## 4 The Importance of Biomarkers in Monitoring RT Toxicity  
A molecular biomarker is any molecular indicator of normal and pathogenic biological processes or the pharmacologic responses to therapeutic interventions [35]. Biomarkers improve prediction, characterization, and treatment of human diseases. In the oncology field, biomarkers guide informed decisions of clinicians regarding chemo- and radiotherapeutic strategies, relative to the risk of potential side effects and tumor recurrence. Biomarkers are measured, if possible, in readily accessible biological samples before, during, and after RT. Medical imaging with new combined techniques and higher definition, together with assays in biological fluids, constitute the current main strategy in the clinical evaluation of RT-induced radiosensitivity and toxicity. In radiation response investigations, blood and its components, serum/plasma and cells, mostly lymphocytes, are considered a readily accessible source of biomarkers to study IR toxicity.  
An ideal blood biomarker would fulfill the following criteria: (a) precise targeting of a biological process related to the radiosensitivity of the peripheral immune system; (b) specificity for a certain type of cancer with alterations in the systemic immune response; (c) tumor reactivity to RT mirrored in peripheral blood; (d) measurement accuracy in blood samples and validation of the detection method according to international standards; (e) distinct delimitation of the biomarker levels between patients with a certain type and stage of cancer and patients with systemic inflammatory processes; (f) independence from diverse environmental factors (e.g., dietary habits, alcohol intake, etc.) or treatments unrelated to disease therapy; (g) detection of measurable changes during disease evolution and/or therapy; (h) reliability of laboratory measurements and generation of results and; (i) undetectability, if possible, when patients attain remission. In fact, and to the best of our knowledge, currently, there is no biomarker that fulfills all the criteria mentioned above; rather, several biomarkers are estimated in conjunction with other clinical findings.  
The advancement of our understanding of genomic and epigenomic processes, including mutations, gene expression changes, and post-translational modifications, has shifted radiobiology research to gene and protein biomarkers that are indicative of the radiation-induced responses in normal and cancer cells. Deep-sequencing approaches confirmed that complex DNA damage and repair mechanisms, along with chromosomal aberrations and IR-induced cell apoptosis in various irradiated tissue samples can be considered predictors of radiosensitivity and post-irradiation toxicity. Protein biomarkers can also be used for the estimation of the received dose and response of the irradiated biological system (cell/tissue), the assessment of radiosensitivity of different human cell lines, the investigation of susceptibility of an irradiated individual as a whole organism, the detection of early signs arising from radiation-induced disease, and the evaluation of late health effects that are present a long period of time after exposure before the initiation of an associated disease. At the same time, progress in the field of biomarkers that can be widely used in the clinic is rather slow. This is because for a biomarker to qualify as indicative of a clinical outcome, the variation in its values must be strongly correlated with the corresponding changes in disease status. In this process, statistics must prove that there is enough clinical evidence in multiple observations that confirm the hypothesized correlation.