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A letter to the editor is presented which discusses a case study of a successful pregnancy in a Crohn's disease (CD) and paradoxical psoriasis patient under ustekinumab treatment.

Restaging after neoadjuvant therapy aims to reduce the number of patients undergoing esophagectomy in case of distant (interval) metastases. The aim of this study is to systematically review and meta-analyze the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and 18F-FDG PET/CT for the detection of distant interval metastases after neoadjuvant therapy in patients with esophageal cancer. PubMed/MEDLINE, Embase, and the Cochrane library were systematically searched. The analysis included diagnostic studies reporting on the detection of distant interval metastases with 18F-FDG PET(/CT) in patients with esophageal cancer who received neoadjuvant therapy and both baseline staging and restaging after neoadjuvant therapy with 18F-FDG PET(/CT) imaging. The primary outcome measure was the proportion of patients in whom distant interval metastases were detected by 18F-FDG PET(/CT) as confirmed by pathology or clinical follow-up (i.e. true positives). The secondary outcome measure was the proportion of patients in whom 18F-FDG PET(/CT) restaging was false positive for distant interval metastases (i.e. false positives). Risk of bias and applicability concerns were assessed using the QUADAS-2 tool. Random-effect models were used to estimate pooled outcomes and examine potential sources of heterogeneity. Fourteen studies were included comprising a total of 1,110 patients who received baseline staging with 18F-FDG PET(/CT) imaging of whom 1,001 (90%) underwent restaging with 18F-FDG PET(/CT) imaging. Studies were generally of moderate quality. The pooled proportion of patients in whom true distant interval metastases were detected by 18F-FDG PET(/CT) restaging was 8% (95% confidence interval [CI]: 5–13%). The pooled proportion of patients in whom false positive distant findings were detected by 18F-FDG PET(/CT) restaging was 5% (95% CI: 3–9%). In conclusion,18F-FDG PET(/CT) restaging after neoadjuvant therapy for esophageal cancer detects true distant interval metastases in 8% of patients. Therefore, 18F-FDG PET(/CT) restaging can considerably impact on treatment decision-making. However, false positive distant findings occur in 5% of patients at restaging with 18F-FDG PET(/CT), underlining the need for pathological confirmation of suspected lesions. [ABSTRACT FROM AUTHOR]

Background: In cT4b esophageal cancer, accurate assessment of tracheobronchial tree invasion after definitive chemoradiotherapy (dCRT) aids in the selection of patients for whom an oncologic radical esophagectomy can be achieved. The current report aimed to determine the accuracy of endobronchial ultrasound in assessing tumor invasion in the tracheobronchial tree after dCRT in patients with cT4b esophageal cancer., Methods: Esophageal cancer patients with suspicion of tracheobronchial tree invasion on the diagnostic contrast-enhanced computed tomography (CT) who underwent a staging endobronchial ultrasonography (EBUS) were eligible for inclusion in this study. To assess the accuracy of the EBUS in assessing tumor ingrowth in the tracheobronchial tree after dCRT, patients who had an EBUS during restaging and underwent surgery were included in the final analysis., Results: The final analysis included 26 patients. For 18 (90%) of 20 patients in whom the anatomy of the tracheobronchial tree was restored on the restaging EBUS and tumor invasion was considered to be absent, a radical esophagectomy was achieved. In six patients, persistent ingrowth was observed during the restaging EBUS. For these patients, the EBUS was repeated after a median of 9 weeks. Tumor invasion was considered to be absent in four patients, and a radical resection was achieved in three of these patients., Conclusion: The EBUS provides valuable information on the assessment of tracheobronchial tree invasion in cT4b esophageal cancer patients after dCRT. This information could aid in the proper selection of patients who benefit from a curative but highly invasive esophagectomy., Competing Interests: Disclosure: Money was paid to the insititution of Nadia Haj Mohammad, who served on the advisory boards of BMS, Merck, Astra Zeneca, Eli Lily, and Servier. The remaining authors have no conflicts of interest., (© 2024. The Author(s).)

Background: For the elderly patients with gastric cancer, it may be more challenging to tolerate complete neoadjuvant therapy (NAT). The impact of discontinued NAT on the surgical safety and pathological outcomes of elderly patients with poor tolerance remains poorly understood., Methods: Gastric cancer patients received gastrectomy with curative intent from the Dutch upper GI cancer audit (DUCA) database were included in this study. The independent association of age with not initiating and discontinuation of NAT was assessed with restricted cubic splines (RCS). According to the RCS results, age ≥ 70 years was defined as elderly. Short-term postoperative outcomes and pathological results were compared between elderly patients who completed and discontinued NAT., Results: Between 2011- 2021, total of 3049 patients were included. The risk of not initiating NAT increased from 70 years. In 1954 (64%) patients receiving NAT, the risk of discontinuation increased from 55 years, reaching the peak around 74 years. In the elderly, discontinued NAT was not independently associated with worse 30-day mortality, overall complications, anastomotic leakage, re-intervention, and pathologic complete response, but was associated with a higher risk of R1/2 resection (p-value = 0.001), higher ypT stage (p-value = 0.004), ypN + (p-value = 0.008), and non-response ( p-value = 0.012)., Conclusion: A decreased utilization of NAT has been observed in Dutch gastric cancer patients from 70 years due to old age considerations, possibly because of their high risk of discontinuation. Increasing the utilization of NAT may not adversely impact the surgical safety of gastric cancer population ≥ 70 years and may contribute to better pathological results., (© 2024. The Author(s).)

Introduction: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD)., Methods: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD., Results: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18 F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended., Discussion: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment., Competing Interests: Declaration of Competing Interest Dr. van Laarhoven reports a consultant or advisory role: Amphera, Anocca, Astellas, AstraZeneca, Beigene, Boehringer, Daiichy-Sankyo, Dragonfly, MSD, Myeloid, Servier; Research funding, medication supply, and/or other research support: Auristone, Incyte, Merck, ORCA, Servier; Speaker role: Astellas, Beigene, Benecke, BMS, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Springer, Travel Congress Management B.V. Dr. Muijs reports institutional grants from: Elekta, IBA, RaySearch, Siemens, Mirada, Bergoz Instrumentation and Medical Data Works, KWF, all outside the submitted work. Dr. van Hillegersberg has a consulting and advisory role at Intuitive Surgical, Medtronic, Olympus and J&J Ethicon. Dr. de Manzoni reports personal fees from Lilly, outside the submitted work. Dr. Gani reports travel grants from Elekta and departmental research cooperation, outside the submitted work. Dr. Smyth is supported by the NIHR Biomedical Research Centre at Oxford (the views expressed in this Article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health) and resports personal fees/grants from: Astra Zeneca, Beigene, BMS, Amal Therapeutics, Amgen, Daiichi Sankyo, Merck, Servier, Novartis, Pfizer, Roche, and Zymeworks, all outside the submitted work. Dr. Haj Mohammad reports consulation fees from: Merck, BMS, Eli Lilly, Astra Zeneca, and research funding from Servier, all outside the submitted work. Dr. Adenis reports grants and personal fees from Bayer, personal fees and non-financial support from MSD, personal fees from: BMS, Novartis, Pierre-Fabre, non-financial support from Servier, grants from Sanofi, all outside the submitted work. Dr. Lordick reports grants from: BMS and Gilead, personal fees from: Amgen, Astellas, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Elsevier, Incyte, Merck, MSD, Roche, Servier, all outside the submitted work. Dr. Slingerland reports an advisory role at BMS and Lilly. Dr. van Berge Henegouwen received researcher-initiated grant from Stryker and is consultant for Alesi Surgical, Johnson and Johnson, Medtronic, BBraun and Viatris. Dr Nilsson reports advisory roles for BMS and Medtronic. Dr. Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc; and also educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). Dr. Tabernero declares institutional financial interest in form of financial support for clinical trials or contracted research for Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK. Dr. Nieuwenhuijzen reports advisory/speaker roles from Medtronic and Lilly. All remaining authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

Introduction: The optimal therapeutic strategy for patients with cT4bM0 esophageal cancer is controversial and varies internationally. This study aimed to describe treatment and survival of patients with cT4bM0 esophageal cancer in the Netherlands., Methods: Patients staged with cT4bM0 esophageal cancer who were registered in the Netherlands Cancer Registry (NCR) were included. All patients were categorized by the treatment modality received. The Kaplan-Meier method was used to estimate the overall survival of them., Results: Between 2015 and 2020, 286 patients with cT4bM0 esophageal cancer were included. Treatment consisted of preoperative chemoradiotherapy/chemotherapy followed by surgery (8%), chemoradiotherapy alone (35%), chemotherapy alone (6%), radiotherapy alone (19%), and best supportive care (32%). The median follow-up was 28.1 months. The 1-, 3-, and 5-year survival rates of each group were 82%, 58%, 49% for preoperative therapy plus surgery; 53%, 27%, 16% for chemoradiotherapy only; 13%, 0%, 0% for chemotherapy only; 13%, 0%, 0% for radiotherapy only; and 5%, 0%, 0% for best supportive care., Conclusion: In a selected group of patients, preoperative therapy followed by esophagectomy may lead to improved survival, which is comparable to patients with <cT4bM0 tumors. Therefore, reevaluation following chemo(radio)therapy is recommended in these patients to evaluate the possibility of additional surgical resection., (© 2024 S. Karger AG, Basel.)

