BACKGROUND:Respiration-induced motion hampers accurate radiotherapy, and diagnostic image quality. Ventilatory motion management strategies (VMMS, i.e. continuous positive airway pressure, jet ventilation, non-invasive mechanical ventilation, percussive ventilation and high-flow nasal oxygen) have emerged as novel respiratory motion management strategies. This evidence map aims to summarise these approaches of non-invasive respiratory motion-control to assess feasibility, comfort, potential benefits for radiotherapy and diagnostic imaging, and the identification of current research gaps. METHODS:Medline, Embase, and Web of Science were searched for publications evaluating VMMS in healthy volunteers or patients to reduce respiratory motion or alter organ positioning during radiotherapy or imaging, published in Dutch, English, or German until October 2024. RESULTS:We identified 114 studies, of which 55 were included for analysis. Ventilatory motion management strategies, ventilator settings, and patient groups appeared to be heterogenous. . Most (50/55) studies reported reduced motion, favourably changed organ shape/position and/or prolonged breath-hold durations, resulting in reduced organs-at-risk dose, improved time-efficiency or higher diagnostic image quality. In 17/55 studies, most subjects found ventilation comfortable. CONCLUSIONS:VMMS are feasible, versatile and highly beneficial in radiotherapy and diagnostic imaging, warranting further prospective comparative studies. Identified research gaps included lack of clinical outcomes and standardized reporting and terminology.

Abstract Background The introduction of (m)FOLFIRINOX and gemcitabine-nab-paclitaxel has changed the perspective for patients with locally advanced pancreatic cancer (LAPC). Consequently, in experienced centres 23% of patients with LAPC undergo a resection with 5-year overall survival (OS) rates of up to 25%. In the Netherlands, the nationwide resection rate for LAPC remains low at 8%. The PREOPANC-4 program aims for a nationwide implementation of the international multidisciplinary best-practice to improve patient outcome. Methods Nationwide program implementing the international multidisciplinary best-practice for LAPC. In the training phase, multidisciplinary and surgical webinars are given by 4 international experts, leading to a clinical protocol, followed by surgical off-site and on-site proctoring sessions. In the implementation phase, the clinical protocol will be implemented in all centres, including a nationwide expert panel (2022–2024). Healthcare professionals will be trained in shared decision-making. Consecutive patients diagnosed with pathology-proven LAPC (i.e., arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion [DPCG criteria]) are eligible. Primary outcomes are median and 5-year OS from diagnosis, resection rate, in-hospital/30-day mortality and major morbidity (i.e., Clavien-Dindo grade ≥ IIIa), and radical resection (R0) rate. Secondary outcomes include quality of life, functioning, side effects, and patients’ healthcare satisfaction in all included patients. Outcomes will be compared with patients with borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX in the PREOPANC-2 trial (EudraCT: 2017–002036-17) and a historical cohort of patients with LAPC from the PACAP registry (NCT03513705). The existing prospective LAPC Registry and PACAP PROMs (NCT03513705) will be used for data collection. In qualitative interviews, treatment preferences, values, and experiences of LAPC patients, their relatives, and healthcare professionals will be assessed for the development of shared decision-making supportive tools. It is hypothesized that the program will double the nationwide LAPC resection rate to 16% with major morbidity < 50% and mortality ≤ 5%, and OS following resection similar to that observed in patients with BRPC. Discussion The PREOPANC-4 program aims to safely implement the international multidisciplinary best-practice for LAPC leading to benchmark outcomes for both short-term morbidity, mortality, and OS. Trial registration PREOPANC-4 program was registered at ClinicalTrials.gov (NCT05524090) on September 1, 2022.

