PURPOSE:This guideline provides evidence-based recommendations on the use of radiation therapy (RT) for the treatment of pancreatic cancer in a variety of clinical settings including patients with resectable, borderline resectable, locally advanced, metastatic, and symptomatic disease. METHODS:The American Society for Radiation Oncology convened a multidisciplinary task force to address 4 key questions: (1) indications for and timing of RT for patients with nonmetastatic pancreatic cancer; (2) appropriate RT dose-fractionation regimens and target volumes for nonmetastatic disease; (3) preferred RT planning and delivery techniques for nonmetastatic disease; and (4) indications for RT in the locally recurrent, metastatic, reirradiation, and palliative settings. Recommendations are based on a systematic literature review and were created using a predefined consensus-based methodology with a system for grading evidence quality and recommendation strength. RESULTS:Multidisciplinary evaluation and decision-making are recommended for all patients. For patients with nonmetastatic pancreatic cancer, RT is conditionally recommended in the preoperative and postoperative settings for resectable disease. RT is recommended preoperatively for borderline resectable disease and definitively in the locally advanced setting. For preoperative RT, conventional fractionation or moderate hypofractionation is recommended. For postoperative RT, conventional fractionation is recommended. In the definitive setting, conventional fractionation is appropriate although emerging evidence supports dose escalation using either stereotactic body radiation therapy or moderate hypofractionation. Adaptive RT is recommended for dose-escalated stereotactic body radiation therapy. Elective coverage of at-risk anatomic regions is recommended for preoperative, postoperative, and definitive RT. In the locally recurrent setting, RT is recommended for patients without prior RT and conditionally recommended for those who have previously received RT. Palliative RT is recommended for patients with bleeding, pain, and obstruction. For patients with oligometastatic and oligoprogressive pancreatic cancer, RT is conditionally recommended to metastatic lesions and the primary tumor if not previously treated with definitive local therapy. Target volumes, simulation and planning techniques, and treatment recommendations are provided. CONCLUSIONS:These evidence-based recommendations provide guidance on the optimal use of RT for pancreatic cancer. Ongoing and future studies should further refine RT indications, sequencing with other therapies, and impact on patient outcomes.

Abstract Introduction Metastasis-directed radiotherapy is of increasing importance in the multidisciplinary management of oligometastatic non-small cell lung cancer (NSCLC), but outcome patterns for stereotactic body radiotherapy (SBRT) of bone oligometastases (BoM) remain insufficiently defined. We aimed to determine oncological outcomes and prognostic factors of SBRT for BoM of NSCLC. Materials and methods Patients with NSCLC treated with SBRT for < 5 BoM between 2010 and 2024 at 15 European cancer centers were retrospectively analyzed. Outcomes included freedom from local recurrence (FFLR), progression-free survival (PFS), overall survival (OS), and adverse events. Results With a median follow-up of 14 months (IQR: 7–24 months), 85 patients with 111 treated BoM were analyzed. The 2-year FFLR was 87.2% (95%-CI: 73.3%-94.1%). The 1-/2-year PFS for singular BoM was 60.1% (CI: 44.6%-72.5%)/ 39.9% (CI: 24.6%-54.8%), while for 2–3 BoM they amounted to 10.2% (95%-CI: 0.6%-35.8%) and 0%. In multivariable analysis, less favorable outcome for OS and PFS was associated with larger BoM (HR 1.003; p < 0.01 and HR 1.005, p < 0.001) and increased number of treated BoM (HR 1.72; p = 0.03 and HR 1.93; p < 0.01). Treatment was well tolerated, with fracture rates of 5.4% and no grade 4 and 5 adverse events. Conclusion This multicenter cohort analysis revealed that SBRT of BoM from NSCLC appears to be an effective and well-tolerated treatment. Presence of singular BoM was a favorable prognostic factor. Prospective studies are needed to confirm these findings and to determine the role of SBRT in the multidisciplinary management of oligometastases.

