## 3 Brachytherapy Combined with Teleradiotherapy in Advanced, Non-Operative Stages  
Most patients with esophageal cancer are in poor general condition and with advanced local disease, where treatment with the intention of surgery is impossible. A multicenter, randomized phase III trial (NROG-001) [31] showed that in the high-dose arm (59.4 Gy) there was no improvement in OS (HR = 0.93, \(p\) = 0.54), but an improvement in PFS was demonstrated (29.1 months-20.0 months, HR = 0.77, \(p\) = 0.023) compared with the lower dose arm (50.4 Gy). In the study by [PERSON] et al. [32], the median OS was 8.9 months in the group with radiotherapy alone and 12.5 months in patients with radiochemotherapy. In non-operative cases, attempts to improve treatment results were made by escalating the dose using brachytherapy (Table 2). The most frequently used radiotherapy doses were in the range of 40-50 Gy, conventionally fractionated [33; 34; 35; 36; 37], although in some studies, the dose administered using EBRT was as high as 60 Gy [38; 39; 40; 41]. The dose from brachytherapy ranged from 10 Gy to 24 Gy hypoffractionated in the range of 5-10 Gy/fraction [33; 34; 35; 36; 37; 38; 39; 40; 41]. Some studies also used chemotherapy. Due to the poor prognosis in this group of patients, some regimens included hypoffractionated radiotherapy with a brachytherapy boost, and the aim of the treatment was primarily palliative. Dose escalation using brachytherapy increased the local effectiveness, but at the cost of an increased rate of complications such as ulceration, esophageal stenosis, and bleeding. Because the results of treatment with radiotherapy alone are poor and the combination with chemotherapy or surgery does not bring satisfactory results, checkpoint inhibitors (CPIs) are introduced. In the PALACE-1 trial [45], pembrolizumab was added to typical chemoradiotherapy from the CROSS trial. At this point, the available data showed good treatment tolerance with a pCR (pathological complete response) rate of 55.6%. Currently, the PALACE 2 phase 2 study is underway. In the ongoing CRISEC study [46], tisleizumab was added to chemoradiotherapy according to the same regimen. The interim analysis of this study showed a high pathological response of 86.7% with good tolerability of the combination of immunotherapy and chemoradiotherapy. Similarly, the atezolizumab trial [47] only analyzed the pCR rate. pCR was 25% and was similar to that in the CROSS study. Also, the addition of toripalimab to induction chemoradiotherapy in the phase II study [48] did not bring any breakthrough. The pCR rate was 50% and 36% in the immunotherapy group and chemoradiotherapy alone group, respectively. Although it differed numerically, this difference was not statistically significant. The first survival data on small groups of patients in combination with Camelizumab showed 12 m and 24 m OS of 85.0% and 69.6%, and 12 m and 24 m PFS of 80.0% and 65.0%, and in combination with pembrolizumab, 6, 12, and 18 m OS of 89.3%, 80.8%, and 73.1%, respectively [49; 50]. Taking into account the still unsatisfactory results of neoadjuvant immunotherapy, further research on adjuvant immunotherapy after chemoradiotherapy was conducted. The study with the addition of durvalumab turned out to be negative, with no differences in DFS or OS [51]. However, the study on nivolumab turned out to be positive [49]. However, not all patients were included in this study, but only those who did not achieve pCR after chemoradiotherapy. The addition of nivolumab extended mDFS from 11.0 to 22.4 months [52].