L'objectif général du travail de cette thèse est de proposer des méthodes robustes pour permettre d’obtenir des critères sur l’évolution de la pathologie tumorale à partir d’études dynamiques. Actuellement, l’appréciation de l’efficacité d’un traitement antiangiogénique (destruction des vaisseaux alimentant la tumeur) repose principalement sur l’imagerie fonctionnelle dont l’objectif est de quantifier la microcirculation tumorale à partir d’acquisitions dynamiques de perfusion. Cependant, différentes limites concernant le suivi de la réponse précoce des lésions par imagerie existent (mauvaise maîtrise des mouvements respiratoires, pas de consensus sur les paramètres permettant de quantifier la microcirculation tumorale, estimation paramétrique faite à partir de données extrêmement bruitées et pour un grand nombre de zones - une estimation par voxel de la séquence dynamique d’images). Dans un contexte clinique extrêmement contraignant, nous avons mis en place un cadre rigoureux comprenant l’ensemble des étapes nécessaires pour une caractérisation plus fiable de la microcirculation tumorale à partir de séquences d’images acquises sous perfusion de produit de contraste : les contributions principales de cette thèse couvrent ainsi l’optimisation des paramètres de reconstruction, le développement d’une méthode de recalage adaptée à nos données, la sélection argumentée d’un modèle de perfusion et enfin le développement d’une méthode robuste d’estimation des paramètres. Ces travaux permettent d’envisager l’utilisation des modèles de perfusion pour la caractérisation et la prédiction de la réponse d’un patient à différents traitements antitumoraux. / The main objective is to propose robust methods to allow estimation of functional markers reflecting the tumor evolution from dynamic studies. Currently, in this domain, assessing of the efficiency evaluation of an anti-angiogenic therapy (destruction of vessels which feed the tumor) is mainly based on the functional imaging of the microcirculation, which the objective is to quantify the tumor microcirculation by dynamic acquisitions with injection of contrast product. However, several limitations are present (lack of control of the breathing movement, no consensus on the parameters permitting the quantification of tumor microcirculation, parameter estimation computed from noisy data and a large number of regions - one estimation by voxel or group of voxel of the dynamic image sequence). In a restrictive clinical context (noisy data, few number), we have developed a complete pipeline with a set of necessary steps to a reliable characterization of the tumor microcirculation from dynamic perfusion image sequence: the main contributions of this thesis cover the reconstruction parameters optimization, the development of a registration method, the argued selection of a perfusion model and the development of a robust method of parameter estimation. With these works, we can envision the utilization of these perfusion models to the characterization and the prediction of the therapy response of a patient

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<b>Background:</b> Systemic chemotherapy and radiotherapy play an important role in the treatment of colorectal cancer. Tumour perfusion and oxygenation is known to influence radiosensitivity and chemosensitivity. In this thesis, I propose that the evaluation of changes in tumour perfusion using perfusion CT (pCT) and dynamic contrast-enhanced (Dce) MRI can guide the rational sequencing of drugs and radiation. <b>Methods:</b> Dce-MRI and pCT scans were incorporated into a clinical trial of hypofractionated pelvic radiotherapy and nelfinavir in 10 patients with rectal cancer. Toxicity and tissue biomarkers (tumour cell density, microvessel density, CAIX, HIF1-alpha, phospho-Akt and phospho-PRAS40) were evaluated. pCT liver scans were incorporated into an imaging study in patients with colorectal liver metastases randomised to receive either oxaliplatin/ 5FU chemotherapy or oxaliplatin/ 5FU chemotherapy plus selective internal radiotherapy. <b>Results:</b> After 7 days of nelfinavir concurrent with hypo-fractionated pelvic radiotherapy, there was a mean 42&percnt; increase in median K^trans (P=0.03, paired t test) on Dce-MRI and a median 30&percnt; increase in mean blood flow on pCT (P=0.028, Wilcoxon Rank Sum), although no statistically significant changes in perfusion parameters were demonstrated after 7 days of nelfinavir prior to radiotherapy. The feasibility of evaluating tumour cell density in rectal biopsies before and after radiotherapy and a radiosensitising drug as an early endpoint of response was demonstrated. In patients with colorectal liver metastases who received oxaliplatin and modified de Gramont chemotherapy alone, after 4 cycles of chemotherapy, a 28&percnt; decrease in the mean hepatic arterial fraction was observed (P=0.018, paired t test). Between pCT scans 2 days before SIRT and 39-47 days following SIRT and continued 2-weekly chemotherapy, there was a mean 62&percnt; (P=0.009) reduction in Blood Flow and 61&percnt; (P=0.006) reduction in Blood Volume (paired t test). <b>Conclusions</b> This research does not support the hypothesis that nelfinavir before radiotherapy improves blood flow to human rectal cancer. Increases in rectal tumour perfusion during radiotherapy and concurrent nelfinavir are likely to be primarily explained by the acute biological effects of radiation. Four or more cycles of oxaliplatin and modified de Gramont chemotherapy may result in changes in tumour perfusion of colorectal liver metastases which would be detrimental to subsequent radiotherapy. Selective internal radiotherapy resulted in substantial reductions in tumour perfusion 39-47 days after the treatment. Perfusion imaging can be used to detect changes in tumour perfusion in response to radiotherapy and systemic therapy which have implications for the sequencing of therapies.

Applying mathematical models to dynamic contrast enhanced MRI (DCE MRI) data to perform quantitative tracer kinetic analysis enables the estimation of tissue characteristics such as vascular permeability and the fractional volume of plasma in a tissue. However, it is unclear to what extent modeling assumptions, particularly regarding water exchange between tissue compartments, impacts parameter estimates derived from clinical DCE MRI data. In this work, a new model is developed which includes water exchange effects, termed the water exchange modified two compartment exchange model (WX-2CXM). Two boundaries of this model (the fast and no exchange limits) were used to analyse a clinical DCE MRI bladder cancer dataset. Comparisons with DCE CT, which is not affected by water exchange, suggested that water exchange may have affected estimates of vp, the fractional volume of plasma. Further investigation and simulations led to the development of a DCE MRI protocol which was sensitised to water exchange, in order to further evaluate the water exchange effects found in the bladder cancer dataset. This protocol was tested by imaging the parotid glands in eight healthy volunteers, and confirmed evidence of water exchange effects on vp, as well as flow Fp and the fractional volume of extravascular extracellular space ve. This protocol also enabled preliminary estimates of the water residence times in parotid tissue, however, these estimates had a large variability and require further validation. The work presented in this thesis suggests that, although water exchange effects do not have a large effect on clinical data, the effect is measurable, and may lead to the ability to estimate of tissue water residence times. Results do not support a change in the current practise of neglecting water exchange effects in clinical DCEMRI acquisitions.