Background and purpose:The interdisciplinary treatment concept for bone metastases (BoM) of oligometastatic breast cancer includes metastasis-directed radiotherapy. We evaluated oncological outcomes of BoM treated with stereotactic body radiotherapy (SBRT) in a large European cohort. Material and methods:Data of breast cancer patients treated with SBRT for BoM between 2010 and 2024 at 17 European cancer centers were retrospectively collected. Treatment and dose concepts were analyzed regarding their impact on freedom from local recurrence (FFLR), overall survival (OS), progression-free survival (PFS), and safety profile. Results:With a median follow-up of 29.6 months (interquartile range: 15.0-48.0), 109 patients with 147 BoM were analyzed. SBRT was performed with a prescribed dose of median 35 Gy in median 5 fractions. 1-/3-year FFLR for mean biologically effective dose (BED10) ≥ 50 Gy in the gross tumor volume (GTVmean) was 98.1% (95%-CI: 92.7%-99.5%) and 93.9% (95%-CI: 85.5%-97.5%), respectively. For GTVmean BED10 ≥ 50 Gy, 1-/3-year PFS was 62.1% (95%-CI: 43.6%-76.0%)/26.7% (95%-CI: 11.0%-45.4%) for non-spine BoM and 66.2% (95%-CI: 50.8%-77.8%)/35.8% (95%-CI: 21.3%-50.4%) for spine BoM. In multivariable analysis, systemic therapy (HR [hazard ratio] 0.22; p < 0.001) was associated with improved OS, while higher GTVmean BED10 (HR 0.96; p < 0.001) was associated with improved PFS and spine localization with worse PFS (HR 1.81; p = 0.02). Adverse events were rare, with fracture rates of 2.7%. Conclusion:In this multicenter retrospective cohort analysis, SBRT of BoM from breast cancer was a well-tolerated, effective treatment. Prospective studies are needed to investigate these findings further and determine the role of standardized SBRT concepts in the multidisciplinary management of oligometastatic breast cancer.

Die Radiotherapie ist zunehmend relevant in der multidisziplinären Behandlung des hepatozellulären Karzinoms (HCC) und des Cholangiokarzinoms (CCC). Die stereotaktische Körperstrahlentherapie (SBRT) ermöglich ablative Strahlendosen unter bildgesteuerter Bewegungskontrolle und geht mit konstant hohen Raten der lokalen Kontrolle (LC) bei nichtresektablen oder lokal fortgeschrittenen Tumoren einher. Beim HCC weist die SBRT für verschiedene klinische Bedingungen gute Ergebnisse, beispielsweise als definitive Therapie bei inoperablen Tumoren, die denen bereits etablierter lokoregionaler Therapien – wie der transarteriellen Chemoembolisation (TACE) und der Radiofrequenzablation (RFA) – ähneln. Vergleichsstudien zufolge zeigt die SBRT häufig bessere Raten der LC, insbesondere bei größeren Läsionen oder Tumoren an anatomisch schwierigen Lokalisationen, bei weitgehend vergleichbarem Gesamtüberleben (OS) im Vergleich zu anderen lokalen Therapiemodalitäten. Darüber hinaus wird die SBRT erfolgreich als Bridgingtherapie oder zum Downstaging vor einer Lebertransplantation eingesetzt, mit hohen Raten pathologischem Tumoransprechen ohne nachteilige Auswirkungen auf die Transplantationseignung. Zunehmend wird die SBRT auch in Kombination mit systemischen Therapien untersucht, wobei frühe Daten ermutigende Ergebnisse insbesondere in Kombination mit Immuncheckpoint-Inhibitoren (ICI) zeigen. Beim CCC hat die Radiotherapie aufgrund der hohen Lokalrezidivraten nach kurativ intendierter Operation an Bedeutung gewonnen. Im adjuvanten Setting ist die Radiotherapie mit einem verbesserten Überleben assoziiert, insbesondere bei Patienten mit ungünstigen pathologischen Merkmalen wie positiven Resektionsrändern oder nodalem Befall. In ausgewählten Fällen mit lokal fortgeschrittenen oder anatomisch ungünstig gelegenen Tumoren kann eine neoadjuvante Radiochemotherapie vorteilhaft sein.

Hepatocellular carcinoma (HCC) represents one of the leading contributors to cancer-related deaths, with the majority of patients diagnosed at stages where curative treatment is no longer possible. Combining stereotactic body radiotherapy (SBRT) with immune checkpoint inhibition (ICI) has gained increasing attention as a therapeutic approach. Beyond its ability to provide high local tumor control (LC), SBRT can provoke immunogenic tumor cell death, promote antigen release and presentation, and modulate the tumor microenvironment in ways that enhance systemic antitumor immunity.In this narrative review, we outline the scientific rationale for integrating SBRT with ICIs, discuss mechanistic and translational findings and summarize results from key clinical trials. The currently available data indicate a synergistic interaction, most notably reflected in improved survival and response rates. Nevertheless, variability in dose and fractionation schedules, treatment sequencing, and patient characteristics complicates interpretation. Well-designed prospective studies are needed to establish optimal protocols and identify predictive biomarkers to guide patient selection.