Introduction: Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is a promising treatment modality for pancreatic cancer and is being employed by an increasing number of centers worldwide. However, clinical outcomes have only been reported on a small scale, often from single institutes and in the context of clinical trials, in which strict patient selection might limit generalizability of outcomes. This study presents clinical outcomes of a large, international cohort of patients with (peri)pancreatic tumors treated with online adaptive MRgRT., Methods: We evaluated clinical outcomes and treatment details of patients with (peri)pancreatic tumors treated on a 1.5 Tesla (T) MR-linac in two large-volume treatment centers participating in the prospective MOMENTUM cohort (NCT04075305). Treatments were evaluated through schematics, dosage, delivery strategies, and success rates. Acute toxicity was assessed until 3 months after MRgRT started, and late toxicity from 3-12 months of follow-up (FU). The EORTC QLQ-C30 questionnaire was used to evaluate the quality of life (QoL) at baseline and 3 months of FU. Furthermore, we used the Kaplan-Meier analysis to calculate the cumulative overall survival., Results: A total of 80 patients were assessed with a median FU of 8 months (range 1-39 months). There were 34 patients who had an unresectable primary tumor or were medically inoperable, 29 who had an isolated local recurrence, and 17 who had an oligometastasis. A total of 357 of the 358 fractions from all hypofractionated schemes were delivered as planned. Grade 3-4 acute toxicity occurred in 3 of 59 patients (5%) with hypofractionated MRgRT and grade 3-4 late toxicity in 5 of 41 patients (12%). Six patients died within 3 months after MRgRT; in one of these patients, RT attribution could not be ruled out as cause of death. The QLQ-C30 global health status remained stable from baseline to 3 months FU (70.5 at baseline, median change of +2.7 [P = 0.5]). The 1-year cumulative overall survival for the entire cohort was 67%, and that for the primary tumor group was 66%., Conclusion: Online adaptive MRgRT for (peri)pancreatic tumors on a 1.5 T MR-Linac could be delivered as planned, with low numbers of missed fractions. In addition, treatments were associated with limited grade 3-4 toxicity and a stable QoL at 3 months of FU., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The MOMENTUM Study is financially supported by Elekta AB and through in-kind contributions from all participating institutions., (Copyright © 2023 Eijkelenkamp, Grimbergen, Daamen, Heerkens, van de Ven, Mook, Meijer, Molenaar, van Santvoort, Paulson, Erickson, Verkooijen, Hall and Intven.)

Background: As previous studies showed significant hospital variation in curative treatment of esophagogastric cancer, this study assesses the association between this variation and overall, cancer-specific and recurrence-free survival, and Health-Related Quality of Life (HRQoL)., Methods: Patients diagnosed with potentially curable esophageal or gastric cancer between 2015 and 2018 as registered in the Netherlands Cancer Registry were included. Data on overall survival was available for all patients, data on cancer-specific and recurrence-free survival and HRQoL was available for subgroups. Patients were classified according to diagnosis in hospitals with low, medium or high probability of treatment with curative intent (LP, MP or HP). Multivariable models were used to assess the association between LP, MP and HP hospitals and HRQoL and survival., Results: This study includes 7,199 patients with esophageal, and 2,407 with gastric cancer. Overall and cancer-specific survival was better for patients diagnosed in HP versus LP hospitals for both esophageal (HR = 0.82, 95%CI:0.77-0.88 and HR = 0.82, 95%CI:0.75-0.91, respectively), and gastric cancer (HR = 0.82, 95%CI:0.73-0.92 and HR = 0.74, 95%CI:0.64-0.87, respectively). These differences disappeared after adjustments for treatment. Recurrence-free survival was worse for gastric cancer patients diagnosed in HP hospitals (HR = 1.50, 95%CI:1.14-1.96), which disappeared after adjustment for radicality of surgery. Minor, but no clinically relevant, differences in HRQoL were observed., Conclusions: Patients diagnosed in hospitals with a high probability of treatment with curative intent have a better overall and cancer-specific but not recurrence-free survival, while minor differences in HRQoL were observed., Competing Interests: Declaration of competing interest RV received a research grant from Bristol Myers Squibb and has served as consultant for Daiichi Sankyo. HvL reports grants or advisory/speaker role from: Astellas, BMS, Daiichy, Dragonfly, Lilly, Merck, Novartis, Nordic Pharma, Servier; research funding or medical supply from: Bayer, BMS, Celgene, Janssen, Incyte, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier; and has received unrestricted research funding (non-commercial) from: Dutch Cancer Society, NWO/ZonMw, European Research Council, MaagLeverDarm Stichting. GN reports grants or advisory/speaker role from: Medtronic and Lilly and has received unrestricted research funding (non-commercial) from: Dutch Cancer Society and CZ Healthcare Insurance. MS reports an advisory role for Lilly and BMS. BW reports research grant and speaker role from BMS. The other authors have nothing to declare., (© 2023 Published by Elsevier Ltd.)

Background: For cancer patients to effectively engage in decision making, they require comprehensive and understandable information regarding treatment options and their associated outcomes. We developed an online prediction tool and supporting communication skills training to assist healthcare providers (HCPs) in this complex task. This study aims to assess the impact of this combined intervention (prediction tool and training) on the communication practices of HCPs when discussing treatment options., Methods: We conducted a multicenter intervention trial using a pragmatic stepped wedge design (NCT04232735). Standardized Patient Assessments (simulated consultations) using cases of esophageal and gastric cancer patients, were performed before and after the combined intervention (March 2020 to July 2022). Audio recordings were analyzed using an observational coding scale, rating all utterances of treatment outcome information on the primary outcome-precision of provided outcome information-and on secondary outcomes-such as: personalization, tailoring and use of visualizations. Pre vs. post measurements were compared in order to assess the effect of the intervention., Findings: 31 HCPs of 11 different centers in the Netherlands participated. The tool and training significantly affected the precision of the overall communicated treatment outcome information ( p  = 0.001, median difference 6.93, IQR (-0.32 to 12.44)). In the curative setting, survival information was significantly more precise after the intervention ( p  = 0.029). In the palliative setting, information about side effects was more precise ( p < 0.001)., Interpretation: A prediction tool and communication skills training for HCPs improves the precision of treatment information on outcomes in simulated consultations. The next step is to examine the effect of such interventions on communication in clinical practice and on patient-reported outcomes., Funding: Financial support for this study was provided entirely by a grant from the Dutch Cancer Society (UVA 2014-7000)., Competing Interests: M. Slingerland: Advisory role: Lilly, AstraZeneca en BMS. H.W.M. van Laarhoven: Financial support by the Dutch Cancer Society, Bayer, BMS, Celgene, Janssen, Incyte, Eli Lilly, MSD, Nordic Pharma, Philips, Roche, Servier. Consulting fees from Amphera, AstraZeneca, Beigene, BMS, Daiichy-Sankyo, Dragonfly, Eli Lilly, MSD, Nordic Pharma, Servier. Spealer role: Astellas, Benecke, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Travel Congress Management B.V. The other authors declare no conflicts of interest., (© 2023 The Author(s).)

