Lucas Goense

Endoscopic biopsy and EUS for the detection of pathologic complete response after neoadjuvant chemoradiotherapy in esophageal cancer: a systematic review and meta-analysis

BACKGROUND AND AIMS Accurate determination of residual cancer status after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer could assist in selecting the optimal treatment strategy. The aim of this study was to review the evidence on the diagnostic accuracy of endoscopic biopsy and EUS after nCRT for detecting residual cancer at the primary tumor site (ypT+) and regional lymph nodes (ypN+) as opposed to a pathologic complete response (ypT0 and ypN0). METHODS PubMed/Medline, Embase, and the Cochrane library were systematically searched. The analysis included diagnostic studies reporting on the accuracy of endoscopic biopsy or EUS in detecting residual cancer versus complete response after nCRT for esophageal cancer with histopathology as the reference standard. Bivariate random-effects models were used to estimate pooled sensitivities and specificities and examine sources of heterogeneity. RESULTS Twenty-three studies comprising 12 endoscopic biopsy studies (1281 patients), 11 EUS studies reporting on ypT status (593 patients), and 10 EUS studies reporting on ypN status (602 patients), were included. Pooled estimates for sensitivity of endoscopic biopsy after nCRT for predicting ypT+ were 34.5% (95% confidence interval [CI], 26.0%-44.1%) and for specificity 91.0% (95% CI, 85.6%-94.5%). Pooled estimates for sensitivity of EUS after nCRT were 96.4% (95% CI, 91.7%-98.5%) and for specificity were 10.9% (95% CI, 3.5%-29.0%) for detecting ypT+, and 62.0% (95% CI, 46.0%-75.7%) and 56.7% (95% CI, 41.8%-70.5%) for detecting ypN+, respectively. CONCLUSIONS Endoscopic biopsy after nCRT is a specific but not sensitive method for detecting residual esophageal cancer. Although EUS after nCRT yields a high sensitivity, only a limited number of patients will have negative findings at EUS with still a substantial false-negative rate. Furthermore, EUS provides only moderate accuracy for detecting residual lymph node involvement. Based on these findings, these endoscopic modalities cannot be used to withhold surgical treatment in test-negative patients after nCRT. ( CLINICAL TRIAL REGISTRATION NUMBER CRD42015016527.).

Diagnostic Performance of F-18-FDG PET and PET/CT for the Detection of Recurrent Esophageal Cancer After Treatment with Curative Intent: A Systematic Review and Meta-Analysis

The aim of this study was to assess the diagnostic performance of 18F-FDG PET and integrated 18F-FDG PET/CT for diagnosing recurrent esophageal cancer after initial treatment with curative intent. Methods: The PubMed, Embase, and Cochrane library were systematically searched for all relevant literature using the key words “18F-FDG PET” and “esophageal cancer” and synonyms. Studies examining the diagnostic value of 18F-FDG PET or integrated 18F-FDG PET/CT, either in routine clinical follow-up or in symptomatic patients in whom recurrence of esophageal cancer was suspected, were deemed eligible for inclusion. The primary outcome was the presence of recurrent esophageal cancer as determined by histopathologic biopsy or clinical follow-up. Risk of bias and applicability concerns were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Sensitivities and specificities of individual studies were meta-analyzed using bivariate random-effects models. Results: Eight eligible studies were included for meta-analysis, comprising 486 patients with esophageal cancer who underwent 18F-FDG PET or PET/CT after previous treatment with curative intent. The quality of the included studies assessed by the QUADAS-2 tool was considered reasonable; there were few concerns with regard to the risk of bias and applicability. Integrated 18F-FDG PET/CT and standalone 18F-FDG PET were used in 4 and 3 studies, respectively. One other study analyzed both modalities separately. In 4 studies, 18F-FDG PET or PET/CT was performed as part of routine follow-up, whereas in 4 other studies the diagnostic test was performed on indication during clinical follow-up. Pooled estimates of sensitivity and specificity for 18F-FDG PET and PET/CT in diagnosing recurrent esophageal cancer were 96% (95% confidence interval, 93%–97%) and 78% (95% confidence interval, 66%–86%), respectively. Subgroup analysis revealed no statistically significant difference in diagnostic accuracy according to type of PET scanner (standalone PET vs. integrated PET/CT) or indication of scanning (routine follow-up vs. on indication). Conclusion: 18F-FDG PET and PET/CT are reliable imaging modalities with a high sensitivity and moderate specificity for detecting recurrent esophageal cancer after treatment with curative intent. The use of 18F-FDG PET or PET/CT particularly allows for a minimal false-negative rate. However, histopathologic confirmation of 18F-FDG PET– or PET/CT-suspected lesions remains required, because a considerable false-positive rate is noticed.

