**5.2.1 Dynamic Contrast Enhanced MRI**

DCE-MRI consists in the acquisition of serial MR images before, during, and after the administration of an intravenous contrast agent (CA) to produce time series images that enable pixel-by-pixel analysis of contrast kinetics within a tumor. Pharmacokinetic models provide a means of summarizing contrast enhancement data in terms of parameters that relate to the underlying vascular anatomy and physiology. As described by Tofts et al. (1999), the essential features of a variety of models are covered by the generalized kinetic model. Most methods of analyzing dynamic contrast-enhanced T1-weighted data acquired with low molecular contrast medium use a compartmental analysis to obtain some combination of the three principal parameters: the transfer constant Ktrans in min-1 (volume transfer constant between blood plasma and ESS), the rate constant Kep in min-1 (rate constant between blood plasma and extravascular extracellular space [ESS]) and the volume of ESS per unit volume of tissue space, Vp (no unit). DCE-MRI has evolved from an

Targeting Tumor Perfusion and Oxygenation Modulates

**7. Acknowledgements** 

**8. References** 

email: pierre.sonveaux@uclouvain.be.

No.18, pp. 2941-2943.

8366-8371.

Hypoxia and Cancer Sensitivity to Radiotherapy and Systemic Therapies 303

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.

Works at the authors' labs are supported by grants from the European Research Council (FP7/2007-2013 ERC Independent Researcher Starting Grant 243188 TUMETABO to P.S.), the Belgian *Fonds National de la Recherche Scientifique* (F.R.S.-FNRS), the *Communauté Française de Belgique* (ARC 09/14-020), the *Fondation Belge Contre le Cancer* (200-2008), the *Fonds Joseph Maisin*, the Saint-Luc Foundation, and the *Pôle d'Attraction Interuniversitaire* PAI VI (P6/38). B.F.J. and P.S. are F.R.S.-FNRS Research Associates. For any correspondence contact P.S.;

Ang, KK. (2010). More lessons learned from the suffocation of hypoxia. *J Clin Oncol.*, Vol.28,

Angelo, M.; Singel, D.J. & Stamler, J.S. (2006). An S-nitrosothiol (SNO) synthase function of

Ansiaux, R.; Baudelet, C.; Jordan, BF.; Beghein, N.; Sonveaux, P.; De Wever, J.; Martinive, P.;

hemoglobin that utilizes nitrite as a substrate. *P Natl Acad Sci USA,* Vol.103, pp.

Gregoire, V.; Feron, O. & Gallez, B. (2005). Thalidomide radiosensitizes tumors

experimental technique to a clinically feasible adjunct procedure that can be integrated into a standard morphologic imaging protocol. It does provide unique non-invasive functional information on the properties of tumors related to microcirculation (distribution volume, permeability, and perfusion). This information can improve diagnostic characterization, the follow-up of therapy, and tumor staging; and it provides tools to facilitate advanced molecular imaging. Preclinical and clinical studies suggest that a successful antivascular treatment results in a decrease in the rate of enhancement along with a decreased amplitude and a slower washout, and that poor response can result in persistent abnormal enhancement (Gillies et al., 2002).

#### **5.2.2 Positron emission tomography**

Generally, PET measures of tumor perfusion have used (15O)-labeled radiotracers. The socalled steady state method requires inhalation of 15O-CO2 and the dynamic method requires an intravenous bolus injection of 15O-H2O (Jennings et al., 2008). A requirement for quantification of perfusion using dynamic methods is an accurate determination of an arterial input function, which can be obtained non-invasively in a purely arterial region of interest, such as the aorta.

#### **5.2.3 Computed tomography**

In X-ray CT, the tissue contrast is based on variable attenuation coefficients of the object absorbing the X-rays. Hemodynamic parameters may be extracted from dynamic changes in X-ray attenuation caused by the intravenous injection of an iodinated contrast agent. Perfusion CT data can deliver quantitative hemodynamic information, such as blood volume, blood flow, permeability surface-area product and mean transit time (MTT) (Jennings et al., 2008).

#### **5.2.4 Doppler ulstrasound**

There are several different ultrasonic approaches designed specifically to measure blood flow including transit time, continuous-wave Doppler, pulsed and color Doppler, and power Doppler flowmeters, requiring the use of microbubbles (filled with air, perfluorocarbon, sulfur hexafluoride or nitrogen), which expand and contract because of pressure from the acoustical transmit pulse, and the primary mode of echogenicity is the impedance mismatch between the microbubble–blood interface, making them significantly more echogenic than normal tissue. Typical parameters that are estimated using Doppler ultrasound include: percent intratumor contrast agent uptake, enhancement timing and pattern, percent blood volume fraction, red blood cell velocity, and perfusion; depending on the type of study and tracer used (Jennings et al., 2008).
