title: Pretherapeutic evaluation of patients with upper gastrointestinal tract cancer using endoscopic and laparoscopic ultrasonography.
abstract: BACKGROUND
  A detailed and correct pretherapeutic evaluation of stage and resectability is mandatory for an optimal treatment strategy and results in patients with cancer of the esophagus, stomach or pancreas (UGIC). Curative surgery should only be attempted in patients with limited extent of their disease, patients with locally advanced disease should be allocated for neo-adjuvant therapy, while the remaining patients should be referred for palliative measures following a quick, lenient and correct pretherapeutic evaluation. This thorough evaluation and subsequent treatment assignment is also valuable in the identification of uniform patient cohorts for new treatment protocols as well as for the continuing comparison of research data. But despite the importance of accurate pretherapeutic assessment being repeatedly emphasized insufficient staging has been - and is still accepted as - leading to high rates of explorative surgery as well as heterogeneous selection of patients for new treatment trials. Based on the results from the authors PhD thesis he concluded that endoscopic ultrasonography (EUS) as a single imaging modality provided detailed information that hitherto had been inaccessible. EUS was considered a significant progress regarding the loco-regional assessment of stage and resectability, but it was also evident that EUS alone was incapable of providing all the necessary information. In addition, there were no evidence regarding the EUS safety profile, patient tolerance of the procedure and no data on the clinical impact of both EUS and EUS guided fine-needle aspiration biopsy (EUS-FNA) in UGIC patients. Therefore, the author chose to conduct additional EUS trials and to test the use of EUS-FNA, laparoscopy (LAP), laparoscopic ultrasonography (LUS) and LUS guided biopsy in order to improve the overall pretherapeutic evaluation and thus the patient selection. The aim of this thesis was to describe the sequential development, testing and clinical results of a new pretherapeutic evaluation strategy based on EUS and LUS.
  
  
  RESULTS
  
  
  
