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.

Hospital practice variation in the proportion of patients with esophagogastric cancer discussed during an expert multidisciplinary team meeting.

BACKGROUND: Multidisciplinary team meetings (MDTM) and especially MDTMs in which expert centres are involved (expert MDTMs) are a key element in adequate cancer care. However, variation among hospitals in the proportion of patients presented during an expert MDTM has been described. This study aims to investigate national practice variation in the proportion of patients with oesophageal or gastric cancer being discussed during an expert MDTM. METHODS: Patients diagnosed with oesophageal or gastric cancer in 2018-2019 were selected from the Netherlands Cancer Registry (n = 6,921). Multilevel logistic regression analyses were used to analyse the association between patient, and tumour characteristics, and the probability to be discussed in an expert MDTM. Variation was analysed according to the hospital and region of diagnosis for: all patients, patients with a potentially curable (cT1-4A cTX, any cN, cM0) or incurable tumour stage (cT4b and/or cM1). RESULTS: In total, 79% of patients were discussed during an expert MDTM, of whom 84% (n = 3,424) and 71% (n = 2,018) with potentially curable, or incurable oesophageal or gastric cancer, respectively. The proportion of patients discussed during an expert MDTM ranged from 54% to 98%, and 17% to 100% between hospitals for potentially curable and incurable patients, respectively (all p < 0.0001). Adjusted analyses showed significant hospital (all p < 0.0001), but no regional variation regarding the patients discussed during an expert MDTM. CONCLUSION: For patients with oesophageal or gastric cancer the probability of being discussed during an expert MDTM varies considerably according to the hospital of diagnosis.

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.

Contemporary radiotherapy: present and future.

Oncology care is increasingly a multidisciplinary endeavour, and radiation therapy continues to have a key role across the disease spectrum in nearly every cancer. However, the field of radiation oncology is still one of the most poorly understood of the cancer disciplines. In this Review, we attempt to summarise and contextualise developments within the field of radiation oncology for the non-radiation oncologist. We discuss advancements in treatment technologies and imaging, followed by an overview of the interplay with advancements in systemic therapy and surgical techniques. Finally, we review new frontiers in radiation oncology, including advances within the metastatic disease continuum, reirradiation, and emerging types of radiation therapy.

Motion-compensated FDG PET/CT for oesophageal cancer.

PURPOSE: Respiratory-induced motion of oesophageal tumours and lymph nodes can influence positron-emission tomography/computed tomography (PET/CT). The aim was to compare standard three-dimensional (3D) and motion-compensated PET/CT regarding standardized uptake value (SUV), metabolic tumour volume (MTV) and detection of lymph node metastases. METHODS: This prospective observational study (NCT02424864) included 37 newly diagnosed oesophageal cancer patients. Diagnostic PET/CT was reconstructed in 3D and motion-compensated PET/CT. MTVs of the primary tumour were calculated using an automated region-growing algorithm with SUV thresholds of 2.5 (MTV2.5) and ≥ 50% of SUVmax (MTV50%). Blinded for reconstruction method, a nuclear medicine physician assessed all lymph nodes showing 18F­fluorodeoxyglucose uptake for their degree of suspicion. RESULTS: The mean (95% CI) SUVmax of the primary tumour was 13.1 (10.6-15.5) versus 13.0 (10.4-15.6) for 3D and motion-compensated PET/CT, respectively. MTVs were also similar between the two techniques. Bland-Altman analysis showed mean differences between both measurements (95% limits of agreement) of 0.08 (-3.60-3.75), -0.26 (-2.34-1.82), 4.66 (-29.61-38.92) cm3 and -0.95 (-19.9-18.0) cm3 for tumour SUVmax, lymph node SUVmax, MTV2.5 and MTV50%, respectively. Lymph nodes were classified as highly suspicious (30/34 nodes), suspicious (20/22) and dubious (66/59) for metastases on 3D/motion-compensated PET/CT. No additional lymph node metastases were found on motion-compensated PET/CT. SUVmax of the most intense lymph nodes was similar for both scans: mean (95% CI) 6.6 (4.3-8.8) and 6.8 (4.5-9.1) for 3D and motion-compensated, respectively. CONCLUSION: SUVmax of the primary oesophageal tumour and lymph nodes was comparable on 3D and motion-compensated PET/CT. The use of motion-compensated PET/CT did not improve lymph node detection.

High CD8+ tumour-infiltrating lymphocyte density associates with unfavourable prognosis in oesophageal adenocarcinoma following poor response to neoadjuvant chemoradiotherapy.