Background and Purpose: The apparent diffusion coefficient (ADC), a potential imaging biomarker for radiotherapy response, needs to be reproducible before translation into clinical use. The aim of this study was to evaluate the multi-centre delineation- and calculation-related ADC variation and give recommendations to minimize it., Materials and Methods: Nine centres received identical diffusion-weighted and anatomical magnetic resonance images of different cancerous tumours (adrenal gland, pelvic oligo metastasis, pancreas, and prostate). All centres delineated the gross tumour volume (GTV), clinical target volume (CTV), and viable tumour volume (VTV), and calculated ADCs using both their local calculation methods and each of the following calculation conditions: b-values 0-500 vs. 150-500 s/mm 2 , region-of-interest (ROI)-based vs. voxel-based calculation, and mean vs. median. ADC variation was assessed using the mean coefficient of variation across delineations (CV D ) and calculation methods (CV C ). Absolute ADC differences between calculation conditions were evaluated using Friedman's test. Recommendations for ADC calculation were formulated based on observations and discussions within the Elekta MRI-linac consortium image analysis working group., Results: The median (range) CV D and CV C were 0.06 (0.02-0.32) and 0.17 (0.08-0.26), respectively. The ADC estimates differed 18% between b-value sets and 4% between ROI/voxel-based calculation (p-values < 0.01). No significant difference was observed between mean and median (p = 0.64). Aligning calculation conditions between centres reduced CV C to 0.04 (0.01-0.16). CV D was comparable between ROI types., Conclusion: Overall, calculation methods had a larger impact on ADC reproducibility compared to delineation. Based on the results, significant sources of variation were identified, which should be considered when initiating new studies, in particular multi-centre investigations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Diffusion weighted magnetic resonance imaging (DW-MRI) can be prognostic for response to neoadjuvant chemotherapy (nCRT) in patients with esophageal cancer. However, manual tumor delineation is labor intensive and subjective. Furthermore, noise in DW-MRI images will propagate into the corresponding apparent diffusion coefficient (ADC) signal. In this study a workflow is investigated that combines a denoising algorithm with semi-automatic segmentation for quantifying ADC changes., Materials and Methods: Twenty patients with esophageal cancer who underwent nCRT before esophagectomy were included. One baseline and five weekly DW-MRI scans were acquired for every patient during nCRT. A self-supervised learning denoising algorithm, Patch2Self, was used to denoise the DWI-MRI images. A semi-automatic delineation workflow (SADW) was next developed and compared with a manually adjusted workflow (MAW). The agreement between workflows was determined using the Dice coefficients and Brand Altman plots. The prognostic value of ADC mean increases (%/week) for pathologic complete response (pCR) was assessed using c-statistics., Results: The median Dice coefficient between the SADW and MAW was 0.64 (interquartile range 0.20). For the MAW, the c-statistic for predicting pCR was 0.80 (95% confidence interval (CI):0.56-1.00). The SADW showed a c-statistic of 0.84 (95%CI:0.63-1.00) after denoising. No statistically significant differences in c-statistics were observed between the workflows or after applying denoising., Conclusions: The SADW resulted in non-inferior prognostic value for pCR compared to the more laborious MAW, allowing broad scale applications. The effect of denoising on the prognostic value for pCR needs to be investigated in larger cohorts., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

The analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry holds promise as a platform for immune checkpoint inhibition (ICI) biomarker identification. Our aim was to characterize the systemic immune compartment in resectable esophageal adenocarcinoma patients treated with neoadjuvant ICI therapy. In total, 24 patients treated with neoadjuvant chemoradiotherapy (nCRT) and anti-PD-L1 (atezolizumab) from the PERFECT study (NCT03087864) were included and 26 patients from a previously published nCRT cohort. Blood samples were collected at baseline, on-treatment, before and after surgery. Response groups for comparison were defined as pathological complete responders (pCR) or patients with pathological residual disease (non-pCR). Based on multicolor flow cytometry of PBMCs, an immunosuppressive phenotype was observed in the non-pCR group of the PERFECT cohort, characterized by a higher percentage of regulatory T cells (Tregs), intermediate monocytes, and a lower percentage of type-2 conventional dendritic cells. A further increase in activated Tregs was observed in non-pCR patients on-treatment. These findings were not associated with a poor response in the nCRT cohort. At baseline, immunosuppressive cytokines were elevated in the non-pCR group of the PERFECT study. The suppressive subsets correlated at baseline with a Wnt/β-Catenin gene expression signature and on-treatment with epithelial-mesenchymal transition and angiogenesis signatures from tumor biopsies. After surgery monocyte activation (CD40), low CD8+Ki67+ T cell rates, and the enrichment of CD206+ monocytes were related to early recurrence. These findings highlight systemic barriers to effective ICI and the need for optimized treatment regimens., Competing Interests: MIvBH is consultant for Mylan, Johnson & Johnson, Alesi Surgical, BBraun and Medtronic, and received unrestricted research grants from Stryker. All fees paid to institution. NHM has served as a consultant for MSD, BMS, Astra Zeneca, Servier and Lilly. MFB received research funding from Celgene and Lead Pharma and has acted as a consultant for Servier. HWMvL: Consultant or advisory role: BMS, Daiichy, Dragonfly, Eli Lilly, MSD, Nordic Pharma, Servier. Research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Eli Lilly, MSD, Nordic Pharma, Philips, Roche, Servier. Speaker role: Astellas, Daiichy, Novartis. TDdG reports to be in an advisory role for GE Healthcare, Mendus and LAVA Therapeutics, to have received a research grant from Idera Pharmaceuticals, and to be co-founder and owner of stocks of LAVA Therapeutics, outside of the submitted work. The other authors report no conflict of interest., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: In the West, patients with cervical lymph node metastasis of resectable esophageal cancer at diagnosis are generally precluded from curative treatment. This study prospectively explored the safety and feasibility of neoadjuvant chemoradiotherapy followed by robot-assisted minimally invasive esophagectomy (RAMIE) with three-field lymphadenectomy for these patients., Methods: Between 2015 and 2021, patients with resectable thoracic esophageal cancer and cervical lymph node metastasis were recruited nationwide in the Netherlands. Patients without interval metastasis following neoadjuvant chemoradiotherapy and good physical condition underwent RAMIE with bilateral three-field lymphadenectomy. Safety was predefined as ≤50% Clavien-Dindo grade ≥3b postoperative complications., Results: Neoadjuvant chemoradiotherapy was administered to 29 patients (19 (66%) adenocarcinoma and 10 (34%) squamous cell carcinoma). After restaging, nine (31%) patients were excluded (interval metastasis, clinical deterioration, or withdrawn consent). RAMIE was performed in 20 patients (R0-rate 95%). A median of 42 [range 21-71] lymph nodes were resected of which 13 [range 2-35] were cervical. Only 1 (5%) patient had an unexpected contralateral cervical lymph node metastasis. Complications grade ≥3b occurred in 50%. Most frequent complications of any grade were recurrent laryngeal nerve palsy (45%) and pneumonia (40%). Overall survival at 1 year was 85% and quality of life at 6 months was comparable to esophageal cancer patients treated with curative intent., Conclusions: RAMIE with three-field lymphadenectomy following neoadjuvant chemoradiotherapy for patients with resectable esophageal cancer presenting with cervical lymph node metastasis is feasible in a Western population. Because contralateral cervical metastasis is rare, a unilateral neck dissection would suffice in the majority of cases., Clinical Trial: gov Identifier: NCT02426879. Dutch trial register Identifier: NTR 4552., (© 2023. Society of Surgical Oncology.)

Background: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer., Methods: In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%)., Results: A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement)., Conclusion: The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. van Laarhoven reports grants or advisory/speaker role from: Astellas, BMS, Dragonfly, Lilly, Merck, Novartis, Nordic Pharma, Servier; research funding or medical supply from: Bayer, BMS, Celgene, Janssen, Incyte, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier; and has received unrestricted research funding (non-commercial) from: Dutch Cancer Society, NWO/ZonMw, European Research Council, MaagLeverDarm Stichting. Dr. Muijs reports institutional grants from: Elekta, IBA, RaySearch, Siemens, Mirada, Bergoz Instrumentation and Medical Data Works, KWF, all outside the submitted work. Dr. van Hillegersberg has a consulting and advisory role at Intuitive Surgical. Dr. de Manzoni reports personal fees from Lilly, outside the submitted work. Dr. Gani reports travel grants from Elekta and departmental research cooperation, outside the submitted work. Dr. Smyth reports personal fees/grants from: Astra Zeneca, Beigene, BMS, Amal Therapeutics, Amgen, Daiichi Sankyo, Merck, Servier, Novartis, Pfizer, Roche, and Zymeworks, all outside the submitted work. Dr. Haj Mohammad reports consulation fees from: Merck, BMS, Eli Lilly, Astra Zeneca, and research funding from Servier, all outside the submitted work. Dr. Adenis reports grants and personal fees from Bayer, personal fees and non-fianciel support from MSD, personal fees from: BMS, Novartis, Pierre-Fabre, non-financial support from Servier, grants from Sanofi, all outside the submitted work. Dr. Lordick reports grants from: BMS and Gilead, personal fees from: Amgen, Astellas, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Elsevier, Incyte, Merck, MSD, Roche, Servier, all outside the submitted work. Dr. Slingerland reports an advisory role at BMS and Lilly. Dr. van Berge Henegouwen received researcher-initiated grant from Stryker and is consultant for Alesi Surgical, Johnson and Johnson, Medtronic, Braun and Mylan. Dr Nilsson reports advisory roles for BMS and Medtronic. All remaining authors have declared no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Intrafraction motion during magnetic resonance (MR)-guided dose delivery of esophageal cancer tumors was retrospectively analyzed. Deformable image registration of cine-MR series resulted in gross tumor volume motion profiles in all directions, which were subsequently filtered to isolate respiratory and drift motion. A large variability in intrafraction motion patterns was observed between patients. Median 95% peak-to-peak motion was 7.7 (3.7 - 18.3) mm, 2.1 (0.7 - 5.7) mm and 2.4 (0.5 - 5.6) mm in cranio-caudal, left-right and anterior-posterior directions, relatively. Furthermore, intrafraction drift was generally modest (<5mm). A patient specific approach could lead to very small margins (<3mm) for most patients., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Radiation Oncology Department of the University Medical Center Utrecht receives financial and technical support under research agreements as well sponsoring for travels and scientific symposia from: Elekta AB (Stockholm, Sweden), Philips NV (Best, The Netherlands)., (© 2023 The Authors.)