  METHODS
  The value of EUS and EUS-FNA in the primary diagnosis of esophageal and gastric cancer was limited, but EUS-FNA was diagnostically relevant in 25% of the patients with pancreatic lesions and malignancy was confirmed in 86% of these patients. Comparison with other studies were difficult since no other trials have specifically focused on the clinical need for EUS-FNA regarding the primary diagnosis and resectability assessment.   Stage and resectability assessment: TN staging based on EUS only provided accuracies above 80% for all cancer types when compared with histopathological or intraoperative findings. A similar high overall accuracy of EUS regarding pretherapeutic resectability assessment dropped to a significantly lower value when re-evaulated in a larger study under routine settings. There may be several explanations for this observation, but the move from a protocolled trial to a routine setting and the possibility of using LAP and LUS in the latter material may have influenced the decision and thus the results. The number of patients where EUS-FNA was indicated and performed remained constant over time, indicating adherence to the stringent biopsy criteria also outside a protocolled setup. EUS-FNA demonstrated a small (12%) but significant impact on the staging/resectability assessment and subsequent patient management. There were no differences between the impact in esophageal, gastric and pancreatic cancer, and the EUS-FNA verification of distant lymph nodes metastases was the major contributor to these results. Although EUS could detect and biopsy lesions not seen by CT, these imaging modalities were considered supplementary, but neither of these nor a combination of both was able to perform a complete evaluation of the TNM stage or the resectability.   EUS tolerability, complications and patient satisfaction: Minor transient complaints after the EUS procedure was seen in one-third of the patients, but re-admission (0.7%), or contact to the patients GP (6.1%) due to complaints thought to be related to the EUS procedure were seldom. Overall EUS related morbidity and mortality in UGIC patients were 0.61% and 0.07%, respectively, and this was comparable to later series. Two-thirds of the complications in this study occurred in esophageal cancer patients as potential life threatening perforations. The conduction and evaluation of patient satisfaction surveys are complex and with a high risk of bias. Despite the reported pain, anxiety and discomfort more than 90% were prepared to undergo another EUS examination, and a similar proportion of patients were satisfied with the level of information provided before and after the examination.   Treatment impact of EUS and the combination of EUS and LUS: The impact of EUS on treatment decisions in UGIC patients seemed lower than would have been expected from the EUS test performance. This observation suggested that the final treatment decision was based on several parameters, but at the same time stressed the importance of stringent EUS statements based on predefined standards. Lack of knowledge regarding advantages and limitations of EUS, situations where EUS was performed by non-surgeons, confusing terminology and conclusions as well as different treatment traditions may have influenced the comparison of data on the clinical impact of EUS. The inter-observer agreement on the treatment of UGIC patients was improved by EUS, and the ability to detect patients with non-resectable disease was the main reason for this among the one-third of all patients where EUS led to a change in the treatment approach. The clinical effect of a wrong EUS conclusion was limited, but EUS false positive resectability assessment may have denied up to 2% of the patients of a potentially curative resection. The combination of EUS and LUS solved the majority of problems related to EUS as a single imaging modality and related to the lack of deep vision during laparoscopy. The combination of EUS and LUS predicted R0 resection in 91% of the patients, thus significantly increasing the overall accuracy when compared to EUS alone. The prediction of R1/R2 resections showed similar results but with wide confidence intervals. Following EUS and LUS the number of futile laparotomies was reduced to 5%, and this figure dropped to 2.4% when patients who needed surgical by-pass were excluded.   LUS guided biopsy: After having developed and tested a new system for LUS guided fine-needle aspiration biopsy and true-cut biopsy the author evaluated the need for biopsy using the same stringent indications as for EUS-FNA. LUS guided biopsies were indicated in 12% of the patients with a final malignant diagnosis. The major overall indication was lack of biopsy from the primary tumour. Adequate material was obtained in 95% of the biopsies despite being taken by six different surgeons. The overall combined impact of laparoscopic and LUS guided biopsy in patient management amounted to 27%.   Cost-effectiveness of different imaging strategies in the detection of patients with non-resectable disease: In a retrospective design monitoring the costs on a departmental level EUS and LUS - or a combination with either of these - was cost-effective regarding the detection of patients with non-resectable or disseminated disease. The combination of non-invasive methods (e.g. CT and EUS) seemed attractive from an economical view-point, but such a strategy would be associated with futile surgery in 20% of the patients. However, the combination of EUS and LUS almost eliminated futile laparotomies, and at the same time remained cost-effective. Although not reported the data proved resistant to significant changes in both costs and effect, and the sequential use of EUS followed by laparoscopy and LUS seemed to be a cost-effective strategy.   Combined pretherapeutic EUS and LUS as predictors of long-term survival: The literature has suggested a correlation between specific pretherapeutic EUS findings and the prognosis in UGIC patients. Based on an improved evaluation by the combination of EUS and LUS it was relevant to relate the pretherapeutic findings of this strategy to the final prognosis, and to do a stratified analysis based on both the stage and the resectability assessment. The combined approach of EUS and LUS provided relevant and significant stratification estimates of the prognosis in all three cancer types whether based on stage or on resectability assessment. EUS and LUS seemed superior to other imaging strategies regarding the identification of patients who may undergo a "true" R0 resection. Thus, EUS and LUS may have a positive impact on the prognosis of R0 resected UGIC patients.
  
  
  CONCLUSIONS
  With the results from the present thesis the author has defined and tested a new evaluation strategy based on the combination of EUS and LUS. This combination was supplemented by EUS and LUS guided biopsies in those situations, where a malignant biopsy would change the subsequent treatment strategy. The combination of EUS and LUS was lenient, safe and cost-effective and at the same time provided additional, important pretherapeutic information regarding possible treatment options and the prognosis. It may be speculated if the improved patient selection has had a positive impact on the prognosis of the R0 resected patients. The combined strategy may also allow a more homogenous selection of patients for future treatment trials.
authors.affiliation: Department of Surgery, Odense University Hospital, 5000 Odense C, Denmark. m.bau@dadlnet.dk
authors.forename: Michael Bau
authors.initials: MB
authors.lastname: Mortensen
mesh_terms: D044963:Biopsy, Fine-Needle / Q000379:methods; D004067:Digestive System Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery; D019160:Endosonography / Q000379:methods*; D004938:Esophageal Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D061705:Image-Guided Biopsy / Q000379:methods; D007150:Immunohistochemistry; D010535:Laparoscopy / Q000379:methods*; D008297:Male; D009367:Neoplasm Staging; D015588:Observer Variation; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology / Q000601:surgery; D011300:Preoperative Care / Q000379:methods; D012680:Sensitivity and Specificity; D013274:Stomach Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology / Q000601:surgery; D018608:Ultrasonography, Doppler / Q000379:methods