A Propensity Score Matched Analysis of Open Versus Minimally Invasive Transthoracic Esophagectomy in the Netherlands

Objective: The aim of this study was to compare open esophagectomy (OE) with minimally invasive esophagectomy (MIE) in a population-based setting. Background: Randomized controlled trials and cohort studies have shown that MIE is associated with reduced pulmonary complications and shorter hospital stay as compared to OE. Methods: Patients who underwent transthoracic esophagectomy for cancer between 2011 and 2015 were selected from the national Dutch Upper Gastrointestinal Cancer Audit. Hybrid, transhiatal, and emergency procedures were excluded. Patients who underwent OE were compared with those treated by MIE. Propensity score matching was used to correct for differences in baseline characteristics. The primary endpoint was postoperative pulmonary complications; secondary endpoints were morbidity, mortality, convalescence, and pathology. Results: Some 1727 patients were included. After propensity score matching the percentage of patients with 1 or more complications was 62.6% after OE (N = 433) and 60.2% after MIE (N = 433) (P = 0.468). Pulmonary complication rate did not differ between groups: 34.2% (OE) versus 35.6% (MIE) (P = 0.669). Anastomotic leak (15.5% vs 21.2%, P = 0.028) and reintervention rates (21.1% vs 28.2%, P = 0.017) were higher after MIE. Mortality was 3.0% in the OE group and 4.7% in the MIE group (P = 0.209). Median hospital stay was shorter after MIE (14 vs 13 days, P = 0.001). Percentages of R0 resections (93%) did not differ between groups. The median (range) lymph node count was 18 (2–53) (OE) versus 20 (2–52) (MIE) (P < 0.001). Conclusions: This population-based study showed that mortality and pulmonary complications were similar for OE and MIE. Anastomotic leaks and reinterventions were more frequently observed after MIE. MIE was associated with a shorter hospital stay.

Dynamic contrast-enhanced MRI for treatment response assessment in patients with oesophageal cancer receiving neoadjuvant chemoradiotherapy.

PURPOSE To explore and evaluate the potential value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal cancer. MATERIAL AND METHODS Twenty-six patients underwent DCE-MRI before, during (week 2-3) and after nCRT, but before surgery (pre/per/post, respectively). Histopathologic tumour regression grade (TRG) was assessed after oesophagectomy. Tumour area-under-the-concentration time curve (AUC), time-to-peak (TTP) and slope were calculated. The ability of these DCE-parameters to distinguish good responders (GR, TRG 1-2) from poor responders (noGR, TRG⩾3), and pathologic complete responders (pCR) from no-pCR was assessed. RESULTS Twelve patients (48%) showed GR of which 8 patients (32%) pCR. Analysis of AUC change throughout treatment, AUCper-pre, was most predictive for GR, at a threshold of 22.7% resulting in a sensitivity of 92%, specificity of 77%, PPV of 79%, and a NPV of 91%. AUCpost-pre was most predictive for pCR, at a threshold of -24.6% resulting in a sensitivity of 83%, specificity of 88%, PPV of 71%, and a NPV of 93%. TTP and slope were not associated with pathologic response. CONCLUSIONS This study demonstrates that changes in AUC throughout treatment are promising for prediction of histopathologic response to nCRT for oesophageal cancer.

