Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans

Abstract

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R(2)* pixel maps were produced for each tumour and at each time point and changes in R(2)* induced by carbogen were determined. There was a mean reduction in R(2)* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R(2)* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R(2)* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients.

Figure 1

Baseline values and the effect of carbogen gas breathing on the median R₂^* value of individual DU145 xenografts (left panel) and PC3 xenografts (right panel). Each line represents an individual tumour. Lines with filled black circles represent tumours with a change in R₂^* that was statistically significant at the 95% confidence level and not simply a result of natural test variability. There was a mean reduction in R₂^* of 3.52 s⁻¹ or 6.4% (P=0.003) for the DU145 tumours and 3.04 s⁻¹ or 5.8% (P=0.007) for the PC3 tumours.

Figure 2

The temporal effect of carbogen breathing on the oxygenation of the 23 DU145 xenografts (left panel) and 17 PC3 xenografts (right panel). R₂^* values fall rapidly after the commencement of carbogen breathing (arrow), as tumour oxygen levels increase. In both DU145 and PC3 tumours, R₂^* values seem to begin a return towards their baseline reading before the carbogen exposure was terminated (dotted arrow).

Figure 3

The effect of carbogen gas breathing on the median R₂^* value of 14 individual human prostate cancers (age=56–76 years, Gleason grade=6–8, PSA 1.9–32.0 ng ml⁻¹). Each line represents an individual tumour; lines with filled black circles represent tumours with a change in R₂^* that was statistically significant at the 95% confidence level, and not simply a result of natural test variability. There was a mean reduction in R₂^* of 3.52 s⁻¹ or 21.6% (P=0.0005).