Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. METHODS: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. DISCUSSION: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.

Assessment of the quality of surgery within randomised controlled trials for the treatment of gastro-oesophageal cancer: a systematic review.

Multicentre, randomised, controlled trials (RCTs) provide level 1 evidence for surgery in the treatment of gastro-oesophageal cancer. This systematic review investigated whether standardisation of surgical techniques in RCTs reduces the variation in lymph-node harvest, in-hospital mortality, and locoregional cancer recurrence. The range in the coefficients of variation for lymph-node harvest (0.07-0.61), proportion of patients with locoregional cancer recurrence (1.1-46.2%), and in-hospital mortality (0-10%) was wide. Credentialing of surgeons through assessment of operative reports and monitoring of their performance through data collection were important factors that reduced the variation in lymph-node harvest. Factors that reduced adjusted in-hospital mortality included credentialing surgeons through procedural volume and operative reports, and standardisation of surgical techniques. Future RCTs should include an assessment of surgical performance as an important aspect of study design to reduce variation in clinical outcomes.

The 30-day versus in-hospital and 90-day mortality after esophagectomy as indicators for quality of care.

OBJECTIVE: To describe causes of death in the first year after esophagectomy and determine the time frame that should be used for measurement of quality of surgery. A case-mix adjustment model was developed for the comparison between hospitals. BACKGROUND: The time period in which postoperative mortality should be measured as a performance indicator is debated. METHODS: Cause of death was identified for patients in a tertiary referral hospital who died within 1 year after surgery and classified as surgery related or not surgery related. Sensitivity and specificity for detecting deaths related to surgery were calculated for different periods of follow-up. Case-mix adjustment models for 30-day mortality (30DM), in-hospital mortality, and 90-day mortality (90DM) were developed. RESULTS: In total, 1282 patients underwent esophagectomy. 30DM was 2.9%, the in-hospital mortality rate was 5.1% and 90DM was 7%. Beyond 30 days, a substantial number of deaths were related to the operation, especially due to anastomotic leakage. Postdischarge nononcological mortality was most frequently caused by sudden death. One in 5 patients died because of recurrent disease, being the most important threat in the first year after surgery. The 30DM had a sensitivity for detecting surgery-related deaths of 33% and a specificity of 100%. The 90DM had a sensitivity of 74% and a specificity of 96%. CONCLUSIONS: A period of postoperative follow-up longer than 30 days needs to be considered when comparing surgical performance between institutes. In the case-mix adjustment model for 90DM, no other variables have to be taken into account compared to those involved in 30DM.

Preoperative assessment of tumor location and station-specific lymph node status in patients with adenocarcinoma of the gastroesophageal junction.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Preoperative risk assessment and prevention of complications in patients with esophageal cancer.

In this review the preoperative risk assessment and prevention of complications in patients undergoing esophagectomy for cancer is discussed. Age, pulmonary and cardiovascular condition, nutritional status, and neoadjuvant chemo(radio)therapy are known predictive factors. None of these factors is a valid exclusion criterion for esophagectomy, but may help in careful patient selection. Both anesthetists and surgeons play an important role in intraoperative risk reduction by means of appropriate fluid management and application of optimal surgical techniques.

Diagnostic strategies for pre-treatment staging of patients with oesophageal cancer.

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.

NEOadjuvant therapy monitoring with PET and CT in Esophageal Cancer (NEOPEC-trial).

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 costs of neoadjuvant chemoradiotherapy without prediction of response (reference strategy). DISCUSSION: The NEOPEC-trial could be the first sufficiently powered study that helps justify implementation of FDG-PET for response-monitoring in patients with esophageal cancer in clinical practice. TRIAL REGISTRATION: ISRCTN45750457.

Value of bronchoscopy after EUS in the preoperative assessment of patients with esophageal cancer at or above the carina.

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.

Patients' perception of diagnostic tests in the preoperative assessment of esophageal cancer.

