Predicting Long-term Disease-free Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Nationwide Cohort Study.

OBJECTIVE: To develop a prediction model for long-term (≥5 years) disease-free survival (DFS) after the resection of pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Despite high recurrence rates, ~10% of patients have long-term DFS after PDAC resection. A model to predict long-term DFS may aid individualized prognostication and shared decision-making. METHODS: This nationwide cohort study included all consecutive patients who underwent PDAC resection in the Netherlands (2014-2016). The best-performing prognostic model was selected by Cox-proportional hazard analysis and Akaike's Information Criterion, presented by hazard ratios (HRs) with 95% confidence intervals (CIs). Internal validation was performed, and discrimination and calibration indices were assessed. RESULTS: In all, 836 patients with a median follow-up of 67 months (interquartile range 51-79) were analyzed. Long-term DFS was seen in 118 patients (14%). Factors predictive of long-term DFS were low preoperative carbohydrate antigen 19-9 (logarithmic; HR 1.21; 95% CI 1.10-1.32), no vascular resection (HR 1.33; 95% CI 1.12-1.58), T1 or T2 tumor stage (HR 1.52; 95% CI 1.14-2.04, and HR 1.17; 95% CI 0.98-1.39, respectively), well/moderate tumor differentiation (HR 1.44; 95% CI 1.22-1.68), absence of perineural and lymphovascular invasion (HR 1.42; 95% CI 1.11-1.81 and HR 1.14; 95% CI 0.96-1.36, respectively), N0 or N1 nodal status (HR 1.92; 95% CI 1.54-2.40, and HR 1.33; 95% CI 1.11-1.60, respectively), R0 resection margin status (HR 1.25; 95% CI 1.07-1.46), no major complications (HR 1.14; 95% CI 0.97-1.35) and adjuvant chemotherapy (HR 1.74; 95% CI 1.47-2.06). Moderate performance (concordance index 0.68) with adequate calibration (slope 0.99) was achieved. CONCLUSIONS: The developed prediction model, readily available at www.pancreascalculator.com, can be used to estimate the probability of long-term DFS after resection of pancreatic ductal adenocarcinoma.

The Value of Biological and Conditional Factors for Staging of Patients with Resectable Pancreatic Cancer Undergoing Upfront Resection: A Nationwide Analysis.

BACKGROUND: 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. PATIENTS AND METHODS: 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% confidence interval (CI). RESULTS: Overall, 688 patients were analyzed with a median overall survival (OS) of 20 months (95% CI 19-23). OS was 14 months (95% CI 10 months-median not reached) in 20 RB+C+ patients (3%; HR 1.61, 95% CI 0.86-2.70), 13 months (95% CI 11-15) in 156 RB+C- patients (23%; HR 1.86, 95% CI 1.50-2.31), and 21 months (95% CI 12-41) in 47 RB-C+ patients (7%; HR 1.14, 95% CI 0.80-1.62) compared with 24 months (95% CI 22-27) in 465 patients with RB-C- PDAC (68%; reference). CONCLUSIONS: Survival after upfront resection of anatomically resectable PDAC is worse in patients with CA19-9 ≥ 500 U/mL, while performance status had no impact. This supports consideration of CA19-9 in preoperative staging of resectable PDAC.

Timing of rectal cancer surgery after short-course radiotherapy: national database study.

BACKGROUND: Previous randomized trials found that a prolonged interval between short-course radiotherapy (SCRT, 25 Gy in 5 fractions) and surgery for rectal cancer (4-8 weeks, SCRT-delay) results in a lower postoperative complication rate and a higher pCR rate than SCRT and surgery within a week (SCRT-direct surgery). This study sought to confirm these results in a Dutch national database. METHODS: Patients with intermediate-risk rectal cancer (T3(mesorectal fascia (MRF)-) N0 M0 and T1-3(MRF-) N1 M0) treated with either SCRT-delay (4-12 weeks) or SCRT-direct surgery in 2018-2021 were selected from a Dutch national colorectal cancer database. Confounders were adjusted for using inverse probability of treatment weighting (IPTW). The primary endpoint was the 90-day postoperative complication rate. Secondary endpoints included the pCR rate. Endpoints were compared using log-binomial and Poisson regression. RESULTS: Some 664 patients were included in the SCRT-direct surgery and 238 in the SCRT-delay group. After IPTW, the 90-day postoperative complication rate was comparable after SCRT-direct surgery and SCRT-delay (40.1 versus 42.3 per cent; risk ratio (RR) 1.1, 95 per cent c.i. 0.9 to 1.3). A pCR occurred more often after SCRT-delay than SCRT-direct surgery (10.7 versus 0.4 per cent; RR 39, 11 to 139). CONCLUSION: There was no difference in surgical complication rates between SCRT-delay and SCRT-direct, but SCRT-delay was associated with more patients having a pCR.