Objective: To identify risk factors for tumor positive resection margins after neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for esophageal cancer., Summary Background Data: Esophagectomy after nCRT is associated with tumor positive resection margins in 4% to 9% of patients. This study evaluates potential risk factors for positive resection margins after nCRT followed by esophagectomy., Methods: All patients who underwent an elective esophagectomy following nCRT in 2011 to 2017 in the Netherlands were included. A multivariable logistic regression was performed to assess the association between potential risk factors and tumor positive resection margins., Results: In total, 3900 patients were included. Tumor positive resection margins were observed in 150 (4%) patients. Risk factors for tumor positive resection margins included tumor length (in centimeters, OR: 1.1, 95% CI: 1.0-1.1), cT4-stage (OR: 3.0, 95% CI: 1.2-6.7), and an Ivor Lewis esophagectomy (OR: 1.6, 95% CI: 1.0-2.6). Predictors associated with a lower risk of tumor positive resection margins were squamous cell carcinoma (OR: 0.4, 95% CI: 0.2-0.7), distal tumors (OR: 0.5, 95% CI: 0.3-1.0), minimally invasive surgery (OR: 0.6, 95% CI: 0.4-0.9), and a hospital volume of >60 esophagectomies per year (OR: 0.6, 95% CI: 0.4-1.0)., Conclusions: In this nationwide cohort study, tumor and surgical related factors (tumor length, histology, cT-stage, tumor location, surgical procedure, surgical approach, hospital volume) were identified as risk factors for tumor positive resection margins after nCRT for esophageal cancer. These results can be used to improve the radical resection rate by careful selection of patients and surgical approach and are a plea for centralization of esophageal cancer care., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Patients with cancer of the oesophagus or gastro-oesophageal junction have a high risk of recurrence after treatment with curative intent. The aim of this study was to analyse the site of recurrence, treatment, and survival in patients with recurrent disease., Methods: Patients with non-metastatic oesophageal or junctional carcinoma treated with curative intent between January 2015 and December 2016 were selected from the Netherlands Cancer Registry. Data on recurrence were collected in the second half of 2019. Overall survival (OS) was assessed by Kaplan-Meier methods., Results: In total, 862 of 1909 patients (45.2 per cent) for whom information on follow-up was available had disease recurrence, and 858 patients were included. Some 161 of 858 patients (18.8 per cent) had locoregional recurrence only, 415 (48.4 per cent) had distant recurrence only, and 282 (32.9 per cent) had combined locoregional and distant recurrence. In all, 518 of 858 patients (60.4 per cent) received best supportive care only and 315 (39.6 per cent) underwent tumour-directed therapy. Patients with locoregional recurrence alone more often received chemoradiotherapy than those with distant or combined locoregional and distant recurrence (19.3 per cent versus 0.7 and 2.8 per cent), and less often received systemic therapy (11.2 per cent versus 30.1 and 35.8 per cent). Median OS was 7.6, 4.2, and 3.3 months for patients with locoregional, distant, and combined locoregional and distant recurrence respectively (P < 0.001)., Conclusion: Disease recurred after curative treatment in 45.2 per cent of patients. Locoregional recurrence developed in only 18.8 per cent. The vast majority of patients presented with distant or combined locoregional and distant recurrence, and received best supportive care., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: In patients with gastric or gastroesophageal junction (GEJ) cancer treated with curative intent, distant interval metastases may be detected after start of neoadjuvant chemotherapy or during surgery. The aim of this study was to explore characteristics, allocated treatment and overall survival (OS) in gastric/GEJ cancer patients with interval metastases, and to compare OS with synchronous metastatic gastric/GEJ cancer patients who started palliative chemotherapy., Methods: Patients with interval metastases were selected from the Netherlands Cancer Registry by including patients with potentially curable gastric/GEJ adenocarcinoma (2010-2018) who started chemotherapy without concurrent radiotherapy. The OS since start of neoadjuvant treatment of patients with interval metastases was compared with a propensity score-matched cohort of patients with synchronous metastases who received palliative systemic treatment., Results: 164 patients with interval metastases diagnosed in 2010-2018 were included. Metastases were most frequently detected during surgery (83%) and most frequently located in the peritoneum (77%). Peritoneal interval metastases were observed in 63% and 80% of the patients who did and did not have a diagnostic laparoscopy prior to neoadjuvant treatment, respectively (P = 0.041). Median OS was 8.9 months (IQR 5.5-13.4), compared to 8.0 months (IQR 4.1-14.1) in matched synchronous metastatic patients calculated from start of neoadjuvant and palliative systemic treatment, respectively (P = 0.848)., Conclusion: This population-based study shows that gastric/GEJ cancer patients who started neoadjuvant treatment and were diagnosed with interval metastases most frequently suffered from peritoneal metastases detected during (exploratory) surgery, even when a diagnostic laparoscopy was performed before start of treatment. OS was comparable to patients with synchronous metastatic gastric/GEJ cancer., Competing Interests: Declaration of competing interest RHAV reports grants from BMS and Roche. NHM reports a consult/advisory role for BMS, MSDServier, Eli Lilly, reserach grant from Servier. SSG reports a research grant from Olympus and consulting fees from Medtronic. MGHvO reports grants from Amgen, BMS, Lilly, Nordic, Merck, Roche and Servier. HWMvL reports a consult/advisory role for BMS, Celgene, Lilly, Merck, and Nordic, and Servier and has received unrestricted research funding from Bayer, BMS, Celgene, Lilly, Merck Serono, MSD, Nordic, Philips, Roche and Servier. The other authors declare that they have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: This nationwide population-based study analyzed the outcomes of local treatment (i.e. stereotactic body radiotherapy [SBRT] or metastasectomy) or systemic therapy for oligometastatic disease (OMD) in patients with esophagogastric cancer in The Netherlands., Materials and Methods: Between 2015 and 2016, all patients in The Netherlands with esophagogastric cancer and synchronous or metachronous OMD were eligible for inclusion. Patients who underwent local treatment of OMD (SBRT or metastasectomy) and/or systemic therapy were included. OMD was defined as distant metastases in 1 organ or 1 extra-regional lymph node region. The primary outcomes were overall survival (OS) and independent prognostic factors for OS. OS was calculated from diagnosis of OMD. Prognostic factors for OS were analyzed using a multivariable Cox proportional hazard model., Results: A total of 594 patients were included, of whom 83 underwent local treatment for OMD alone, 22 local treatment plus systemic therapy, and 489 systemic therapy alone. Median OS after local treatment for OMD alone was 16.0 months, local treatment plus systemic therapy 22.7 months, and after systemic therapy alone 8.5 months. Improved OS was independently associated with local treatment for OMD alone or combined with systemic therapy as compared with systemic therapy alone (hazard ratio [HR] 0.52, 95% CI: 0.31-0.90 and HR 0.42, 95% CI: 0.22-0.82, respectively) and a controlled primary tumor(HR 0.48, 95% CI: 0.27-0.86). Worse OS was independently associated with worse performance scores (HR 1.41, 95%: 1.32-1.75), poorly or undiffertumor as compared with good or moderadifferentiated tumor (HR 1.37, 95% CI: 1.06-1.76), and peritoneal as compared with lymph mode metastases (HR 1.39, 95% CI: 1.00-1.93)., Conclusion: Local treatment of OMD alone or combined with systemic therapy was independently associated with improved OS as compared with systemic therapy alone in this population-based cohort study in The Netherlands. Randomized controlled trials are warranted to confirm these results., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. van Laarhoven reports consultant or advisory role: BMS, Dragonfly, Lilly, Merck, Nordic Pharma, Servier; research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier; Dr. Verhoeven reports grants from Bristol-Myer Squibb and Roche, outside the submitted work; Dr. Haj Mohammad reports personal fees from BMS, Lilly, MSD, Servier, and Astra Zeneca, outside the submitted work; the other authors have nothing to disclose.., (© 2022 The Author(s).)

Background: The primary goal of this study was to determine overall survival (OS) in patients who underwent local treatment (metastasectomy or stereotactic body radiotherapy [SBRT]) or systemic therapy (chemotherapy or targeted therapy) for oligometastatic esophagogastric cancer. The secondary goal was to determine prognostic factors for OS., Methods: Patients with synchronous or metachronous oligometastatic esophagogastric cancer who underwent local treatment or systemic therapy were included in this single-center, retrospective cohort study. Oligometastatic disease (OMD) included 1 organ or 1 extraregional lymph node station with ≤ 3 lesions. OS was determined after OMD detection. Treatment for OMD was categorized as (1) local treatment, (2) local plus systemic, (3) systemic therapy. The primary tumor was controlled after resection or definitive chemoradiotherapy., Results: In total, 85 patients were included. Treatment for OMD was local treatment (58%), local plus systemic (14%), or systemic therapy (28%). The primary tumor was controlled in 68% of patients. Most patients were diagnosed with distal esophageal cancer (61%), with adenocarcinoma histology (76%), and presented with synchronous OMD (51%). OS after local treatment was 17 months (95% confidence interval [CI] 12-40), after local plus systemic therapy 35 months (95% CI 29-NA), and after systemic therapy 16 months (95% CI 11-NA). Better OS was independently associated with local plus systemic compared with local treatment (hazard ratio [HR] 2.11, 95% CI 1.05-5.07) or systemic therapy (HR 2.28, 95% CI 1.04-6.07)., Conclusions: Local plus systemic therapy for oligometastatic esophagogastric cancer was independently associated with improved OS and better OS compared with either systemic therapy or local treatment., (© 2022. The Author(s).)