OBJECTIVE: Defining an optimal staging strategy requires an evaluation of the effectiveness and costs of diagnostic tests and may include the burden of these tests for patients. This study evaluated the burden of cervical ultrasonography (US), endoscopic ultrasonography (EUS), computed tomography (CT) and positron emission tomography (PET) in patients with esophageal carcinoma (EC). METHODS: Consenting consecutive patients underwent a standard preoperative work-up. Burden of testing was evaluated with a self-report questionnaire addressing anxiety, embarrassment, and discomfort, each measured on a 1(none) to 5 (extreme) point-scale. An overall burden score was calculated by summing the three item scores. In addition, patients were asked to rank the four tests from least to most inconvenient. Statistical analysis was performed with nonparametric tests. RESULTS: 82 patients (67 , 15 ; mean age 64.3 yrs) participated. For most tests and most dimensions of burden, the large majority of subjects was in categories 1 and 2.With respect to anxiety, the rank order (from highest burden to lowest burden) was EUS, US, PET, and CT (average scores 1.7, 1.5, 1.4, and 1.2, respectively). For embarrassment, the rank order was EUS, PET, US, and CT (1.9, 1.5, 1.4, and 1.3 respectively). For discomfort, the rank order was EUS, PET, US and CT (2.0, 1.6, 1.4, and 1.2, respectively). And for total burden, the rank order was EUS, PET, US and CT (5.6, 4.6, 4.2, and 3.7). PET was ranked as least inconvenient by 35% of patients and as most inconvenient by 16% compared with the other tests. CONCLUSION: Significant but small differences were observed in patient burden for imaging tests to evaluate EC. The perceived burden of PET was lower than that of EUS, but higher than the burden of CT. However absolute values were low for all tests and therefore patient burden will not be a key feature for the construction of an optimal staging algorithm for EC.

Esophageal cancer: CT, endoscopic US, and FDG PET for assessment of response to neoadjuvant therapy--systematic review.

PURPOSE: To compare diagnostic accuracy of computed tomography (CT), endoscopic ultrasonography (US), and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) for assessment of response to neoadjuvant therapy in patients with esophageal cancer by using a systematic review of the literature. MATERIALS AND METHODS: MEDLINE and EMBASE databases and Cochrane Database of Systematic Reviews were searched for relevant studies. Two reviewers independently assessed the methodological quality of each study. Summary receiver operating characteristic (ROC) analysis was used to summarize and compare the diagnostic accuracy of the three modalities. RESULTS: Four studies with CT, 13 with endoscopic US, and seven with FDG PET met inclusion criteria. Percentages of the maximum score in regard to methodological quality ranged from 15% to 100%. Summary ROC analysis could be performed for three studies with CT, four with endoscopic US, and four with FDG PET. The maximum joint values for sensitivity and specificity were 54% for CT, 86% for endoscopic US, and 85% for FDG PET. Accuracy of CT was significantly lower than that of FDG PET (P < .006) and of endoscopic US (P < .003). Accuracy of FDG PET and that of endoscopic US were similar (P = .839). In all patients, CT was always feasible, whereas endoscopic US was not feasible in 6% of the patients, and FDG PET was not feasible in less than 1%. CONCLUSION: CT has poor accuracy for assessment of response to neoadjuvant therapy in patients with esophageal cancer. Endoscopic US and FDG PET have equivalent good accuracy, but endoscopic US is not always feasible after chemotherapy and radiation therapy. FDG PET seems to be a promising noninvasive tool for assessment of neoadjuvant therapy in patients with esophageal cancer.

Incidence and management of chyle leakage after esophagectomy.

BACKGROUND: Postoperative chyle leakage is a rare but well-recognized complication after esophageal surgery. The aim of this study was to identify its incidence and potentially predisposing factors and to assess the consequences and management. METHODS: A consecutive series of 536 patients who underwent esophagectomy for malignant disease of the esophagus or gastroesophageal junction was reviewed. RESULTS: There were 20 patients (3.7%) with chyle leakage. After transthoracic esophagectomy the risk for the development of chyle leakage was higher than after transhiatal resection (p = 0.006). Chyle leakage was associated with more positive nodes (p = 0.041). Patients with chyle leakage had significantly more pulmonary complications (p < 0.001) and longer intensive care unit (p = 0.015) and hospital stays (p = 0.001). No patient with chyle leakage died. Conservative management, consisting of no enteral feeding and total parenteral nutrition, was instituted in all patients, but was abandoned in 4 patients (20%) because of persistence of high chyle output through the chest tube. In contrast to patients who were successfully treated with conservative measures, patients who eventually needed a reoperation had a drain output of more than 2 L on the day conservative therapy was started and 1 and 2 days later. CONCLUSIONS: Chyle leakage is seen more often in patients who undergo transthoracic esophagectomy and in patients who have more positive nodes. Patients with chyle leakage have more pulmonary complications. Conservative therapy is often successful, but operative therapy should be seriously considered in patients with a persistently high daily output of more than 2 L after 2 days of optimal conservative therapy.

Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus.

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 survival at five years with the extended transthoracic approach.