Patient- and physician-reported radiation-induced toxicity of short-course radiotherapy with a prolonged interval to surgery for rectal cancer.

AIM: A prolonged interval (>4 weeks) between short-course radiotherapy (25 Gy in five fractions) (SCRT-delay) and total mesorectal excision for rectal cancer has been associated with a decreased postoperative complication rate and offers the possibility of organ preservation in the case of a complete tumour response. This prospective cohort study systematically evaluated patient-reported bowel dysfunction and physician-reported radiation-induced toxicity for 8 weeks following SCRT-delay. METHOD: Patients who were referred for SCRT-delay for intermediate risk, oligometastatic or locally advanced rectal cancer were included. Repeated measurements were done for patient-reported bowel dysfunction (measured by the low anterior resection syndrome [LARS] questionnaire and categorized as no, minor or major LARS) and physician-reported radiation-induced toxicity (according to Common Terminology Criteria for Adverse Events version 4.0) before start of treatment (baseline), at completion of SCRT and 1, 2, 3, 4, 6 and 8 weeks thereafter. RESULTS: Fifty-one patients were included; 31 (61%) were men and the median age was 67 years (range 44-91). Patient-reported bowel dysfunction and physician-reported radiation-induced toxicity peaked at weeks 1-2 after completion of SCRT and gradually declined thereafter. Major LARS was reported by 44 patients (92%) at some time during SCRT-delay. Grade 3 radiation-induced toxicity was reported in 17 patients (33%) and concerned predominantly diarrhoea. No Grade 4-5 radiation-induced toxicity occurred. CONCLUSION: During SCRT-delay, almost every patient experiences temporary mild-moderate radiation-induced toxicity and major LARS, but life-threatening toxicity is rare. SCRT-delay is a safe alternative to SCRT-direct surgery that should be proposed when counselling rectal cancer patients on neoadjuvant strategies.

Detection, Treatment, and Survival of Pancreatic Cancer Recurrence in the Netherlands: A Nationwide Analysis.

OBJECTIVE: To evaluate whether detection of recurrent pancreatic ductal adenocarcinoma (PDAC) in an early, asymptomatic stage increases the number of patients receiving additional treatment, subsequently improving survival. SUMMARY OF BACKGROUND DATA: International guidelines disagree on the value of standardized postoperative surveillance for early detection and treatment of PDAC recurrence. METHODS: A nationwide, observational cohort study was performed including all patients who underwent PDAC resection (2014-2016). Prospective baseline and perioperative data were retrieved from the Dutch Pancreatic Cancer Audit. Data on follow-up, treatment, and survival were collected retrospectively. Overall survival (OS) was evaluated using multivariable Cox regression analysis, before and after propensity-score matching, stratified for patients with symptomatic and asymptomatic recurrence. RESULTS: Eight hundred thirty-six patients with a median follow-up of 37 months (interquartile range 30-48) were analyzed. Of those, 670 patients (80%) developed PDAC recurrence after a median follow-up of 10 months (interquartile range 5-17). Additional treatment was performed in 159/511 patients (31%) with symptomatic recurrence versus 77/159 (48%) asymptomatic patients (P < 0.001). After propensity-score matching on lymph node ratio, adjuvant therapy, disease-free survival, and recurrence site, additional treatment was independently associated with improved OS for both symptomatic patients [hazard ratio 0.53 (95% confidence interval 0.42-0.67); P < 0.001] and asymptomatic patients [hazard ratio 0.45 (95% confidence interval 0.29-0.70); P < 0.001]. CONCLUSIONS: Additional treatment of PDAC recurrence was independently associated with improved OS, with asymptomatic patients having a higher probability to receive recurrence treatment. Therefore, standardized postoperative surveillance aiming to detect PDAC recurrence before the onset of symptoms has the potential to improve survival. This provides a rationale for prospective studies on standardized surveillance after PDAC resection.

Online adaptive MR-guided stereotactic radiotherapy for unresectable malignancies in the upper abdomen using a 1.5T MR-linac.