Background: The probability of undergoing treatment with curative intent according to the hospital of diagnosis varies for esophagogastric cancer in the Netherlands. Little is known about the factors contributing to this variation. This study aimed to improve the understanding of the differences between the multidisciplinary team meeting treatment proposal and the treatment that was actually carried out and to qualitatively investigate the differences in treatment decision-making after the multidisciplinary team meeting treatment proposal between hospitals., Methods: To gain an in-depth understanding of treatment decision-making, quantitative data (i.e., multidisciplinary team meeting proposal and treatment that was carried out) were collected from the Netherlands Cancer Registry. Changes in the multidisciplinary team meeting proposal and applied treatment comprised changes in the type of treatment option (i.e., curative or palliative, or no change) and were calculated according to the multivariable multilevel probability of undergoing treatment with curative intent (low, middle, and high). Qualitative data were collected from eight hospitals, including observations of 26 outpatient clinic consultations, 30 in-depth interviews with clinicians, seven focus groups with clinicians, and three focus groups with patients. Clinicians and patients' perspectives were assessed using thematic content analysis., Results: The multidisciplinary team meeting proposal and applied treatment were concordant in 97% of the cases. Clinicians' implementation of treatment decision-making in clinical practice varied, which was mentioned by the clinicians to be due to the clinician's personality and values. Differences between clinicians consisted of discussing all treatment options versus only the best fitting treatment option and the extent of discussing the benefits and harms. Most patients aimed to undergo curative treatment regardless of the consequences, since they believed this could prolong their life., Conclusion: Since changes in the multidisciplinary team meeting-proposed treatment and actual treatment were rarely observed, this study emphasizes the importance of an adequately formulated multidisciplinary team meeting proposal., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Patients with esophageal cancer can develop distant metastases between the start of neoadjuvant chemoradiotherapy (nCRT) and planned surgery (ie, interval distant metastases). 18F-FDG PET/CT restaging after nCRT detects interval distant metastases in ~8% of patients. This study aimed to identify patients for whom 18F-FDG PET/CT restaging after nCRT could be omitted using an existing prediction model predicting for interval distant metastases or by using clinical stage groups., Patients and Methods: Patients with locally advanced esophageal cancer who underwent baseline and restaging 18F-FDG PET/CT, nCRT, and were planned for esophagectomy between 2017 and 2021 were eligible for inclusion in this retrospective study. The primary outcome was the existing model's external performance (ie, discrimination and calibration) for predicting interval distant metastases. The existing model predictors included tumor length, cN status, squamous cell carcinoma histology, and baseline SUVmax. The secondary outcome determined the clinical stage groups (AJCC/UICC eighth edition) for adenocarcinoma and squamous cell carcinoma for which the incidence of interval distant metastases was <10%., Results: In total, 127 patients were included, of whom 17 patients developed interval distant metastases (13%; 95% confidence interval [CI], 8%-21%) and 9 patients were deemed to have false-positive lesions on 18F-FDG PET/CT (7%; 95% CI, 2%-11%). Applying the existing model to this cohort yielded a discriminatory c-statistic of 0.56 (95% CI, 0.40-0.72). The calibration of the existing model was poor (ie, mostly underestimating the actual risk). The incidence of true-positive versus false-positive interval distant metastases for patients with clinical stage II disease was 5% versus 0%; clinical stage III, 14% versus 8%; and clinical stage IVa, 22% versus 9%., Conclusions: The existing prediction model cannot reliably identify patients at risk for developing interval distant metastases after nCRT for esophageal cancer. Omission of 18F-FDG PET/CT restaging after nCRT could be considered in patients with clinical stage II esophageal cancer., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: This R-Ideal stage 1b/2a study describes the workflow and feasibility of long-course fractionated online adaptive MR-guided chemoradiotherapy with reduced CTV-to-PTV margins on the 1.5T MR-Linac for patients with esophageal cancer., Methods: Patients with esophageal cancer scheduled to undergo chemoradiation were treated on a 1.5T MR-Linac. Daily MR-images were acquired for online contour adaptation and replanning. Contours were manually adapted to match the daily anatomy and an isotropic CTV-to-PTV margin of 6 mm was applied. Time was recorded for all individual steps in the workflow. Feasibility and patient tolerability were defined as on-table time of ≤60 min and completion of >95% of the fractions on the MR-Linac, respectively. Positioning verification and post-treatment MRIs were retrospectively analyzed and dosimetric parameters were compared to standard non-adaptive conventional treatment plans., Results: Nine patients with esophageal cancer were treated with chemoradiation; eight patients received 41.4 Gy in 23 fractions and one received 50.4 Gy in 28 fractions. Four patients received all planned fractions on the MR-Linac, whereas for two patients >5% of fractions were rescheduled to a conventional linac for reasons of discomfort. A total of 183 (86%) of 212 scheduled fractions were successfully delivered on the MR-Linac. Three fractions ended prematurely due to technical issues and 26 fractions were rescheduled on a conventional linac due to MR-Linac downtime (n = 10), logistical reasons (n = 3) or discomfort (n = 13).The median time per fraction was 53 min (IQR = 3 min). Daily adapted MR-Linac plans had similar target coverage, whereas dose to the organs-at-risk was significantly reduced compared to conventional treatment (26% and 12% reduction in mean lung and heart dose, respectively)., Conclusion: Daily online adaptive fractionated chemoradiotherapy with reduced PTV margins is moderately feasible for esophageal cancer and results in better sparing of heart and lungs. Future studies should focus on further optimization and acceleration of the current workflow., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Radiation Oncology Department of the University Medical Center Utrecht receives financial and technical support under research agreements as well sponsoring for travels and scientific symposia from: Elekta AB (Stockholm, Sweden), Philips NV (Best, The Netherlands)., (© 2022 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Results of CheckMate 577 show an improved disease-free survival for patients with resected esophageal or gastroesophageal junction cancer treated with adjuvant nivolumab compared with placebo (22.4 versus 11.0 months). Population-based data can provide insights in outcomes from clinical practice. The aim of our study was to investigate disease-free and overall survival in a nationwide population aligned with the inclusion criteria of CheckMate 577., Patients and Methods: Resected patients with stage II/III esophageal or gastroesophageal junction cancer (2015-2016) treated with neoadjuvant chemoradiotherapy were selected from the Netherlands Cancer Registry. Patients with cervical esophageal cancer, irradical resection, or complete pathological response were excluded. Disease-free and overall survival were assessed from 12 weeks after resection using Kaplan-Meier methods. In addition, to adjust for differences in characteristics between CheckMate 577 and our population-based cohort, a matching-adjusted indirect comparison was performed for pathological lymph node status and pathological tumor status., Results: We identified 634 patients. Sixty percent of patients were diagnosed with recurrence or were deceased at the end of follow-up. Median disease-free survival was 19.7 months and median overall survival was 32.2 months. After the matching procedure, the median disease-free survival was 17.2 months and median overall survival was 28.2 months., Conclusions: Disease-free survival in our population-based study was considerably longer than the placebo population of CheckMate-577 (19.7 versus 11.0 months). Possible explanations are differences in characteristics, quality of esophageal cancer care, or differential strategies for evaluation of recurrence. In the Netherlands postoperative imaging is not part of the standard follow-up as opposed to the standard postoperative imaging in the CheckMate 577 trial. The difference in postoperative imaging could partially explain the longer disease-free survival observed in our study. Quality and optimization of current treatment modalities remain important aspects of esophageal cancer care., Competing Interests: Conflict of interest statement: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MIvBH reports unrestricted research grants from Stryker and Olympus with fees paid to the institution and an advisory role for Johnson & Johnson, BBraun Alesi Surgical, Mylan, and Medtronic. MM reports grants and nonfinancial support from Arbeitsgemeinschaft Internistische Onkologie, German Ministry of Education and Research, the European Organisation for Research and Treatment of Cancer, and German Cancer Aid during the conduct of the study; personal fees from Amgen, Bristol Myers Squibb, Falk Foundation, Lilly, MCI Group, Merck Serono, Merck Sharp & Dohme Corp., Pfizer, and Roche; grants to the university from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme Corp., and Pfizer; and nonfinancial support from Amgen and Bristol Myers Squibb outside the submitted work. HWMvL reports grants from Roche; has served as a consultant for Bristol Myers Squibb, Celgene, Lilly, and Nordic; and has received unrestricted research funding from Bayer, Bristol Myers Squibb, Celgene, Lilly, Merck Serono, MSD, Nordic, Philips, and Roche. RHAV reports grants from Bristol Myers Squibb and Roche. MP, PAJV, LVB, SML, and SM have no disclosures to declare., (© The Author(s), 2022.)