AIMS: Determining prognosis following poor response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma (OAC) remains challenging. An immunosuppressive tumour microenvironment (TME) as well as immune infiltrate density and composition are considered to play a critical role in the immune interaction between host and tumour and can predict therapy response and survival in many cancers, including gastrointestinal malignancies. The aim of this study was to establish the TME characteristics associated with survival following a poor response to nCRT. METHODS AND RESULTS: The prognostic significance of OAC-associated CD3+ , CD4+ , CD8+ , forkhead box protein 3 (FoxP3+ ) and programmed cell death ligand 1 (PD-L1) expression was studied by immunohistochemistry and quantified by automated image analysis in 123 patients who underwent nCRT and curative resection. Results from good and poor responders were contrasted and immune infiltration was related to disease course in both groups. Subsequently a cohort of 57 patients with a moderate response to nCRT was analysed in a similar fashion. Tumour cell percentage positively correlated to immune infiltration markers. In good and moderate responders, none of the immune infiltrate parameters was associated with survival; in poor responders CD8+ was an independent negative predictor of OS in univariate analysis (P = 0.03) and high CD8+ infiltration was associated with worse OS (15 versus 32 months, P = 0.042). CONCLUSION: A high CD8+ density is an independent biomarker of poor OS in poor responders to nCRT, but not in good and moderate responders. Our results suggest that patients with a poor response to nCRT but concomitant high CD8+ counts in the resection specimen require adjuvant therapy.

Clinical response assessment on DW-MRI compared with FDG-PET/CT after neoadjuvant chemoradiotherapy in patients with oesophageal cancer.

PURPOSE: In about 30% of patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection for locally advanced oesophageal cancer no vital tumour is found in the resection specimen. Accurate clinical response assessment is critical if deferral from surgery is considered in complete responders. Our study aimed to compare the performance of MRI and of FDG-PET/CT for the detection of residual disease after nCRT. METHODS: Patients with oesophageal cancer eligible for nCRT and oesophagectomy were prospectively included. All patients underwent FDG-PET/CT and MRI before and between 6 and 8 weeks after nCRT. Two radiologists scored the MRI scans, and two nuclear medicine physicians scored the FDG-PET/CT scans using a 5-point score for residual disease. Histopathology after oesophagectomy represented the reference standard. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated for detection of residual tumour (ypT+), residual nodal disease (ypN+), and any residual disease (ypT+Nx/ypT0N+). RESULTS: Seven out of 33 (21%) patients had a pathological complete response. The AUCs for individual readers to detect ypT+ were 0.71/0.70 on diffusion-weighted (DW)-MRI and 0.54/0.57 on FDG-PET/CT, and to detect ypN+ were 0.89/0.81 on DW-MRI and 0.75/0.71 on FDG-PET/CT. The AUCs/sensitivities/specificities for the individual readers to detect any residual disease were 0.74/92%/57% and 0.70/96%/43% on MRI; these were 0.49/69%/29% and 0.60/69%/43% on FDG-PET/CT, respectively. CONCLUSION: MRI reached higher diagnostic accuracies than FDG-PET/CT for the detection of residual tumour in oesophageal cancer patients at 6 to 8 weeks after nCRT.

A national study to assess outcomes of definitive chemoradiation regimens in proximal esophageal cancer.

Background: Proximal esophageal cancer (EC) is commonly treated with definitive chemoradiation (CRT). The radiation dose and type of chemotherapy backbone are still under debate. The objective of this study was to compare the treatment outcomes of contemporary CRT regimens.Material and Methods: In this retrospective observational cohort study, we included patients with locally advanced squamous cell cancer of the proximal esophagus, from 11 centers in the Netherlands, treated with definitive CRT between 2004 and 2014. Each center had a preferential CRT regimen, based on cisplatin (Cis) or carboplatin-paclitaxel (CP) combined with low (≤50.4 Gy) or high (>50.4 Gy) dose radiotherapy (RT). Differences in overall survival (OS) between CRT regimens were assessed using a fully adjusted Cox proportional hazards and propensity score (PS) weighted model. Safety profiles were compared using a multilevel logistic regression model.Results: Two hundred patients were included. Fifty-four, 39, 95, and 12 patients were treated with Cis-low-dose RT, Cis-high-dose RT, CP-low-dose RT, and CP-high-dose RT, respectively. Median follow-up was 62.6 months (95% CI: 47.9-77.2 months). Median OS (21.9 months; 95% CI: 16.9-27.0 months) was comparable between treatment groups (logrank p = .88), confirmed in the fully adjusted and PS weighted model (p > .05). Grades 3-5 acute adverse events were less frequent in patients treated with CP-low-dose RT versus Cis-high-dose RT (OR 3.78; 95% CI: 1.31-10.87; p = .01). The occurrence of grades 3-5 late toxicities was not different between treatment groups.Conclusion: Our study was unable to demonstrate a difference in OS between the CRT regimens, probably related to the relatively small sample size. Based on the superior safety profile, carboplatin and paclitaxel-based CRT regimens are preferred in patients with locally advanced proximal EC.

