Mark van Heijl

Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial

BackgroundThis 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.MethodsThis 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.ResultsThere 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.ConclusionsPreoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC.

Fluorodeoxyglucose Positron Emission Tomography for Evaluating Early Response During Neoadjuvant Chemoradiotherapy in Patients With Potentially Curable Esophageal Cancer

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. Conclusions: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.

Risk factors for development of benign cervical strictures after esophagectomy.

Objective:To identify independent risk factors for development of benign cervical anastomotic strictures in general and specifically for refractory strictures after esophagectomy in a large series of patients. Summary Background Data:Benign strictures develop frequently when a cervical anastomosis is performed after esophagectomy, causing burdensome symptoms and poor quality of life. Methods:From 1996 to 2006, all patients in the Academic Medical Center prospective database undergoing esophagectomy with a cervical anastomosis were included. Stricture was defined as dysphagia requiring endoscopic dilation of the anastomosis. Prediction of stricture was assessed using uni- and multivariate logistic regression analysis. Evaluation of risk factors was also performed for refractory strictures (>2 times the median number of dilations in all patients with stricture) in a similar fashion. Results:A total of 607 patients underwent potentially curative esophagectomy, with an in-hospital mortality of 2.5%. During follow-up, 253 (41.7%) patients developed a stricture after a median time of 74 days, requiring a median number of 5 dilations. Cardiovascular disease (P = 0.002), gastric tube compared with colonic interposition (P = 0.03), and anastomotic leakage (P = 0.002) were predictive for development of stricture in multivariate analysis. Development of stricture within 90 days after surgery (P = 0.001), chemoradiotherapy (P = 0.02), and anastomotic leakage (P = 0.03) were independent predictors for refractory strictures requiring over 10 dilations. Conclusions:The benign cervical stricture rate after esophagectomy was relatively high. Cardiovascular disease, gastric tube compared with colonic interposition and postoperative anastomotic leakage were independent predictors for development of benign anastomotic stricture. Anastomotic leakage, chemoradiotherapy and early development of stricture were independently associated with the development of refractory strictures, requiring a higher number of dilations. Prevention of anastomotic stricture formation should be focused on prevention of anastomotic leakage.

Influence of ROI definition, partial volume correction and SUV normalization on SUV-survival correlation in oesophageal cancer

ObjectiveAn explanation for the discrepancies in the reported correlations between standardized uptake value (SUV) and survival might be the application of different SUV methodologies. The primary aim of this study was to examine the influence of using different methodologies on SUV–survival correlation. MethodsData were used from a prospective cohort study consisting of oesophageal cancer patients in whom preoperative fluorodeoxyglucose positron emission tomography was performed. Various methodologies of SUV calculation/correction were correlated with the default (SUV A41% corrected for body surface area): different volume of interest definitions, different SUV normalization, with and without serum glucose correction, and with (PVC+) and without partial volume correction (PVC−). Receiver operating characteristic (ROC) curves using any type of SUV for the identification of potential correlation with disease-free survival were also compared. ResultsFifty-two patients were included for this study. Significant correlations were found between SUV A41% and all the other described SUVs: SUV 50% (r2=0.99; P<0.001), SUV A50% (r2=0.98; P<0.001), SUVmax (r2=0.98; P<0.001), SUV A41% PVC+ (r2=0.97; P<0.001) and SUV A41% glucose (r2=0.93; P<0.001). No correlation was found between volume of interest 41% and SUV A41%, with or without, PVC (P=0.85 and P=0.41). Significant correlations were found between SUVmax corrected for body surface area, SUVmax corrected for body weight (r2=0.96; P<0.001) and SUV corrected for lean body mass (r2=0.98; P<0.001). ROC curves for various SUV methodologies showed an almost identical area under the curve for any type of SUV. ConclusionA strong correlation was found between all the investigated SUV methodologies. Moreover, when looking for correlations between SUV and disease-free survival, the areas under the ROC curves were almost identical for any type of SUV methodology.

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

BackgroundSurgical 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/designPrognostic 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).DiscussionThe 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 registrationISRCTN45750457

Anteroinferior versus superior plating of clavicular fractures

BACKGROUND Open reduction and plate fixation has gained recognition as an effective treatment for certain types of clavicular fractures. However, 88% of cases report some implant-related problems. To determine the optimal plate position, the aim of the present study was to compare implant-related irritation and proportion of plate removal in patients with clavicular fractures undergoing plate fixation by an anteroinferior or superior approach. METHODS Retrospectively collected data of 39 patients who underwent anteroinferior plating for displaced midshaft clavicular fractures were compared with prospectively collected data of 60 patients who were treated with superior plate fixation as part of a multicenter randomized controlled trial. Electronic medical records were reviewed for reports of complications, in particular, implant-related irritation and implant removal during follow-up. In addition, all patients were contacted in June 2014 to obtain additional information. The primary outcome parameter was implant-related irritation. RESULTS Univariate and multivariate regression analysis showed plate position was not significantly associated with implant-related irritation. Higher rates of asymptomatic patients with the plate still in place were observed in the anteroinferior group (46% vs 22%, P = .01). Almost an equal percentage of implant removals was seen in both groups because of implant irritation (36% vs 37%, P = .938). CONCLUSIONS The present study found the surgical approach of clavicular plating was not associated with implant-related irritation. Future studies are needed to determine whether there is an optimal approach for clavicle plating.