Background: The thoracic lymphadenectomy during an esophagectomy for esophageal cancer includes resection of the thoracic duct (TD) compartment containing the TD lymph nodes (TDLNs). The role of TD compartment resection is still a topic of debate since metastatic TDLNs have only been demonstrated in squamous cell carcinomas in Eastern esophageal cancer patients. Therefore, the aim of this study was to assess the presence and metastatic involvement of TDLNs in a Western population, in which adenocarcinoma is the predominant type of esophageal cancer., Methods: From July 2017 to May 2020, all consecutive patients undergoing an open or robot-assisted transthoracic esophagectomy with concurrent lymphadenectomy and resection of the TD compartment in the University Medical Center Utrecht in Utrecht, the Netherlands, and the Città della Salute e della Scienza University Hospital in Turin, Italy, were included. The TD compartment was resected en bloc and was separated in the operation room by the operating surgeon after which it was macroscopically and microscopically assessed for (metastatic) TDLNs by the pathologist., Results: A total of 117 patients with an adenocarcinoma (73%) or squamous cell carcinoma (27%) of the esophagus were included. In 61 (52%) patients, TDLNs were found, containing metastasis in 9 (15%) patients. No major complications related to TD compartment resection were observed., Conclusions: This study demonstrates the presence of metastatic TDLNs in adenocarcinomas of the esophagus. This result provides a valid argument to routinely extend the thoracic lymphadenectomy with resection of the TD compartment during an esophagectomy for esophageal cancer., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: In esophageal cancer patients, distant metastases develop between the start of neoadjuvant chemoradiotherapy and planned surgery, so-called interval metastases. The primary aim of this study was to assess management, overall survival (OS), and prognostic factors for OS in these patients. A secondary aim was to compare OS with synchronous metastatic patients., Methods: Esophageal cancer patients with interval distant metastases were identified from the Netherlands Cancer Registry (2010 to 2017). Management was categorized into metastasis-directed therapy (MDT), primary tumor resection, or best supportive care (BSC). The OS was calculated from the diagnosis of the primary tumor. Prognostic factors affecting OS were studied using Cox proportional hazard models. Propensity score-matching (1:3) generated matched cases with synchronous distant metastases., Results: In all, 208 patients with interval metastases were identified: in 87 patients (42%) MDT was initiated; in 10%, primary tumor resection only; in 7%, primary tumor resection plus MDT; and in 41%, BSC. Median OS was 10 months (interquartile range, 8.6 to 11.1). Compared with BSC, superior OS was independently associated with MDT (hazard ratio [HR] 0.36; 95% confidence interval [CI], 0.26 to 0.49), primary tumor resection (HR 0.55; 95% CI, 0.33 to 0.94), and primary tumor resection plus MDT (HR 0.20; 95% CI, 0.10 to 0.38). Worse OS was independently associated with signet ring cell carcinoma (HR 1.92; 95% CI, 1.12 to 3.28) and poor differentiation grade (HR 1.96; 95% CI, 1.35 to 2.83). The OS was comparable between matched patients with interval and synchronous distant metastases (10.2 versus 9.4 months, P = .760)., Conclusions: In esophageal cancer patients treated with neoadjuvant chemoradiotherapy with interval distant metastases, the OS was poor and comparable to that of synchronous metastatic patients., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium., Methods and Materials: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment)., Results: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed., Conclusions: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging., (Copyright © 2021. Published by Elsevier Inc.)

Background: The incidence of grade 4 lymphopenia in patients treated with chemoradiotherapy (CRT) according to Chemoradiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) regimen is unclear. The primary aim was to determine the incidence of grade 4 lymphopenia during CROSS for esophageal cancer. Secondary aims were to externally validate a prediction model for grade 4 lymphopenia and compare overall survival between patients with and without grade 4 lymphopenia., Methods: Patients who underwent CRT for esophageal cancer between 2014 and 2019 were eligible for inclusion. Patients with a planned radiation dose of 41.4 Gy (CROSS) or 50.4 Gy ("extended-CROSS") and concurrent carboplatin and paclitaxel were included. The primary outcome was the incidence of grade 4 lymphopenia during CRT defined according to Common Terminology Criteria for Adverse Events version 5.0 (i.e. lymphocyte count nadir < 0.2 µL). The secondary outcome measures were the prediction model's external performance (i.e. discrimination and calibration). Overall survival for patients with versus without grade 4 lymphopenia was compared using Kaplan-Meier analysis., Results: A total of 219 patients were included of whom 176 patients (80%) underwent CROSS and 43 patients (20%) extended-CROSS. The incidence of grade 4 lymphopenia was 11% in CROSS and 33% in extended-CROSS (p < 0.001). External discrimination yielded a c-statistic of 0.80 (95% confidence interval: 0.70-0.89). External calibration of the model was poor in CROSS but fair in extended-CROSS. Adjusted calibration using intercept correction (adjusted for the lower a-priori risk for grade 4 lymphopenia in CROSS) showed fair agreement between the observed and predicted risk for grade 4 lymphopenia. Median overall survival in patients with versus without grade 4 lymphopenia was 12.7 versus 42.5 months (p = 0.045)., Conclusion: The incidence of grade 4 lymphopenia is significantly higher in esophageal cancer patients receiving extended-CROSS compared to those receiving CROSS. The prediction model demonstrated good external performance in the setting of the CROSS-regimen and could be used to identify patients at high-risk for grade 4 lymphopenia who might be eligible for lymphopenia-mitigating strategies., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the dosimetric benefits of online MR-guided radiotherapy (MRgRT) for esophageal cancer patients and to assess how these benefits could be translated into a local boosting strategy to improve future outcomes., Methods: Twenty-nine patients were in-silico treated with both a MRgRT regimen and a conventional image guided radiotherapy (IGRT) regimen using dose warping techniques. Here, the inter and intrafractional changes that occur over the course of treatment (as derived from 5 MRI scans that were acquired weekly during treatment) were incorporated to assess the total accumulated dose for each regimen., Results: A significant reduction in dose to the organs-at-risk (OARs) was observed for all dose-volume-histogram (DVH) parameters for the MRgRT regimen without concessions to target coverage compared to the IGRT regimen. The mean lung dose was reduced by 28%, from 7.9 to 5.7 Gy respectively and V20Gy of the lungs was reduced by 55% (6.3-2.8%). A reduction of 24% was seen in mean heart dose (14.8-11.2 Gy), while the V25Gy of the heart was decreased by 53% (14.3-6.7%) and the V40Gy of the heart was decreased by 69% (3.9-1.2%). In addition, MRgRT dose escalation regimens with a boost up to 66% of the prescription dose to the primary tumor yielded approximately the same dose levels to the OARs as from the conventional IGRT regimen., Conclusion: This study revealed that MRgRT for esophageal cancer has the potential to significantly reduce the dose to heart and lungs. In addition, online high precision targeting of the primary tumor opens new perspectives for local boosting strategies to improve outcome of the local management of this disease., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The CROSS trial established neoadjuvant chemoradiotherapy (nCRT) for patients with resectable esophageal adenocarcinoma (rEAC). In the PERFECT trial, we investigated the feasibility and efficacy of nCRT combined with programmed-death ligand-1 (PD-L1) inhibition for rEAC., Patients and Methods: Patients with rEAC received nCRT according to the CROSS regimen combined with five cycles of atezolizumab (1,200 mg). The primary endpoint was the feasibility of administering five cycles of atezolizumab in ≥75% patients. A propensity score-matched nCRT cohort was used to compare pathologic response, overall survival, and progression-free survival. Exploratory biomarker analysis was performed on repeated tumor biopsies., Results: We enrolled 40 patients of whom 85% received all cycles of atezolizumab. Immune-related adverse events of any grade were observed in 6 patients. In total, 83% proceeded to surgery. Reasons for not undergoing surgery were progression ( n = 4), patient choice ( n = 2), and death ( n = 1). The pathologic complete response rate was 25% (10/40). No statistically significant difference in response or survival was found between the PERFECT and the nCRT cohort. Baseline expression of an established IFNγ signature was higher in responders compared with nonresponders ( P = 0.043). On-treatment nonresponders showed either a high number of cytotoxic lymphocytes (CTL) with a transcriptional signature consistent with expression of immune checkpoints, or a low number of CTLs., Conclusions: Combining nCRT with atezolizumab is feasible in patients with rEAC. On the basis of our exploratory biomarker study, future studies are necessary to elucidate the potential of neoadjuvant immunotherapy in patient subgroups. See related commentary by Catenacci, p. 3269 ., (©2021 American Association for Cancer Research.)

