Breast cancer is the most frequently diagnosed cancer among women in the Western world. Currently, no imaging technique assesses tumor heat generation and vasculature changes during radiotherapy in viable tumor and as adjuvant therapy. Thermography is a non-ionizing, non-invasive, portable and low-cost imaging modality. The purpose of this study was to investigate the use of thermography in cancer treatment monitoring for feedback purposes. Six stage-IV breast cancer patients with viable breast tumor and 8 patients (9 breasts) who underwent tumor resection were monitored by a thermal camera prior to radiotherapy sessions over several weeks of radiation treatment. The thermal changes over the treated breast were calculated and analyzed for comparison with healthy surrounded breast tissue or contralateral breast. A model of a breast with a tumor was created. The COMSOL FEM software was used to carry out the analysis. The effects of tumor metabolism and breast tissue perfusion on the temperature difference were analyzed. All patients with active tumors exhibited drops in maximal temperature of the tumor during radiation therapy. The patients who underwent radiotherapy as adjuvant treatment exhibited a rise in maximal temperature over the treated breast in correlation with skin erythema during radiation. This difference between the groups was statistically significant (P=0.001). The simulated human breast cancer models analysis showed that tumor aggressiveness reduction causes decrease in the tumor temperature. Inflammation causes vasodilatation and increases tissue perfusion, resulted in an increase in breast tissue temperature. A correlation was demonstrated between the clinical outcome and the simulation. We report a method for monitoring cancer response to radiation therapy, which measures the physiological response along with clinical response. These anticipatory efficacy evaluations of radiotherapy during treatment may further promote changes in treatment regimen, either radiation associated or combination as in chemo-radiation protocols. The probable treatment delivery changes may incorporate the total dose delivery, fraction dose and intensity as well as adding chemotherapy for non-responding tumors during radiotherapy. All the above possibilities will contribute to the advances of individualized, personalized cancer treatment for optimal treatment effectiveness.