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Contains fulltext : 193356.pdf (publisher's version ) (Open Access), BACKGROUND: Initial staging of gastric cancer consists of computed tomography (CT) and gastroscopy. In locally advanced (cT3-4) gastric cancer, fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT or PET) and staging laparoscopy (SL) may have a role in staging, but evidence is scarce. The aim of this study is to evaluate the impact and cost-effectiveness of PET and SL in addition to initial staging in patients with locally advanced gastric cancer. METHODS: This prospective observational cohort study will include all patients with a surgically resectable, advanced gastric adenocarcinoma (cT3-4b, N0-3, M0), that are scheduled for treatment with curative intent after initial staging with gastroscopy and CT. The modalities to be investigated in this study is the addition of PET and SL. The primary outcome of this study is the proportion of patients in whom the PET or SL lead to a change in treatment strategy. Secondary outcome parameters are: diagnostic performance, morbidity and mortality, quality of life, and cost-effectiveness of these additional diagnostic modalities. The study recently started in August 2017 with a duration of 36 months. At least 239 patients need to be included in this study to demonstrate that the diagnostic modalities are break-even. Based on the annual number of gastrectomies in the participating centers, it is estimated that approximately 543 patients are included in this study. DISCUSSION: In this study, it is hypothesized that performing PET and SL for locally advanced gastric adenocarcinomas results in a change of treatment strategy in 27% of patients and an annual cost-reduction in the Netherlands of euro916.438 in this patient group by reducing futile treatment. The results of this study may be applicable to all countries with comparable treatment algorithms and health care systems. TRIAL REGISTRATION: NCT03208621 . This trial was registered prospectively on June 30, 2017.

Item does not contain fulltext, BACKGROUND: Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. METHODS: Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2-3N0-1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m(2) of body-surface area] for 23 days) with concurrent radiotherapy (41.4 Gy, given in 23 fractions of 1.8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. FINDINGS: Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171

Item does not contain fulltext, BACKGROUND: Patients with locoregionally advanced oesophageal tumours or disputable distant metastases are referred for induction chemotherapy with the aim to downstage the tumour before an oesophagectomy is considered. STUDY DESIGN: Patients who underwent induction chemotherapy between January 2005 and December 2012 were identified from an institutional database. Treatment plan was discussed in the multidisciplinary team. Response to chemotherapy was assessed by CT. Survival was calculated using the Kaplan Meier method. Uni- and multivariable analyses were performed to identify prognostic factors for survival. RESULTS: In total 124 patients received induction chemotherapy mainly for locoregionally advanced disease (n = 80). Surgery was withheld in 35 patients because of progressive disease (n = 16) and persistent unresectability (n = 19). The median overall survival of this group was 13 months (IQR: 8-19). The remaining 89 patients underwent surgery of which 13 still had unresectable tumour or distant metastases. Of the 76 patients that underwent an oesophagectomy, 50 patients had tumour free resection margins (66%) with an estimated 5-year survival of 37%. A positive resection margin (HR 4.148, 95% CI 2.298-7.488, p < 0.0001) was associated with a worse survival in univariable analysis, but only pathological lymph node status with increasing hazard ratio's (6.283-10.283, p = 0.001) remained significant after multivariable analysis. CONCLUSION: Induction chemotherapy downstages the tumour and facilitates a radical oesophagectomy in patients with advanced oesophageal cancer. Pathological lymph node status is an independent prognostic factor for overall survival.

Item does not contain fulltext, PURPOSE: To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. PATIENTS AND METHODS: Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. RESULTS: Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. CONCLUSION: Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.

