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Background: Tumour hypoxia is associated with increased radioresistance and poor response to radiotherapy. Pre-treatment assessment of tumour oxygenation could therefore give the possibility to tailor the treatment by calculating the required boost dose needed to overcome the increased radioresistance in hypoxic tumours. This study concerned the derivation of a non-linear conversion function between the uptake of the hypoxia-PET tracer F-18-HX4 and oxygen partial pressure (pO(2)).Material and methods: Building on previous experience with FMISO including experimental data on tracer uptake and pO(2), tracer-specific model parameters were derived for converting the normalised HX4-uptake at the optimal imaging time point to pO(2). The conversion function was implemented in a Python-based computational platform utilising the scripting and the registration modules of the treatment planning system RayStation. Subsequently, the conversion function was applied to determine the pO(2) in eight non-small-cell lung cancer (NSCLC) patients imaged with HX4-PET before the start of radiotherapy. Automatic segmentation of hypoxic target volumes (HTVs) was then performed using thresholds around 10mmHg. The HTVs were compared to sub-volumes segmented based on a tumour-to-blood ratio (TBR) of 1.4 using the aortic arch as the reference oxygenated region. The boost dose required to achieve 95% local control was then calculated based on the calibrated levels of hypoxia, assuming inter-fraction reoxygenation due to changes in acute hypoxia but no overall improvement of the oxygenation status.Results: Using the developed conversion tool, HTVs could be obtained using pO(2) a threshold of 10mmHg which were in agreement with the TBR segmentation. The dose levels required to the HTVs to achieve local control were feasible, being around 70-80Gy in 24 fractions.Conclusions: Non-linear conversion of tracer uptake to pO(2) in NSCLC imaged with HX4-PET allows a quantitative determination of the dose-boost needed to achieve a high probability of local control.

Hyperthermic isolated limb perfusion (ILP) with recombinant tumour necrosis factor alpha (TNF) and melphalan contributes to limb-saving treatment in patients with locally advanced extremity soft tissue sarcoma (STS). This study was conducted to evaluate the dynamic changes of tumour oxygenation and temperature during ILP and their effects on treatment response.Tumour oxygenation (pO(2)) and tumour temperature were measured by intratumourally placed O(2)-sensitive catheter electrodes in 34 patients who underwent ILP for locally advanced or recurrent STS. Tumour response to ILP was assessed by the fraction of tumour necrosis in the resection specimen.Mean tumour pO(2) prior to application of TNF and melphalan was 36 mm Hg (range: 2-116 mm Hg) and dropped significantly to 13 mm Hg (range: 0-67 mm Hg, p = 0.03) during ILP. Mean tumour tissue temperature increased from 34.4°C (range 32.4-36.4) to 38.5°C (range 34.1-40.4, p = 0.0001). The mean fraction of necrosis in the resection specimen was 65% (range 5-99). Only the tumour tissue temperature at the onset of ILP correlated with the extent of tumour necrosis (p = 0.01).ILP with TNF and melphalan induces severe oxygen deprivation in soft tissue sarcoma. However, changes in tumour oxygenation did not correlate with treatment response.

The purpose of this study was to evaluate the feasibility of polarographic oxygen electrode measurements and phosphorus magnetic resonance spectroscopy (31P-MRS) in extravisceral soft tissue tumours, designated to receive preoperative radiotherapy. Pretreatment tumour oxygenation was determined in 41 cases and 31P-MRS was amenable to lesions in 34 patients. Biopsies were characterized histopathologically as 25 primary soft tissue sarcomas (STS), 2 recurrent STS, 9 benign and 5 other malignancies. Evaluation of phosphorus (31P) spectra was possible in 11 cases. The oxygenation status of normal tissue was higher than that of tumours, whereas no difference was found between oxygenation status of benign lesions and that of STS. There was substantial variation between tumours in the median pO2 and the bioenergetic status (beta-NTP/Pi). No correlation was found between tumour pO2 and volume (n = 25). Moreover, there was no correlation between beta-NTP/Pi and the median tumour pO2, the fraction of pO2 valuesor =2.5 mmHg or tumour volume (n = 10), respectively. In conclusion, oxygen electrode assessment was found to be a clinically applicable and feasible technique for measuring tumour oxygenation status, whereas the success of 31P-MRS in human neoplasms was limited by a very poor resolution in the phosphorus signal that allowed analysis of 31P spectra in 11 tumours out of 34 cases.

The oxygenation status of C3H mammary carcinomas, grown in the feet of CDF1 mice, was measured with an Eppendorf oxygen electrode. Tumours were locally heated in a water bath at temperatures of 38.5-41.5°C for 1 h. Measurements made during heating showed temperature-dependent increases in tumour oxygenation. However, measurements performed after heating showed a rapid return to normal oxygenation status. Mild hyperthermia thus improves tumour oxygenation and this can explain the radiosensitization seen with low heat treatments, but only when the heat and radiation are administered concurrently, which is typically not the way that are given clinically.

Tumour oxygenation and bioenergetic status were measured in the same tumour and these results related to radiobiological hypoxia. A C3H mouse mammary carcinoma grown in the feet of CDF1 mice was used. Bioenergetic status was assessed by 31P MRS using a SISCO 7 Tesla magnet, oxygen measurements were done by a polarographic electrode and the hypoxic fraction was determined from direct analysis of the radiation dose-response data. During all examinations restrained, non-anaesthetized mice were allowed to breathe either 100% oxygen, carbogen, normal air, carbon monoxide (CO) at 75, 220, or 660 ppm or had blood flow occluded by clamping. Results showed a significant correlation between the radiobiological hypoxic fraction and % pO2

The relationship between tumour tissue oxygenation and necrosis at different tumour sizes was investigated in a C3H mammary carcinoma implanted in the feet of female CDF1 mice. Experiments were performed using tumours that ranged in size from 80 to 800 mm3. Necrosis was estimated histologically. Tumour tissue oxygenation (pO2) was estimated with an Eppendorf electrode. Our results showed that as tumour volume increased there was a corresponding increase in necrotic fraction ranging from 1% in small tumours up to 51% in large tumours. The percentage of pO2 valuesor = 5 mmHg increased from 2% up to 79%, in small and large tumours respectively. After correcting for necrosis, the apparent, significant increase in the % of pO2 valuesor = 5 mmHg was lost. We conclude that correcting for necrotic fraction in this tumour model is necessary when attempting to measure tumour oxygenation using electrodes.