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.

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.

The Presence of Metastatic Thoracic Duct Lymph Nodes in Western Esophageal Cancer Patients: A Multinational Observational Study.

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.

An in-silico assessment of the dosimetric benefits of MR-guided radiotherapy for esophageal cancer patients.

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.

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.

The anatomy of the thoracic duct at the level of the diaphragm: A cadaver study.

BACKGROUND: Injury and subsequent leakage of unrecognized thoracic duct tributaries during transthoracic esophagectomy may lead to chylothorax. Therefore, we hypothesized that thoracic duct anatomy at the diaphragm is more complex than currently recognized and aimed to provide a detailed description of the anatomy of the thoracic duct at the diaphragm. BASIC PROCEDURES: The thoracic duct and its tributaries were dissected in 7 (2 male and 5 female) embalmed human cadavers. The level of origin of the thoracic duct and the points where tributaries entered the thoracic duct were measured using landmarks easily identified during surgery: the aortic and esophageal hiatus and the arch of the azygos vein. MAIN FINDINGS: The thoracic duct was formed in the thoracic cavity by the union of multiple abdominal tributaries in 6 cadavers. In 3 cadavers partially duplicated systems were present that communicated with interductal branches. The thoracic duct was formed by a median of 3 (IQR: 3-5) abdominal tributaries merging 8.3cm (IQR: 7.3-9.3cm) above the aortic hiatus, 1.8cm (IQR: -0.4 to 2.4cm) above the esophageal hiatus, and 12.3cm (IQR: 14.0 to -11.0cm) below the arch of the azygos vein. CONCLUSION: This study challenges the paradigm that abdominal lymphatics join in the abdomen to pass the diaphragm as a single thoracic duct. In this study, this occurred in 1/7 cadavers. Although small, the results of this series suggest that the formation of the thoracic duct above the diaphragm is more common than previously thought. This knowledge may be vital to prevent and treat post-operative chyle leakage.

Two-Field Lymphadenectomy During Esophagectomy: The Presence of Thoracic Duct Lymph Nodes.

BACKGROUND: Resection of the thoracic duct is part of the formal en bloc mediastinal esophagolymphadenectomy for cancer, although with the adaptation of minimally invasive techniques, some centers started to leave the thoracic duct compartment in situ. However, previous studies reported thoracic duct lymph nodes in this compartment that may contain metastasis. The aim of this study was to assess the presence and number of lymph nodes in the fatty tissue surrounding the thoracic duct. METHODS: A right-sided thoracoscopic esophagectomy was performed on seven fresh-frozen human cadavers (male, n = 3; female, n = 4). The esophagus and lymph node stations 7, 8, and 9 were resected en bloc, followed by resection of the thoracic duct compartment consisting of the fatty tissue covering the aorta, the thoracic duct and thoracic duct lymph nodes. Lymph nodes were visualized by a hematoxylin and eosin stain and counted macroscopically and microscopically. RESULTS: Thoracic duct lymph nodes were found in 6 of 7 cadavers (86%), with a median number of 1 (range, 0 to 6). Nodes were predominantly located in the area of the azygos vein. A median of 4 subcarinal nodes (range, 1 to 8) and 2 periesophageal nodes (range, 1 to 4) were present. CONCLUSIONS: This study shows that thoracic duct lymph nodes are located within the fatty tissue surrounding the thoracic duct. Resection of this compartment during an esophagectomy for cancer increases lymph node yield.