1 november 2014, Item does not contain fulltext, OBJECTIVES: We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. BACKGROUND: Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently "sterilize" regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. METHODS: Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. RESULTS: One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98). CONCLUSIONS: The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

Contains fulltext : 125789.pdf (publisher's version ) (Closed access), In esophageal cancer patients preoperative staging will determine the type of surgical procedure and use of neoadjuvant therapy. Tumor location and lymph node status play a pivotal role in this tailored strategy. The aim of the present study was to prospectively evaluate the accuracy of preoperative assessment of tumor location according to the Siewert classification and lymph node status per station with endoscopy/endoscopic ultrasound (EUS) and computed tomography (CT).In 50 esophagectomy patients with adenocarcinoma of the gastroesophageal junction (GEJ), tumor location according to Siewert and N-stage per nodal station as determined preoperatively by endoscopy/EUS and CT were compared with the histopathologic findings in the resection specimen.Overall accuracy in predicting tumor location according to the Siewert classification was 70 \% for endoscopy/EUS and 72 \% for CT. Preoperative data could not be compared with the pathologic assessment in 11 patients (22 \%), as large tumors obscured the landmark of the gastric folds. The overall accuracy for predicting the N-stage in 250 lymph node stations was 66 \% for EUS and 68 \% for CT. The accuracy was good for those stations located high in the thorax, but poor for celiac trunk nodes.Given the frequent discrepancy between the endoscopic and pathologic location of the GEJ and the common problem of advanced tumors obscuring the landmarks used in the assessment of the Siewert classification, its usefulness is limited. The overall accuracy for EUS and CT in predicting the N-stage per station was moderate.

Item does not contain fulltext, OBJECTIVE: To investigate the 5-year effect of surgeon experience with laparoscopic Nissen fundoplication (LNF). In 2000, a randomized controlled trial (RCT) was prematurely terminated because LNF for gastroesophageal reflux disease was associated with a higher risk to develop dysphagia than conventional Nissen fundoplication (CNF). Criticism focused on alleged bias caused by the relative lack of experience with the laparoscopic approach of the participating surgeons. DESIGN: Multicenter RCT and prospective cohort study. SETTING: University medical centers and tertiary teaching hospitals. PATIENTS: In the RCT, 74 patients underwent CNF and 93 patients underwent LNF (LNFI). The complete setup of the cohort study (LNFII) (n = 121) mirrored the RCT, except that surgeon experience increased from more than 5 to more than 30 LNFs per surgeon. INTERVENTIONS: Conventional Nissen fundoplication, LNFI, and LNFII. MAIN OUTCOME MEASURES: Intraoperative and in-hospital characteristics, objective reflux control, and clinical outcome. RESULTS: In LNFII, operating time (110 vs 165 minutes; P < .001), dysphagia (2.5% vs 12.3%; P = .008), dilatations for dysphagia (0.8% vs 7.0%; P = .02), and conversions (3.5% vs 7.7%; P = .19) were reduced compared with LNFI. Moreover, in LNFII, hospitalization (4.2 vs 5.6 days; P = .07 and 4.2 vs 7.6 days; P < .001) and in-hospital complications (5.1% vs 13.5%; P = .046 and 5.1% vs 19.3%; P = .005) were reduced compared with LNFI and CNF, respectively. In LNFII, the 6-month reintervention rate was reduced compared with LNFI (0.8% vs 10.1%; P = .002). Esophagitis and esophageal acid exposure at 3 months and reflux symptoms, proton-pump inhibitor use, and quality of life at 5 years improved similarly. CONCLUSIONS: Operating time, complications, hospitalization, early dysphagia, dilatations for dysphagia, and reintervention rate after LNF improve significantly when surgeon experience increases from more than 5 to more than 30 LNFs. In contrast, short