Purpose: Accurate radiation therapy (RT) for lung cancer is challenging because of the respiratory motion of the tumor and surrounding organs at risk. Recently, non-invasive mechanical ventilation (NIMV) has been investigated as a novel respiratory motion management strategy. Using NIMV, respiratory motion can be minimized, while a larger lung volume yields less overall lung dose. The purpose of this study was to determine the potential benefit of NIMV to improve lung cancer RT using magnetic resonance imaging (MRI) data of healthy volunteers. Methods and Materials: Twelve healthy volunteers practiced NIMV at 60 breaths per minute (NIMV60) with added positive end-expiratory pressure (PEEP) in 2 sessions and subsequently underwent NIMV60 in 2 MRI sessions. We acquired single-slice sagittal 2-dimensional MRI images at 2.6 Hz for 6 minutes during free breathing and NIMV60. We quantified the motion of all visible cross-sections of lung arteries, as a surrogate for lung tumors, in cranio-caudal and anterior-posterior directions using deformable image registration, distinguishing between 4 quadrants in the lungs (posterior-cranial, posterior-caudal, anterior-caudal, and anterior-cranial). Also, we analyzed average lung area, as a surrogate for lung volume, on the sagittal images using automatic segmentation. Results: All volunteers were successfully trained to be ventilated with NIMV60, and completed all sessions. The reduction of the median lung artery motion in each of the quadrants varied from 61% to 67% (from 10.7-29.9 to 3.8-11.7 mm) in cranio-caudal direction and from 51% to 68% (from 8.0-13.7 to 3.0-5.1 mm) in anterior-posterior direction using NIMV60. NIMV60 increased the sagittal lung area by 35% compared with free breathing. Conclusions: NIMV60 with added PEEP is a promising way to improve lung cancer RT because of reduced respiratory motion and increased lung area compared with free breathing.

BACKGROUND:Postoperative pancreatic fistula is the main driver of morbidity and mortality after pancreatoduodenectomy. In high-risk patients, the rate of postoperative pancreatic fistula approaches 50%, whereas it is below 5% in patients with pancreatic cancer who receive neoadjuvant chemoradiotherapy. The aim of this study was to evaluate the safety, feasibility, and efficacy of preoperative stereotactic body radiotherapy on the pancreatic neck transection margin in high-risk patients undergoing pancreatoduodenectomy to prevent postoperative pancreatic fistula. METHODS:In this prospective multicentre open-label single-arm trial (progressing from a safety run-in phase to a phase II design), patients undergoing pancreatoduodenectomy for neoplasms other than pancreatic ductal adenocarcinoma received a single preoperative stereotactic body radiotherapy dose of 12 Gy. Primary endpoints included safety (less than or equal to 15% grade 3-5 toxicity), feasibility (a significant change in pancreatic texture measured using a durometer), and efficacy (a 15% reduction in the grade B/C postoperative pancreatic fistula rate compared with patients from the Dutch Pancreatic Cancer Audit who were eligible but not included in this study). Secondary endpoints assessed tissue fibrosis (collagen density). RESULTS:Overall, 38 patients were included, of whom 33 (87%) completed the study protocol and were included in the per-protocol analysis. The safety cut-off was met, with 3% grade 3-5 toxicity. Pancreatic tissue treated with stereotactic body radiotherapy showed increased firmness using a durometer (median of 47 (interquartile range 36-57) versus 37 (interquartile range 30-41) Shore OO units; P < 0.001) and a higher collagen density (median of 6.1% (interquartile range 4.4%-9.5%) versus 4.6% (interquartile range 2.5%-7.4%); P = 0.003). The grade B/C postoperative pancreatic fistula rate with stereotactic body radiotherapy was 57.6% (95% c.i. 41% to 74%), compared with 34% (95% c.i. 27% to 42%) in audit controls (P = 0.011). CONCLUSION:Preoperative stereotactic body radiotherapy is safe in high-risk patients undergoing pancreatoduodenectomy and increases parenchymal firmness and fibrosis, but fails to show evidence of efficacy.

