Jikke M. T. Omloo

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.

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.

FDG-PET Parameters as Prognostic Factor in Esophageal Cancer Patients: A Review

Background18F-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.MethodsA 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.ResultsIn 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.ConclusionsMeasuring 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.

Importance of fluorodeoxyglucose-positron emission tomography (FDG-PET) and endoscopic ultrasonography parameters in predicting survival following surgery for esophageal cancer

BACKGROUND AND STUDY AIMS To assess the prognostic importance of standardized uptake value (SUV) for 18F-fluorodeoxyglucose (FDG) at positron emission tomography (PET) and of EUS parameters, in esophageal cancer patients primarily treated by surgery. PATIENTS AND METHODS Between October 2002 and August 2004 a prospective cohort study involved 125 patients, with histologically proven cancer of the esophagus, without evidence of distant metastases or locally irresectable disease based on extensive preoperative work-up, and fit to undergo major surgery. Follow-up was complete until October 2006, ensuring a minimal potential follow-up of 25 months. RESULTS The median SUV was 0.27 (interquartile range 0.13 - 0.45), and was used as cutoff value between high (n = 62) and low (n = 63) SUV. Patients with a high SUV had a significantly worse disease-specific survival compared with patients with a low SUV (P = 0.04). Tumor location (P = 0.005), EUS T stage (P < 0.001), EUS N stage (P = 0.006) and clinical stage (P < 0.006) were also associated with disease-specific survival. However, in multivariate analysis only EUS T stage appeared to be of independent prognostic significance (P = 0.007). CONCLUSION In esophageal cancer patients, EUS T stage, EUS N stage, location and SUV of the primary tumor are pretreatment factors that are associated with disease-specific survival. However, only EUS T stage is an independent prognostic factor.

Accuracy and reproducibility of 3D-CT measurements for early response assessment of chemoradiotherapy in patients with oesophageal cancer.

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.

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.

Short and long-term advantages of transhiatal and transthoracic oesophageal cancer resection

Two major surgical strategies to improve survival rates after oesophagectomy for oesophageal cancer have emerged during the past decades; (limited) transhiatal oesophagectomy and (extended) transthoracic oesophagectomy with two-field lymphadenectomy. This overview describes short and long-term advantages of these two strategies. In the short term, transhiatal oesophagectomy is accompanied by less morbidity. In the long term, this strategy is only preferable for patients with tumours located at the gastro-oesophageal junction, without involved lymph nodes in the proximal compartment of the chest. For patients with tumours located in the oesophagus, the transthoracic route with extended lymphadenectomy is probably preferred, because of improved long-term survival.

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

Additional Value of External Ultrasonography of the Neck after CT and PET Scanning in the Preoperative Assessment of Patients with Esophageal Cancer

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.

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.