Contains fulltext : 70883.pdf (publisher's version ) (Open Access), BACKGROUND: Surgical resection is the preferred treatment of potentially curable esophageal cancer. To improve long term patient outcome, many institutes apply neoadjuvant chemoradiotherapy. In a large proportion of patients no response to chemoradiotherapy is achieved. These patients suffer from toxic and ineffective neoadjuvant treatment, while appropriate surgical therapy is delayed. For this reason a diagnostic test that allows for accurate prediction of tumor response early during chemoradiotherapy is of crucial importance. CT-scan and endoscopic ultrasound have limited accuracy in predicting histopathologic tumor response. Data suggest that metabolic changes in tumor tissue as measured by FDG-PET predict response better. This study aims to compare FDG-PET and CT-scan for the early prediction of non-response to preoperative chemoradiotherapy in patients with potentially curable esophageal cancer. METHODS/DESIGN: Prognostic accuracy study, embedded in a randomized multicenter Dutch trial comparing neoadjuvant chemoradiotherapy for 5 weeks followed by surgery versus surgery alone for esophageal cancer. This prognostic accuracy study is performed only in the neoadjuvant arm of the randomized trial. In 6 centers, 150 consecutive patients will be included over a 3 year period. FDG-PET and CT-scan will be performed before and 2 weeks after the start of the chemoradiotherapy. All patients complete the 5 weeks regimen of neoadjuvant chemoradiotherapy, regardless the test results. Pathological examination of the surgical resection specimen will be used as reference standard. Responders are defined as patients with < 10% viable residual tumor cells (Mandard-score).Difference in accuracy (area under ROC curve) and negative predictive value between FDG-PET and CT-scan are primary endpoints. Furthermore, an economic evaluation will be performed, comparing survival and costs associated with the use of FDG-PET (or CT-scan) to predict tumor response with survival and

Contains fulltext : 52887.pdf (publisher's version ) (Closed access), PURPOSE: Standardised uptake values (SUVs) depend on acquisition, reconstruction and region of interest (ROI) parameters. SUV quantification in multi-centre trials therefore requires standardisation of acquisition and analysis protocols. However, standardisation is difficult owing to the use of different scanners, image reconstruction and data analysis software. In this study we evaluated whether SUVs, obtained at three different institutes, may be directly compared after calibration and correction for inter-institute differences. METHODS: First, an anthropomorphic thorax phantom containing variously sized spheres and activities, simulating tumours, was scanned and processed in each institute to evaluate differences in scanner calibration. Secondly, effects of image reconstruction and ROI method on recovery coefficients were studied. Next, SUVs were derived for tumours in 23 subjects. Of these 23 patients, four and ten were scanned in two institutes on an HR+ PET scanner and nine were scanned in one institute on an ECAT EXACT PET scanner. All phantom and clinical data were reconstructed using iterative reconstruction with various iterations, with both measured (MAC) and segmented attenuation correction (SAC) and at various image resolutions. Activity concentrations (AC) or SUVs were derived using various ROI isocontours. RESULTS: Phantom data revealed differences in SUV quantification of up to 30%. After application-specific calibration, recovery coefficients obtained in each institute were equal to within 15%. Varying the ROI isocontour value resulted in a predictable change in SUV (or AC) for both phantom and clinical data. Variation of image resolution resulted in a predictable change in SUV quantification for large spheres/tumours (>5 cc) only. For smaller tumours (<2 cc), differences of up to 40% were found between high (7 mm) and low (10 mm) resolution images. Similar differences occurred when data were reconstructed with a small number of iterations. Finally

Contains fulltext : 57702.pdf (publisher's version ) (Closed access), PURPOSE: To compare the validity, reliability and responsiveness of a single, global quality of life question to multi-item scales. METHOD: Data were obtained from 83 consecutive patients with oesophageal adenocarcinoma undergoing either transhiatal or transthoracic oesophagectomy. Quality of life was measured at baseline, 5 weeks, 3 and 12 months post-operatively with a single-item Visual Analogue Scale (VAS) ranging from 0 to 100, the multi-item Medical Outcomes Study Short Form-20 (MOS SF-20) and Rotterdam Symptom Check-List (RSCL). Convergent and discriminant validity, test-retest reliability and both distribution-based and anchor-based responsiveness were evaluated. MAJOR FINDINGS: At baseline and at 5 weeks, the VAS showed high correlations with the MOS SF-20 health perceptions scale (r = 0.70 and 0.72) and moderate to high correlations with all other subscales of the MOS SF-20 and RSCL (r = 0.29-0.70). The test-retest reliability intra-class correlation for the VAS was 0.87. At 5 weeks post-operatively, the distribution-based responsiveness was moderate for the VAS (standardised response mean: -0.47; effect size: -0.56), high for the physical subscales of the MOS SF-20 and RSCL (-1.08 to -1.51) and low for the psychological subscales (0.11 to -0.25). Five weeks post-operatively, anchor-based responsiveness was highest for the VAS (r = 0.54). CONCLUSION: The VAS is an instrument with good validity, excellent reliability, moderate distribution-based responsiveness and good anchor-based responsiveness compared to multi-item questionnaires. Its use is recommended in clinical trials to assess global quality of life.