BACKGROUND: Introduction of online adaptive MR-guided radiotherapy enables stereotactic body radiation therapy (SBRT) of upper abdominal tumors. This study aimed to evaluate the feasibility of MR-guided SBRT on a 1.5 T MR-linac in patients with unresectable upper abdominal malignancies. MATERIAL AND METHODS: Patients treated at the UMC Utrecht (April 2019 to December 2020) were identified in the prospective 'Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac' (MOMENTUM) study. Feasibility of treatment was arbitrarily defined as an on-table time interval of ≤60 min for >75% of delivered fractions and completion of >95% of fractions as scheduled, reflecting patient tolerability. Acute treatment-related toxicity was assessed at 3 months of follow-up and graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events version 5.0. RESULTS: Twenty-five consecutive patients with a median follow-up time of 8 (range 4-23) months were treated with 35 Gray (n = 4) and 40 Gray (n = 21) in five fractions over 2 weeks. For all fractions, contours were adapted based on the daily anatomy and delivered within 47 min/fraction (range 30-74). In 98/117 fractions (84%), adapted treatment was completed within 1 h. All patients received the scheduled irradiation dose as planned. No acute grade 3 toxicity or higher was reported. Treatment resulted in pain alleviation in 11/13 patients. DISCUSSION: Online adaptive MR-guided SBRT on a 1.5 T MR-linac is feasible and well-tolerated in patients with unresectable upper abdominal malignancies. Dose escalation studies, followed by comparative studies, are needed to determine the optimal radiation dose for irradiation of upper abdominal malignancies.

Preoperative predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma.

BACKGROUND: This study aimed to identify predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) resection with and without neoadjuvant therapy. METHODS: Included were patients who underwent PDAC resection (2014-2016). Multivariable multinomial regression was performed to identify preoperative predictors for manifestation of recurrence within 3, 6 and 12 months after PDAC resection. RESULTS: 836 patients with a median follow-up of 37 (interquartile range [IQR] 30-48) months and overall survival of 18 (IQR 10-32) months were analyzed. 670 patients (80%) developed recurrence: 82 patients (10%) <3 months, 96 patients (11%) within 3-6 months and 226 patients (27%) within 6-12 months. LogCA 19-9 (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and neoadjuvant treatment (OR 0.09 [95% CI 0.01-0.68]; P = 0.02) were associated with recurrence <3 months. LogCA 19-9 (OR 1.23 [95% CI 1.10-1.38]; P < 0.001) and 0-90° venous involvement on CT imaging (OR 2.93 [95% CI 1.60-5.37]; P < 0.001) were associated with recurrence within 3-6 months. A Charlson Age Comorbidity Index ≥4 (OR 1.53 [95% CI 1.09-2.16]; P = 0.02) and logCA 19-9 (OR 1.24 [95% CI 1.14-1.35]; P < 0.001) were related to recurrence within 6-12 months. CONCLUSION: This study demonstrates preoperative predictors that are associated with the manifestation of early and very early recurrence after PDAC resection. Knowledge of these predictors can be used to guide individualized surveillance and treatment strategies.

Patient-Reported Work Ability During the First Two Years After Rectal Cancer Diagnosis.

