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.

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.

Association of no epidural analgesia with postoperative morbidity and mortality after transthoracic esophageal cancer resection.

BACKGROUND: The aim of this study was to compare morbidity and mortality of patients who had epidural analgesia for at least 2 days after transthoracic esophagectomy for cancer with those who did not have epidural analgesia at all or who had it for less than 2 days. STUDY DESIGN: We analyzed 182 patients, 7 of whom were excluded. Patients were divided into two groups; 90 patients (51%) with epidural analgesia for at least 2 days (epidural group) and 85 patients (49%) who did not have epidural analgesia or had it for less than 2 days (no epidural group). To identify prognostic factors for pneumonia, univariate and multivariate logistic regression analyses were performed. RESULTS: There were no notable differences in clinicopathologic characteristics or intraoperative measurements. In favor of the epidural group, marked differences were found in pneumonia (28% versus 48%, p = 0.005), reintubation (17% versus 34%, p = 0.011), ICU-stay (median 2.8 versus 5.8 days, p = 0.001), hospital stay (median 17 versus 21 days, p = 0.015), and in-hospital mortality (0 versus 8 patients, p = 0.003). No epidural analgesia (odds ratio [OR] 2.48, 95% CI 1.30 to 4.71, p = 0.006) and atelectasis (OR 2.06, 95% CI 1.08 to 3.90, p = 0.028) were independent predictors for pneumonia. There were eight in-hospital deaths. CONCLUSIONS: No epidural analgesia for more than 2 days after a transthoracic esophageal cancer resection is associated with increased postoperative morbidity. To optimize postoperative recovery, it is of vital importance to ensure adequate epidural analgesia in these patients.

[A man with abnormal blood vessels]. / Een man met afwijkende bloedvaten.

A central venous catheter was inserted in a 37-year-old man. During placement the catheter took a route to the left side of the heart. On CT it appeared the catheter was placed in a persisting left V. cava superior.

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

OBJECTIVE: An 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. METHODS: Data 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. RESULTS: Fifty-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. CONCLUSION: A 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.

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.

Differential responses of cellular immunity in patients undergoing neoadjuvant therapy followed by surgery for carcinoma of the oesophagus.

BACKGROUND: To compare immune responses following neoadjuvant chemoradiation therapy in combination with hyperthermia plus surgery to those induced by surgery alone in patients with oesophageal cancer. METHODS: Thirty-two patients with histopathologically proven oesophageal cancer, scheduled for potentially curative transhiatal or transthoracic oesophagectomy with (neo, n = 20) or without (control, n = 12) neoadjuvant thermochemoradiation therapy (ThCR) were included. Peripheral blood samples were obtained before ThCR, after 2 weeks of ThCR, 1 day before surgery, on postoperative days 1, 3, 7, and 6 weeks after surgery, for white blood cell counts, lymphocyte subsets and T helper type 1 (Th1) and type 2 (Th2) lymphocyte responses. RESULTS: Neo patients showed a significant decrease in granulocytes and lymphocyte subsets, and T cell cytokines after 2 weeks of ThCR. Only CD8+ (cytotoxic) T cells recovered after ThCR to reach normal levels prior to surgery. In contrast, CD4+ T (helper) cells, and NK- and B cells in neo patients did not recover prior to surgery (all P < 0.05). Oesophagectomy induced a significant increase in granulocytes and a decrease in lymphocytes (and subsets). Only those subsets that had not recovered after ThCR (CD4+ T cells, NK and B cells but not CD8+ T cells), were significantly lower (all P < 0.05) during the entire postoperative study period. Postoperatively, the stimulated cytokine production capacity of Th1 and Th2 cells, corrected for number of T cells, was not significantly different between the groups. CONCLUSION: Neoadjuvant thermochemoradiation for oesophageal cancer caused significant disturbances of host cellular immunity with reduced T, NK and B cell counts, and differential recovery of cytotoxic and helper T cells leading to prolonged T cell imbalance that extends beyond the time of surgery. The functional and anti-tumour consequences of this immunodisturbance need further investigation, as recovery of T helper cytokine production towards surgery was less impaired than T helper cell counts.

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.

Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial.

OBJECTIVE: To determine whether extended transthoracic esophagectomy for adenocarcinoma of the mid/distal esophagus improves long-term survival. BACKGROUND: A randomized trial was performed to compare surgical techniques. Complete 5-year survival data are now available. METHODS: A total of 220 patients with adenocarcinoma of the distal esophagus (type I) or gastric cardia involving the distal esophagus (type II) were randomly assigned to limited transhiatal esophagectomy or to extended transthoracic esophagectomy with en bloc lymphadenectomy. Patients with peroperatively irresectable/incurable cancer were excluded from this analysis (n = 15). A total of 95 patients underwent transhiatal esophagectomy and 110 patients underwent transthoracic esophagectomy. RESULTS: After transhiatal and transthoracic resection, 5-year survival was 34% and 36%, respectively (P = 0.71, per protocol analysis). In a subgroup analysis, based on the location of the primary tumor according to the resection specimen, no overall survival benefit for either surgical approach was seen in 115 patients with a type II tumor (P = 0.81). In 90 patients with a type I tumor, a survival benefit of 14% was seen with the transthoracic approach (51% vs. 37%, P = 0.33). There was evidence that the treatment effect differed depending on the number of positive lymph nodes in the resection specimen (test for interaction P = 0.06). In patients (n = 55) without positive nodes locoregional disease-free survival after transhiatal esophagectomy was comparable to that after transthoracic esophagectomy (86% and 89%, respectively). The same was true for patients (n = 46) with more than 8 positive nodes (0% in both groups). Patients (n = 104) with 1 to 8 positive lymph nodes in the resection specimen showed a 5-year locoregional disease-free survival advantage if operated via the transthoracic route (23% vs. 64%, P = 0.02). CONCLUSION: There is no significant overall survival benefit for either approach. However, compared with limited transhiatal resection extended transthoracic esophagectomy for type I esophageal adenocarcinoma shows an ongoing trend towards better 5-year survival. Moreover, patients with a limited number of positive lymph nodes in the resection specimen seem to benefit from an extended transthoracic esophagectomy.

Monitoring of response to pre-operative chemoradiation in combination with hyperthermia in oesophageal cancer by FDG-PET.

PURPOSE: To evaluate the use of positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) to assess early response to pre-operative chemoradiation therapy in combination with external locoregional hyperthermia in patients with oesophageal cancer by correlating the reduction of metabolic activity with histopathologic response. MATERIAL AND METHODS: Twenty-six patients with histopathologically proven intra-thoracic oesophageal cancer (with < or =2 cm gastric involvement), scheduled to undergo a 5-week course of pre-operative chemoradiation therapy and hyperthermia, were included. FDG-PET was performed before (n = 26) and 2 weeks after initiation of therapy (n = 17). FDG uptake was quantitatively assessed by standardized uptake values. RESULTS: After neoadjuvant therapy, 24 of the 26 patients underwent surgery. In 16 patients changes in FDG uptake were correlated to histopathologic response. In these patients, histopathologic evaluation revealed less than 10% viable tumour cells in eight patients (responders) and more than 10% viable tumour cells in eight patients (non-responders). In responders, FDG uptake decreased by a median -44% (-75 to 2); in non-responders, it decreased by a median of -15% (-46 to 40). At a threshold of 31% decrease of FDG uptake compared with baseline, sensitivity to detect response was 75%, with a corresponding specificity of 75%. The positive and negative predictive values were both 75%. CONCLUSION: FDG-PET is a promising tool for early response monitoring in patients undergoing chemoradiation therapy in combination with hyperthermia.

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.