Contains fulltext : 57955.pdf (publisher's version ) (Closed access), PURPOSE: To assess 3 years of quality of life in patients with esophageal cancer in a randomized trial comparing limited transhiatal resection with extended transthoracic resection. PATIENTS AND METHODS: Quality-of-life questionnaires were sent at baseline and at 5 weeks; 3, 6, 9, and 12 months; and 1.5, 2, 2.5, and 3 years after surgery. Physical and psychological symptoms, activity level, and global quality of life were assessed with the disease-specific Rotterdam Symptom Checklist. Generic quality of life was measured with the Medical Outcomes Study Short Form-20. RESULTS: A total of 199 patients participated. Physical symptoms and activity level declined after the operation and gradually returned toward baseline within the first year (P < .01). Psychological well-being consistently improved after baseline (P < .01), whereas global quality of life showed a small initial decline followed by continuous gradual improvement (P < .01). Quality of life stabilized in the second and third year. Three months after the operation, patients in the transhiatal esophagectomy group (n = 96) reported fewer physical symptoms (P = .01) and better activity levels (P < .01) than patients in the transthoracic group (n = 103), but no differences were found at any other measurement point. For psychological symptoms and global quality of life, no differences were found at any follow-up measurement. A similar pattern was found for generic quality of life. CONCLUSION: No lasting differences in quality of life of patients who underwent either transhiatal or transthoracic resection were found. Compared with baseline, quality of life declined after the operation but was restored within a year in both groups.

Contains fulltext : 58505.pdf (publisher's version ) (Open Access), PURPOSE: The extent of lymph node dissection appropriate for gastric cancer is still under debate. We have conducted a randomized trial to compare the results of a limited (D1) and extended (D2) lymph node dissection in terms of morbidity, mortality, long-term survival and cumulative risk of relapse. We have reviewed the results of our trial after follow-up of more than 10 years. PATIENTS AND METHODS: Between August 1989 and June 1993, 1,078 patients with gastric adenocarcinoma were randomly assigned to undergo a D1 or D2 lymph node dissection. Data were collected prospectively, and patients were followed for more than 10 years. RESULTS: A total of 711 patients (380 in the D1 group and 331 in the D2 group) were treated with curative intent. Morbidity (25% v 43%; P <.001) and mortality (4% v 10%; P =.004) were significantly higher in the D2 dissection group. After 11 years there is no overall difference in survival (30% v 35%; P =.53). Of all subgroups analyzed, only patients with N2 disease may benefit of a D2 dissection. The relative risk ratio for morbidity and mortality is significantly higher than one for D2 dissections, splenectomy, pancreatectomy, and age older than 70 years. CONCLUSION: Overall, extended lymph node dissection as defined in this study generated no long-term survival benefit. The associated higher postoperative mortality offsets its long-term effect in survival. For patients with N2 disease an extended lymph node dissection may offer cure, but it remains difficult to identify patients who have N2 disease. Morbidity and mortality are greatly influenced by the extent of lymph node dissection, pancreatectomy, splenectomy and age. Extended lymph node dissections may be of benefit if morbidity and mortality can be avoided.

