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Background: Periampullary adenocarcinoma consists of pancreatic adenocarcinoma (PDAC), distal cholangiocarcinoma (DC), ampullary cancer (AC), and duodenal adenocarcinoma (DA). The aim of this study was to assess treatment modalities and overall survival by tumor origin., Methods: Patients diagnosed with non-metastatic periampullary cancer in 2012-2018 were identified from the Netherlands Cancer Registry. OS was studied with Kaplan-Meier analysis and multivariable Cox regression analyses, stratified by origin., Results: Among the 8758 patients included, 68% had PDAC, 13% DC, 12% AC, and 7% DA. Resection was performed in 35% of PDAC, 56% of DC, 70% of AC, and 59% of DA. Neoadjuvant and/or adjuvant therapy was administered in 22% of PDAC, 7% of DC, 7% of AC, and 12% of DA. Three-year OS was highest for AC (37%) and DA (34%), followed by DC (21%) and PDAC (11%). Adjuvant therapy was associated with improved OS among PDAC (HR = 0.62; 95% CI 0.55-0.69) and DC (HR = 0.69; 95% CI 0.48-0.98), but not AC (HR = 0.87; 95% CI 0.62-1.22) and DA (HR = 0.85; 95% CI 0.48-1.50)., Conclusion: This retrospective study identified considerable differences in treatment modalities and OS between the four periampullary cancer origins in daily clinical practice. An improved OS after adjuvant chemotherapy could not be demonstrated in patients with AC and DA., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To analyze the effect of radiation dose escalation to the primary tumor on local tumor control in definitive chemoradiation (dCRT) for patients with esophageal cancer., Patients and Methods: Patients with medically inoperable and/or irresectable esophageal carcinoma, referred for dCRT, were randomly assigned between a standard dose (SD) of 50.4 Gy/1.8 Gy for 5.5 weeks to the tumor and regional lymph nodes and a high dose (HD) up to a total dose of 61.6 Gy to the primary tumor. Chemotherapy consisted of courses of concurrent carboplatin (area under the curve 2) and paclitaxel (50 mg/m 2 ) in both arms once a week for 6 weeks. The primary end point was local progression-free survival., Results: Between September 2012 and June 2018, 260 patients were included. Squamous cell carcinoma (SCC) was present in 61% of patients, and 39% had adenocarcinoma (AC). Radiation treatment was completed by 94%, and 85% had at least five courses of chemotherapy. The median follow-up time for all patients was 50 months. The 3-year local progression-free survival (LPFS) was 70% in the SD arm versus 73% in the HD arm (not significant). The LPFS for SCC and AC was 75% versus 79% and 61% versus 61% for SD and HD, respectively (not significant). The 3-year locoregional progression-free survival was 52% and 59% for the SD and HD arms, respectively ( P = .08). Overall, grade 4 and 5 common toxicity criteria were 12% and 5% in the SD arm versus 14% and 10% in the HD arm, respectively ( P = .15)., Conclusion: In dCRT for esophageal cancer, radiation dose escalation up to 61.6 Gy to the primary tumor did not result in a significant increase in local control over 50.4 Gy. The absence of a dose effect was observed in both AC and SCC., Competing Interests: Mark I. van Berge HenegouwenConsulting or Advisory Role: Medtronic, Johnson & Johnson, Mylan, Alesi SurgicalResearch Funding: Olympus, StrykerTravel, Accommodations, Expenses: Johnson & Johnson Jeanin E. van HooftConsulting or Advisory Role: Boston Scientific, Cook Medical, Medtronic, Olympus Medical Systems Hanneke W. M. van LaarhovenConsulting or Advisory Role: Lilly/ImClone, Nordic Group, Bristol Myers Squibb, ServierResearch Funding: Bristol Myers Squibb, Bayer Schering Pharma, Celgene, Janssen-Cilag, Lilly, Nordic Group, Philips Healthcare, Roche, Merck Sharp & Dohme, Servier, Merck KGaATravel, Accommodations, Expenses: AstraZenecaNo other potential conflicts of interest were reported.