Added value of MRI to endoscopic and endosonographic response assessment after neoadjuvant chemoradiotherapy in oesophageal cancer.

OBJECTIVES: In order to select oesophageal cancer patients after neoadjuvant chemoradiotherapy (nCRT) for organ-preserving treatment instead of surgery, a high diagnostic accuracy is required. The aim of this study was to evaluate whether MRI had additional value to gastroscopy with biopsies and endosonographic ultrasound (EUS) with fine needle aspiration (FNA) for the detection of residual tumour after nCRT. METHODS: Twenty-two patients with oesophageal cancer eligible for nCRT followed by oesophagectomy were prospectively included. All patients underwent (T2- and diffusion-weighted) MRI and gastroscopy+EUS before and after nCRT. Histopathology after oesophagectomy was the reference standard with pathological complete response (pCR) defined as ypT0N0. Diagnostic performance regarding the detection of residual tumour was calculated for gastroscopic biopsies and for EUS-FNA without and with MRI. RESULTS: Nineteen of the 22 patients (86%) did not achieve pCR after nCRT (7 ypT+N+, 11 ypT+N0, 1 ypT0N+). Biopsies detected residual tumour in 6 of 18 ypT+ patients. After adding MRI, 16 of 18 residual tumours were assessed correctly. EUS-FNA detected 3 out of 8 ypN+ patients, while MRI did not improve detection. Overall, adding MRI improved sensitivity for detection of residual tumour to 89% (17 of 19) from 47% (9 of 19) with endoscopic biopsies and EUS-FNA only. CONCLUSION: In this small study, the detection of residual tumour after nCRT in oesophageal cancer patients was improved by the addition of MRI to gastroscopy and EUS. KEY POINTS: • In this small study, the detection of residual tumour after neoadjuvant chemoradiotherapy in oesophageal cancer patients was improved by adding MRI including diffusion-weighted images to gastroscopy and endosonographic ultrasound. • With the addition of MRI assessment to gastroscopy and endosonographic ultrasound, the considerable risk of missing residual tumours decreased from 53 to 11%, while the pitfall was overstaging in one out of three complete responders.

Preoperative Prediction of Pathologic Response to Neoadjuvant Chemoradiotherapy in Patients With Esophageal Cancer Using 18F-FDG PET/CT and DW-MRI: A Prospective Multicenter Study.

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

Diffusion-weighted MRI with ADC mapping for response prediction and assessment of oesophageal cancer: A systematic review.

PURPOSE: The aim was to perform a systematic review on the value of diffusion-weighted MRI (DW-MRI) with apparent diffusion coefficient (ADC) mapping in the prediction and assessment of response to chemo- and/or radiotherapy in oesophageal cancer. MATERIALS AND METHODS: A systematic search was performed on Pubmed, Embase, Medline and Cochrane databases. Studies that evaluated the ADC for response evaluation before, during or after chemo- and/or radiotherapy were included. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the quality of the included studies. RESULTS: Fourteen studies, comprising 516 patients, in which the response to treatment in oesophageal cancer was evaluated on ADC maps were included. Acquisition parameter settings for DW-MRI and ROI placement varied substantially. The reference standard was RECIST or endoscopic assessment in eight non-surgery studies and histopathology after surgery in six studies. A high pre-treatment ADC significantly correlated with good response in three out of 12 studies; conversely, one study reported a significantly higher pre-treatment ADC in poor responders. In five out of eight studies good responders showed a significantly larger relative increase in ADC two weeks after the onset of treatment (range 23-59%) than poor responders (range 1.5-17%). After chemo- and/or radiotherapy ADC results varied considerably, amongst others due to large variation in the interval between completion of therapy and DW-MRI. CONCLUSION: DW-MRI for response evaluation to chemo- and/or radiotherapy in oesophageal cancer shows variable methods and results. A large relative ADC increase after two weeks of treatment seems most predictive for good response.