Item does not contain fulltext, BACKGROUND: Controversy exists about the best surgical treatment for esophageal carcinoma. METHODS: We randomly assigned 220 patients with adenocarcinoma of the mid-to-distal esophagus or adenocarcinoma of the gastric cardia involving the distal esophagus either to transhiatal esophagectomy or to transthoracic esophagectomy with extended en bloc lymphadenectomy. Principal end points were overall survival and disease-free survival. Early morbidity and mortality, the number of quality-adjusted life-years gained, and cost effectiveness were also determined. RESULTS: A total of 106 patients were assigned to undergo transhiatal esophagectomy, and 114 to undergo transthoracic esophagectomy. Demographic characteristics and characteristics of the tumor were similar in the two groups. Perioperative morbidity was higher after transthoracic esophagectomy, but there was no significant difference in in-hospital mortality (P=0.45). After a median follow-up of 4.7 years, 142 patients had died--74 (70 percent) after transhiatal resection and 68 (60 percent) after transthoracic resection (P=0.12). Although the difference in survival was not statistically significant, there was a trend toward a survival benefit with the extended approach at five years: disease-free survival was 27 percent in the transhiatal-esophagectomy group, as compared with 39 percent in the transthoracic-esophagectomy group (95 percent confidence interval for the difference, -1 to 24 percent [the negative value indicates better survival with transhiatal resection]), whereas overall survival was 29 percent as compared with 39 percent (95 percent confidence interval for the difference, -3 to 23 percent). CONCLUSIONS: Transhiatal esophagectomy was associated with lower morbidity than transthoracic esophagectomy with extended en bloc lymphadenectomy. Although median overall, disease-free, and quality-adjusted survival did not differ statistically between the groups, there was a trend toward improved long-term surviv

Contains fulltext : 185512.pdf (publisher's version ) (Closed access), To assess patients' utilities for health state outcomes after transhiatal or transthoracic oesophagectomy for oesophageal cancer and to investigate the patients' treatment preferences for either procedure. The study group consisted of 48 patients who had undergone either transhiatal or transthoracic oesophagectomy. In an interview they were presented with eight possible health states following oesophagectomy. Visual Analogue Scale and standard gamble techniques were used to measure utilities. Treatment preference for either transhiatal or transthoracic oesophagectomy was assessed. Highest scores were found for the patients' own current health state (Visual Analogue Scale: 0.77; standard gamble: 0.97). Lowest scores were elicited for the health state "irresectable tumour" (Visual Analogue Scale: 0.13; standard gamble: 0.34). The Visual Analogue Scale method produced lower estimates (P<0.001) than the standard gamble method for all health states. Most patient characteristics and clinical factors did not correlate with the utilities. Ninety-five per cent of patients who underwent a transthoracic procedure and 52% of patients who underwent a transhiatal resection would prefer the transthoracic treatment. No significant associations between any patient characteristics or clinical characteristics and treatment preference were found. Utilities after transhiatal or transthoracic oesophagectomy were robust because they generally did not vary by patient or clinical characteristics. Overall, most patients preferred the transthoracic procedure.

Item does not contain fulltext, OBJECTIVES: In quality-adjusted life-years (QALY) models, it is customary to weigh life-years with quality of life via multiplication. As a consequence, for positive health states a longer duration has more QALYs than a shorter duration (i.e., longer is better). However, we have found that for poor health states, many prefer to live only a limited amount of time (i.e., longer is worse). Such preferences are said to be maximum endurable time (MET). In the present contribution, the following questions are asked: a) How low does the utility have to be in order for a MET to arise? and b) Do MET preferences occur when patients judge hypothetical health states? METHODS AND RESULTS: We reanalyzed data from 176 students for the hypothetical health states of "living with migraines" and "living with metastasized cancer." For utilities smaller than 0.7 (ranging from 0 to 1), the MET preference rate was larger than 50%. High MET preference rates were also found in two new studies on migraine and esophageal cancer patients, who evaluated hypothetical health states related to their disease. CONCLUSIONS: We discuss the interpretation of the MET preferences and the preference reversal phenomenon. Standard QALY models imply that longer is better. However, we find that more often, longer is worse for poorly evaluated health states. Consider the following question: are 3 years with a weight of 0.3 equally as valuable as 1 year with a weight of 0.9? Our results suggest that the 3-year period may be less valuable because for poor health, many will prefer a 1-year over a 3-year period.

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