Introduction: Ampullary cancer is rare and as a result epidemiological data are scarce. The aim of this population-based study was to determine the trends in incidence, treatment and overall survival (OS) in patients with ampullary adenocarcinoma in the Netherlands between 1989 and 2016., Methods: Patients diagnosed with ampullary adenocarcinoma were identified from the Netherlands Cancer Registry. Incidence rates were age-adjusted to the European standard population. Trends in treatment and OS were studied over (7 years) period of diagnosis, using Kaplan-Meier and Cox regression analyses for OS and stratified by the presence of metastatic disease., Results: In total, 3840 patients with ampullary adenocarcinoma were diagnosed of whom, 55.0% were male and 87.1% had non-metastatic disease. The incidence increased from 0.59 per 100,000 in 1989-1995 to 0.68 per 100,000in 2010-2016. In non-metastatic disease, the resection rate increased from 49.5% in 1989-1995 to 63.9% in 2010-2016 (p < 0.001). The rate of adjuvant therapy increased from 3.1% to 7.9%. In non-metastatic disease, five-year OS (95% CI) increased from 19.8% (16.9-22.8) in 1989-1995 to 29.1% (26.0-31.2) in 2010-2016 (logrank p < 0.001). In patients with metastatic disease, median OS did not significantly improve (from 4.4 months (3.6-5.0) to 5.9 months (4.7-7.1); logrank p = 0.06). Cancer treatment was an independent prognostic factor for OS among all patients., Conclusion: Both incidence and OS of ampullary cancer increased from 1989 to 2016 which is most likely related to the observed increased resection rates and use of adjuvant therapy., Competing Interests: Declaration of competing interest Drs. de Vos-Geelen reports grants, personal fees and non-financial support from Servier, personal fees from AstraZeneca, personal fees from MSD, personal fees from Pierre Fabre, personal fees from Amgen, outside the submitted work. Dr. ir. Geurts reports grants from Roche, grants from Pfizer, grants from Novartis, grants from Eisai, grants from Lilly, outside the submitted work. Dr. Haj Mohammad reports non-financial support from Servier, non-financial support from MSD, non-financial support from BMS, non-financial support from Eli Lily, non-financial support from Astra Zeneca, outside the submitted work. Dr. van Laarhoven reports grants and non-financial support from BMS, grants and non-financial support from Celgene, grants and non-financial support from Lilly, grants and non-financial support from Nordic, grants and non-financial support from Servier, grants from Bayer, grants from Merck Serono, grants from MSD, grants from Philips, outside the submitted work. Dr. Tjan-Heijnen reports grants and personal fees from Roche, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants and personal fees from Lilly, personal fees from Accord Healthcare, grants from AstraZeneca, grants from Eisai, grants from Daiichi Sankyo, outside the submitted work. Dr. Valkenburg-van Iersel reports non-financial support from Servier, non-financial support from Pierre Fabre, non-financial support from Roche, outside the submitted work. Dr. Wilmink reports grants and non-financial support from Servier, non-financial support from MSD, non-financial support from AstraZeneca, grants and non-financial support from Celgene, grants from Halozyme, grants from Merck, grants from Roche, grants from Pfizer, grants from Amgen, grants from Novartis, outside the submitted work. The other authors have declared no conflicts of interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: In selected rectal cancer patients with residual local disease following neoadjuvant chemoradiation (CRT) and the preference of an organ preservation pathway, additional treatment with dose escalation by endoluminal radiotherapy (RT) may ultimately result in a clinical complete response. To date, the widespread introduction of selective endoluminal radiation techniques is hampered by a lack of evidence-based guidelines that describe the radiation treatment volume in relation to the residual tumor mass. In order to convert an incomplete response into a complete one with additional treatment such as dose-escalation with endoluminal RT from a theoretical perspective, it seems important to treat all remaining microscopic tumor cells after CRT. In this setting, residual tumor extension beneath normal appearing mucosa (microscopic intramural spread - MIS) becomes relevant for accurate tumor volume and margin estimation. With the goal of providing evidence-based guidelines that define an appropriate treatment volume and patient selection, we present results from a meta-analysis based on individual patient data of studies that have assessed the extent or range of MIS of rectal cancers after neoadjuvant CRT. This meta-analysis should provide an estimate of the residual tumor volume/extension that needs to be targeted by any additional radiation therapy boost in order to achieve complete tumor eradication after initial incomplete or near-complete response following standard CRT., Methods and Materials: A PubMed search was performed. Additional articles were selected based on identification from reference lists. Papers were eligible when reporting MIS in patients who were treated by total mesorectal excision or local excision/transanal endoscopic microsurgery (TEM) after neo-adjuvant long-course CRT. The mean MIS was calculated for the entire group along with the 70th until 95th percentiles. Additional exploratory subgroup analyses were performed., Results: Individual patient data from 349 patients with residual disease from five studies were analyzed. 80% of tumors showed no MIS. In order to appropriately treat MIS in 95% of rectal cancer patients after CRT, a margin of 5.5 mm around the macroscopic tumor would suffice. An exploratory subgroup analysis showed that T-stage after CRT (ypT) and time interval between neoadjuvant CRT and surgery are significant factors predicting the extent of MIS (p < 0.001.) The group of ypT1 had the smallest MIS, followed by the ypT3-4 group, while the ypT2 group had the largest MIS (p < 0.001). Regarding time interval between CRT and surgery, a statistically significant difference was seen when comparing the three time-interval groups (less than 8 weeks, 8-12 weeks, and more than 12 weeks), where waiting more than 12 weeks after CRT resulted in the largest MIS (p < 0.0001)., Conclusion: Based on this meta-analysis, in order to treat the MIS for 95% of rectal cancer patients after CRT, a Clinical Target Volume (CTV) margin of 5.5 mm from the lateral most edge of the macroscopic tumor would suffice. 80% of tumors showed no MIS and would not require an extra CTV margin for treatment. These findings support the feasibility of localized radiotherapy boosts for dose-escalation to improve response among patients with incomplete response after standard CRT and can also be applied in the surgical setting., Competing Interests: Declaration of Competing Interest Authors E.J. Van Limbergen, M. Berbee, A. Verrijssen, F. Verhaegen and J. Melenhorst report a research grant from Varian Medical Systems on “Phase-II trial on endoluminal boosting in rectal cancer using the MAASTRO applicator”. In addition, authors E.J. Van Limbergen, M. Berbee, F. Verhaegen, M. Bellezzo and G. Paiva Fonseca have a patent EP16204735, rectal brachytherapy applicator with royalties paid to Maastro Clinic/University Maastricht., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the toxicity and efficacy of the combination of external beam radiation therapy (EBRT) followed by high-dose-rate endorectal brachytherapy (HDREBT) boost in elderly and medically inoperable patients with rectal cancer., Methods and Materials: A phase 1 dose-escalation study was performed. Treatment consisted of EBRT (13 × 3 Gy) followed by 3 weekly brachytherapy applications 6 weeks later. The HDREBT dose started at 5 Gy per fraction, increasing with 1 Gy per fraction if dose-limiting toxicity (DLT, defined as grade ≥3 proctitis <6 weeks after HDREBT) occurred in ≤2 patients per dose level. The primary endpoint was the maximum tolerated dose, defined as 1 dose level below the dose at which 3 patients experienced DLT. Secondary endpoints were toxicity, clinical tumor response, freedom from local progression, and local progression-free and overall survival (L-PFS and OS)., Results: Thirty-eight patients with a median age of 83 years were included in the study. Thirty-two were evaluable for DLT and late toxicity and 33 for response evaluation. Maximum delivered dose was 8 Gy per fraction, resulting in a recommended dose of 7 Gy per fraction. Response occurred in 29 of 33 patients (87.9%), with 60.6% complete response (CR). The L-PFS and OS rates were 42% and 