Hypoxia imaging and radiotherapy: bridging the resolution gap

Abstract

Oxygen distribution is a major determinant of treatment success in radiotherapy, with well-oxygenated tumour regions responding by up to a factor of three relative to anoxic volumes. Conversely, tumour hypoxia is associated with treatment resistance and negative prognosis. Tumour oxygenation is highly heterogeneous and difficult to measure directly. The recent advent of functional hypoxia imaging modalities such as fluorine-18 fluoromisonidazole positron emission tomography have shown promise in non-invasively determining regions of low oxygen tension. This raises the prospect of selectively increasing dose to hypoxic subvolumes, a concept known as dose painting. Yet while this is a promising approach, oxygen-mediated radioresistance is inherently a multiscale problem, and there are still a number of substantial challenges that must be overcome if hypoxia dose painting is to be successfully implemented. Current imaging modalities are limited by the physics of such systems to have resolutions in the millimetre regime, whereas oxygen distribution varies over a micron scale, and treatment delivery is typically modulated on a centimetre scale. In this review, we examine the mechanistic basis and implications of the radiobiological oxygen effect, the factors influencing microscopic heterogeneity in tumour oxygenation and the consequent challenges in the interpretation of clinical hypoxia imaging (in particular fluorine-18 fluoromisonidazole positron emission tomography). We also discuss dose-painting approaches and outline challenges that must be addressed to improve this treatment paradigm.

Figure 1.

Oxygen-mediated treatment resistance as a multiscale problem.

Figure 2.

A typical oxygen enhancement ratio (OER) curve, saturating at p > 20 mmHg.

Figure 3.

Oxygen fixation hypothesis: a high-energy electron created by an X-ray photon (e⁻) impinges on a water molecule, liberating a proton (p⁺) and creating a hydroxyl radical (OH˙). This reactive molecule then impacts on deoxyribonucleic acid (DNA˙), resulting in ionization damage, DNA. This can be readily repaired to its original state (DNA-H), but in the presence of molecular oxygen, a peroxy radical is formed (DNA-OO˙), fixing damage into a permanent irreparable state. Taken from Grimes and Partridge with permission from Institute of Physics (IOP).

Figure 4.

A DLD1 tumour spheroid, with external boundary marked in red. The oxygen-limited anoxic core (blue outline) is also shown. Green staining is the ki-67 proliferation marker and red is the hypoxia marker EF5. Adapted from Grimes et al with permission from Royal Society Interface.

Figure 5.

Illustration of the non-linear binding relationship for fluoromisonidazole (FMISO) as function of PO₂. The points show experimental data from Rasey et al, and the line shows a hyperbolic functional form fitted to autoradiographic data from tumour spheroids. (a) Logarithmic axis; (b) linear axis at low PO₂.

Figure 6.

A simulated mean oxygen and fluoromisonidazole (FMISO) uptake in 4-mm voxels (a–f) using a two-dimensional vessel map with varying vascularity, calculated by the methods described in Warren and Partridge. Red points indicate simulated blood vessel positions. Voxels (e) and (f) are predicted to show very similar binding, despite a large difference in PO₂, due to the extent of necrosis in voxel (e).

Figure 7.

(a) A simulated microscopic oxygen distribution in a 5-cm diameter spherical tumour; inset: heterogeneity within the region with size equivalent to a positron emission tomography voxel (map and histogram, dashed line represents mean). (b) A simulated fluoromisonidazole (FMISO) distributions for a spherical tumour under different assumptions (see text: Discussion and Conclusions, paragraph 3 for details). (c) Planned volumetric modulated arc therapy treatment. (d) An example line profile of planned dose through the gross tumour volume, plotted against prescription (green: vascularized rim; red: boost to hypoxic core).