http://repub.eur.nl/res/aut/29140/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33894/ 2011-12-01T00:00:00Z Background: Chemoradiotherapy is increasingly applied in patients with oesophageal cancer. The aim of the present study was to determine whether 3D-CT volumetry is able to differentiate between responding and non-responding oesophageal tumours early in the course of neoadjuvant chemoradiotherapy. Patients and methods: Serial CT before and after two weeks of neoadjuvant chemoradiotherapy was performed in the multimodality treatment arm of a randomised trial including patients with oesophageal carcinoma. CT response was measured with the change in tumour volume between baseline and after 14 days of neoadjuvant therapy. Receiver Operating Characteristic (ROC) analysis was used to evaluate the ability of 3D-CT as an early imaging marker of response. Results: CT response analysis was performed in 39 patients, of whom 26 patients were histopathological responders. Median tumour volume increased between baseline and after 14 days of chemoradiotherapy in histopathological responders as well as in non-responders, though changes were not statistically significant. The area under the ROC curve was 0.71. Conclusion: Tumour volume changes after 14 days of neoadjuvant chemoradiotherapy as measured by 3D-CT were not associated with histopathological tumour response. CT volumetry should not be used for early response assessment in patients with potentially curable oesophageal cancer treated with neoadjuvant chemoradiotherapy. http://repub.eur.nl/res/pub/34143/ 2011-11-01T00:00:00Z Background:18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been used extensively to explore whether FDG Uptake can be used to provide prognostic information for esophageal cancer patients. The aim of the present review is to evaluate the literature available to date concerning the potential prognostic value of FDG uptake in esophageal cancer patients, in terms of absolute pretreatment values and of decrease in FDG uptake during or after neoadjuvant therapy. Methods: A computer-aided search of the English language literature concerning esophageal cancer and standardized uptake values was performed. This search focused on clinical studies evaluating the prognostic value of FDG uptake as an absolute value or the decrease in FDG uptake and using overall mortality and/or disease-related mortality as an end point. Results: In total, 31 studies met the predefined criteria. Two main groups were identified based on the tested prognostic parameter: (1) FDG uptake and (2) decrease in FDG uptake. Most studies showed that pretreatment FDG uptake and postneoadjuvant treatment FDG uptake, as absolute values, are predictors for survival in univariate analysis. Moreover, early decrease in FDG uptake during neoadjuvant therapy is predictive for response and survival in most studies described. However, late decrease in FDG uptake after completion of neoadjuvant therapy was predictive for pathological response and survival in only 2 of 6 studies. Conclusions: Measuring decrease in FDG uptake early during neoadjuvant therapy is most appealing, moreover because the observed range of values expressed as relative decrease to discriminate responding from nonresponding patients is very small. At present inter-institutional comparison of results is difficult because several different normalization factors for FDG uptake are in use. Therefore, more research focusing on standardization of protocols and inter-institutional differences should be performed, before a PET-guided algorithm can be universally advocated. http://repub.eur.nl/res/pub/25352/ 2011-05-19T00:00:00Z Background: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.Methods: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.Results: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.Conclusions: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC. http://repub.eur.nl/res/pub/23726/ 2011-01-01T00:00:00Z Background: Neoadjuvant chemoradiotherapy before surgery can improve survival in patients with potentially curable esophageal cancer, but not all patients respond. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been proposed to identify nonresponders early during neoadjuvant chemoradiotherapy. The aim of the present study was to determine whether FDG-PET could differentiate between responding and nonresponding esophageal tumors early in the course of neoadjuvant chemoradiotherapy. Methods: This clinical trial comprised serial FDG-PET before and 14 days after start of chemoradiotherapy in patients with potentially curable esophageal carcinoma. Histopathologic responders were defined as patients with no or less than 10% viable tumor cells (Mandard score on resection specimen). PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic analysis was used to evaluate the ability of SUV in distinguishing between histopathologic responders and nonresponders. Results: In 100 included patients, 64 were histopathologic responders. The median SUV decrease 14 days after the start of therapy was 30.9% for histopathologic responders and 1.7% for nonresponders (P = 0.001). In receiver operating characteristic analysis, the area under the curve was 0.71 (95% CI = 0.60-0.82). Using a 0% SUV decrease cutoff value, PET correctly identified 58 of 64 responders (sensitivity 91%) and 18 of 36 nonresponders (specificity 50%). The corresponding positive and negative predictive values were 76% and 75%, respectively. Background: SUV decrease 14 days after the start of chemoradiotherapy was significantly associated with histopathologic tumor response, but its accuracy in detecting nonresponders was too low to justify the clinical use of FDG-PET for early discontinuation of neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer. http://repub.eur.nl/res/pub/27421/ 2010-12-01T00:00:00Z Background: Both endoscopic and surgical treatments are recommended for m3- or sm1-adenocarcinomas of the esophagus, depending on patients' lymph nodal status. Lymphatic dissemination is related to tumor infiltration depth, but varying incidences have been reported in m3- and sm1-adenocarcinomas. The study aim was to investigate whether the presence of occult tumor cells in lymph nodes could explain this variation. Methods Sixty-three node-negative (N0) patients with early esophageal adenocarcinoma (m2/m3/sm1-tumors) were included. Multilevel-sectioning of lymph nodes was performed; sections were stained by means of immunohistochemistry with cytokeratin marker CAM5.2. Two pathologists searched for micrometastases (0.2-2.0 mm) and isolated tumor cells (ITCs, <0.2 mm). Results Positive CAM5.2 staining in lymph nodes was not seen in any of the 18 m2-patients. In 2/25 m3-tumors (8.0%) an ITC was found, but no micrometastases. Tumor cells were identified in 4/20 sm1-tumors (20.0%): three micrometastases and one ITC. Median follow-up was 121 months. Two m3-patients (3.2%) died due to disease recurrence, including one patient in whom an ITC was detected. Conclusions Lymphatic migration of tumor cells was found in node-negative m3- and sm1-adenocarcinomas of the esophagus (8.0% and 20.0%, respectively). However, the clinical relevance of these occult tumor cells should become apparent from large series of endoscopically treated patients. http://repub.eur.nl/res/pub/27592/ 2010-11-01T00:00:00Z Aims: According to the classification established by the Japanese Society for Oesophageal Disease, early oesophageal cancer can be subdivided into six successive layers of the mucosa or submucosa, which influences the treatment strategy and prognosis of the individual patient. However, the reproducibility of this classification in terms of inter- and intraobserver variability is unclear. Methods: Histological slides from 105 surgical resection specimens of patients who had undergone oesophagectomy for early oesophageal adenocarcinoma were reviewed independently by three gastrointestinal pathologists, andwere classified according to the Japanese criteria (m1/m2/m3/sm1/sm2/sm3 tumours). Inter- and intraobserver variation was determined by κ-statistics. Results: The interobserver reproducibility was good between pathologist 1 and 2 (κ=0.61, 95% CI 0.55 to 0.67), and moderate between pathologist 1 and 3 (κ=0.51, 95% CI 0.45 to 0.57) and between pathologist 2 and 3 (κ=0.50, 95% CI 0.38 to 0.61). The intraobserver agreement as assessed by the expert pathologist was good (κ=0.76), with a 95% CI that was interpreted as good to very good (0.67 to 0.85). Most agreement was achieved at the lower (m1) and upper site (sm2, sm3) of the spectrum, whereas the m2 tumours reflected the most discrepant stage. The majority of the observed discrepancy included the variation in one substage only. Conclusions: The reproducibility of the Japanese classification is good in terms of inter- and intraobserver variability when grading early oesophageal adenocarcinoma on surgical resection specimens. The present data confirm that dedicated gastrointestinal pathologists with broad experience are preferred when grading the resection specimens of patients with early oesophageal adenocarcinoma. http://repub.eur.nl/res/pub/27373/ 2010-05-01T00:00:00Z Background: A possible advantage of cervical oesophagogastrostomy over intrathoracic anastomosis after oesophagectomy is the presumed mild clinical course of cervical anastomotic leakage. The incidence and consequences of intrathoracic manifestations after cervical anastomotic leakage remain unclear, and were investigated in this study. Methods: Consecutive patients undergoing potentially curative transhiatal oesophagectomy (THO) or transthoracic oesophagectomy (TTO) with cervical oesophagogastrostomy between 1993 and 2007 were included. Intrathoracic manifestations after cervical anastomotic leakage were compared following THO and TTO. Multivariable logistic regression analysis was used to identify potential risk factors for intrathoracic manifestations. Results: Seventy-nine (15-8 per cent) of 501 patients developed anastomotic leakage after THO compared with 50 (15.3 per cent) of 327 after TTO (P = 0.853). Intrathoracic manifestations developed in 21 (27 per cent) and 22 (44 per cent) patients respectively (P = 0.041). A transthoracic approach was the only independent predictor of the development of intrathoracic manifestations in patients with cervical leakage (odds ratio 2.60; P = 0.022). Total hospital stay (P < 0.001), intensive care unit stay (P < 0.001) and in-hospital mortality (P = 0.035) were greater in patients with intrathoracic manifestations than in those without. Conclusion: Intrathoracic manifestations of cervical anastomotic leakage are associated with a prolonged hospital stay, carry a higher mortality and occur more