Abstract Topic Esophageal Cancer: Adjuvant and Neo-Adjuvant Therapies Background Radiation-induced lymphopenia (RIL) is an established prognostic factor associated with poorer pathologic response, disease-free survival (DFS), and overall survival (OS) in locally advanced esophageal cancer patients undergoing concurrent chemoradiotherapy (CRT). In resectable patients, standard treatment can consist of neoadjuvant CRT followed by surgery, with adjuvant nivolumab indicated (since 2022) for incomplete pathologic response. As immunotherapy efficacy relies on lymphocyte function, we hypothesize that RIL may attenuate nivolumab benefit. This study evaluates whether RIL during neoadjuvant CRT predicts nivolumab efficacy in esophageal cancer. Methods In this multicenter retrospective cohort study (2020–2024), patients from six hospitals with esophageal cancer showing incomplete pathologic response after neoadjuvant CRT and esophagectomy and available absolute lymphocyte counts (ALCs) at baseline and during CRT, were analyzed. To avoid immortal time bias, only patients surviving ≥90 days post-surgery were included. Severe RIL was predefined as grade ≥3 lymphopenia (ALC <0.5K/μL) in week 3 of CRT; the threshold best distinguishing survival in the largest series to date. Baseline characteristics were compared between groups with versus without severe RIL, and subsequent survival analyses for patients with nivolumab versus without nivolumab were analyzed within each group. DFS and OS were calculated from esophagectomy using Kaplan-Meier analyses, and compared between nivolumab and no nivolumab using Cox regression analyses. Baseline differences between nivolumab and no nivolumab groups were primarily driven by diagnosis year (i.e. reimbursement), but residual imbalances were adjusted via inverse-probability-of-treatment-weighting (IPTW). Results Among 264 patients, those with severe RIL (n=117 [44%]) had significantly higher cN- and overall clinical stage, and lower baseline ALC. In the 147 patients without severe RIL, significantly better outcomes were observed with nivolumab (n=63; DFS: hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.20-0.90; OS: HR 0.20, 95%CI 0.08-0.53; Figure 1), even after IPTW-adjustment (DFS: HR 0.44, 95%CI 0.19-1.01; OS: HR 0.19, 95%CI 0.07-0.54). In the 117 patients with severe RIL, no significant outcome advantages were observed with nivolumab (n=55; DFS: HR 0.92, 95%CI 0.47-1.82; OS: HR 0.67, 95%CI 0.34-1.32; Figure 2), also not after IPTW-adjustment (DFS: HR 0.64, 95%CI 0.41-1.74; OS: HR 0.56, 95%CI 0.27-1.15). Conclusion Patients with severe RIL during neoadjuvant CRT do not seem to benefit from adjuvant nivolumab for esophageal cancer. The DFS and OS benefit of adjuvant nivolumab appears confined to patients without severe RIL. How this relates to PD-L1-status is under investigation. This hypothesis-generating study indicates RIL might serve as predictive biomarker for nivolumab benefit in esophageal cancer.

BACKGROUND:Physical activity (PA) is associated with improved overall survival (OS) among colorectal cancer (CRC) patients, but research on PA changes after diagnosis remains limited. This study examines associations between OS and changes in PA from CRC diagnosis onward, across stage- and treatment-related subgroups. METHODS:Data were analyzed from patients in two large CRC cohorts (PLCRC and COLON) enrolled between August 2010 and December 2022 (follow-up until February 1st, 2024). This included 3395 stage I-IIA patients who underwent surgery only, 2406 stage IIB/C-III patients who received (neo-)adjuvant therapy, and 669 metastatic CRC (mCRC) patients. PA was assessed via the validated SQUASH questionnaire at diagnosis (T0), and at 6, 12, and 24 months post-diagnosis (T6 to T24). Moderate-to-vigorous-intensity recreational activity was quantified by calculating Metabolic Equivalent of Task (MET) hours per week. Associations with OS were examined for change (active [tertile 2 and 3] vs inactive [tertile 1]) between timepoints using multivariable Cox proportional hazards models. RESULTS:Among surgery-only patients, change from inactivity to activity between T0 and T6 was significantly associated with OS (HR = 0.58, 95% CI = 0.35 to 0.96). For (neo-)adjuvantly treated patients, significant associations were observed between T6 and T12 (HR = 0.53, 95% CI = 0.31 to 0.90). Among mCRC patients, a significant association was observed between T6 and T12 (HR = 0.53, 95% CI = 0.29 to 0.99). CONCLUSION:Changing from inactivity to activity is significantly associated with prolonged survival during the early months post-diagnosis for surgery-only CRC patients, and later for those undergoing (neo-)adjuvant therapy or with metastatic disease. Validation is warranted in interventional studies.

