that we are able to geometrically conform the radiation, the logical step is to do so on the basis of regional ‘sensitivity maps’ considering, among other factors, hypoxia [14]. Editorial 0143-3636  c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MNM.0b013e32834eacb7 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.