**6. Conclusions**

Heterogeneities in blood flow and oxygenation are key characteristics of solid tumors and constitute a therapeutic challenge when these tumors are treated with radiotherapy or systemic therapies. Because oxygen stabilizes DNA lesions, tumors become increasingly resistant to radiotherapy and to several forms of chemotherapy when the tumor pO2 decreases below a threshold of 10 mmHg. In the past decades, basic and preclinical researches have identified several adjuvant treatments aimed at transiently increasing tumor oxygenation at the time of radiotherapy. Their identification was based on an increasing understanding of the origins of tumor hypoxia, which logically opened two main avenues: co-treatments designed to (1) improve the oxygen supply from blood vessels at the time of radiotherapy (with different strategies such as increasing the O2 content of blood, inducing tumor-specific vasodilation, or normalizing vascular structures), and (2) reduce the rate of O2 consumption by tumor cells through metabolic interventions. Theoretical models now validated preclinically have revealed that the metabolic strategy has the highest impact on tumor radiosensitivity, but the best opportunity still resides in treatments combining both vascular and metabolic effects, as perfectly illustrated with hyperthermia. Most systemic anticancer treatments are also confronted to the difficulty to reach a target often located at distance from blood vessels, thus indicating that in this case increased tumor perfusion (i.e., decreased resistance to flow) could improve tumor bioavailability. NO-donors, ET-1 inhibitors, radiotherapy or heat as adjuvant provascular treatments, or anti-angiogenic therapies and chemotherapy used in a 'vascular normalization' mode, have all demonstrated their capacity to chemosensitize tumors in preclinical settings. Most of the adjuvant treatments described here could theoretically be exploited therapeutically by the off-label use of existing FDA-approved drugs, but it has also become evident that a given tumor in a given patient would respond differently than the tumor of the patient next-door. It is therefore urgent to develop and implement in the clinics imaging techniques able not only to provide predictive markers but also biological markers of the response to such combinational interventions. The MR and PET techniques that we reviewed here are among the most-sensitive non-invasive techniques having proved their highly valuable power as to measure changes in tumor perfusion and oxygenation preclinically. Current challenges include the FDA approval of exogenous tracers and sensors when needed, scaling-up tools initially dedicated for small laboratory animals and adapting imaging protocols to the clinical situation, the transfer to the clinics of the expertise needed for protocol design and data interpretation and, as importantly, a careful consideration of societal cost issues.
