Peter S.N. van Rossum

Imaging strategies in the management of oesophageal cancer: what’s the role of MRI?

ObjectivesTo outline the current role and future potential of magnetic resonance imaging (MRI) in the management of oesophageal cancer regarding T-staging, N-staging, tumour delineation for radiotherapy (RT) and treatment response assessment.MethodsPubMed, Embase and the Cochrane library were searched identifying all articles related to the use of MRI in oesophageal cancer. Data regarding the value of MRI in the areas of interest were extracted in order to calculate sensitivity, specificity, predictive values and accuracy for group-related outcome measures.ResultsAlthough historically poor, recent improvements in MRI protocols and techniques have resulted in better imaging quality and the valuable addition of functional information. In recent studies, similar or even better results have been achieved using optimised MRI compared with other imaging strategies for T- and N-staging. No studies clearly report on the role of MRI in oesophageal tumour delineation and real-time guidance for RT so far. Recent pilot studies showed that functional MRI might be capable of predicting pathological response to treatment and patient prognosis.ConclusionsIn the near future MRI has the potential to bring improvement in staging, tumour delineation and real-time guidance for RT and assessment of treatment response, thereby complementing the limitations of currently used imaging strategies.Key Points• MRI’s role in oesophageal cancer has been somewhat limited to date.• However MRI’s ability to depict oesophageal cancer is continuously improving.• Optimising TN-staging, radiotherapy planning and response assessment ultimately improves individualised cancer care.• MRI potentially complements the limitations of other imaging strategies regarding these points.

Diffusion-weighted magnetic resonance imaging for the prediction of pathologic response to neoadjuvant chemoradiotherapy in esophageal cancer

PURPOSE To explore the value of diffusion-weighted magnetic resonance imaging (DW-MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer. MATERIAL AND METHODS In 20 patients receiving nCRT for esophageal cancer DW-MRI scanning was performed before nCRT, after 8-13 fractions, and before surgery. The median tumor apparent diffusion coefficient (ADC) was determined at these three time points. The predictive potential of initial tumor ADC, and change in ADC (ΔADC) during and after treatment for pathologic complete response (pathCR) and good response were assessed. Good response was defined as pathCR or near-pathCR (tumor regression grade [TRG] 1 or 2). RESULTS A pathCR after nCRT was found in 4 of 20 patients (20%), and 8 patients (40%) showed a good response to nCRT. The ΔADCduring was significantly higher in pathCR vs. non-pathCR patients (34.6%±10.7% [mean±SD] vs. 14.0%±13.1%, p=0.016), as well as in good vs. poor responders (30.5%±8.3% vs. 9.5%±12.5%, p=0.002). The ΔADCduring was predictive of residual cancer at a threshold of 29% (sensitivity of 100%, specificity of 75%, PPV of 94%, and NPV of 100%), and for poor pathologic response at a threshold of 21% (sensitivity of 82%, specificity of 100%, PPV of 100%, and NPV of 80%). CONCLUSIONS In this exploratory study, the treatment-induced change in ADC during the first 2-3weeks of nCRT for esophageal cancer seemed highly predictive of histopathologic response. Larger series are warranted to verify these results.

Residual esophageal cancer after neoadjuvant chemoradiotherapy frequently involves the mucosa and submucosa

Objectives: To gain insight into the exact location of residual esophageal cancer in the esophageal wall and regional lymph nodes after neoadjuvant chemoradiotherapy (nCRT) and to determine the pattern of regression. Background: Data from the recently published chemoradiotherapy for oesophageal cancer followed by surgery study trial showed that 49% of squamous cell carcinomas and 23% of adenocarcinomas had a pathologically complete response (pCR) in the resection specimen after nCRT. These results impose the ethical imperative to reconsider the necessity of esophagectomy with its substantial morbidity and mortality in patients with pCR. However, it remains challenging to accurately identify these patients before resection. Methods: Between January 2003 and July 2011, all patients with esophageal cancer in a tertiary referral center, who underwent nCRT (5 weekly courses of carboplatin and paclitaxel plus 41.4 Gy concurrent radiotherapy) and surgical resection, were analyzed. The resection specimens were carefully re-evaluated by an experienced gastrointestinal pathologist. Tumor regression grade (TRG) was meticulously scored for each specific layer of the esophageal wall and for all removed lymph nodes. Results: One hundred two consecutive patients were included. Seventy-one (70%) of 102 patients were noncomplete responders (≥TRG2) and in 63 of these patients (89%), residual tumor cells were seen in the mucosa and/or submucosa. Five of 8 patients without involvement of the mucosa and the submucosa had isolated remnants in the muscle layer (5/102 = 5%); the other 3 patients had tumor cells only in a single lymph node (3/102 = 3%). The surrounding stroma showed the highest percentage of TRG1 (= pCR: 47%). In patients with pretreatment lymph node positivity, the percentage of TRG1 in all lymph nodes was also favorable (52%). Overall regression showed a nonrandom mixed pattern of both concentric regression and regression toward the lumen. Conclusions: After nCRT for esophageal cancer, both the mucosa and the submucosa show frequent residual malignant involvement. The surrounding stroma and the regional lymph nodes show the highest percentage of pCR and the overall regression pattern is most frequently a mixed pattern of both concentric regression and regression toward the lumen. This overall regression pattern lends support to careful testing of a wait-and-see approach in a subgroup of patients with esophageal cancer after nCRT.

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.