In this review, we outline the potential benefits and the future role of MRI and MR-guided radiotherapy (MRgRT) in the management of esophageal cancer. Although not currently used in most clinical practice settings, MRI is a useful non-invasive imaging modality that provides excellent soft tissue contrast and the ability to visualize cancer physiology. Chemoradiation therapy with or without surgery is essential for the management of locally advanced esophageal cancer. MRI can help stage esophageal cancer, delineate the gross tumor volume (GTV), and assess the response to chemoradiotherapy. Integrated MRgRT systems can help overcome the challenge of esophageal motion due to respiratory motion by using real-time imaging and tumor tracking with respiratory gating. With daily on-table MRI, shifts in tumor position and tumor regression can be taken into account for online-adaptation. The combination of accurate GTV visualization, respiratory gating, and online adaptive planning, allows for tighter treatment volumes and improved sparing of the surrounding normal organs. This could lead to a reduction in radiotherapy induced cardiac toxicity, pneumonitis and post-operative complications. Tumor physiology as seen on diffusion weighted imaging or dynamic contrast enhancement can help individualize treatments based on the response to chemoradiotherapy. Patients with a complete response on MRI can be considered for organ preservation while patients with no response can be offered an earlier resection. In patients with a partial response to chemoradiotherapy, areas of residual cancer can be targeted for dose escalation. The tighter and more accurate targeting enabled with MRgRT may enable hypofractionated treatment schedules., Competing Interests: MB reports non-financial support from Viewray Inc, outside the submitted work, and MERCK Clinical Trial Support, Astra Zeneca Clinical Trial Support, EMD Serono Clinical Trial Support. SL reports non-financial support from ViewRay, outside the submitted work. GM and SM are both members of the international MR-linac Consortium, which is financially supported by Elekta. The UMC Utrecht Department of Radiotherapy is financially supported by Elekta., (Copyright © 2021 Lee, Bassetti, Meijer and Mook.)

Purpose: MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. Methods and Results: In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). Conclusion: The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer., (Copyright © 2020 de Mol van Otterloo, Christodouleas, Blezer, Akhiat, Brown, Choudhury, Eggert, Erickson, Faivre-Finn, Fuller, Goldwein, Hafeez, Hall, Harrington, van der Heide, Huddart, Intven, Kirby, Lalondrelle, McCann, Minsky, Mook, Nowee, Oelfke, Orrling, Sahgal, Sarmiento, Schultz, Tersteeg, Tijssen, Tree, van Triest, Hall and Verkooijen.)

Background: Neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer causes tumor regression during treatment. Tumor regression can induce changes in the thoracic anatomy, with smaller target volumes and displacement of organs at risk (OARs) surrounding the tumor as a result. Adaptation of the radiotherapy treatment plan according to volumetric changes during treatment might reduce radiation dose to the OARs, while maintaining adequate target coverage. Data on the magnitude of the volumetric changes and its impact on the thoracic anatomy is scarce. The aim of this study was to assess the volumetric changes in the primary tumor during nCRT for esophageal cancer based on weekly MRI scans. Material and methods: In this prospective study, patients with adeno- or squamous cell carcinoma of the esophagus treated with neoajduvant chemoradiotherapy according to the CROSS regimen (carboplatin + paclitaxel + 23 × 1.8 Gy) were included. Of each patient, six sequential MRI scans were acquired: one prior to nCRT, and five in each subsequent week during nCRT. Tumor volumes were delineated on the transversal T2 weighted images by two radiation oncologists. Volumetric changes were analyzed using linear mixed effects models. Results: A total of 170 MRI scans from 29 individual patients were included. The mean (± standard deviation (SD)) tumor volume at baseline was 45 cm 3 (± 23). Tumor volume regression started after the first week of nCRT with a significant decrease in tumor volumes every subsequent week. A decrease to 42 cm 3 (91% of initial volume), 38 cm 3 (81%), 35 cm 3 (77%), and 32 cm 3 (72%) was observed in the second, third, fourth and fifth week of nCRT, respectively. Conclusion: Based on weekly MRI scanning during nCRT for esophageal cancer, a considerable decrease in tumor volume was observed during treatment. Volume regression and consequential anatomical changes suggest the possible benefit of adaptive radiotherapy.

Purpose: Accurate preoperative prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal cancer could enable omission of esophagectomy in patients with a pathologic complete response (pCR). This study aimed to evaluate the individual and combined value of 18 F-fluorodeoxyglucose positron emission tomography with integrated computed tomography ( 18 F-FDG PET/CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) during and after nCRT to predict pathologic response in patients with esophageal cancer., Methods and Materials: In this multicenter prospective study, patients scheduled to receive nCRT followed by esophagectomy for esophageal cancer underwent 18 F-FDG PET/CT and DW-MRI scanning before the start of nCRT, during nCRT, and before esophagectomy. Response to nCRT was based on histopathologic evaluation of the resection specimen. Relative changes in 18 F-FDG PET/CT and DW-MRI parameters were compared between patients with pCR and non-pCR groups. Multivariable ridge regression analyses with bootstrapped c-indices were performed to evaluate the individual and combined value of 18 F-FDG PET/CT and DW-MRI., Results: pCR was found in 26.1% of 69 patients. Relative changes in 18 F-FDG PET/CT parameters after nCRT (Δ standardized uptake value [SUV] mean,post P = .016, and Δ total lesion glycolysis post P = .024), as well as changes in DW-MRI parameters during nCRT (Δ apparent diffusion coefficient [ADC] during P = .008) were significantly different between pCR and non-pCR. A c-statistic of 0.84 was obtained for a model with ΔADC during , ΔSUV mean,post , and histology in classifying patients as pCR (versus 0.82 for ΔADC during and 0.79 for ΔSUV mean,post alone)., Conclusions: Changes on 18 F-FDG PET/CT after nCRT and early changes on DW-MRI during nCRT can help identify pCR to nCRT in esophageal cancer. Moreover, 18 F-FDG PET/CT and DW-MRI might be of complementary value in the assessment of pCR., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: This study was conducted in order to determine the optimal timing of diffusion-weighted magnetic resonance imaging (DW-MRI) for prediction of pathologic complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer., Methods: Patients with esophageal adenocarcinoma or squamous cell carcinoma who planned to undergo nCRT followed by surgery were enrolled in this prospective study. Patients underwent six DW-MRI scans: one baseline scan before the start of nCRT and weekly scans during 5 weeks of nCRT. Relative changes in mean apparent diffusion coefficient (ADC) values between the baseline scans and the scans during nCRT (ΔADC(%)) were compared between pathologic complete responders (pCR) and non-pCR (tumor regression grades 2-5). The discriminative ability of ΔADC(%) was determined based on the c-statistic., Results: A total of 24 patients with 142 DW-MRI scans were included. pCR was observed in seven patients (29%). ΔADC(%) from baseline to week 2 was significantly higher in patients with pCR versus non-pCR (median [IQR], 36% [30%, 41%] for pCR versus 16% [14%, 29%] for non-pCR, p = 0.004). The ΔADC(%) of the second week in combination with histology resulted in the highest c-statistic for the prediction of pCR versus non-pCR (0.87). The c-statistic of this model increased to 0.97 after additional exclusion of patients with a small tumor volume (< 7 mL, n = 3) and tumor histology of the resection specimen other than adenocarcinoma or squamous cell carcinoma (n = 1)., Conclusion: The relative change in tumor ADC (ΔADC(%)) during the first 2 weeks of nCRT is the most predictive for pathologic complete response to nCRT in esophageal cancer patients., Key Points: • DW-MRI during the second week of neoadjuvant chemoradiotherapy is most predictive for pathologic complete response in esophageal cancer. • A model including ΔADC week 2 was able to discriminate between pathologic complete responders and non-pathologic complete responders in 87%. • Improvements in future MRI studies for esophageal cancer may be obtained by incorporating motion management techniques.

