Background: Stereotactic Radiotherapy (SRT) in pancreatic and biliary tract cancer (PBC) suffers from proximity to any organ(s) at risk (OARs). Some strategies to manage this issue have previously been proposed, such as Simultaneous Integrated Protection (SIP), with the aim of maintaining a biological effective dose prescription while reducing toxicities. We performed a systematic review of the literature about SRT techniques applied in patients with tumor in proximity to OARs, with the aim of testing safety and efficacy. Methods: using PRISMA guidelines, we selected studies from a pool of more than 25,000 articles published from 2010 to 30 January 2023 that explored the use of SRT to deliver targeted treatment for PBC. We then selected the ones referring to decreases in prescription doses (for SRT only) in the area of overlap between planning target volume (PTV) and OARs. Local control (LC) and toxicities being detailed were exclusion criteria for articles. Results: 9 studies were included in our review, considering 368 patients. One-year LC probability ranges between 67% and 98.3% were reported. Late G3 toxicities ranged between 0% and 5.3%, while G4-G5 late toxicities were both reported as 0.3%. Conclusion: prioritizing critical OAR constraints limits severe toxicities while preserving LC in PBC SRT. Improving in-study reporting is essential to confirm these promising results.

The impact of the microbiota on radiation (RT)-induced toxicity and cancer response to radiotherapy is an emerging area of interest. In this review, we summarize the available preclinical and clinical evidence concerning microbiota modulation of RT toxicity and efficacy in the main gastrointestinal (GI) districts. A huge amount of data supports the clinical application of microbiota modulation, particularly through prebiotics and probiotics, to prevent or mitigate radiotherapy-induced toxicity in rectal cancer. Preclinical and clinical studies also support the observation of microbiota modulation to impact the toxicity and efficacy of treatment in esophageal cancer, hepatocellular carcinoma (HCC), and anal squamous cell carcinoma (ASCC). However, insufficient evidence remains to endorse microbiota modulation as a strategy to enhance tumor radiosensitivity in clinical practice. Well-designed studies focusing on prebiotics, probiotics, and fecal microbiota transplantation are needed across all GI sites to evaluate their potential to improve treatment efficacy, as suggested by promising preclinical findings. The impact of pre-treatment microbiota analyses should be addressed in prospective studies to verify the efficacy of patient-level tailored strategies. Additionally, the repurposing of radioprotective agents with innovative delivery systems, such as encapsulated amifostine, holds significant promise for mitigating small bowel toxicity, thereby enabling more effective RT treatment.

Here, we report the clinical case of a 44-year-old lady, affected by synovial sarcoma (SS) of the mediastinum which was treated in 2014, and relapsed in the upper abdomen in 2020. SS is a relatively radioresistant disease, radiotherapy (RT) is routinely reserved for the neoadjuvant/adjuvant or palliative context. In our scenario, stereotactic RT consisting in 45Gy in 6 fractions was proposed to manage the upper abdominal relapse. Exploiting simultaneous integrated protection, a deliberated reduction in the dose prescription in area of planning target volume overlapped with stomach was achieved, obtaining reasonable dosimetric goals. Acute toxicity in the patient was acceptable, and she did not experience late toxicity and was still free from disease, as noted in last follow-up, 15 months after treatment.

Background: One of the challenges in treating pancreatic ductal adenocarcinoma (PDAC) with stereotactic radiotherapy (SRT) is to manage lesions abutted to the duodenum, bowel and stomach. Simultaneous integrated protection (SIP) is one of the proposed approaches to increase plan reproducibility and quality. However, no clinical data are available regarding the dosimetric objectives impacting local control probability. Methods: This is a prospective, single-arm study. Key inclusion criteria were as follows: PDAC histology; tumor abutment with duodenum, stomach, or small bowel; and SRT schedule consisting of 45 Gy in six fractions. Delineation of the PTV overlapped with critical OARs (PTV_SIP) and PTV outside critical OARs (PTV_Dominant) was mandatory. Dose constraints were as follows: (near) maximum dose, D2cc, and D20cc to critical OARs 38 Gy, 32 Gy, and 24 Gy, respectively. This study was designed to prospectively investigate the main clinical and dosimetric parameters impacting freedom from local recurrence (FFLR). Results: From June 2019 to January 2024, 104 patients were enrolled. One-year FFLR was 91.7%. Fifteen events of local failure occurred (17.6%). Mapping of local relapses showed a relapse inside the PTV_SIP area in nine patients and outside the PTV_SIP in six cases (NS). Whole PTV > 69 cc, PTV_SIP > 4 cc, PTV-SIP/whole PTV ratio > 7%, (near) Dmin to PTV_SIP < 25 Gy, mean dose to PTV_SIP < 28 Gy, and (near) Dmin to PTV_Dominant < 29 Gy were associated with worse FFLR. Multivariable analysis showed PTV_SIP absolute volume of more than 4 cc, mean dose to PTV_SIP < 28 Gy and whole PTV > 69 cc were independently related to worse FFLR. One case of acute G4 toxicity and two cases of acute G3 toxicity occurred, with two late toxicity deaths not certainly due to treatment. Conclusions: In this prospective study, SIP planning strategy with six fractions is safe and effective in pancreatic targets with critical contact with critical OARs. Given its potential advantages, SIP planning is a potential innovative strategy that should be compared to standard SRT planning in an ad hoc trial design.