BACKGROUND: Rectal cancer treatment is associated with substantial short- and longer-term morbidity that may affect patients' ability to work. OBJECTIVE: We evaluated patient-reported work ability during the first 2 years after rectal cancer diagnosis, relative to the Dutch general population. Also, we assessed the association between clinical factors and work ability. DESIGN: This is a prospective cohort study. SETTINGS: This study was conducted at the Radiation-Oncology Department of a tertiary center. PATIENTS: Patients with rectal cancer, <67 years of age, and treated with curative intent were selected. MAIN OUTCOME MEASURES: Work ability was assessed with the Work Ability Index before the start of treatment (baseline) and at 3, 6, 12, 18, and 24 months after. The Work Ability Index scores of patients with paid employment were compared with the scores of matched population controls. Mixed models were used to estimate the impact of clinical factors on work ability. RESULTS: Of the 230 eligible patients, 172 (75%) had paid employment. Work ability decreased at 3 and 6 months compared with baseline. At 12 months, work ability recovered to baseline level but remained significantly lower than in population controls up to 24 months. Fifty-four percent reported 100 to 365 days of sick leave during the first 12 months of treatment versus 2% in the general population. At 24 months, 32% needed substantial adaptations in work activities, worked reduced hours, or were unable to work due to the disease versus 6% in the general population. Female sex, multiple comorbidities, oligometastatic disease, chemoradiation, and abdominoperineal resection were associated with lower work ability. LIMITATIONS: The study was limited by a decrease in questionnaire response rate from 83% to 64% over time. CONCLUSIONS: Patient-reported work ability deteriorates during rectal cancer treatment. Within 24 months after diagnosis, work ability returns to pretreatment level but remains lower than that of the general population. See Video Abstract at http://links.lww.com/DCR/B175. CAPACIDAD DE TRABAJO REPORTADO POR PACIENTES DURANTE LOS PRIMEROS DOS AÑOS DESPUÉS DEL DIAGNÓSTICO DE CÁNCER RECTAL: El tratamiento del cáncer rectal se asocia con una morbilidad significante a corto y largo plazo que puede afectar la capacidad de trabajo de pacientes.Evaluamos la capacidad de trabajo reportado por pacientes durante los primeros dos años después del diagnóstico de cáncer rectal, en relación con la población general holandesa. Además, evaluamos la asociación entre los factores clínicos y capacidad para trabajar.Estudio de cohorte prospectivo.Este estudio se realizó en el Departamento de Radiación Oncológica de en un centro de referencia de tercer nivel.Se seleccionaron pacientes con cáncer rectal, <67 años de edad, y tratados con intención curativa.La capacidad de trabajo se evaluó con el índice de capacidad de trabajo antes del inicio del tratamiento (línea de base) y a los 3, 6, 12, 18 y 24 meses después. Los puntajes de capacidad laboral de los pacientes con empleo remunerado se compararon con los puntajes de los controles de población pareados. Se utilizaron modelos mixtos para estimar el impacto de los factores clínicos en la capacidad laboral.De los 230 pacientes elegibles, 172 (75%) tenían empleo remunerado. La capacidad de trabajo disminuyó a los 3 y 6 meses en comparación con la línea de base. A los 12 meses, la capacidad de trabajo se recuperó al nivel de referencia, pero se mantuvo significativamente más baja que en los controles de la población hasta 24 meses. Durante los primeros 12 meses, el 54% reportó 100-365 días de baja por enfermedad versus el 2% en la población general. A los 24 meses, el 32% necesitaba adaptaciones sustanciales en las actividades laborales, trabajó horas reducidas o no pudo trabajar debido a la enfermedad frente al 6% en la población general. El sexo femenino, las comorbilidades múltiples, la enfermedad oligometastásica, la quimiorradiación y la resección abdominoperineal se asociaron con una menor capacidad de trabajo.El estudio estuvo limitado por una disminución en la tasa de respuesta al cuestionario del 83% al 64% a lo largo plazo.La capacidad laboral informada por el paciente se deteriora durante el tratamiento del cáncer rectal. Dentro de los 24 meses posteriores al diagnóstico, la capacidad laboral vuelve al nivel de pretratamiento, pero sigue siendo inferior a la de la población general. Consulte Video Resumen en http://links.lww.com/DCR/B175. (Traducción-Dr. Adrian Ortega).

Health-related quality of life in rectal cancer patients undergoing neoadjuvant chemoradiation with delayed surgery versus short-course radiotherapy with immediate surgery: a propensity score-matched cohort study.

BACKGROUND: Neoadjuvant chemoradiation with delayed surgery (CRT-DS) and short-course radiotherapy with immediate surgery (SCRT-IS) are two commonly used treatment strategies for rectal cancer. However, the optimal treatment strategy for patients with intermediate-risk rectal cancer remains a discussion. This study compares quality of life (QOL) between SCRT-IS and CRT-DS from diagnosis until 24 months after treatment. METHODS: In a prospective colorectal cancer cohort, rectal cancer patients with clinical stage T2-3N0-2M0 undergoing SCRT-IS or CRT-DS between 2013 and 2017 were identified. QOL was assessed using EORTC-C30 and EORTC-CR29 questionnaires before the start of neoadjuvant treatment (baseline) and at 3, 6, 12, 18 and 24 months after. Patients were 1:1 matched using propensity sore matching. Between- and within-group differences in QOL domains were analyzed with linear mixed-effects models. Symptoms and sexual interest at 12 and 24 months were compared using logistic regression models. RESULTS: 156 of 225 patients (69%) remained after matching. The CRT-DS group reported poorer emotional functioning at 3, 6, 12, 18 and 24 months (mean difference with SCRT-IS: -9.4, -12.1, -7.3, -8.0 and -7.9 respectively), and poorer global health, physical-, role-, social- and cognitive functioning at 6 months (mean difference with SCRT-IS: -9.1, -9.8, -14.0, -9.2 and -12.6, respectively). Besides emotional functioning, all QOL domains were comparable at 12, 18 and 24 months. Within-group changes showed a significant improvement of emotional functioning after baseline in the SCRT-IS group, whereas only a minor improvement was observed in the CRT-DS group. Symptoms and sexual interest in male patients at 12 and 24 months were comparable between the groups. CONCLUSIONS: In rectal cancer patients, CRT-DS may induce a stronger decline in short-term QOL than SCRT-IS. From 12 months onwards, QOL domains, symptoms and sexual interest in male patients were comparable between the groups. However, emotional functioning remained higher after SCRT-IS than after CRT-DS.