Objective.To investigate the evolution of beam quality in the Papillon+ contact x-ray therapy device and its dosimetric impact, a fast and straightforward beam quality index (QI) measurement method was proposed and validated. Additionally, the dosimetric consequences of tumour intrusion into the applicator tube were examined through Monte Carlo (MC) simulations and, for the first time, direct in-applicator dose measurements.Approach.QI measurements were performed every four weeks from mid-2022. Half-value layer (HVL) and depth-dose profile measurements in a plastic water low energy range phantom were conducted twice, with a two-year interval. Dose distributions for tumour intrusion scenarios (2.5-10 mm) were assessed using MC simulations and Gafchromic film measurements inside the applicator tube. Gross tumour volume (GTV) dose calculations (physical and EQD2) were performed for varying tumour thicknesses, intrusion depths, and diameters.Main results.All methods consistently demonstrated progressive beam hardening over time, with the HVL increasing from 0.77 mm Al to 0.93 mm Al. This spectral shift, attributed to x-ray tube ageing and radiation-induced material changes, was reversibly corrected after service replacement of the flattening filter, restoring the soft spectrum (HVL ≈ 0.69 mm Al). Tumour intrusion produced the strongest dosimetric effect, with surface dose increases up to 2.4-fold at 10 mm intrusion, exceeding MC predictions. GTV D90 decreased with tumour thickness but increased sharply with intrusion depth, whereas tumour diameter and surrounding medium had a negligible impact.Significance.This work highlights the importance of systematic beam quality follow-up in contact x-ray brachytherapy systems. Routine QI monitoring, together with well-defined beam-quality specifications and action limits, enables early detection of deviations, timely maintenance, and sustained compliance of the delivered beam quality in clinical practice. Tumour positioning relative to and protrusion into the applicator remains the dominant factor affecting dose distribution, underscoring the need for precise clinical setup and ongoing device characterisation to ensure clinical accuracy and patient safety.

Introduction: Due to the rarity of anal cancer, real-world data on treatment outcomes are scarce. However, its incidence is increasing in the Netherlands with > 300 new cases and 70 deaths yearly. Standard of care consists of chemoradiotherapy (CRT) or radiotherapy alone (RT). The primary objective of our nationwide study was twofold; to evaluate real-world outcomes after curatively intended CRT/RT for anal squamous cell carcinoma (ASCC), and to create a large, high-quality dataset as a national benchmark to guide future prospective research. Material and methods: Data were collected retrospectively from 16 Dutch institutions treating ASCC between 2015 and 2018. Primary endpoint was locoregional recurrence free survival (LRFS). Secondary endpoints were overall survival (OS), disease specific survival (DSS), colostomy free survival (CFS), complete response (CR) and toxicity. Results: A total of 462 patients were analysed. Most patients received CRT (85%), with mitomycin-capecitabine as a radiosensitizer in 86% of cases. After median follow-up of 5 years, LRFS for all patients was 80% at 3 years and 78% at 5 years. In total 82% of patients had reached CR, with a median interval to define CR of 3 months. At 3 years, OS, DSS and CFS were 78%, 86% and 88%, respectively. Conclusion: These real-world data demonstrate that curatively intended CRT/RT for ASCC results in LRFS of 80% at 3 years. Organ preservation outcomes were favourable with a CFS of 88% at 3 years. These findings support the current treatment approach as the reference standard for these patients and provide a national benchmark to guide future prospective research.

