## 4 The Importance of Biomarkers in Monitoring RT Toxicity
### Secreted Soluble Protein Biomarkers
This observation is sustained by the study of [PERSON] et al., 2022 on 39 patients with localized or locally advanced prostate cancer treated with RT, showing that increased serum levels of IL-6 and TGF-\(\beta\)1 influence the severity of acute genitourinary radiotoxicity and fatigue in these patients [139]. The proinflammatory cytokine interleukin-1 beta (IL-1\(\beta\)) shows promise as a cancer biomarker with pleiotropic effects on cancer cell proliferation, angiogenesis, migration, and metastasis, as well as on immune cells [140]. It has been shown that IL-1\(\beta\) induces the expression of the gene encoding the proinflammatory inducible form of cyclooxygenase 2 (COX-1) in several cancer cell lines through mechanisms involving p38 and p44/p42 mitogen-activated protein kinase pathways and enhances the activity of the CDK2 [141; 142]. IL-1\(\beta\) was also found to elicit the above-mentioned overproduction of IL-6 through the activation of NF-kB, which has been shown to be crucial for COX-2 induction [143]. IL-1\(\beta\) is also linked to angiogenesis through VEGF production together with IL-6 [144]. It has been shown that increased levels of IL-1\(\beta\) are significantly linked to poor prognosis in patients with gastric and colorectal adenocarcinoma, and are an important survival predictor in patients undergoing RT [145; 146]. According to [PERSON] et al., 2011, IL-1\(\beta\) is also an indicator of shorter survival in oesophageal cancer patients [147]. [PERSON] et al., 2020, reported an increase in this biomarker in peripheral CCR6\({}^{\rm neg}\)Th lymphocytes after their irradiation with \({}^{137}\)Cs [107], and [PERSON] et al., 2011, observed a secretion of IL-1\(\beta\) in CD4\({}^{+}\)CD25\({}^{+}\) radiosensitive T cells in blood samples collected from patients with hepatocellular cancer in response to low-dose \(\gamma\)-rays [106]. The study of [PERSON] et al., 2021, has recently shown, via single-cell RNA sequencing, that IL-1\(\beta\) blockade can remodel the myeloid compartment through non-redundant, relatively T-cell-independent mechanisms, concluding that IL-1\(\beta\) represents a potential target for kidney cancer immunotherapy [148]. Another candidate biomarker is tumor necrosis factor \(\alpha\) (TNF-\(\alpha\)), a proinflammatory cytokine that is a potent apoptosis inducer, having dual roles in pro-tumorigenic and anti-tumorigenic receptors [149; 150]. [PERSON] et al., 2019, showed that TNF-\(\alpha\) levels remained high in the cells of lung cancer patients after repeated radiation treatments and proposed the use of this cytokine as a critical biomarker for treatment evaluation [151]. Other studies have also reported high levels of TNF-\(\alpha\) after RT [152; 153; 154; 155]. On the other hand, [PERSON] et al., 2016 reported a bioinformatic analysis of 982 patients, showing that increased levels of TNF-\(\alpha\) were associated with a low risk of lung cancer progression after RT [157]. Other cytokines, like IL-2, IL-13, IL-23, and interferon-\(\gamma\) have been reported to be associated with RT-induced toxicity [110, 158], but there is a need for more studies in this field. Vascular Endothelial Growth Factor (VEGF) is an angiogenic factor associated with endothelial cell proliferation, cell migration, and autophagy [159]. It is acknowledged that VEGF is a basic mediator of neovascularization, presenting a high expression in neoplastic cells and especially in the stromal cells in the tumor niche [160]. It has been demonstrated that VEGF also prevents apoptosis induced by serum starvation through the phosphatidylinositol (PI)-3-kinase-Akt pathway and induces the expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells [161]. The detection of VEGF-A in the serum of patients with primary cervical cancer in advanced FIGO stages Ib-IIb before and after RT combined with chemotherapy was reported by the study of [PERSON] et al., 2013 [162]. More specifically, in this study was shown that a decrease in VEGF-A leads to an increase in patients' survival rate.