BACKGROUND:Guidelines recommend a time to adjuvant chemotherapy (TTC) within 12 weeks after pancreatic ductal adenocarcinoma (PDAC) resection. The aim of this study to evaluate the association between TTC and clinical outcomes in patients undergoing PDAC resection in the Netherlands. METHODS:Patients undergoing upfront, macroscopically radical PDAC resection (2014-2019) in the Netherlands were included. Patients were stratified into receiving no adjuvant chemotherapy, TTC 0-6 weeks, TTC 6-12 weeks, and TTC ≥12 weeks. Multivariable cox and logistic regression analyses were used to assess the association between TTC and overall survival (OS), and between TTC and adjuvant chemotherapy completion. RESULTS:Of 1459 patients, 543 (37 %) did not receive adjuvant chemotherapy, while TTC was 0-6 weeks in 245 (17 %), 6-12 weeks in 612 (42 %), and ≥12 weeks in 59 (4 %) patients. TTC in weeks (HR 0.99, 95 %CI 0.97-1.01, P = 0.39) and different TTC groups were not associated with OS (TTC 6-12 weeks vs TTC 0-6 weeks: HR 1.06, 95 %CI 0.76-1.49, P = 0.72, TTC ≥12 weeks vs TTC 0-6 weeks: (HR 0.62, 95 %CI 0.32-1.21, P = 0.16). Adjuvant chemotherapy completion was associated with improved OS (HR 0.81, 95 %CI 0.51-0.98, P = 0.04). Compared to TTC 0-6 weeks, TTC 6-12 weeks was associated with adjuvant chemotherapy completion (OR 1.57, 95 %CI 1.33-1.84, P < 0.001), while TTC ≥12 weeks was not (OR 1.13, 95 %CI 0.85-1.51, P = 0.39). CONCLUSION:TTC in patients with upfront PDAC resection was not associated with survival, but TTC 6-12 weeks was associated with adjuvant chemotherapy completion. These findings support prioritizing postoperative recovery rather than pushing early adjuvant chemotherapy initiation.

BACKGROUND:This study aimed to investigate the feasibility and yield of blood sample collection in an investigator-initiated nationwide randomized controlled trial (RCT). METHODS:In the PREOPANC-2 trial, 375 patients with (borderline) resectable pancreatic cancer were randomly assigned to two neoadjuvant regiments in 19 centers in the Netherlands (2018-2021). Blood sample collection was scheduled at seven time points before, during, and after treatment. The primary outcome was the proportion of successfully collected blood samples at each scheduled time point. RESULTS:Of the 375 randomized patients, 12 were excluded from blood sample collection before any treatment. From the remaining 363 patients, 1513 (87 %) of 1748 blood samples were collected, processed, mailed, and centrally stored. The blood samples were collected before treatment from 347 (96 %) of the 363 patients, after the first neoadjuvant cycle from 322 (94 %) of 343 patients, after neoadjuvant treatment (i.e., before surgery) from 260 (83 %) of 313 patients, and after surgery from 210 (77 %) of 271 patients. During the follow-up visits, blood samples were collected from 147 (82 %) of 179 patients 12 months after randomization and from 83 (77 %) of 108 patients after 24 months. A total of 220 samples (13 %) were missing. The most common causes for missing blood samples were scheduling oversights, unsuccessful blood draw attempts, and mailing failures (151 times, 69 %). Blood sample collection was canceled 69 times (31 %) due to COVID-19. CONCLUSION:Blood sample collection in the PREOPANC-2 trial had a yield of 96 % before treatment and an overall yield of 87 %. Collection of blood samples for biomarker studies is feasible in a nationwide RCT.

Background Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy, most patients experience local and/or distant PDAC recurrence within 2 years. High-level evidence regarding the benefits of recurrence-focused surveillance after PDAC resection is missing, and the impact of early detection and treatment of recurrence on survival and quality of life is unknown. In most European countries, recurrence-focused follow-up after surgery for PDAC is currently lacking. Consequently, guidelines regarding postoperative surveillance are based on expert opinion and other low-level evidence. The recent emergence of more potent local and systemic treatment options for PDAC recurrence has increased interest in early diagnosis. To determine whether early detection and treatment of recurrence can lead to improved survival and quality of life, we designed an international randomized trial.Methods This randomized controlled trial is nested within an existing prospective cohort in pancreatic cancer centers in the Netherlands (Dutch Pancreatic Cancer Project; PACAP) and the United Kingdom (UK) (Pancreas Cancer: Observations of Practice and survival; PACOPS) according to the "Trials within Cohorts" (TwiCs) design. All PACAP/PACOPS participants with a macroscopically radical resection (R0-R1) of histologically confirmed PDAC, who provided informed consent for TwiCs and participation in quality of life questionnaires, are included. Participants randomized to the intervention arm are offered recurrence-focused surveillance, existing of clinical evaluation, serum cancer antigen (CA) 19-9 testing, and contrast-enhanced computed tomography (CT) of chest and abdomen every three months during the first 2 years after surgery. Participants in the control arm of the study will undergo non-standardized clinical follow-up, generally consisting of clinical follow-up with imaging and serum tumor marker testing only in case of onset of symptoms, according to local practice in the participating hospital. The primary endpoint is overall survival. Secondary endpoints include quality of life, patterns of recurrence, compliance to and costs of recurrence-focused follow-up, and the impact on recurrence-focused treatment.Discussion The RADAR-PANC trial will be the first randomized controlled trial to generate high level evidence for the current clinical equipoise regarding the value of recurrence-focused postoperative surveillance with serial tumor marker testing and routine imaging in patients after PDAC resection. The Trials within Cohort design allows us to study the acceptability of recurrence-focused surveillance among cohort participants and increases the generalizability of findings to the general population. While it is strongly encouraged to offer all trial participants treatment at time of recurrence diagnosis, type and timing of treatment will be determined through shared decision-making. This might reduce the potential survival benefits of recurrence-focused surveillance, although insights into the impact on patients' quality of life will be obtained.Trial registration Clinicaltrials.gov, NCT04875325. Registered on May 6, 2021.

