Surrogate MR markers of response to chemo‐ or radiotherapy in association with co‐treatments: a retrospective analysis of multi‐modal studies

Abstract

The study of magnetic resonance (MR) markers over the past decade has provided evidence that the tumor microenvironnement and hemodynamics play a major role in determining tumor response to therapy. The aim of the present work is to predict and monitor the efficacy of co-treatments to radio- and chemotherapy by noninvasive MR imaging. Ten different co-treatments were involved in this retrospective analysis of our previously published data, including NO-mediated co-treatments (insulin and isosorbide dinitrate), anti-inflammatory drugs (hydrocortisone, NS-398), anti-angiogenic agents (thalidomide, SU5416 and ZD6474), a vasoactive agent (xanthinol nicotinate), botulinum toxin and carbogen breathing. Dynamic contrast enhanced (DCE) MRI, intrinsic susceptibility-weighted (BOLD) MRI and electronic paramagnetic resonance (EPR) oximetry all reflect tumor microenvironment hemodynamic variables that are known to influence tumor response. Eight MR-derived parameters (markers) were tested for their ability to predict therapeutic outcome (factor of increase in regrowth delay) in experimental tumor models (TLT and FSaII) after radiation therapy and/or chemotherapy with cyclophosphamide, namely tumor pO₂ and O₂ consumption rate (using EPR oximetry); tumor blood flow and permeability, i.e. V(p), K(trans), K(ep) and percentage of perfused vessels (using DCE-MRI); and BOLD signal intensity and R₂* (using functional MRI). This multi-modal comparison of co-treatment efficacy points out the limitations of each MR marker and identifies in vivo pO₂ as a relevant endpoint for radiation therapy. DCE parameters (V(p) and K(ep)) were identified as a relevant endpoints for cyclophosphamide chemotherapy in our tumor models. This study helps qualify relevant imaging endpoints in the preclinical setting of cancer therapy.

Assessing Tumor Oxygenation for Predicting Outcome in Radiation Oncology: A Review of Studies Correlating Tumor Hypoxic Status and Outcome in the Preclinical and Clinical Settings

“…Furthermore, skewness in the distribution of the k trans parameter was also correlated with poorer patient outcome, highlighting the heterogeneity of perfusion within these tumors (80). Conversely, a study on fibrosarcoma was not able to show any correlation between DCE-related parameters ( k trans , v p , K ep , % of perfused voxels) and the outcome of radiation therapy (81). With respect to validation of the technique with other oximetric methods, attempts have been made in preliminary clinical studies to assess correlations between the level of hypoxia and permeability, with mixed results, in head and neck cancer and gliomas using pimonidazole staining (an immunohistological staining aimed at detecting tumor hypoxia) and in cervical cancer using polarographic electrodes (82–84).…”

“…However, these measurements are restricted to surface tissues: in vivo EPR is performed with “L-band” spectrometers, operating at 1 GHz or less, allowing the penetration of microwaves up to a 10-mm maximum depth into the tissue (127). Although EPR spectrometry provides no anatomical information on tumor hypoxia, it has been successfully used in several tumor models to monitor changes in oxygenation levels induced by an increase in oxygen delivery (128–136), or by an inhibition of tumor consumption (76, 81, 137–143), or both (69, 144–149). As a quantitative technique, EPR oximetry is also predictive of tumor response to radiotherapy and can also be applied to monitor tumor reoxygenation after the administration of a radiosensitizer in order to determine the best therapeutic window in which radiotherapy should be performed (81).…”

Qualification of a Noninvasive Magnetic Resonance Imaging Biomarker to Assess Tumor Oxygenation

“…Hypoxic challenges were performed by the injection of the antivascular agent CA4, described to induce a vascular shutdown as early as 3 hours after the administration of the drug (36), whereas hypoxic challenges were induced by a carbogen breathing (95%O 2 /5%CO 2 ) known to acutely increase tumor oxygenation in a wide range of tumor models/xenografts and in human tumors (36)(37)(38)(39)(40)31). Oxygenation was assessed in matching tumors (the same tumors underwent both EPR and MRI experiments) using EPR oximetry as a method of reference for the quantitative assessment of the tumor pO 2 .…”

Diffusion MRI and Novel Texture Analysis in Osteosarcoma Xenotransplants Predicts Response to Anti-Checkpoint Therapy

“…An appealing alternative MRI technique is diffusion-weighted MRI (DWI), which generally has a lower test-retest variance[15]. DWI provides information about the extent and direction of restricted water motion.…”