Value of Bronchoscopy after EUS in the Preoperative Assessment of Patients with Esophageal Cancer at or Above the Carina

IntroductionEsophageal 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 MethodsBetween 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 DiscussionAfter 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.ConclusionFor 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.

Accuracy of prehospital triage protocols in selecting severely injured patients : A systematic review

BACKGROUND Prehospital trauma triage ensures proper transport of patients at risk of severe injury to hospitals with an appropriate corresponding level of trauma care. Incorrect triage results in undertriage and overtriage. The American College of Surgeons Committee on Trauma recommends an undertriage rate below 5% and an overtriage rate below 50% for prehospital trauma triage protocols. To find the most accurate prehospital trauma triage protocol, a clear overview of all currently available protocols and corresponding outcomes is necessary. OBJECTIVES The aim of this systematic review was to evaluate the current literature on all available prehospital trauma triage protocols and determine accuracy of protocol-based triage quality in terms of sensitivity and specificity. METHODS A search of Pubmed, Embase, and Cochrane Library databases was performed to identify all studies describing prehospital trauma triage protocols before November 2016. The search terms included “trauma,” “trauma center,” or “trauma system” combined with “triage,” “undertriage,” or “overtriage.” All studies describing protocol-based triage quality were reviewed. To assess the quality of these type of studies, a new critical appraisal tool was developed. RESULTS In this review, 21 articles were included with numbers of patients ranging from 130 to over 1 million. Significant predictors for severe injury were: vital signs, suspicion of certain anatomic injuries, mechanism of injury, and age. Sensitivity ranged from 10% to 100%; specificity from 9% to 100%. Nearly all protocols had a low sensitivity, thereby failing to identify severely injured patients. Additionally, the critical appraisal showed poor quality of the majority of included studies. CONCLUSION This systematic review shows that nearly all protocols are incapable of identifying severely injured patients. Future studies of high methodological quality should be performed to improve prehospital trauma triage protocols. LEVEL OF EVIDENCE Systematic review, level III.

Inter- and intraobserver variation in the histopathological evaluation of early oesophageal adenocarcinoma

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, and were 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.

High Irritation and Removal Rates After Plate or Nail Fixation in Patients With Displaced Midshaft Clavicle Fractures

BackgroundStudies comparing plate with intramedullary nail fixation of displaced midshaft clavicle fractures show faster recovery in the plate group and implant-related complications in both groups after short-term followup (6 or 12 months). Knowledge of disability, complications, and removal rates beyond the first postoperative year will help surgeons in making a decision regarding optimal implant choice. However, comparative studies with followup beyond the first year or two are scarce.Questions/purposesWe asked: (1) Does plate fixation or intramedullary nail fixation for displaced midshaft clavicle fractures result in less disability? (2) Which type of fixation, plate or intramedullary, is more frequently associated with implant-related irritation and implant removal? (3) Is plate or intramedullary fixation associated with postoperative complications beyond the first postoperative year?MethodsBetween January 2011 and August 2012, patients with displaced midshaft clavicle fractures were enrolled and randomized to plate or intramedullary nail fixation. A total of 58 patients with plate and 62 patients with intramedullary nails initially were enrolled. Minimum followup was 30 months (mean, 39 months; range, 30–51 months). Two patients (3%) with plate fixation and two patients (3%) with intramedullary nails were lost to followup. The QuickDASH was obtained at final followup and compared between patients who had plate fixation and those who had intramedullary nail fixation. Postoperative complications measured include infection, implant-related irritation, implant failure, nonunion, and refracture after implant removal. Indications for implant removal included implant-related irritation, implant failure, nonunion, patient’s wish, or surgeon’s preference.ResultsBetween patients with plate versus intramedullary nail fixation, there were no differences in QuickDASH scores (plate, 1.8 ± 3.6; intramedullary nail, 1.8 ± 7.2; mean difference, −0.7; 95% CI, −2.2 to 2.04; p = 0.95). The proportion of patients having implant-related irritation was not different (39 of 56 [70%] versus 41 of 62 [66%]; relative risk, 1.05; 95% CI, 0.82–1.35; p = 0.683). Intramedullary fixation was associated with a higher likelihood of implant removal (51 of 62 [82%] versus 28 of 56 [50%]; relative risk, 1.65; 95% CI, 1.24–2.19; p < 0.001). Among the removed implants more plates than intramedullary nails were removed after the 1-year followup (12 of 28 [43%] versus six of 51 [12%]; p = 0.002). There were no infections, implant breakage, nonunions, or refractures between the 1-year and final followup in either group.ConclusionsAfter a mean followup of 39 months, disability scores were excellent. Major complications did not occur after the 1-year followup. A frequent and bothersome problem after both surgical treatments is implant-related irritation, resulting in high rates of implant removal, after 1 year. Future research could focus on analyzing risk factors for implant irritation or removal.Level of EvidenceLevel II, therapeutic study.