## 4 Brachotherapy in the Palliative Treatment of Esophageal Cancer
The benefit of immunotherapy has also been demonstrated in patients with adenocarcinoma. The CheckMate 649 study showed an OS benefit in CPS greater than or equal to five when nivolumab was added to standard chemotherapy, and the Keynote 590 study showed a benefit with pembrolizumab [58; 60]. A benefit in OS was also highlighted for second and subsequent lines of treatment for esophageal cancer with pembrolizumab in the Keynote 181 study (for CPS 10 and above) and for nivolumab in the ATTRACTION-3 study (squamous or adenocarcinoma) [61, 62]. The primary predictor of response to immunotherapy in esophageal cancer is the PD-1 (programmed death receptor-1) receptor protein, the high expression of which is responsible for a 25% response rate to immunotherapy in this cancer. Studies indicate the possibility of increasing the expression of the PD-1 molecule under the influence of chemoradiotherapy. In a study by [PERSON] et al. [63], it was shown that in a tumor burden, there is an increased level of interferon \(\gamma\) and activated CD8+ T cells. The upregulation of PD-L1 and many other immune checkpoints, including TIM3 (T-cell immunoglobulin and mucin domain 3), GITR (glucocorticoid-induced tumor necrosis factor receptor family-related protein IDO1(Indoleamine 2,3-dioxygenase 1), LAG3 (lymphocyte-activation gene 3), OX40 and KIRs (killer immunoglobulin-like receptors), have also been demonstrated. The upregulation of PD-L1 is dose-dependent and transiently elevated after radiation exposure. Similar conclusions come from the study by [PERSON] et al. [64] in which 28 patients with stomach and gastrointestinal junction cancer were analyzed in terms of PD1 and PDL1 expression before and after chemoradiotherapy, as well as the impact of PD1 expression on prognosis. Increased PD1 expression has been shown to be associated with poor OS in gastroesophageal (GE) cancer patients. Neoadjuvant chemoradiotherapy increases both PDL1 and PD1 levels. In patients with stomach cancer, this led to significantly poorer survival. In general, higher doses of radiation appear to have more immunostimulatory effects, while lower doses of radiation (approximately 2 Gy) may produce greater immunosuppressive and anti-inflammatory effects [65]. It is believed that brachytherapy may have a potential advantage over EBRT in terms of stimulating the immune response within the tumor. Whereas in EBRT radiation, beams pass through a significant volume of healthy tissue to achieve appropriate dose distribution in the target volume, brachytherapy allows for a highly conformal dose distribution, with a rapid dose decay outside the irradiated target volume and a high but also heterogeneous radiation dose in the target volume (Figure 3). This dose heterogeneity depends on the distance of the source from the target volume [66]. [PERSON] et al. [65] assumed that a highly conformal dose distribution in the target volume allows the sparing of healthy tissue, especially the circulating components of the immune system and lymphatic tissue, which minimizes the immunological effect outside the target volume. The dose gradient resulting from the inverse square law produces multiple immunological mechanisms, ranging from immunogenic cell death and the release of tumor-specific antigens in the highest dose regions, to increased cytokine release in the mid-dose region, and finally to the short-term depletion of tumor-infiltrating suppressive lymphocytes in the surrounding cancer tissues [65]. Current progress in radiotherapy largely relies on the precise administration of high fractional doses. However, the effect of damaging cancer cells outside the irradiation area has long been described [66]. The so-called abscopal effect results from the activation of the body's immune system caused by radiation. The mechanism of the abscopal effect is based on several phenomena. In addition to double-strand DNA breaks, the tumor microenvironment is damaged by the action of reactive oxygen species on the endothelium of tumor blood vessels [67].