BACKGROUND:This study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection preceded by gemcitabine-based neoadjuvant chemoradiotherapy (nCRT). METHODS:Patients originated from the PREOPANC randomised controlled trial. Upfront surgery was performed in 82 patients, and 66 received nCRT before resection. The impact of sex on overall survival (OS) was investigated using Cox proportional hazards models. The immunological landscape within the tumour microenvironment (TME) was mapped using transcriptomic and spatial proteomic profiling. RESULTS:The 5-year OS rate differed between the sexes following resection preceded by nCRT, with 43% for women compared with 22% for men. In multivariate analysis, the female sex was a favourable independent prognostic factor for OS only in the nCRT group (HR 0.19; 95% CI 0.07 to 0.52). Multivariate heterogeneous treatment effects analysis revealed a significant interaction between sex and treatment, implying increased nCRT efficacy among women with resected PDAC. The TME of women contained fewer protumoural CD163+MRC1+M2 macrophages than that of men after nCRT, as indicated by transcriptomic and validated using spatial proteomic profiling. CONCLUSION:PDAC tumours of women are more sensitive to gemcitabine-based nCRT, resulting in longer OS after resection compared with men. This may be due to enhanced immunity impeding the infiltration of protumoral M2 macrophages into the TME. Our findings highlight the importance of considering sex disparities and mitigating immunosuppressive macrophage polarisation for personalised PDAC treatment.

Background: Postoperative pancreatic fistula remains the leading cause of significant morbidity after pancreatoduodenectomy for pancreatic ductal adenocarcinoma. Preoperative chemoradiotherapy has been described to reduce the risk of postoperative pancreatic fistula, but randomized trials on neoadjuvant treatment in pancreatic ductal adenocarcinoma focus increasingly on preoperative chemotherapy rather than preoperative chemoradiotherapy. This study aimed to investigate the impact of preoperative chemotherapy and preoperative chemoradiotherapy on postoperative pancreatic fistula and other pancreatic-specific surgery related complications on a nationwide level.

Novel definitions suggest that resectability status for pancreatic ductal adenocarcinoma (PDAC) should be assessed beyond anatomical criteria, considering both biological and conditional factors. This has, however, yet to be validated on a nationwide scale. This study evaluated the prognostic value of biological and conditional factors for staging of patients with resectable PDAC. A nationwide observational cohort study was performed, including all consecutive patients who underwent upfront resection of National Comprehensive Cancer Network resectable PDAC in the Netherlands (2014–2019) with complete information on preoperative carbohydrate antigen (CA) 19-9 and Eastern Cooperative Oncology Group (ECOG) performance status. PDAC was considered biologically unfavorable (RB+) if CA19-9 ≥ 500 U/mL and favorable (RB−) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (RC+) and favorable otherwise (RC−). Overall survival (OS) was assessed using Kaplan–Meier and Cox-proportional hazard analysis, presented as hazard ratios (HRs) with 95