4014 Background: The ESOPEC trial (NCT02509286) showed that perioperative chemotherapy improved overall and progression free survival in pts with esophageal adenocarcinoma (EAC) compared with preoperative chemoradiotherapy. Understanding of the pattern of recurrence is important for the development of more effective future treatment strategies. Methods: Pts with cT1 cN+ cM0 or cT2-4a cNany cM0 EAC undergoing preoperative chemotherapy with FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) or preoperative chemoradiotherapy with CROSS (41.4Gy/carboplatin/paclitaxel) plus tumor resection from the ESOPEC trial were eligible. Recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and patterns of local, regional and distant recurrence were analyzed. Treatment groups were compared with respect to sites of recurrence by calculating 3-year cumulative incidences considering competing events, and by Cox regression models for event-specific hazards stratified by trial center and including treatment assignment (FLOT vs CROSS), cN stage (cN0 vs cN+), and age as covariates. Event-specific hazard ratios (HR) with two-sided 95% confidence intervals (CI) and p-values are presented. Results: Of the 438 pts enrolled in ESOPEC, 192 of 221 (86.9%) in the FLOT group and 179 of 217 (82.5%) in the CROSS group underwent tumor resection and represent the population for this analysis. R0 resection was achieved in 354 pts (182 (94.8%) FLOT; 172 (96.1%) CROSS). 142 (74.0%) pts in FLOT received postoperative chemotherapy. After a median follow-up of 56 months 178 pts had disease recurrence (81 FLOT; 97 CROSS), and 28 pts died without recurrence (12 FLOT; 16 CROSS). The 3-year RFS rate was 54.5% in FLOT vs 39.0% in CROSS (HR for recurrence or death 0.67; 95% CI, 0.51 - 0.89, p = 0.005). The 3-year DMFS rate was 57.6% in FLOT vs 41.0% in CROSS (HR for distant recurrence or death 0.64; 95% CI, 0.48 – 0.85, p = 0.002). Conclusions: Perioperative chemotherapy with FLOT improves RFS and DMFS compared to preoperative chemoradiotherapy with CROSS in EAC. The prognosis of pts is determined by distant recurrence, which is less common after FLOT than CROSS. Clinical trial information: NCT02509286 . Treatment group comparisons regarding site of recurrence. Site of recurrence FLOTN=192 CROSSN=179 FLOT vs CROSS N (%)* N (%)* HR(for recurrence) 95% CI P-value Locoregional 39 (20.2) 32 (17.4) 1.00 0.62 – 1.61 0.99 Local 19 (9.5) 15 (8.1) 1.03 0.51 – 2.06 0.94 Regional 29 (15.1) 27 (14.5) 0.89 0.52 – 1.52 0.68 Distant 64 (31.5) 89 (47.2) 0.59 0.43 – 0.82 0.002 Distant lymphatic 21 (9.3) 31 (15.6) 0.60 0.34 – 1.05 0.074 Hematogenous 33 (17.2) 48 (26.1) 0.59 0.37 – 0.92 0.021 Pleural/Peritoneal 24 (12.0) 31 (16.4) 0.63 0.36 – 1.09 0.10 *% calculated as 3-year cumulative incidence.