Quantification of Esophageal Tumor Motion and Investigation of Different Image-Guided Correction Strategies.

PURPOSE: To accurately quantify esophageal tumor position variability and to optimize image guided correction strategies. MATERIAL AND METHODS: Esophageal cancer patients receiving chemoradiotherapy (41.4-50.4 Gy in 23-28 fractions combined with carboplatin plus paclitaxel) were included in a prospective cohort study (NCT02139488). Gold fiducial markers were inserted into the esophageal tumors during diagnostic endoscopic ultrasound. Four-dimensional (4D) planning computed tomography (CT) and daily 4D cone beam (CB) CT scans were acquired. Each CBCT was registered to the planning CT using different regions of interest (bone; 3D), and carina, diaphragm, clinical target volume (CTV), and fiducial markers (4D) for alignment and using the fiducial markers as the true tumor position. Subsequently, a planning target volume (PTV) margin accounting for residual uncertainties, including the average respiratory motion, was calculated for each of these registrations. RESULTS: Fifty-six patients with tumors located in the proximal (n = 1), mid (n = 7), or distal esophagus (n = 25) or at the gastroesophageal junction (n = 23) were included. The average peak-to-peak respiratory tumor motion was 0.20, 0.92, and 0.34 cm on the planning CT in left-right (LR), cranial-caudal (CC), and anterior-posterior (AP) directions, respectively. The required PTV margin with average motion amplitude, depending on the correction strategy used for image guidance, ranged from 0.8 cm to 1.0 cm, 1.1 cm to 1.6 cm, and 0.7 cm to 0.9 cm in LR, CC, and AP direction, respectively. A registration based on the CTV resulted in the smallest PTV margins (0.8, 1.1, and 0.7 cm in LR, CC, and AP direction, respectively). For bone registration the calculated PTV margins were 1.0, 1.3, and 0.7 cm in LR, CC, and AP directions, respectively. The registration based on the diaphragm increased PTV margins. CONCLUSIONS: Substantial and anisotropic position variability of esophageal tumors was observed during radiation therapy, and nonuniform margins should be considered. Cranial-caudal PTV margins need to be larger than those commonly used. Target positioning during image-guided radiotherapy could be improved with a CTV registration-based correction strategy.

Gross Tumor Delineation in Esophageal Cancer on MRI Compared With 18F-FDG-PET/CT.

PURPOSE: Current delineation of the gross tumor volume (GTV) in esophageal cancer relies on computed tomography (CT) and combination with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). There is increasing interest in integrating magnetic resonance imaging (MRI) in radiation treatment, which can potentially obviate CT- or FDG-PET/CT-based delineation. The aim of this study is to evaluate the feasibility of target delineation on T2-weighted (T2W) MRI and T2W including diffusion-weighted MRI (T2W + DW-MRI) compared with current-practice FDG-PET/CT. METHODS: Ten observers delineated primary esophageal tumor GTVs of 6 patients on FDG-PET/CT, T2W-MRI, and T2W + DW-MRI. GTVs, generalized conformity indices, in-slice delineation variation (root mean square), and standard deviations in the position of the most cranial and caudal delineated slice were calculated. RESULTS: Delineations on MRI showed smaller GTVs compared with FDG-PET/CT-based delineations. The main variation was seen at the cranial and caudal border. No differences were observed in conformity indices (FDG-PET/CT, 0.68; T2W-MRI, 0.66; T2W + DW-MRI, 0.68) and in-slice variation (root mean square, 0.13 cm on FDG-PET/CT; 0.10 cm on T2W-MRI; 0.14 cm on T2W + DW-MRI). In the 2 tumors involving the gastroesophageal junction, addition of DW-MRI to T2W-MRI significantly decreased caudal border variation. CONCLUSIONS: MRI-based target delineation of the esophageal tumor is feasible with interobserver variability comparable to that with FDG-PET/CT, despite limited experience with delineation on MRI. Most variation was seen at cranial-caudal borders, and addition of DW-MRI to T2W-MRI may reduce caudal delineation variation of gastroesophageal junction tumors.

A Novel Liquid Fiducial Marker in Esophageal Cancer Image Guided Radiation Therapy: Technical Feasibility and Visibility on Imaging.