Utility Scores and Preferences for Surgical and Organ-Sparing Approaches for Treatment of Intermediate and High-Risk Rectal Cancer.

BACKGROUND: Organ-sparing approaches, including wait-and-see and local excision, are increasingly being offered to patients with rectal cancer following a good response to neoadjuvant therapy. Preferences regarding these treatment strategies are yet unknown. OBJECTIVE: This study aimed to determine the preferences and utility scores for rectal cancer treatment approaches. DESIGN: This is a cross-sectional study. SETTING: This study was conducted at the Radiation-Oncology Department of the University Medical Center Utrecht. PATIENTS: Fifty-seven patients with a history of rectal cancer and 38 volunteers were included. MAIN OUTCOME MEASURES: Participants assessed 6 hypothetical treatment-outcome scenarios, including short-course radiotherapy or chemoradiation followed by abdominoperineal resection, low anterior resection, local excision, or a wait-and-see approach. The hierarchy in preferences between scenarios was assessed by using ranking. Utilities were estimated with a visual analog scale and time trade-off. RESULTS: Organ-sparing approaches were ranked as the first preferred treatment option by 51% of the participants. Among all scenarios, wait-and-see was most often ranked highest by patients and volunteers (36% and 50%). Meanwhile, a substantial proportion ranked wait-and-see as their lowest preference (38% in patients and 35% in volunteers). Utility scores differed significantly between scenarios. Wait-and-see received a significantly higher score on the visual analog scale than the scenarios including abdominoperineal resection and the scenario including chemoradiation with low anterior resection, and a score similar to the scenarios including local excision and short-course radiotherapy with low anterior resection. LIMITATIONS: The study population consisted of patients with a history of rectal cancer treatment and volunteers related to patients. This may have influenced preferences. CONCLUSIONS: This study suggests that there is a wide disparity in preferences concerning organ-sparing approaches for rectal cancer in both patients with a history of rectal cancer and volunteers. Wait-and-see is often the highest preferred treatment, but it is also among the least preferred treatment options. These findings give insights into how patients may value the current rectal cancer treatment options. See Video Abstract at http://links.lww.com/DCR/A521.

Systematic review on the role of serum tumor markers in the detection of recurrent pancreatic cancer.

BACKGROUND: Biomarker testing can be helpful to monitor disease progression after resection of pancreatic cancer. This systematic review aims to give an overview of the literature on the diagnostic value of serum tumor markers for the detection of recurrent pancreatic cancer during follow-up. METHODS: A systematic search was performed to 2 October 2017. All studies reporting on the diagnostic value of postoperatively measured serum biomarkers for the detection of pancreatic cancer recurrence were included. Data on diagnostic accuracy of tumor markers were extracted. Forest plots and pooled values of sensitivity and specificity were calculated. RESULTS: Four articles described test results of CA 19-9. A pooled sensitivity and specificity of respectively 0.73 (95% CI 0.66-0.80) and 0.83 (95% CI 0.73-0.91) were calculated. One article reported on CEA, showing a sensitivity of 50% and specificity of 65%. No other serum tumor markers were discussed for surveillance purposes in the current literature. CONCLUSION: Although testing of serum CA 19-9 has considerable limitations, CA 19-9 remains the most used serum tumor marker for surveillance after surgical resection of pancreatic cancer. Further studies are needed to assess the role of serum tumor marker testing in the detection of recurrent pancreatic cancer and to optimize surveillance strategies.

Interobserver variation in tumor delineation of liver metastases using Magnetic Resonance Imaging.