Calcification of Arteries Supplying the Gastric Tube: A New Risk Factor for Anastomotic Leakage after Esophageal Surgery

PURPOSE To evaluate the association between the amount and location of calcifications of the supplying arteries of the gastric tube, as determined with a vascular calcification scoring system, and the occurrence of anastomotic leakage after esophagectomy with gastric tube reconstruction in patients with esophageal cancer. MATERIALS AND METHODS Institutional review board approval was obtained, and the informed consent requirement was waived for this retrospective study. Consecutive patients who underwent elective esophagectomy for cancer with gastric tube reconstruction and cervical anastomosis between 2003 and 2012 were identified from a prospective database. Vascular calcification scores were retrospectively assigned by reviewing the routine preoperative computed tomographic (CT) images. In patients with anastomotic leakage, presence and severity of calcifications of the aorta (score of 0-2), celiac axis (score of 0-2), right postceliac arteries (common hepatic, gastroduodenal, and right gastroepiploic arteries; score of 0-1), and left postceliac arteries (splenic and left gastroepiploic arteries, score of 0-1) along with patient- and procedure-related characteristics were compared with those of patients without leakage by using multivariate logistic regression analysis. RESULTS Of 246 patients, 58 (24%) experienced anastomotic leakage. No significant differences in patient-related factors were found between patients with leakage and those without leakage, with the exception of more chronic use of steroids in the leakage group (7% [four of 58] vs 0% [0 of 188], P = .003). At univariate analysis, leakage was more common in patients with calcification of the aorta (27% [28 of 102] and 35% [13 of 37] vs 16% [17 of 107], P = .029) and the right postceliac arteries (55% [six of 11] vs 22% [52 of 235], P = .013). At multivariate analysis, both minor (odds ratio, 2.00; 95% confidence interval: 1.02, 3.94) and major (odds ratio, 2.87; 95% confidence interval: 1.22, 6.72) aortic calcifications were associated with leakage. Also, an independent association with leakage was found for calcifications of the right postceliac arteries (odds ratio, 4.22; 95% confidence interval: 1.24, 14.4). CONCLUSION Atherosclerotic calcification of the aorta and right postceliac arteries that supply the gastric tube is an independent risk factor for anastomotic leakage after esophagectomy.

Internal and External Validation of a multivariable Model to Define Hospital-Acquired Pneumonia After Esophagectomy

BackgroundPneumonia is an important complication following esophagectomy; however, a wide range of pneumonia incidence is reported. The lack of one generally accepted definition prevents valid inter-study comparisons. We aimed to simplify and validate an existing scoring model to define pneumonia following esophagectomy.Patients and methodsThe Utrecht Pneumonia Score, comprising of pulmonary radiography findings, leucocyte count, and temperature, was simplified and internally validated using bootstrapping in the dataset (n = 185) in which it was developed. Subsequently, the intercept and (shrunk) coefficients of the developed multivariable logistic regression model were applied to an external dataset (n = 201)ResultsIn the revised Uniform Pneumonia Score, points are assigned based on the temperature, the leucocyte, and the findings of pulmonary radiography. The model discrimination was excellent in the internal validation set and in the external validation set (C-statistics 0.93 and 0.91, respectively); furthermore, the model calibrated well in both cohorts.ConclusionThe revised Uniform Pneumonia Score (rUPS) can serve as a means to define post-esophagectomy pneumonia. Utilization of a uniform definition for pneumonia will improve inter-study comparability and improve the evaluations of new therapeutic strategies to reduce the pneumonia incidence.

Ischemic Conditioning of the Stomach in the Prevention of Esophagogastric Anastomotic Leakage After Esophagectomy.

Esophagectomy with esophagogastric anastomosis is a major procedure, and its most feared complication is anastomotic leakage. Ischemic conditioning of the stomach is a method used with the aim of reducing the risk of leakage. It consists of partial gastric devascularization through embolization or laparoscopy followed by esophagectomy and anastomosis at a second stage, thus providing the time for the gastric conduit to adapt to the acute ischemia at the time of its formation. This review analyzes the information from all currently available experimental and clinical studies with the purpose of assessing the current role of the technique and to provide future recommendations.

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.

Impact of Lymph Node Yield on Overall Survival in Patients Treated With Neoadjuvant Chemoradiotherapy Followed by Esophagectomy for Cancer: A Population-based Cohort Study in the Netherlands

Objective: To evaluate the impact of lymph node yield (LNY) on survival in patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for cancer. Background: The value of an extended lymphadenectomy after nCRT for esophageal cancer is debated. Recent reports demonstrate no association between LNY and survival. This association has not yet been evaluated in larger cohorts. Methods: All patients who underwent nCRT followed by esophagectomy between 2005 and 2014 were identified from the Netherlands Cancer Registry. The association between LNY and overall survival was analyzed using multivariable Cox regression analyses, adjusting for diagnosis year, referral, hospital volume, age, sex, malignancy history, tumor location, histology, cTN-stage, surgical approach, radicality, and ypTN-stage. Analyses were performed with LNY as categorized predictor (<15 vs ≥15 nodes) and continuous predictor (per 10 additionally nodes). Results: A total of 2698 patients were included with a median overall survival of 34 months (range 4–143). A higher LNY was significantly associated with improved overall survival, both as categorized predictor (hazard ratio 0.77, 95% confidence interval 0.68–0.86) and as continuous predictor (hazard ratio 0.84, 95% confidence interval 0.78–0.90). Furthermore, a higher LNY was associated with favorable hazard ratios across subgroups, including both squamous cell carcinoma and adenocarcinoma, both cN0 and cN+, both transthoracic and transhiatal approaches, and both ypN0 and ypN+. Conclusions: This large population-based cohort study demonstrates an association between LNY and overall survival, indicating a therapeutic value of extended lymphadenectomy during esophagectomy. Therefore, an extended lymphadenectomy should be the standard of care after nCRT.