Purpose: Lymphomas are generally radiosensitive; therefore, disease volume tends to shrink during radiotherapy courses. As MRI-linac provides excellent soft tissue definition and allows daily re-contouring of gross tumor volume and clinical target volume, its adoption could be beneficial for the treatment of lymphomas. Nonetheless, at this time there is a lack of literature regarding the use of MR-linac in this context. Methods: A prospective observational study was conducted on patients affected by non-Hodgkin lymphoma (NHL) involving head and neck (H&N) sites and treated with Elekta Unity^® MR-Linac. The clinical and dosimetric data of the first eight patients were collected and integrated with relevant data from medical records. Results: Seven patients had B-cell lymphoma (three DLBCL, two MALT, one follicular, and one mantle-cell) and one T-cell/NK lymphoma. The intent of RT was radical for four patients, salvage treatment for three, and CAR-T bridging for one. Two patients presented orbital localizations and six cervical lymphonodal sites. Median GTV was 5.74 cc, median CTV 127.01 cc, and median PTV 210.37 cc. The prescribed dose was 24–50 Gy in 2 Gy fractions for seven patients and 24 Gy in 3 Gy fractions for one patient. All the patients experienced acute toxicity, the maximum grade was G1 for five patients and G2 for three at the end of RT. One month after radiotherapy seven patients still experienced G1 toxicity, but no toxicity grade ≥ 2 was reported. First radiological assessment was performed for all the patients after a median of 101.5 days, reporting complete response in all the cases. After a median follow up of 330 days, no patient experienced local disease progression, while one patient developed distant progression. Conclusions: radiotherapy for NHL with H&N localization using a 1.5 T MR-linac was feasible, with no >G2 toxicity and optimal response rate and disease control.

Introduction: Recent randomized evidence suggests that stage II–IV non metastatic esophageal adenocarcinoma is best managed with perioperative chemotherapy (CHT) and surgery. Intensification of neoadjuvant chemotherapy and radiochemotherapy are proposed before surgery in high-volume centers with the aim of increasing both systemic and locoregional control. However, few data comparing intensified RTCHT, CHT plus RTCHT and perioperative CHT with FLOT in real-life scenarios are available. Methods: This is a multicenter, retrospective series, including three cohorts of patients treated for esophageal adenocarcinoma: Cohort A: nRTCHT; Cohort B: TCF plus RTCHT, defined as triplet chemotherapy followed by dose-reduced triplet therapy + RT; Cohort C: perioperative chemotherapy with FLOT regimen. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were pathologic complete response (pCR), pathologic lymph-node complete response (ypN0), overall survival (OS), and perioperative acute toxicity. Results: From January 2013 to December 2023, 142 patients were identified. All patients received multimodal therapy with radical esophagectomy. A total of 95% of patients were male; the majority of patients presented with stage cT3cN1. A total of 63 patients were treated in Cohort A (31 cases with doublet 5FU-CDDP concurrent to 50.4 Gy and 32 cases with CROSS regimen), 36 in Cohort B, and 43 in Cohort C. After a median FU of 36 months, the 3-year DFS resulted 58.6%. pCR occurred in 26 cases (18.6%). Three-year OS had a value of 72%. At univariate analysis, ypN0 was related to better DFS; cN+ disease was related with worse OS. The treatment cohort did not impact survival outcomes; however, an effect on CR was shown, with pCR in 15% (A), 36.3% (B), 11% (C) of cases, respectively (χ: 0.008). A total of 67% of patients in Cohort B experienced a ypN0. Two treatment-related deaths occurred (one in Cohort A and one in C) with a slight increase in G3 toxicity in cohort C. Conclusions: In this real-life multicenter series, oncological results were adequate for all three neoadjuvant strategies. TCF plus RTCHT guaranteed a higher pCR and ypN0 rate without increasing toxicity. An intensified neoadjuvant schedule, such as TCF plus RTCHT, may be useful in cases where higher tumor and nodal responses are needed. Taken together, our data highlight that further investigation is warranted before abandoning radiotherapy-based neoadjuvant approaches in esophageal and GEJ adenocarcinoma.