Background and purpose: Magnetic Resonance Imaging (MRI) guided stereotactic body radiotherapy (SBRT) of liver metastases is an upcoming high-precision non-invasive treatment. Interobserver variation (IOV) in tumor delineation, however, remains a relevant uncertainty for planning target volume (PTV) margins. The aims of this study were to quantify IOV in MRI-based delineation of the gross tumor volume (GTV) of liver metastases and to detect patient-specific factors influencing IOV. Materials and methods: A total of 22 patients with liver metastases from three primary tumor origins were selected (colorectal(8), breast(6), lung(8)). Delineation guidelines and planning MRI-scans were provided to eight radiation oncologists who delineated all GTVs. All delineations were centrally peer reviewed to identify outliers not meeting the guidelines. Analyses were performed both in- and excluding outliers. IOV was quantified as the standard deviation (SD) of the perpendicular distance of each observer's delineation towards the median delineation. The correlation of IOV with shape regularity, tumor origin and volume was determined. Results: Including all delineations, average IOV was 1.6 mm (range 0.6-3.3 mm). From 160 delineations, in total fourteen single delineations were marked as outliers after peer review. After excluding outliers, the average IOV was 1.3 mm (range 0.6-2.3 mm). There was no significant correlation between IOV and tumor origin or volume. However, there was a significant correlation between IOV and regularity (Spearman's ρs = -0.66; p = 0.002). Conclusion: MRI-based IOV in tumor delineation of liver metastases was 1.3-1.6 mm, from which PTV margins for IOV can be calculated. Tumor regularity and IOV were significantly correlated, potentially allowing for patient-specific margin calculation.

Conventional versus Hepatic Arteriography and C-Arm CT-Guided Ablation of Liver Tumors (HepACAGA): A Comparative Analysis.

PURPOSE: Hepatic Arteriography and C-Arm CT-Guided Ablation of liver tumors (HepACAGA) is a novel technique, combining hepatic-arterial contrast injection with C-arm CT-guided navigation. This study compared the outcomes of the HepACAGA technique with patients treated with conventional ultrasound (US) and/or CT-guided ablation. MATERIALS AND METHODS: In this retrospective cohort study, all consecutive patients with hepatocellular carcinoma (HCC) or colorectal liver metastases (CRLM) treated with conventional US-/CT-guided ablation between 1 January 2015, and 31 December 2020, and patients treated with HepACAGA between 1 January 2021, and 31 October 2023, were included. The primary outcome was local tumor recurrence-free survival (LTRFS). Secondary outcomes included the local tumor recurrence (LTR) rate and complication rate. RESULTS: 68 patients (120 tumors) were included in the HepACAGA cohort and 53 patients (78 tumors) were included in the conventional cohort. In both cohorts, HCC was the predominant tumor type (63% and 73%, respectively). In the HepACAGA cohort, all patients received microwave ablation. Radiofrequency ablation was the main ablation technique in the conventional group (78%). LTRFS was significantly longer for patients treated with the HepACAGA technique (p = 0.015). Both LTR and the complication rate were significantly lower in the HepACAGA cohort compared to the conventional cohort (LTR 5% vs. 26%, respectively; p < 0.001) (complication rate 4% vs. 15%, respectively; p = 0.041). CONCLUSIONS: In this study, the HepACAGA technique was safer and more effective than conventional ablation for HCC and CRLM, resulting in lower rates of local tumor recurrence, longer local tumor recurrence-free survival and fewer procedure-related complications.

Treatment planning for MR-guided SBRT of pancreatic tumors on a 1.5 T MR-Linac: A global consensus protocol.

Background and purpose: Treatment planning for MR-guided stereotactic body radiotherapy (SBRT) for pancreatic tumors can be challenging, leading to a wide variation of protocols and practices. This study aimed to harmonize treatment planning by developing a consensus planning protocol for MR-guided pancreas SBRT on a 1.5 T MR-Linac. Materials and methods: A consortium was founded of thirteen centers that treat pancreatic tumors on a 1.5 T MR-Linac. A phased planning exercise was conducted in which centers iteratively created treatment plans for two cases of pancreatic cancer. Each phase was followed by a meeting where the instructions for the next phase were determined. After three phases, a consensus protocol was reached. Results: In the benchmarking phase (phase I), substantial variation between the SBRT protocols became apparent (for example, the gross tumor volume (GTV) D99% ranged between 36.8 - 53.7 Gy for case 1, 22.6 - 35.5 Gy for case 2). The next phase involved planning according to the same basic dosimetric objectives, constraints, and planning margins (phase II), which led to a large degree of harmonization (GTV D99% range: 47.9-53.6 Gy for case 1, 33.9-36.6 Gy for case 2). In phase III, the final consensus protocol was formulated in a treatment planning system template and again used for treatment planning. This not only resulted in further dosimetric harmonization (GTV D99% range: 48.2-50.9 Gy for case 1, 33.5-36.0 Gy for case 2) but also in less variation of estimated treatment delivery times. Conclusion: A global consensus protocol has been developed for treatment planning for MR-guided pancreatic SBRT on a 1.5 T MR-Linac. Aside from harmonizing the large variation in the current clinical practice, this protocol can provide a starting point for centers that are planning to treat pancreatic tumors on MR-Linac systems.