BACKGROUND:The best multimodal approach for resectable locally advanced esophageal adenocarcinoma is unclear. An important question is whether perioperative chemotherapy is preferable to preoperative chemoradiotherapy. METHODS:In this phase 3, multicenter, randomized trial, we assigned in a 1:1 ratio patients with resectable esophageal adenocarcinoma to receive perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus surgery or preoperative chemoradiotherapy (radiotherapy at a dose of 41.4 Gy and carboplatin and paclitaxel) plus surgery. Eligibility criteria included a primary tumor with a clinical stage of cT1 cN+, cT2-4a cN+, or cT2-4a cN0 disease, in which T indicates the size and extent of the tumor (higher numbers indicate a more advanced tumor), and N indicates the presence (N+) or absence (N0) of cancer spread to the lymph nodes, without evidence of metastatic spread. The primary end point was overall survival. RESULTS:From February 2016 through April 2020, we assigned 221 patients to the FLOT group and 217 patients to the preoperative-chemoradiotherapy group. With a median follow-up of 55 months, overall survival at 3 years was 57.4% (95% confidence interval [CI], 50.1 to 64.0) in the FLOT group and 50.7% (95% CI, 43.5 to 57.5) in the preoperative-chemoradiotherapy group (hazard ratio for death, 0.70; 95% CI, 0.53 to 0.92; P = 0.01). Progression-free survival at 3 years was 51.6% (95% CI, 44.3 to 58.4) in the FLOT group and 35.0% (95% CI, 28.4 to 41.7) in the preoperative-chemoradiotherapy group (hazard ratio for disease progression or death, 0.66; 95% CI, 0.51 to 0.85). Among the patients who started the assigned treatment, grade 3 or higher adverse events were observed in 120 of 207 patients (58.0%) in the FLOT group and in 98 of 196 patients (50.0%) in the preoperative-chemoradiotherapy group. Serious adverse events were observed in 98 of 207 patients (47.3%) in the FLOT group and in 82 of 196 patients (41.8%) in the preoperative-chemoradiotherapy group. Mortality at 90 days after surgery was 3.1% in the FLOT group and 5.6% in the preoperative-chemoradiotherapy group. CONCLUSIONS:Perioperative chemotherapy with FLOT led to improved survival among patients with resectable esophageal adenocarcinoma as compared with preoperative chemoradiotherapy. (Funded by the German Research Foundation; ESOPEC ClinicalTrials.gov number, NCT02509286.).

BACKGROUND:O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET has a higher specificity than contrast-enhanced T1-weighted MRI (CE-T1MRI) in diagnosing recurrent glioblastoma. We aimed to evaluate whether a FET-PET-based target volume delineation, compared with CE-T1MRI, improves outcomes in patients with recurrent glioblastoma scheduled for re-irradiation. METHODS:GLIAA was a multicentre, open-label, parallel randomised study done in 15 radiation oncology centres in Germany. Patients aged 18 years or older with a Karnofsky performance score greater than 60% and a macroscopic WHO grade IV recurrent glioblastoma (1-6 cm) were randomly assigned (1:1) to receive either FET-PET-based or CE-T1MRI-based target volume delineation followed by re-irradiation with 39 Gy in 13 fractions. Randomisation was performed centrally, using a minimisation technique with a random element and a computer-assisted randomisation tool, stratified by time since first radiotherapy, previous chemotherapy, tumour diameter, MGMT status, and planned chemotherapy. The primary endpoint was progression-free survival from randomisation, assessed in the per-protocol population (patients who initiated treatment per their assigned group). Adverse events were systematically assessed in all patients who commenced therapy. The trial was registered with ClinicalTrials.gov (NCT01252459), German Clinical Trials Registry (DRKS00000634), and European Clinical Trials Database (EudraCT 2012-001121-27), and is completed. FINDINGS:Between Nov 22, 2013, and Aug 18, 2021, 271 patients were recruited and screened for eligibility, 200 of whom were randomly assigned to re-irradiation based on FET-PET (n=100) or CE-T1MRI (n=100). 85 (43%) participants were female and 115 (58%) were male. 98 patients in the FET-PET group and 97 in the CE-T1MRI group were treated per protocol. Median follow-up for censored patients was 12·2 months (IQR 6·6-20·7). Median progression-free survival was 4·0 months (95% CI 3·7-5·2) in the FET-PET group and 4·9 months (3·7-6·0) in the CE-T1MRI group (one-sided stratified log-rank p=0·98; adjusted hazard ratio 1·14 [95% CI 0·85-1·52]; p=0·39; median follow-up for six censored patients 4·1 months [IQR 2·3-6·6]). The most common grade 3-4 adverse event was radionecrosis (eight [8%] of 99 in the FET-PET group vs seven [7%] of 99 in the CE-T1MRI group). Acute and subacute serious adverse events occurred in 15 (15%) of 99 patients in each group; possibly re-irradiation-related late serious adverse events occurred in ten (10%) of 97 patients in the FET-PET group and 18 (19%) of 96 in the CE-T1MRI group. There were no treatment-related deaths. INTERPRETATION:FET-PET-based target volume delineation for re-irradiation did not lead to a significant clinical benefit compared with CE-T1MRI-based treatment in patients with recurrent glioblastoma. Thus, CE-T1MRI remains the preferred delineation method in this setting. FUNDING:Deutsche Krebshilfe.