frequently after TTO than THO. Copyright http://repub.eur.nl/res/pub/24919/ 2009-05-01T00:00:00Z Background/Aims: Current guidelines for staging oesophageal cancer recommend a series of preoperative investigations. There is no consensus on the recommended order for these investigations or whether all investigations are necessary in all patients. Our aim was to determine an efficient strategy for pre-treatment staging of patients with oesophageal cancer. Methods: We retrospectively compared 15 staging strategies, based on all possible orders of all possible subsets of three staging modalities (computed tomography, endoscopic ultrasonography and external ultrasonography of the neck). We assumed that if distant metastases or local irresectability were found and confirmed, no further investigations would be performed. Main outcome was the minimal number of investigations needed to detect all patients with incurable disease. Results: Using all three investigations in all 412 patients would lead to performance of 1,236 investigations. Both strategies starting with computed tomography or endoscopic ultrasonography and ending with external ultrasonography were most efficient, using a total of 1,112 investigations. Conclusion: The use of a conditional staging strategy with a specific order of imaging can reduce the number of tests necessary to identify incurable patients with oesophageal cancer by 10%. In our opinion, this is not enough to recommend implementation of a logistically more complex diagnostic system. Copyright http://repub.eur.nl/res/pub/24915/ 2009-04-01T00:00:00Z Introduction: Lymphatic dissemination of a (non-cervical) esophageal tumor to the neck is generally considered as distant metastasis. The aim of this study was to determine the additional value of external ultrasonography (US) to detect lymphatic metastasis to the neck after normal CT scan (CT) with or without normal PET scan (PET). Methods: Between January 2003 and December 2005, 306 patients were analyzed for esophageal cancer in our department. A total of 233 patients underwent both CT and external US of the neck. PET was performed in 109 of these patients as part of a prospective cohort study. Fine needle aspiration (FNA) was only performed if external US reported suspected lymph nodes. FNA was defined as gold standard. Results: In 176 patients (76%), CT did not identify any suspected nodes, but external US disagreed in 36 of them. In 9 of these patients, FNA confirmed metastasis, resulting in an additional value of external US after normal CT scanning of 5% (9/176). In 74 patients (68%), CT and PET did not identify any suspected nodes, but external US disagreed in 11 of them. In 3 of these patients, FNA confirmed metastasis, resulting in an additional value of external US after normal CT and PET of 4% (3/74). Conclusion: Considering its minimal invasiveness and wide availability in combination with the importance of the potential therapeutic consequences, we conclude that external US of the neck should be part of the routine diagnostic work-up in patients with esophageal cancer, even after normal CT and PET scanning. Copyright http://repub.eur.nl/res/pub/30339/ 2008-12-01T00:00:00Z Background. A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial. Methods/design. The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm. The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up. Discussion. This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen. Trial registration. ISRCTN80832026. http://repub.eur.nl/res/pub/30117/ 2008-11-01T00:00:00Z Introduction: Esophageal cancer is an aggressive disease with a strong tendency to infiltrate into surrounding structures. The aim of the present study is to determine the additional value of bronchoscopy for detecting invasion of the tracheobronchial tree after endoscopic ultrasonography (EUS) in the preoperative assessment of patients with esophageal cancer at or above the carina. Materials and Methods: Between January 1997 and December 2006, 104 patients were analyzed for histologically proven esophageal cancer at or above the carina. All patients underwent both EUS and bronchoscopy (with biopsy on indication) in the preoperative assessment of local resectability. Results and Discussion: After extensive diagnostic workup, 58 of 104 patients (56%) were eligible for potentially curative esophagectomy; nine of these 58 patients (9/58, 15%) appeared to be incurable peroperatively because of ingrowth in the tracheobronchial tree (five patients), ingrowth in other vital structures (two patients) or distant metastases (two patients). Of the 46 non-operable patients, local irresectability (T-stage 4) was identified in 26 patients (26/46, 57%) due to invasion of vital structures on EUS: invasion of the aorta in six patients, invasion of the lung in 11 patients; in 12 patients invasion of the tracheobronchial tree was described, which was confirmed by bronchoscopy in only five patients. No patients with T4 were identified by bronchoscopy alone. Conclusion: For patients with esophageal tumors at or above the carina, no additional value of bronchoscopy (with biopsy on indication) to exclude invasion of the tracheobronchial tree was seen after EUS in a specialized centre. Although based on relatively small numbers, we conclude that bronchoscopy is not indicated if no invasion of the airways is identified on EUS.