Preoperative chemoradiotherapy but not chemotherapy is associated with reduced risk of postoperative pancreatic fistula after pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a nationwide analysis.

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. METHODS: All patients after pancreatoduodenectomy for pancreatic ductal adenocarcinoma were included in the mandatory nationwide prospective Dutch Pancreatic Cancer Audit (2014-2020). Baseline and treatment characteristics were compared between immediate surgery, preoperative chemotherapy, and preoperative chemoradiotherapy. The relationship between preoperative chemotherapy, chemoradiotherapy, and clinically relevant postoperative pancreatic fistula (International Study Group of Pancreatic Surgery grade B/C) was investigated using multivariable logistic regression analyses. RESULTS: Overall, 2,019 patients after pancreatoduodenectomy for pancreatic ductal adenocarcinoma were included, of whom 1,678 underwent immediate surgery (83.1%), 192 (9.5%) received preoperative chemotherapy, and 149 (7.4%) received preoperative chemoradiotherapy. Postoperative pancreatic fistula occurred in 8.3% of patients after immediate surgery, 4.2% after preoperative chemotherapy, and 2.0% after preoperative chemoradiotherapy (P = .004). In multivariable analysis, the use of preoperative chemoradiotherapy was associated with reduced risk of postoperative pancreatic fistula (odds ratio, 0.21; 95% confidence interval, 0.03-0.69; P = .033) compared with immediate surgery, whereas preoperative chemotherapy was not (odds ratio, 0.59; 95% confidence interval, 0.25-1.25; P = .199). Intraoperatively hard, or fibrotic pancreatic texture was most frequently observed after preoperative chemoradiotherapy (53% immediate surgery, 62% preoperative chemotherapy, 77% preoperative chemoradiotherapy, P < .001). CONCLUSION: This nationwide analysis demonstrated that in patients undergoing pancreatoduodenectomy for pancreatic ductal adenocarcinoma, only preoperative chemoradiotherapy, but not preoperative chemotherapy, was associated with a reduced risk of postoperative pancreatic fistula.

Abandonment of Routine Radiotherapy for Nonlocally Advanced Rectal Cancer and Oncological Outcomes.

Importance: Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. Objective: To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. Design, Setting, and Participants: This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. Main Outcomes and Measures: The main outcomes were 4-year local recurrence and overall survival rates. Results: Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P = .99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P < .001), with lower non-cancer-related mortality (13.8% vs 6.3%; P < .001). Conclusions and Relevance: The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally advanced rectal cancer did not compromise cancer-related outcomes at a national level. Optimizing clinical staging and surgery following the Dutch total mesorectal excision trial has potentially enabled safe deintensification of treatment.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Feasibility of delivered dose reconstruction for MR-guided SBRT of pancreatic tumors with fast, real-time 3D cine MRI.

BACKGROUND AND PURPOSE: In MR-guided SBRT of pancreatic cancer, intrafraction motion is typically monitored with (interleaved) 2D cine MRI. However, tumor surroundings are often not fully captured in these images, and motion might be distorted by through-plane movement. In this study, the feasibility of highly accelerated 3D cine MRI to reconstruct the delivered dose during MR-guided SBRT was assessed. MATERIALS AND METHODS: A 3D cine MRI sequence was developed for fast, time-resolved 4D imaging, featuring a low spatial resolution that allows for rapid volumetric imaging at 430 ms. The 3D cines were acquired during the entire beam-on time of 23 fractions of online adaptive MR-guided SBRT for pancreatic tumors on a 1.5 T MR-Linac. A 3D deformation vector field (DVF) was extracted for every cine dynamic using deformable image registration. Next, these DVFs were used to warp the partial dose delivered in the time interval between consecutive cine acquisitions. The warped dose plans were summed to obtain a total delivered dose. The delivered dose was also calculated under various motion correction strategies. Key DVH parameters of the GTV, duodenum, small bowel and stomach were extracted from the delivered dose and compared to the planned dose. The uncertainty of the calculated DVFs was determined with the inverse consistency error (ICE) in the high-dose regions. RESULTS: The mean (SD) relative (ratio delivered/planned) D99% of the GTV was 0.94 (0.06), and the mean (SD) relative D0.5cc of the duodenum, small bowel, and stomach were respectively 0.98 (0.04), 1.00 (0.07), and 0.98 (0.06). In the fractions with the lowest delivered tumor coverage, it was found that significant lateral drifts had occurred. The DVFs used for dose warping had a low uncertainty with a mean (SD) ICE of 0.65 (0.07) mm. CONCLUSION: We employed a fast, real-time 3D cine MRI sequence for dose reconstruction in the upper abdomen, and demonstrated that accurate DVFs, acquired directly from these images, can be used for dose warping. The reconstructed delivered dose showed only a modest degradation of tumor coverage, mostly attainable to baseline drifts. This emphasizes the need for motion monitoring and development of intrafraction treatment adaptation solutions, such as baseline drift corrections.

