MEDIASTinal staging of non-small cell lung cancer by endobronchial and endoscopic ultrasonography with or without additional surgical mediastinoscopy (MEDIASTrial): study protocol of a multicenter randomised controlled trial.
ABSTRACT: In case of suspicious lymph nodes on computed tomography (CT) or fluorodeoxyglucose positron emission tomography (FDG-PET), advanced tumour size or central tumour location in patients with suspected non-small cell lung cancer (NSCLC), Dutch and European guidelines recommend mediastinal staging by endosonography (endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS)) with sampling of mediastinal lymph nodes. If biopsy results from endosonography turn out negative, additional surgical staging of the mediastinum by mediastinoscopy is advised to prevent unnecessary lung resection due to false negative endosonography findings. We hypothesize that omitting mediastinoscopy after negative endosonography in mediastinal staging of NSCLC does not result in an unacceptable percentage of unforeseen N2 disease at surgical resection. In addition, omitting mediastinoscopy comprises no extra waiting time until definite surgery, omits one extra general anaesthesia and hospital admission, and may be associated with lower morbidity and comparable survival. Therefore, this strategy may reduce health care costs and increase quality of life. The aim of this study is to compare the cost-effectiveness and cost-utility of mediastinal staging strategies including and excluding mediastinoscopy.This study is a multicenter parallel randomized non-inferiority trial comparing two diagnostic strategies (with or without mediastinoscopy) for mediastinal staging in 360 patients with suspected resectable NSCLC. Patients are eligible for inclusion when they underwent systematic endosonography to evaluate mediastinal lymph nodes including tissue sampling with negative endosonography results. Patients will not be eligible for inclusion when PET/CT demonstrates 'bulky N2-N3' disease or the combination of a highly suspicious as well as irresectable mediastinal lymph node. Primary outcome measure for non-inferiority is the proportion of patients with unforeseen N2 disease at surgery. Secondary outcome measures are hospitalization, morbidity, overall 2-year survival, quality of life, cost-effectiveness and cost-utility. Patients will be followed up 2 years after start of treatment.Results of the MEDIASTrial will have immediate impact on national and international guidelines, which are accessible to public, possibly reducing mediastinoscopy as a commonly performed invasive procedure for NSCLC staging and diminishing variation in clinical practice.The trial is registered at the Netherlands Trial Register on July 6th, 2017 ( NTR 6528 ).
Project description:<h4>Background</h4>Invasive mediastinal nodal staging is recommended by guidelines in selected patients with resectable non-small cell lung cancer (NSCLC). Endosonography is recommended as initial staging technique, followed by confirmatory mediastinoscopy in case of negative N2 or N3 cytology after endosonography. Confirmatory mediastinoscopy however is under debate owing its limited additional diagnostic value, its associated morbidity and its delay in the start of lung cancer treatment. The MEDIASTrial examines whether confirmatory mediastinoscopy can be safely omitted after negative endosonography in mediastinal nodal staging of NSCLC. The present work is the proposed statistical analysis plan of the clinical consequences of omitting mediastinoscopy, which is submitted before closure of the MEDIASTrial and before knowledge of any results was done to enhance transparency of scientific behaviour.<h4>Methods</h4>The primary outcome measure of this non-inferiority trial will be unforeseen N2 disease resulting from lobe-specific mediastinal lymph node dissection. For non-inferiority, the upper limit of the 95% confidence interval of the unforeseen N2 rate in the group without mediastinoscopy should not exceed 14.3% in order to probably have no negative impact on survival. Since this is a non-inferiority trial, both an intention to treat (ITT) and a per protocol (PP) analyses will be done. The ITT and the PP analyses should both indicate non-inferiority before the diagnostic strategy omitting mediastinoscopy will be interpreted as non-inferior to the strategy with mediastinoscopy. Secondary outcome measures include 30-day major morbidity and mortality, the total number of days of hospital care, overall and disease free 2-year survival, generic and disease-specific health related quality of life and cost-effectiveness and cost-utility of staging strategies with and without mediastinoscopy.<h4>Discussion</h4>The MEDIASTrial will determine if confirmatory mediastinoscopy can be omitted after tumour negative systematic endosonography in invasive mediastinal staging of patients with resectable NSCLC.<h4>Trial registration</h4>Netherlands Trial Register NL6344/NTR6528 . Registered on 2017 July 06.