PURPOSE: To assess the technical feasibility of injection, visibility on imaging modalities, and positional stability of a novel liquid fiducial marker (ie, BioXmark) for radiation therapy in patients with esophageal cancer. METHODS: First, the visibility on imaging of different volumes of the liquid marker was analyzed ex vivo in porcine tissue (ie, on computed tomography [CT], cone beam CT (CBCT), and magnetic resonance imaging [MRI]). Next, for the in vivo part, the liquid fiducial markers were injected under endoscopic (ultrasound) guidance in 10 patients with curable esophageal cancer. The technical feasibility of the injection procedure and the clinical performance (ie, visibility and positional stability on imaging) were evaluated. Planning CT, daily CBCT, and serial MRI images (before, during, and after chemoradiation therapy in a subset of 3 patients) were acquired. RESULTS: Ex vivo, the optimal volume for good visibility without artifacts was 0.1 mL per injected marker. In vivo, a total of 28 markers were injected in 10 patients (range, 0.025-0.1 mL). No adverse effects were identified. The first 2 cases (4 markers) were considered as learning cases. A total of 19 of 24 of the liquid markers (79%) were visible on CT, 3 of 4 (75%) on MRI, and 19 of 24 (79%) on the first CBCT. All markers with an injected volume of >0.05 mL were visible on the different imaging modalities. Positional stability analysis on CBCT identified no time trend during the radiation therapy course. No artifacts could be detected for liquid marker volumes of 0.05 and 0.025 mL in CT or CBCT. CONCLUSIONS: Injection of a liquid fiducial marker for esophageal cancer radiation therapy is technically feasible with no adverse events identified. Volumes of >0.05 mL have an appropriate visibility on CT, CBCT, and MRI, with an excellent positional stability. Liquid fiducial markers are therefore promising for use in image guided radiation therapy.

Elevated Pretreatment CEA and CA19-9 Levels are Related to Early Treatment Failure in Esophageal Adenocarcinoma.

INTRODUCTION: Chemoradiotherapy and surgery are the basis of the potentially curative treatment for esophageal cancer. Approximately 1 in 5 patients, however, do not benefit from this intensive treatment due to early treatment failure. The aim of this study was to evaluate levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 at diagnosis, in relation to survival and early treatment failure (disease recurrence or death within 1 year after surgery). METHODS: Patients with esophageal adenocarcinoma scheduled for chemoradiotherapy followed by surgery between 1998 and 2014 were selected from a retrospectively collected database if both CEA and CA19-9 levels were measured before the start of treatment. RESULTS: Pretreatment CEA and CA19-9 levels were known in 102 patients. Median overall survival differed (P<0.001) between patients with normal levels of both CEA and CA19-9 (n=59; 51 mo), patients with elevated CEA only (n=13; 43 mo), patients with elevated CA19-9 only (n=19; 24 mo), and those with elevated levels of both CEA and CA19-9 (n=11; 11 mo). Elevation of both CEA and CA19-9 was associated with early treatment failure (odds ratio: 10.4; 95% confidence interval: 2.4-45.5, P=0.002). Median time to tumor recurrence was 34 months in patients with normal CEA and CA19-9 levels, and 7 months in those with elevated levels of both (P=0.003). CONCLUSIONS: Pretreatment elevated CEA and CA19-9 levels were significantly associated with early treatment failure and decreased overall survival in this esophageal adenocarcinoma patient cohort treated with curative intent. Until prospective validation, CEA and CA19-9 might play a role in identifying high-risk patients before the start of intensive locoregional therapy.

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.

Advanced Age is Not a Contraindication for Treatment With Curative Intent in Esophageal Cancer.

OBJECTIVES: The objective of this study is to compare long-term outcomes between younger and older (70 y and above) esophageal cancer patients treated with curative intent. MATERIALS AND METHODS: Overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free interval were compared between older (70 y and above) and younger (below 70 y) esophageal cancer patients treated between 1998 and 2013. Treatment consisted of neoadjuvant chemoradiotherapy with surgery or definitive chemoradiotherapy: 36 to 50.4 Gy in 18 to 28 fractions combined with 5-fluorouracil/cisplatin or carboplatin/paclitaxel. RESULTS: The study comprised 253 patients, of whom 76 were 70 years and older. Median age was 64 years (range, 41 to 83). Most patients had stage II-IIIA disease (83%). Planned treatment was neoadjuvant chemoradiotherapy with surgery for 169 patients (41 patients aged 70 y and older) and definitive chemoradiotherapy for 84 patients (31 patients aged 70 y and older). The compliance to radiotherapy was 92%, with no difference between older and younger patients. In 33 patients (13 patients aged 70 y and older) planned surgery was not performed. Median follow-up was 4.9 years. Three-year OS was 42%. The multivariable analysis showed no statistical difference in OS or in DFS comparing older and younger patients: OS (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.61-1.28), DFS (HR, 0.87; 95% CI, 0.60-1.25). Elderly showed a longer locoregional recurrence-free interval; HR, 0.53 (95% CI, 0.30-0.92; P=0.02) and a higher pathologic complete response rate (50% vs. 25%; P=0.02). CONCLUSIONS: Long-term outcomes of older esophageal cancer patients (70 y and above) selected for treatment with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy were comparable with the outcomes of their younger counterparts. Advanced age alone should not be a contraindication for potentially curative chemoradiotherapy-based treatment in esophageal cancer patients.