PURPOSE:In intensity-modulated proton therapy (IMPT) for esophageal cancer, organ motion can cause deviations between planned and delivered dose. Owing to posterior beam arrangements, the heart is particularly vulnerable, as the distal fall-off frequently overlaps cardiac tissue. This study quantified heart dose changes during treatment, identified contributing anatomical factors, and evaluated a heart-dose-guided adaptation protocol. METHODS:We retrospectively analyzed 194 esophageal cancer patients treated with IMPT using weekly repeat CT scans (reCTs). Prescriptions were 23 × 1.8 Gy or 28 × 1.8 Gy (RBE). Plans were recalculated on each reCT to derive mean heart dose (MHD) and heart V40Gy. Dose trends were assessed alongside anatomical changes, including diaphragm baseline shift, heart position and volume, heart displacement, internal target volume (ITV), intraesophageal air, posterior subcutaneous adipose tissue, and dysphagia scores. Significant variables were included in an Elastic Net model to predict MHD changes with 10-fold cross-validation. The effect of an adaptation protocol-triggered by MHD increases >1.5 Gy or target underdosage-was evaluated in 111 patients treated after August 2022, 25 of whom underwent replanning due to increasing MHD. RESULTS:Linear mixed modeling in all reCTs of 194 patients showed significant increases in MHD (0.4 Gy/week, p < 0.001) and heart V40Gy (4.1 cc/week, p < 0.001), alongside increased dysphagia scores, cranio-caudal heart displacement, reduced ITV, and diaphragm baseline shifts relative to planning CTs. Elastic Net modeling identified diaphragm shift and heart volume change as key predictors of MHD increase. In the full cohort, MHD increased by 0.7 Gy, while in the sub group of 25 adapted patients, the MHD increase was reduced from 1.5 Gy to 0.8 Gy (p < 0.01). CONCLUSION:Heart dose increases significantly during IMPT for esophageal cancer due to anatomical changes. Heart-dose-guided adaptive replanning effectively mitigates this increase.

Background and Purpose:For mediastinal lymphoma patients, comparative data on intensity modulated proton therapy in breath-hold (IMPT-BH) versus other radiation techniques remain limited, particularly regarding dose-volume histogram (DVH) metrics and normal tissue complication probability (NTCP) for late side effects. Materials and Methods:This retrospective in silico planning study included 58 lymphoma patients, treated between 2019 and May 2024, having 4D-CT and BH-CT available. Four plans per patient were made: volumetric arc therapy in free-breathing (VMAT-FB), VMAT-BH, IMPT-FB, and IMPT-BH. An absolute dose difference ≥ 1 Gy was considered clinically relevant, and patients were assigned to the optimal technique. Results:IMPT-BH resulted in the lowest average mean heart dose (MHD) at 5.4 Gy (p < 0.01) compared to VMAT-FB (8.0 Gy), VMAT-BH (6.3 Gy) and IMPT-FB (5.8 Gy). IMPT-BH resulted in the lowest average mean lung dose (MLD) at 6.7 Gy (p<0.01), compared to VMAT-FB (9.2 Gy), VMAT-BH (7.5 Gy), and IMPT-FB (7.3 Gy). Average bilateral mean breast dose (MBD) was lower with IMPT (2.1 Gy) compared to VMAT (3.2 Gy; p<0.01). IMPT was optimal for ≥ 69% of patients. Conclusions:IMPT-BH achieved the lowest MHD, MLD, and bilateral MBD compared to IMPT-FB, VMAT-BH, and VMAT-FB in the majority of patients.

Background: Watch-and-Wait (W&W) is an organ-preserving strategy for patients with rectal cancer who achieve a clinical (near-)complete response after neoadjuvant (chemo)radiotherapy, by avoiding major resection surgery. However, long-term functional outcomes, especially beyond 2 years, are poorly documented. We aimed to evaluate 5‑year Quality-of-Life (QoL) and bowel function in a nationwide prospective cohort of patients managed with W&W. Methods: We included 209 patients from a Dutch multicentre prospective cohort study with follow-up at 2 and/or 5 years. General QoL was assessed using the EORTC-QLQ-C30 questionnaire, and colorectal-specific QoL using the EORTC-QLQ-CR29/CR38 questionnaires. Bowel function was evaluated using the Low Anterior Resection Syndrome (LARS) score. Findings: Among 209 patients included, 140 (67%) were male, with a median age of 64 years (44-84). At 5 years, 162 (77%) were still managed with W&W, 12 (6%) underwent local excision, and 35 (17%) underwent (salvage) total mesorectal excision. In the W&W group, only sexual interest in men and women showed clinically meaningful and statistically significant deterioration over time (both p=0·001). QLQ-C30 scores remained largely stable between 2 and 5 years. CR29 analyses demonstrated statistically significant worsening of flatulence (p=0·01), faecal incontinence (p=0·003) and impotence (p=0·03), although none met predefined thresholds for clinical relevance. Mean LARS scores remained stable and the distribution of LARS categories (no/minor/major LARS) did not differ between 2 and 5 years (p=0·23). Interpretation: Five years after neoadjuvant (chemo)radiotherapy, rectal cancer patients managed with W&W preserved good long-term QoL and stable bowel function, without a significant shift in LARS categories. Clinically meaningful deterioration was limited to sexual interest in both men and women. Other colorectal-specific domains showed no clinically relevant changes. These findings may partly reflect long-term radiotherapy effects and advancing age during long-term follow-up. Overall, the results support favourable long-term functional outcomes of the W&W approach.