Purpose: To explore whether a higher neoadjuvant radiation dose increases the probability of a pathological complete response (pCR) or pathological major response (pMR) response in oesophageal cancer patients. Material and methods: Between 2000 and 2017, 1048 patients from four institutions were stratified according to prescribed neoadjuvant radiation doses of 36.0 Gy (13.3%), 40.0 Gy (7.4%), 41.4 Gy (20.1%), 45.0 Gy (25.5%) or 50.4 Gy (33.7%) in 1.8-2.0 Gy fractions. Endpoints were pCR (tumour regression grade (TRG) 1) and pMR (TRG 1 + 2). Multivariable binary (TRG 1 + 2 vs. TRG > 2) and ordinal (TRG 1 vs. TRG 2 vs. TRG > 2) logistic regression analyses were performed, with subgroup analyses according to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)). Variables entered in the regression model along with neoadjuvant radiation dose were clinical tumour stage (cT), histology, chemotherapy regimen, induction chemotherapy and time from neoadjuvant chemoradiation to surgery. Results: A pCR was observed in 312 patients (29.8%); in 22.7% patients with AC and in 49.6% patients with SCC. No radiation dose-response relation was observed for pCR (OR = 1.01, 95% CI: 0.98-1.05 for AC and OR = 1.03, 95% CI: 0.96-1.10 for SCC). A pMR was observed in 597 patients (57.0%); in 53.4% patients with AC and in 67.2% patients with SCC. A higher radiation dose increased the probability of achieving pMR (OR = 1.04, 95% CI: 1.02-1.05). Factors reducing this probability were advanced cT stage (reference = cT1-2; cT3: OR = 0.54, 95% CI: 0.37-0.80; cT4: OR = 0.45, 95% CI: 0.24-0.84), AC histology (reference = SCC; OR = 0.62, 95% CI: 0.44-0.88), the use of non-platinum based chemotherapy in SCC patients (OR = 0.30, 95% CI: 0.10-0.91) and platinum based chemotherapy without induction chemotherapy in patients with AC (OR = 0.56, 95% CI: 0.42-0.76). The radiation dose-response relation was confirmed in a subgroup analysis of histologic subtypes (OR = 1.02, 95% CI: 1.01-1.04 for AC and OR = 1.05, 95% CI: 1.02-1.08 for SCC). Conclusions: Neoadjuvant radiation dose impacts pathological response in terms of pMR in oesophageal cancer patients. No radiation dose-response effect was observed for pCR. Further prospective trials are needed to investigate the dose-response relation in terms of pCR.

Background: Neoadjuvant chemoradiotherapy (nCRT) for resectable esophageal cancer is accompanied by the risk of treatment-related toxicity. The aim of this population-based cohort study was to provide insight in patients who do not proceed to surgical resection after starting nCRT., Methods: Patients who started nCRT for primary esophageal cancer diagnosed in 2015 and 2016 were selected from the nationwide population-based cancer registry. Outcome measurements included omission from surgical resection, reasons for omission of surgical resection, mortality during nCRT (≤90 days after ending nCRT) and 1-year overall survival. Multivariable logistic regression analyses were performed to identify predictive factors for omission of surgical resection., Results: A total of 1521 patients were included, of whom 215 (14.1%) did not undergo surgical resection after starting nCRT. Age (OR:1.04, 95%CI:1.01-1.06), BMI (OR:0.95, 95%CI:0.90-0.99), WHO performance status (WHO 1: OR:1.62, 95%CI:1.16-2.62 and WHO 2: OR:3.53, 95%CI:1.68-7.41) and clinical N status (cN2: OR:1.57, 95% CI:1.04-2.37 and cN3: OR:2.52, 95%CI:1.14-5.55) were significantly associated with omission from surgery. The most frequently reported reasons for omission from surgery were disease progression (44.3%) and physical functioning (22.8%). During nCRT or within the subsequent waiting period to surgery, 38 patients (2.5%) deceased. One year overall survival of the patients who underwent nCRT followed by surgical resection was 94.9%, and 73.5% in the patients who did not undergo surgical resection following nCRT., Conclusions: One in 7 patients who started nCRT for esophageal cancer do not proceed to surgical resection and have a decreased one year overall survival compared to patients who do proceed to surgical resection. Mortality during nCRT is considerable., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background and Purpose: Small cell carcinoma of the esophagus (SCEC) is a rare subtype of esophageal cancer for which optimal treatment is unknown. We analyzed the impact of treatment factors on outcome in patients with nonmetastasized SCEC., Methods: Patients with a histologically confirmed SCEC without distant metastases were analyzed in a nationwide multicenter retrospective cohort. All patients received radiotherapy as part of curative treatment between January 2000 and December 2014. Details on treatment and outcome were retrieved from individual charts. Cox regression analysis was used to determine prognostic factors for survival., Results: Fifty-eight patients were analyzed. Median survival was 16 months (95% confidence interval, 11-21 mo). Infield recurrences occurred in 25%, distant metastases in 45%, and brain metastases in 12%. In total, 63% of patients developed a recurrence. Most recurrences (67%) occurred within 1 year. In univariable analyses an increased number of chemotherapy cycles (>3) and lower radiotherapy doses (<45 Gy) were associated with improved survival. T-stage, N-stage, treatment period, type of chemotherapy, prophylactic cranial irradiation, and age were not associated with survival. In multivariable analyses, only the number of chemotherapy cycles was associated with better survival (hazard ratio, 0.78; P=0.006)., Conclusions: SCEC recurs frequently at distant sites after definitive chemoradiotherapy and usually within 1 year after curative treatment. With a dose of 45 to 50 Gy, infield recurrence rate was low. We found a relationship between number of received chemotherapy cycles and survival with best results obtained after at least 4 cycles of chemotherapy.

Accurate preoperative staging of gastric cancer and the assessment of tumor response to neoadjuvant treatment is of importance for treatment and prognosis. Current imaging techniques, mainly endoscopic ultrasonography (EUS), computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET), have their limitations. Historically, the role of magnetic resonance imaging (MRI) in gastric cancer has been limited, but with the continuous technical improvements, MRI has become a more potent imaging technique for gastrointestinal malignancies. The accuracy of MRI for T- and N-staging of gastric cancer is similar to EUS and CT, making MRI a suitable alternative to other imaging strategies. There is limited evidence on the performance of MRI for M-staging of gastric cancer specifically, but MRI is widely used for diagnosing liver metastases and shows potential for diagnosing peritoneal seeding. Recent pilot studies showed that treatment response assessment as well as detection of lymph node metastases and systemic disease might benefit from functional MRI ( e.g. diffusion weighted imaging and dynamic contrast enhancement). Regarding treatment guidance, additional value of MRI might be expected from its role in better defining clinical target volumes and setup verification with MR-guided radiation treatment.

Background and Purpose: The promise of the MR-linac is that one can visualize all anatomical changes during the course of radiotherapy and hence adapt the treatment plan in order to always have the optimal treatment. Yet, there is a trade-off to be made between the time spent for adapting the treatment plan against the dosimetric gain. In this work, the various daily plan adaptation methods will be presented and applied on a variety of tumour sites. The aim is to provide an insight in the behavior of the state-of-the-art 1.5 T MRI guided on-line adaptive radiotherapy methods., Materials and Methods: To explore the different available plan adaptation workflows and methods, we have simulated online plan adaptation for five cases with varying levels of inter-fraction motion, regions of interest and target sizes: prostate, rectum, esophagus and lymph node oligometastases (single and multiple target). The plans were evaluated based on the clinical dose constraints and the optimization time was measured., Results: The time needed for plan adaptation ranged between 17 and 485 s. More advanced plan adaptation methods generally resulted in more plans that met the clinical dose criteria. Violations were often caused by insufficient PTV coverage or, for the multiple lymph node case, a too high dose to OAR in the vicinity of the PTV. With full online replanning it was possible to create plans that met all clinical dose constraints for all cases., Conclusion: Daily full online replanning is the most robust adaptive planning method for Unity. It is feasible for specific sites in clinically acceptable times. Faster methods are available, but before applying these, the specific use cases should be explored dosimetrically.

Background: The standard curative treatment for patients with esophageal cancer is perioperative chemotherapy or preoperative chemoradiotherapy followed by open transthoracic esophagectomy (OTE). Robot-assisted minimally invasive thoracolaparoscopic esophagectomy (RAMIE) may reduce complications., Methods: A single-center randomized controlled trial was conducted, assigning 112 patients with resectable intrathoracic esophageal cancer to either RAMIE or OTE. The primary endpoint was the occurrence of overall surgery-related postoperative complications (modified Clavien-Dindo classification grade 2-5)., Results: Overall surgery-related postoperative complications occurred less frequently after RAMIE (59%) compared to OTE (80%) [risk ratio with RAMIE (RR) 0.74; 95% confidence interval (CI), 0.57-0.96; P = 0.02]. RAMIE resulted in less median blood loss (400 vs 568 mL, P <0.001), a lower percentage of pulmonary complications (RR 0.54; 95% CI, 0.34-0.85; P = 0.005) and cardiac complications (RR 0.47; 95% CI, 0.27-0.83; P = 0.006) and lower mean postoperative pain (visual analog scale, 1.86 vs 2.62; P < 0.001) compared to OTE. Functional recovery at postoperative day 14 was better in the RAMIE group [RR 1.48 (95% CI, 1.03-2.13; P = 0.038)] with better quality of life score at discharge [mean difference quality of life score 13.4 (2.0-24.7, p = 0.02)] and 6 weeks postdischarge [mean difference 11.1 quality of life score (1.0-21.1; P = 0.03)]. Short- and long-term oncological outcomes were comparable at a medium follow-up of 40 months., Conclusions: RAMIE resulted in a lower percentage of overall surgery-related and cardiopulmonary complications with lower postoperative pain, better short-term quality of life, and a better short-term postoperative functional recovery compared to OTE. Oncological outcomes were comparable and in concordance with the highest standards nowadays.