Purpose:Rectal cancer disproportionately affects the elderly population, with more than half of cases diagnosed in individuals aged 70 years or older. Frail patients in this group often face significant challenges tolerating the standard treatment of total mesorectal excision (TME), due to elevated risks of surgical complications and perioperative morbidity. Advances in radiotherapy techniques offer a viable alternative, providing effective tumor control while minimizing treatment-related toxicity. Recent clinical trials, including OPERA and MORPEUS, have demonstrated that dose-escalated radiotherapy, which integrates external beam (chemo)radiotherapy (EBRT) with high-dose-rate endorectal brachytherapy (HDR-BT) or contact X-ray brachytherapy (CXB), can achieve high clinical response rates and facilitate organ preservation in younger, healthier patient cohorts. Building on these findings, the ACO/ARO/AIO-22 study seeks to adapt these innovative approaches to meet the needs of elderly and frail patients with rectal cancer. Methods/Design:The ACO/ARO/AIO-22 trial is a prospective multicentre controlled trial. Elderly (age ≥70 years) and/or frail patients with non-metastatic rectal adenocarcinoma (cT1-3d N0/+ M0, mrCRM - / +) localized 0-16 cm from the ano-cutaneous line, unable to undergo radical surgery can be included. The initial treatment comprises an external beam radiation (EBRT) regime with 13 × 3 Gy (total: 39 Gy) over a period of two and a half weeks. Following initial restaging 6.5 weeks after completion of EBRT, endorectal HDR-BT will be delivered with 3 weekly fractions of 8 Gy to a total dose of 24 Gy (prescribed at the radial margin of the tumor; with a maximum prescription depth of 10 mm); alternatively, with CXB with 90 Gy in 3 weekly fractions. The primary objective is complete or near complete clinical response (cCR or ncCR) and the second primary endpoint is quality of life (QoL) measured with the EORTC QLQ-ELD14, both at 12 months after treatment start. Discussion:The ACO/ARO/AIO-22 prospective multicentre trial will evaluate organ preservation rates and QoL after combining EBRT with endorectal HDR-BT in elderly and/or frail patients with rectal cancer.Trial Registration:Clinicialtrials.gov number: NCT06729645.

Die S3-Leitlinie "Diagnostik und Therapie des Hepatozellulären Karzinoms und der biliären Karzinome" umfasst zwei Tumorentitäten. Die letzte Version der Leitlinie wurde im August 2023 veröffentlicht.

The ESOPEC trial showed that perioperative chemotherapy with fluorouracil (FU)/leucovorin/oxaliplatin/docetaxel (FLOT) improved survival in patients with nonmetastatic esophageal adenocarcinoma compared with preoperative chemoradiotherapy with CROSS (41.4Gy/carboplatin/paclitaxel). For this analysis, patients from the ESOPEC trial who underwent tumor resection were eligible. The reported end points here include cause-specific mortality, recurrence-free survival (RFS), and sites of recurrence. Of the 438 patients enrolled in ESOPEC, 192 of 221 (86.9%) FLOT patients and 179 of 217 (82.5%) CROSS patients underwent tumor resection. After a median follow-up of 56 months, 178 experienced disease recurrence (81 FLOT; 97 CROSS) and 28 died without recurrence (12 FLOT; 16 CROSS). The 3-year RFS rate was 54.5% in FLOT patients versus 39.0% in CROSS patients (hazard ratio [HR], 0.67 [95% CI, 0.51 to 0.89]; P = .005). Locoregional recurrence occurred in 39 FLOT versus 32 CROSS patients (3-year cumulative incidences 20.2% v 17.4%, HR, 1.00 [95% CI, 0.62 to 1.61]; P = .99). Distant recurrence occurred in 64 FLOT versus 89 CROSS patients (3-year cumulative incidences 31.5% v 47.2%, HR, 0.59 [95% CI, 0.43 to 0.82]; P = .002). Compared with CROSS, perioperative chemotherapy with FLOT improved survival through better systemic tumor control with a reduction in distant tumor recurrences, while locoregional efficacy was similar.