Feasibility of online radial magnetic resonance imaging for adaptive radiotherapy of pancreatic tumors.

Background and purpose: Online adaptive magnetic resonance (MR)-guided treatment planning for pancreatic tumors on 1.5T systems typically employs Cartesian 3D T 2w magnetic resonance imaging (MRI). The main disadvantage of this sequence is that respiratory motion results in substantial blurring in the abdomen, which can hamper delineation accuracy. This study investigated the use of two motion-robust radial MRI sequences as main delineation scan for pancreatic MR-guided radiotherapy. Materials and methods: Twelve patients with pancreatic tumors were imaged with a 3D T 2w scan, a Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction (PROPELLER) scan (partially overlapping strips), and a 3D Vane scan (stack-of-stars), on a 1.5T MR-Linac under abdominal compression. The scans were assessed by three radiation oncologists for their suitability for online adaptive delineation. A quantitative comparison was made for gradient entropy and the effect of motion on apparent target position. Results: The PROPELLER scans were selected as first preference in 56% of the cases, the 3D T 2w in 42% and the 3D Vane in 3%. PROPELLER scans sometimes contained a large interslice variation which would have compromised delineation. Gradient entropy was significantly higher in 3D T 2w patient scans. The apparent target position was more sensitive to motion amplitude in the PROPELLER scans, but substantial offsets did not occur under 10 mm peak-to-peak. Conclusion: PROPELLER MRI may be a superior imaging sequence for pancreatic MRgRT compared to standard Cartesian sequences. The large interslice variation should be mitigated through further sequence optimization before PROPELLER can be adopted for online treatment adaptation.

Precision radiotherapy using MR-linac for pancreatic neuroendocrine tumors in MEN1 patients (PRIME): a protocol for a phase I-II trial, and systematic review on available evidence for radiotherapy of pNETs.

Background: Surgical resection is the standard of care for the treatment of pancreatic neuro-endocrine tumors (pNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1). However, surgery can cause significant short- and long-term morbidity. Magnetic resonance-guided radiotherapy (MRgRT) is a potential effective treatment with little side effects. With traditional radiotherapy techniques, irradiation of pancreatic tumors to high dose levels was hampered by poor visibility of the tumor during treatment. MRgRT uses onboard MRI to guide the treatment, thereby enabling delivery of ablative irradiation doses to the tumor, while sparing surrounding tissues. In this study, we describe results from a systematic review assessing efficacy of radiotherapy in pNET and present the protocol of the PRIME study. Methods: PubMed, Embase and Cochrane Library were searched for articles assessing efficacy and side effects of radiotherapy for the treatment of pNETs. Risk of bias was assessed using the ROBINS-I Risk of Bias Tool for observational studies. Descriptive statistics were used to describe results of included trials. Results: Four studies comprising of 33 patients treated by conventional radiotherapy were included. Despite the heterogeneity of studies, radiotherapy appeared to be effective for the treatment of pNETs with most patients responding (45.5%) or stabilizing (42.4%) in tumor size. Conclusion and trial design: Due to the limited literature available and concerns about damage to surrounding tissue, conventional radiotherapy is currently little used for pNETs. The PRIME study is a phase I-II trial with a single arm prospective cohort study design, investigating the efficacy of MRgRT in MEN1 patients with pNET. MEN1 patients with growing pNETs with a size between 1.0 and 3.0 cm without malignant features are eligible for inclusion. Patients are treated with 40 Gy in 5 fractions on the pNET, using online adaptive MRgRT on a 1.5T MR-linac. The primary endpoint is the change in tumor size at MRI 12 months follow-up. Secondary endpoints include radiotoxicity, quality of life, endocrine and exocrine pancreas function, resection rate, metastatic free and overall survival. When MRgRT is found effective with low radiotoxicity, it could reduce the need for surgery for pNET and preserve quality of life. Systematic Review Registration: PROSPERO https://clinicaltrials.gov/, (CRD42022325542).