Hypoxia Image Guided Radiation Therapy: Current Status and Major Challenges

Review Article

Austin J Nucl Med Radiother. 2016; 3(1): 1014.

Hypoxia Image Guided Radiation Therapy: Current Status and Major Challenges

Hong Yuan1,2*, Zibo Li1,2 and Sha Chang³

¹Department of Radiology, University of North Carolina at Chapel Hill, USA

²Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, USA

³Department of Radiation Oncology, University of North Carolina at Chapel Hill, USA

*Corresponding author: Hong Yuan, Department of Radiology, Campus box #7513, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

Received: January 20, 2016; Accepted: February 01, 2016; Published: February 03, 2016


Tumor hypoxia is a major factor contributing to treatment resistance and local recurrence in radiotherapy. Over the years hypoxia has become a target of modulation to improve tumor control in radiotherapy, including hyperbaric oxygenation, hypoxic radiosensitizers, and in recent years, Hypoxia Image Guided Radiotherapy (HIGRT).The HIGRT is one of the biologic image guided radiotherapy methods aiming to delivering higher radiation dose to hypoxic sub-volumes to overcome hypoxia-induced radio resistance. The concept of delivering higher radiation dose to hypoxic tumor tissue became possible reality only after major developments on the non-invasive imaging on hypoxia, especially the PET imaging with hypoxia probes. Several radiation therapy treatment planning studies have been carried out with modulated radiation dose based on hypoxia PET images. However there are several practical challenges to implement the procedure in real clinical condition due to imaging limitation, physiological variation, and limitations on radiation delivery. The article reviews the current status on clinical and preclinical research on HIGRT and major challenges to be addressed in the future development.

Keywords: Hypoxia imaging; Image guided radiotherapy; Dose escalation


HIGRT: Hypoxia Image Guided Radiotherapy; PET: Positron Emission Tomography; MRI: Magnetic Resonance Imaging; IMRT: Image Modulated Radiotherapy; IGRT: Image Guided Radiotherapy; TCP: Tissue Control Probability; OAR: Organ At Risk; DPBN: Dose Painting By Number; GTV: Gross Tumor Volume; HTV: Hypoxia Tumor Volume; HNSCC: Head And Neck Squamous Cell Carcinoma; SUV: Standardized Uptake Value; FMISO: 18F-Fluoromisonidazole; FAZA: 18F-Fluoroazomycin Arabinofuranoside, FETNIM: 18F-Fluoroerythronitroimidazole, EF5: 18F-[2-(2-nitro-1[H]-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl)-acetamide], HX4: 18F-flortanidazole, Cu-ATSM: Cu-diacetyl-bis(N4-methylthiosemicarbazone); FLT: 3-deoxy-3- [18F]-fluorothymidine; DCE MRI: Dynamic Contrast Enhanced Magnetic Resonance Imaging.


Cancer radiotherapy today largely relies on CT and MRI images to delineate tumor volume and critical structures for treatment planning in order to attempt the optimal balance between tumor control and normal tissue sparing. However, loco regional recurrence remains to be a major obstacle for the treatment of many advanced malignant tumors [1,2]. One contributing factor of local recurrence is tumor hypoxia [1,3]. Hypoxia (low oxygenation) is a characteristic feature in most malignant tumors. Direct measurement using Eppendorf oxygen probe resulted oxygen potential less than 10mmHg with great heterogeneity within tumor in many different type of cancers including lung cancer, cervical cancer, head and neck cancer, etc. [4-6]. Tumor hypoxia has been shown to be closely related with the resistance to radiotherapy and the subsequent tumor recurrence after radiotherapy [7-9]. Over the years hypoxia has become a target of modulation in research to improve tumor control in radiotherapy using methods including hyperbaric oxygenenation [10], hypoxic radiosensitizers [11,12], and in recent years, hypoxia image guided radiotherapy (HIGRT) [13-16]. HIGRT is a biologic image modulated radiotherapy based on functional imaging of tissue hypoxia rather than anatomical structure imaging alone as commonly used in radiation therapy today.

Conventional anatomical imaging based radiotherapy delivers the same radiation dose to all regions of the tumor volume regardless of their radio sensitivities, potentially leaving hypoxia-induced radio resistant cancer cells surviving the radiation. Recent development of hypoxia imaging technique has made the development of HIGRT, especially the rapid development on hypoxia PET imaging which provides spatial distribution and magnitude of tissue oxygenation non-invasively. With hypoxia imaging, HIGRT can utilize hypoxia information to spatially modulate the radiation dose distribution so that higher radiation dose is delivered to hypoxic tumor cells without compromising normal tissue sparing. The goal of HIGRT is to overcome the hypoxia-induced radio resistance, thus enhance radiation therapeutic ratio [17,18].

The first attempt of introducing hypoxia image in radiation planning started about 15 years ago [19]. Chao et al first conducted a feasibility radiation planning study with the guidance from hypoxia PET imaging with 60Cu-ATSM. The study demonstrated that radiation dose can be escalated in the hypoxia sub-volume defined by the 60Cu-ATSM hypoxia images without increased dose on normal tissue. More treatment planning studies have been published since then, however there have been no reports on actual delivery of HIGRT on clinical patients yet. This article will review the current research status both on preclinical and clinical level, and discuss major challenges the HIGRT field faces today.

Current Status

There are two major trends on the HIGRT approaches. One is to define the hypoxic volume by segmenting a volume based on threshold criteria on hypoxia images and deliver a uniform boosting dose to the hypoxia sub-volume [17,19-21]. Another approach is so called Dose Painting by Numbers ((DPBN) Figure 1). The idea of hypoxia DPBN is to use the spatial distribution of hypoxia provided by the PET image directly and apply spatially variant doses according to the degree of the hypoxia, i.e. higher dose in hypoxic foci and lower dose in well oxygenated tissue [22-24]. Both approaches are still under early stage of radiation planning studies, and theoretical simulation studies have been conducted to predict and evaluate the treatment outcomes from HIGRT.