Radiation-induced liver injury mimicking liver metastases on FDG-PET-CT after chemoradiotherapy for esophageal cancer : A retrospective study and literature review.

BACKGROUND: For esophageal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), restaging using F­18-fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET-CT) following nCRT can detect interval metastases, including liver metastases, in almost 10% of patients. However, in clinical practice, focal FDG liver uptake, unrelated to liver metastases, is observed after chemoradiotherapy. This radiation-induced liver injury (RILI) can potentially lead to overstaging. METHODS: A systematic search for potential cases of RILI after (chemo)radiotherapy for esophageal cancer was performed in the electronic reports from all PET-CT scans made between 2006 and 2015 in our hospital. Additional data about potential cases were obtained from the electronic medical records. A literature review of RILI was also performed. RESULTS: Of 205 patients undergoing nCRT, 6 cases with localized increased FDG uptake in the caudate or left liver lobe following nCRT for esophageal cancer were identified. None of these patients had signs of liver metastases with additional imaging, during surgery, on biopsy, or during follow-up (range 11-46 months). At our institute, the incidence of RILI after neoadjuvant chemoradiotherapy for esophageal cancer was 3%. In the literature, RILI is described in about 8% of patients at the time of restaging. FDG-avid lesions occur in the high radiation dose area, usually corresponding to the caudate or left liver lobe. CONCLUSIONS: FDG accumulation in the caudate or left liver lobe after CRT in the area that received a high radiation dose may be caused by metastases or RILI. Awareness of the pitfall of high FDG uptake in RILI is crucial to avoid misinterpretation and overstaging.

Correlation between functional imaging markers derived from diffusion-weighted MRI and 18F-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 F-fluorodeoxyglucose positron emission tomography/computed tomography (F-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 F-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 F-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 F-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.

The prognostic and potentially predictive value of the Laurén classification in oesophageal adenocarcinoma.

AIM: To investigate the histological subtypes of oesophageal adenocarcinoma according to the Laurén classification (intestinal/diffuse/mixed) in relation to tumour response to neoadjuvant treatment, and in relation to patients' survival after potentially curative treatment. METHODS: Data were collected from all oesophageal adenocarcinoma patients who underwent potentially curative treatment in our institute between 1998 and 2014. Treatment consisted of neoadjuvant chemoradiotherapy (36-50 Gy) followed by an oesophagectomy or definitive chemoradiotherapy (50-50.4 Gy). Clinical data were collected from patient records. All endoscopic biopsies and surgical resection specimens were reassessed to determine the histological subtype (intestinal, diffuse or mixed) and the Mandard tumour regression grade (TRG). The impact of the histological subtypes on survival was determined using a Cox model. RESULTS: Median follow-up was 68 months. Diffuse and mixed type cancers accounted for 25% of oesophageal adenocarcinomas. Median overall survival differed significantly between patients with intestinal (n = 121, 39 months), diffuse (n = 28, 18 months) or mixed type (n = 11, 25 months) carcinomas (log rank, p = 0.023). In multivariable analysis, the diffuse type was associated with shorter survival (diffuse versus intestinal: hazard ratios 2.06, p = 0.006). A pathologically (near) complete response (TRG 1 or 2) was seen less frequently in diffuse type than in intestinal type carcinomas (24% versus 60%; p = 0.015). CONCLUSIONS: Patients with diffuse type oesophageal adenocarcinomas had a significantly worse prognosis than those with intestinal type carcinomas. Intestinal type carcinomas showed a better response to neoadjuvant chemoradiotherapy than diffuse type carcinomas. These differences call for the exploration of differentiated approaches in the potentially curative treatment of oesophageal adenocarcinomas.