Discontinuation of neoadjuvant therapy does not influence postoperative short-term outcomes in elderly patients (≥ 70 years) with resectable gastric cancer: a population-based study from the dutch upper gastrointestinal cancer audit (DUCA) data.

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.

Risk Factors for Tumor Positive Resection Margins After Neoadjuvant Chemoradiotherapy for Esophageal Cancer: Results From the Dutch Upper GI Cancer Audit: A Nationwide Population-Based Study.

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.

Metastasectomy or Stereotactic Body Radiation Therapy With or Without Systemic Therapy for Oligometastatic Esophagogastric Cancer.

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.

Population-based study of treatment and outcome of recurrent oesophageal or junctional cancer.

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.

Optimal timing for prediction of pathologic complete response to neoadjuvant chemoradiotherapy with diffusion-weighted MRI in patients with esophageal cancer.

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 ΔADCweek 2was 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.

Tumor volume regression during neoadjuvant chemoradiotherapy for esophageal cancer: a prospective study with weekly MRI.

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 cm3 (± 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 cm3 (91% of initial volume), 38 cm3 (81%), 35 cm3 (77%), and 32 cm3 (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.

Robot-assisted Minimally Invasive Thoracolaparoscopic Esophagectomy Versus Open Transthoracic Esophagectomy for Resectable Esophageal Cancer: A Randomized Controlled Trial.

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.

Radiation dose and pathological response in oesophageal cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery: a multi-institutional analysis.

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.

DW-MRI and DCE-MRI are of complementary value in predicting pathologic response to neoadjuvant chemoradiotherapy for esophageal cancer.

PURPOSE: To explore the potential benefit and complementary value of a multiparametric approach using diffusion-weighted (DW-) and dynamic contrast-enhanced (DCE-) magnetic resonance imaging (MRI) for prediction of response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer. MATERIAL AND METHODS: Forty-five patients underwent both DW-MRI and DCE-MRI prior to nCRT (pre), during nCRT (week 2-3) (per) and after completion of nCRT, but prior to esophagectomy (post). Subsequently, histopathologic tumor regression grade (TRG) was assessed. Tumor apparent diffusion coefficient (ADC) and area-under-the-concentration time curve (AUC) were calculated for DW-MRI and DCE-MRI, respectively. The ability of these parameters to predict pathologic complete response (pCR, TRG1) or good response (GR, TRG ≤ 2) to nCRT was assessed. Furthermore the complementary value of DW-MRI and DCE-MRI was investigated. RESULTS: GR was found in 22 (49%) patients, of which 10 (22%) patients showed pCR. For DW-MRI, the 75th percentile (P75) ΔADCpost-pre was most predictive for GR (c-index = 0.75). For DCE-MRI, P90 ΔAUCper-pre was most predictive for pCR (c-index = 0.79). Multivariable logistic regression analyses showed complementary value when combining DW-MRI and DCE-MRI for pCR prediction (c-index = 0.89). CONCLUSIONS: Both DW-MRI and DCE-MRI are promising in predicting response to nCRT in esophageal cancer. Combining both modalities provides complementary information, resulting in a higher predictive value.

Perioperative chemotherapy versus neoadjuvant chemoradiotherapy for esophageal or GEJ adenocarcinoma: A propensity score-matched analysis comparing toxicity, pathologic outcome, and survival.

OBJECTIVES: To evaluate toxicity, pathologic outcome, and survival after perioperative chemotherapy (pCT) compared to neoadjuvant chemoradiotherapy (nCRT) followed by surgery for patients with resectable esophageal or gastroesophageal junction (GEJ) adenocarcinoma. METHODS: Consecutive patients with resectable esophageal or GEJ adenocarcinoma who underwent pCT (epirubicin, cisplatin, and capecitabine) or nCRT (paclitaxel, carboplatin, and 41.4 Gy) followed by surgery in a tertiary referral center in the Netherlands were compared. Propensity score matching was applied to create comparable groups. RESULTS: Of 193 eligible patients, 21 were discarded after propensity score matching; 86 and 86 patients who underwent pCT and nCRT, respectively, remained. Grade ≥3 thromboembolic events occurred only in the pCT group (19% vs. 0%, P < 0.001), whereas grade ≥3 leukopenia occurred more frequently in the nCRT group (14% vs. 4%, P = 0.015). No significant differences regarding postoperative morbidity and mortality were found. Pathologic complete response was more frequently observed with nCRT (18% vs. 11%, P < 0.001), without significantly improving radicality rates (95% vs. 89%, P = 0.149). Both strategies resulted in comparable 3-year progression-free survival (pCT vs. nCRT: 46% vs. 55%, P = 0.344) and overall survival rates (49% vs. 50%, P = 0.934). At 3-year follow-up, fewer locoregional disease progression occurred in the nCRT group (19% vs. 37%, P = 0.024). CONCLUSIONS: Compared to perioperative chemotherapy, neoadjuvant chemoradiotherapy achieves higher pathologic response rates and a lower risk of locoregional disease progression, without improving survival.

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

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

European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4).

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. 18F-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.

Intrafraction motion analysis in online adaptive radiotherapy for esophageal cancer.

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.

A robust semi-automatic delineation workflow using denoised diffusion weighted magnetic resonance imaging for response assessment of patients with esophageal cancer treated with neoadjuvant chemoradiotherapy.

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 ADCmean 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.

The association between hospital variation in curative treatment for esophagogastric cancer and health-related quality of life and survival.

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.

Clinical outcomes after online adaptive MR-guided stereotactic body radiotherapy for pancreatic tumors on a 1.5 T MR-linac.

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.

Longitudinal immune monitoring of patients with resectable esophageal adenocarcinoma treated with Neoadjuvant PD-L1 checkpoint inhibition.

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/ß-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.

Recommendations for improved reproducibility of ADC derivation on behalf of the Elekta MRI-linac consortium image analysis working group.

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/mm2, 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 (CVD) and calculation methods (CVC). 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) CVD and CVC 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 CVC to 0.04 (0.01-0.16). CVD 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.

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe.

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.

A population-based study in resected esophageal or gastroesophageal junction cancer aligned with CheckMate 577.

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.