BackgroundRobust approaches to quantify tumor heterogeneity are needed to provide early decision support for precise individualized therapy. PurposeTo conduct a technical exploration of longitudinal changes in tumor heterogeneity patterns on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) and FDG positron emission tomography / computed tomography (PET/CT), and their association to radiation therapy (RT) response in cervical cancer. Study TypeProspective observational study with longitudinal MRI and PET/CT pre-RT, early-RT (2 weeks), and mid-RT (5 weeks). PopulationTwenty-one FIGO IB2-IVA cervical cancer patients receiving definitive external beam RT and brachytherapy. Field Strength/Sequence1.5T, precontrast axial T-1-weighted, axial and sagittal T-2-weighted, sagittal DWI (multi-b values), sagittal DCE MRI (<10 sec temporal resolution), postcontrast axial T-1-weighted. AssessmentResponse assessment 1 month after completion of treatment by a board-certified radiation oncologist from manually delineated tumor volume changes. Statistical TestsIntensity histogram (IH) quantiles (DCE SI10% and DWI ADC(10%), FDG-PET SUVmax) and distribution moments (mean, variance, skewness, kurtosis) were extracted. Differences in IH features between timepoints and modalities were evaluated by Skillings-Mack tests with Holm's correction. Area under receiver-operating characteristic curve (AUC) and Mann-Whitney testing was performed to discriminate treatment response using IH features. ResultsTumor IH means and quantiles varied significantly during RT (SUVmean: 28-47%, SUVmax: 30-59%, SImean: 8-30%, SI10%: 8-19%, ADC(mean): 16%, P < 0.02 for each). Among IH heterogeneity features, FDG-PET SUVCoV (16-30%, P=0.011) and DW-MRI ADC(skewness) decreased (P=0.001). FDG-PET SUVCoV was higher than DCE-MRI SICoV and DW-MRI ADC(CoV) at baseline (P < 0.001) and 2 weeks (P=0.010). FDG-PET SUVkurtosis was lower than DCE-MRI SIkurtosis and DW-MRI ADC(kurtosis) at baseline (P=0.001). Some IH features appeared to associate with favorable tumor response, including large early RT changes in DW-MRI ADC(skewness) (AUC=0.86). Data ConclusionPreliminary findings show tumor heterogeneity was variable between patients, modalities, and timepoints. Radiomic assessment of changing tumor heterogeneity has the potential to personalize treatment and power outcome prediction. Level of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1388-1396.