63%, respectively, at 2 years. Patients with CR showed a significantly improved L-PFS (60% at 2 years, P=.006) and a trend in improved OS (80% at 2 years, P=.11). Severe late toxicity occurred in 10 of 32 patients., Conclusion: We found that HDREBT after EBRT results in a high overall response rate, with improved L-PFS for patients with a CR. The high observed rate of severe late toxicity requires further evaluation of the risks and benefits of an HDREBT boost., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Retrospective single-center studies have shown that diffusion-weighted magnetic resonance imaging (DWI) is promising for identification of patients with rectal cancer with a complete tumor response after neoadjuvant chemoradiotherapy (CRT), using certain volumetric thresholds., Objective: This study aims to validate the diagnostic value of these volume thresholds in a larger, independent, and bi-institutional patient cohort., Methods: A total of 112 patients with locally advanced rectal cancer (2 centers) treated with a long course of CRT were enrolled. Patients underwent standard T2W-magnetic resonance imaging and DWI, both pre- and post-CRT. Two experienced readers independently determined pre-CRT and post-CRT tumor volumes (cm) on T2W-magnetic resonance image and diffusion-weighted magnetic resonance image by means of freehand tumor delineation. Tumor volume reduction rates (Δvolume) were calculated. Previously determined T2W and DWI threshold values for prevolume, postvolume, and Δvolume were tested to "prospectively" assess their respective diagnostic value in discriminating patients with a complete tumor response from patients with residual tumor., Results: Twenty patients had a complete response. Using the average measurements between the 2 readers, areas under the curve for the pre-/post-/Δvolumes was 0.73/0.82/0.78 for T2W-magnetic resonance imaging and 0.77/0.92/0.86 for DWI, respectively. For T2W-volumetry, sensitivity and specificity using the predefined volume thresholds were 55% and 74% for pre-, 60% and 89% for post-, and 60% and 86% for Δvolume. For DWI volumetry, sensitivity and specificity were 65% and 76% for pre-, 70% and 98% for post-, and 70% and 93% for Δvolume., Conclusions: Previously established DWI volume thresholds can be reproduced with good results. Post-CRT DWI volumetry offers the best results for the detection of patients with a complete response after CRT with an area under the curve of 0.92, sensitivity of 70%, and specificity of 98%.

Introduction: Recent studies suggest that the use of metformin is associated with reduced cancer incidence and improved prognosis in patients with oesophageal cancer. We explored the relationship between the use of metformin and outcome (pathologic response rate, distant metastasis-free and overall survival) in our mono-institutional cohort of patients treated for oesophageal cancer., Material and Methods: Between 2008 and 2014, a total of 196 patients with oesophageal cancer (ages ranged from 37 to 82 years) eligible for curative treatment entered the study. Patients were categorized as non-diabetic (n = 172), diabetic not taking metformin (n = 5) or diabetic taking metformin (n = 19). The majority of patients were treated with trimodality therapy (n = 189). Pathologic response was graded according to Mandard's tumour regression score at the time of surgery. Distant metastasis-free and overall survival were calculated using the Kaplan-Meier method with log rank comparisons performed to determine significance., Results: The overall pathologic complete response rate for the study population was 26%. It was 25% for patients not using metformin and 39% for diabetics taking metformin (p = 0.260). The two-year overall survival rate for the whole group was 59%. Use of metformin was associated with a significantly better distant metastasis-free survival rate (p = 0.040) or overall survival rate (p = 0.012). Multivariate analysis using Cox regression found that metformin treatment significantly prolonged survival (p = 0.043)., Conclusion: In our population-based study, the use of metformin was associated with an improved overall and distant metastasis-free survival rate in patients with oesophageal cancer. These data are complementary to one other clinical study and warrant further prospective study., (Copyright © 2015 Elsevier Ltd. All rights reserved.)