The peri‐esophageal connective tissue layers and related compartments: visualization by histology and magnetic resonance imaging

An organized layer of connective tissue coursing from aorta to esophagus was recently discovered in the mediastinum. The relations with other peri‐esophageal fascias have not been described and it is unclear whether this layer can be visualized by non‐invasive imaging. This study aimed to provide a comprehensive description of the peri‐esophageal fascias and determine whether the connective tissue layer between aorta and esophagus can be visualized by magnetic resonance imaging (MRI). First, T2‐weighted MRI scanning of the thoracic region of a human cadaver was performed, followed by histological examination of transverse sections of the peri‐esophageal tissue between the thyroid gland and the diaphragm. Secondly, pretreatment motion‐triggered MRI scans were prospectively obtained from 34 patients with esophageal cancer and independently assessed by two radiologists for the presence and location of the connective tissue layer coursing from aorta to esophagus. A layer of connective tissue coursing from the anterior aspect of the descending aorta to the left lateral aspect of the esophagus, with a thin extension coursing to the right pleural reflection, was visualized ex vivo in the cadaver on MR images, macroscopic tissue sections, and after histologic staining, as well as on in vivo MR images. The layer connecting esophagus and aorta was named ‘aorto‐esophageal ligament’ and the layer connecting aorta to the right pleural reflection ‘aorto‐pleural ligament’. These connective tissue layers divides the posterior mediastinum in an anterior compartment containing the esophagus, (carinal) lymph nodes and vagus nerve, and a posterior compartment, containing the azygos vein, thoracic duct and occasionally lymph nodes. The anterior compartment was named ‘peri‐esophageal compartment’ and the posterior compartment ‘para‐aortic compartment’. The connective tissue layers superior to the aortic arch and at the diaphragm corresponded with the currently available anatomic descriptions. This study confirms the existence of the previously described connective tissue layer coursing from aorta to esophagus, challenging the long‐standing paradigm that no such structure exists. A comprehensive, detailed description of the peri‐esophageal fascias is provided and, furthermore, it is shown that the connective tissue layer coursing from aorta to esophagus can be visualized in vivo by MRI.

Postoperative Outcomes of Minimally Invasive Gastrectomy Versus Open Gastrectomy During the Early Introduction of Minimally Invasive Gastrectomy in the Netherlands : A Population-based Cohort Study

Objective: To compare postoperative outcomes of minimally invasive gastrectomy (MIG) to open gastrectomy (OG) for cancer during the introduction of MIG in the Netherlands. Background: Between 2011 and 2015, the use of MIG increased from 4% to 53% in the Netherlands. Methods: This population-based cohort study included all patients with curable gastric adenocarcinoma that underwent gastrectomy between 2011 and 2015, registered in the Dutch Upper GI Cancer Audit. Patients with missing preoperative data, and patients in whom no lymphadenectomy or reconstruction was performed were excluded. Propensity score matching was applied to create comparable groups between patients receiving MIG or OG, using year of surgery and other potential confounders. Morbidity, mortality, and hospital stay were evaluated. Results: Of the 1697 eligible patients, 813 were discarded after propensity score matching; 442 and 442 patients who underwent MIG and OG, respectively, remained. Conversions occurred in 10% of the patients during MIG. Although the overall postoperative morbidity (37% vs 40%, P = 0.489) and mortality rates (6% vs 4%, P = 0.214) were comparable between the 2 groups, patients who underwent MIG experienced less wound complications (2% vs 5%, P = 0.006). Anastomotic leakage occurred in 8% of the patients after MIG, and in 7% after OG (P = 0.525). The median hospital stay declined over the years for both procedures (11 to 8 days, P < 0.001). Overall, hospital stay was shorter after MIG compared with OG (8 vs 10 days, P < 0.001). Conclusions: MIG was safely introduced in the Netherlands, with overall morbidity and mortality comparable with OG, less wound complications and shorter hospitalization.

Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study

BACKGROUND After neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations. METHODS The preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin [area under the curve 2 mg/mL per min] plus paclitaxel [50 mg/m2 of body-surface area] combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4-6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET-CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12-14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed. FINDINGS Between July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% [95% CI 17-50]) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% [95% CI 4-23]) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% [95% CI 17-44]). PET-CT missed six of 41 TRG3 or TRG4 tumours (15% [95% CI 7-28]). PET-CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas). INTERPRETATION After neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET-CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803). FUNDING Dutch Cancer Society.

Current treatment options for esophageal diseases.

Exciting new developments—pharmacologic, endoscopic, and surgical—have arisen for the treatment of many esophageal diseases. Refractory gastroesophageal reflux disease presents a therapeutic challenge, and several new options have been proposed to overcome an insufficient effectiveness of proton pump inhibitors. In patients with distal esophageal spasm, drugs and endoscopic treatments are the current mainstays of the therapeutic approach. Treatment with proton pump inhibitors (or antireflux surgery) should be considered in patients with Barretts esophagus, since a recent meta‐analysis demonstrated a 71% reduction in risk of neoplastic progression. Endoscopic resection combined with radiofrequency ablation is the standard of care in patients with early esophageal adenocarcinoma. Mucosal squamous cancer may also be treated endoscopically, preferably with endoscopic submucosal dissection. Patients with upper esophageal cancer often refrain from surgery. Robot‐assisted, thoracolaparoscopic, minimally invasive esophagectomy may be an appropriate option for these patients, as the robot facilitates a good overview of the upper mediastinum. Induction chemoradiotherapy is currently considered as standard treatment for patients with advanced squamous cell carcinoma, while the role of neoadjuvant therapy for adenocarcinoma remains controversial. A system for defining and recording perioperative complications associated with esophagectomy has been recently developed and may help to find predictors of mortality and morbidity.

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

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.

Correlation between functional imaging markers derived from diffusion-weighted MRI and 18 F-FDG PET/CT in esophageal cancer

Objective Both the apparent diffusion coefficient (ADC) acquired by diffusion-weighted magnetic resonance imaging (DW-MRI) and the standardized uptake value (SUV), acquired by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), are well-established functional parameters in cancer imaging. Currently, it is unclear whether these two markers provide complementary prognostic and predictive information in esophageal cancer. The aim of this study was to evaluate the correlation between ADC and SUV in patients with esophageal cancer. Materials and methods This prospective study included 76 patients with histologically proven esophageal cancer who underwent both DW-MRI and 18F-FDG PET/CT examinations before treatment. The minimum and mean ADC values (ADCmin and ADCmean) of the primary tumor were assessed on MRI. Similarly, the glucose metabolism was evaluated by the maximum and mean SUV (SUVmax and SUVmean) in the same lesions on 18F-FDG PET/CT images. Spearman’s rank correlation coefficients were used to assess the correlation between tumor ADC and SUV values. Results The tumor ADC and SUV values as measures of cell density and glucose metabolism, respectively, showed negligible nonsignificant correlations (ADCmin vs. SUVmax: r=−0.087, P=0.457; ADCmin vs. SUVmean: r=−0.105, P=0.369; ADCmean vs. SUVmax: r=−0.099, P=0.349; ADCmean vs. SUVmean: r=−0.111, P=0.340). No differences in tumor ADC and SUV values were observed between the different histologic tumor types, stages, and differentiation grades. Conclusion This study indicates that tumor cellularity derived from DW-MRI and tumor metabolism measured by 18F-FDG PET/CT are independent cellular phenomena in newly diagnosed esophageal cancer. Therefore, tumor ADC and SUV values may play complementary roles as imaging markers in the prediction of survival and evaluation of response to treatment in esophageal cancer.