Precision oncology relies on access to high-quality data for increasingly smaller patient subgroups. The international atomCAT consortium investigates the potential of federated learning to support this, using anal cancer as a rare cancer exemplar. Here, we show that federated multivariable Cox models trained across 14 centres (1428 patients) and externally validated in two additional centres (277 patients) achieve consistent calibration and discrimination during leave-one-centre-out and external validation (c-indices 0.68-0.79). Lower T stage, absence of nodal involvement, smaller tumour volume, female sex, younger age, and mitomycin- or cisplatin-based chemotherapy are associated with improved overall survival. Lower T stage, smaller tumour volume, and female sex are associated with improved locoregional control, while absence of nodal involvement and smaller tumour volume are associated with better freedom from distant metastases. These findings demonstrate that federated learning enables robust, privacy-preserving prognostic modelling for rare cancers using real-world data, supporting international collaboration without data sharing.

BACKGROUND:Chemoradiotherapy (CRT) plays a key role in treating esophageal cancer (EC) but is associated with significant toxicity. Proton radiotherapy (PRT) may reduce this risk by limiting radiation dose to organs at risk. In the Netherlands, PRT is reimbursed only when eligibility criteria defined in a National Indication Protocol for Proton Therapy (NIPP) are met. This study describes the development and implementation of such a protocol for EC based on model-based selection. MATERIALS AND METHODS:A national multidisciplinary working group was formed aiming to develop the NIPP protocol through literature review, evaluation of prediction models, external model validation, and stakeholder engagement. RESULTS:Cardiac events and overall survival were identified as the most clinically relevant endpoints. As no existing models met the quality criteria for model-based selection, a validated 2-year mortality prediction model originally developed for lung cancer was externally validated in EC patients treated with definitive (dCRT) or neoadjuvant (nCRT) CRT. The model performed well after updates to the intercept (both cohorts) and slope (nCRT). Model-based selection was defined as a ≥ 5 % predicted absolute reduction in 2-year mortality with PRT versus photon radiotherapy, using Mean Heart Dose (MHD) and Gross Tumor Volume (GTV) as predictors. Additional selection criteria included WHO performance status 0-2 and exclusion of cT4, cN3, or cM1 status. The NIPP was approved by the Dutch Society of Radiation Oncology in June 2021 and by the Dutch Health Care Institute in October 2021. National implementation and prospective outcome evaluation are ongoing via the ProTRAIT registry. CONCLUSION:A national indication protocol enabling model-based selection for PRT in EC was successfully implemented in the Netherlands. The NIPP describes eligibility criteria for proton therapy reimbursement and enables reimbursement for individual patients who are expected to benefit from PRT.

Introduction: Target volume delineation in locally recurrent rectal cancer (LRRC) is clinically challenging. To ensure the quality of chemoradiotherapy (CRT) within the PelvEx II trial, a delineation guideline was developed and prospective quality assurance (QA) was instated for all patients. Guideline adherence, the impact of QA on target volumes, and subsequent guideline refinements are described in this paper. Methods and materials: All PelvEx II patients, either RT naive patients (50-50.4 Gy) or reirradiation (30 Gy) patients, were eligible for QA prior to CRT. An online meeting with the treating physician and the QA team was planned for each patient prior to treatment, to peer review delineations. Adherence to each of the 7 (reirradiation) or 8 (RT naive) guideline recommendations was scored. Suggested target volume adjustments and any reasons to deviate from protocol were noted. When applicable, target volumes before and after QA were compared. Possible protocol refinements were discussed amongst the trial QA team. Results: Prospective review of 113 cases of LRRC was performed, resulting in a high QA compliance rate of 90 %. All guideline recommendations were followed in 53 % of cases. Changes to the GTV and CTV were advised in 21 and 39 cases respectively. A median increase of GTV (+29 % (p < 0.001)) and CTV (+15 % (p < 0.001)) was seen in reirradiation patients, versus a median CTV increase of + 6 % (p = 0.002) in RT naive patients following QA. Deviations from protocol were accepted in 30 cases (27 %). Thirteen protocol refinements were agreed upon. Conclusion: Peer-review of LRRC target volumes leads to altered target volumes in up to 48% of cases, resulting in an updated delineation guideline.