The EORTC 22922/10925 trial aimed to investigate the impact on overall survival (OS) of elective internal mammary and medial supraclavicular (IM-MS) radiation therapy (RT) in breast cancer stage I-III. Surgery for the primary tumour and axillary lymph nodes, chest wall RT, boost RT after whole breast RT in breast conserving therapy (BCT), RT to operated axilla, and systemic therapy were per physician's preference. The aim of the current analysis is to assess breast cancer outcomes according to different locoregional and systemic therapy used in the trial. MATERIAL/METHODS:Data with a median follow-up of 15.7 years were extracted from the trial's case report forms. Kaplan-Meier curves of disease-free and OS and cumulative incidence curves of breast cancer events were produced. An exploratory analysis of the effect of the type of locoregional and systemic therapy on breast cancer outcomes was conducted using the Cox model or the Fine & Gray model accounting for competing risks, both models being adjusted for baseline patient and disease characteristics and treatment. The significance level was set at 5 %, 2-sided. RESULTS:Of the 4,004 patients included, 625 (16%) did not receive any postoperative systemic therapy, 1,185 (30%) received endocrine therapy only, 994 (25%) chemotherapy only, and 1,200 (30%) both chemotherapy and endocrine therapy, without differences between the randomisation arms. Administration and type of therapy was associated with age, menopausal status, clinical T- and N-stage and ER status (p < 0.0001). Local control was better with mastectomy (with/without postmastectomy RT) as compared to BCT, but mastectomy was associated with more distant metastasis (DM) as first event. Similarly, DM as first event occurred more in the BCT group that received a boost as compared to no boost and in those who received RT to the lower axillary level. IM-MS RT reduced significantly regional recurrences and improved disease-free survival in a sensitivity stratified analysis. OS was worse with mastectomy as compared to BCT and with irradiation of the axilla but better with sentinel node dissection and adjuvant combined chemo and hormonal therapy. CONCLUSION:Different components of therapy influenced the site of first event. IM-MS RT improved outcomes in different breast cancer outcomes were most probably related that the group were balanced due to the trial arms and stratification methods.

Purpose/Objective(s) Mild hyperthermia (39-43°C) combined with re-irradiation improves complete response compared with re-irradiation alone in locoregional recurrent (LRR) breast cancer. Observational studies analyzing a dichotomized hyperthermia thermal dose (TD) parameter showed that higher hyperthermia TD was associated with better tumor response rate compared with a lower TD. Analyzing the TD-effect relationships utilizing a continuous TD parameter would be more powerful, but has not been done so far. We therefore investigated the effect of a continuous TD parameter on locoregional control (LRC) for predicting LRC in patients with LRR breast cancer treated with postoperative re-irradiation and hyperthermia. Materials/Methods In this study, we retrospectively analyzed the data of 112 women with LRR breast cancer treated in 2010-2017 with postoperative re-irradiation 8x4Gy (n = 34) or 23x2Gy (n = 78), combined with 4-5 weekly hyperthermia sessions guided by invasive thermometry. Among possible parametrizations of CEM43 (cumulative equivalent minutes at 43°C), including the TD parameter based on time-temperature exposures, the logarithm of the session with the highest invasively measured dose CEM43T50 (median CEM43) was selected based on Weibull univariate and stepwise regression analyses. The best fitted locoregional control model was further analyzed under a Bayesian paradigm, assuming 3 informative priors (continuous highest CEM43T50, tumor location breast/chest wall and lymph node involvement). Results Twenty-four patients (21.4%) developed an infield recurrence; the median time to recurrence was 3.4 years (interquartile range (IQR) = 2.7–4.6 years). Median highest session CEM43T50 was 7.2 minutes (equivalent to a median temperature T50 of ∼40.5°C), with an IQR between 2.4–15.9 minutes. Continuous TD parameter analysis showed that a higher TD was significantly associated with an increasing LRC (P = 0.001). Univariate and multivariate Weibull regression analysis showed that over the continuous TD range a twofold increase of TD (equivalent to a ∼0.5°C temperature increase) was associated with a decrease of 47% (hazard ratio, 95% confidence interval (CI) 18%-84%) and 28% in hazard ratio for LRR (adjusted hazard ratio, 95% CI 4%-56%), respectively. Bayesian survival regressions lead to a range of comparable decreasing hazard ratios of recurrence when TD increased. These findings were robust under both an optimistic and a skeptic informative prior assumption on the effect of TD. Conclusion Twofold increase of hyperthermia TD was associated with a significant increase in LRC over the continuous TD range during hyperthermia treatment and postoperative re-irradiation in LRR breast cancer. This result has implications for the importance of achieving excellent dose control during treatment delivery and suggests an Arrhenius-like therapeutic molecular hyperthermia effect in treatment with re-irradiation and hyperthermia.