Project description:Preoperative mediastinal staging is crucial in the management of patients with non-small cell lung cancer (NSCLC), especially to define prognosis and the most proper treatment. To obtain the highest certainty level before lung resection, the current American and European guidelines for preoperative mediastinal nodal staging for NSCLC recommend getting tissue confirmation of regional nodal spread in all cases except in patients with small (?3 cm) peripheral carcinomas with no evidence of nodal involvement on computed tomography (CT) and positron emission tomography (PET). We have a wide variety of surgical methods for mediastinal staging that are well integrated in the current preoperative algorithms. Their main indication is the validation of negative results obtained by minimally invasive endoscopic techniques. However, recent studies have reported the superiority of mediastinoscopy over endosonography methods in terms of accuracy for those tumours classified as clinical (c) N0-1 by CT and PET or with intermediate risk of N2 disease (cN1 and central tumours). Apart from the exploration of the mediastinum, other surgical procedures [parasternal mediastinotomy, extended cervical mediastinoscopy (ECM) and video-assisted thoracoscopic surgery (VATS)] allow the completion of the staging process with the assessment of the primary tumour and metastasis, exploring the lung, pleural cavity, and pericardium when it is required. Transcervical lymphadenectomies represent the evolution of mediastinoscopy and they are already considered the most reliable method for mediastinal staging, mainly in the subgroup of patients in whom endosonography methods have a low sensitivity: tumours with normal mediastinum by CT and PET. In addition to their indication for staging, these procedures have also demonstrated to be feasible as preresectional lymphadenectomy in VATS lobectomy, improving the radicality of the number of lymph nodes and lymph node stations explored, mostly for left-sided tumours for which a complete mediastinal nodal dissection is not always possible by VATS approach.
Project description:This two-step study evaluated the cost-effectiveness of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for presurgery staging of non-small cell lung cancer (NSCLC) in France (EVIEPEB; ClinicalTrial.gov identifier NCT00960271). Step 1 consisted of a high-benchmark EBUS-TBNA-training program in participating hospital centers. Step 2 was a prospective, national, multicenter study on patients with confirmed or suspected NSCLC and an indication for mediastinal staging with at least one lymph node > 1 cm in diameter. Patients with negative or uninformative EBUS-TBNA and positron-emission tomography-positive or -negative nodes, respectively, underwent either mediastinoscopy or surgery. Direct costs related to final diagnosis of node status were prospectively recorded. Sixteen of 22 participating centers were certified by the EBUS-TBNA-training program and enrolled 163 patients in Step 2. EBUS-TBNA was informative for 149 (91%) patients (75 malignant, 74 non-malignant) and uninformative for 14 (9%). Mediastinoscopy was avoided for 80% of the patients. With a 52% malignant-node rate, EBUS-TBNA positive- and negative-predictive values, respectively, were 100% and 90%. EBUS-TBNA was cost-effective, with expected savings of €1,450 per patient, and would have remained cost-effective even if all EBUS-TBNAs had been performed under general anesthesia or the cost of the procedure had been 30% higher (expected cost-saving of €994 and €1,427 per patient, respectively). After EBUS-TBNA training and certification of participating centers, the results of this prospective multicenter study confirmed EBUS-TBNA cost-effectiveness for NSCLC staging.
Project description:With nonsmall cell lung cancer (NSCLC), accurate mediastinal nodal staging is crucial to determine whether a patient is or is not a surgical candidate. Traditionally, computed tomography (CT) and fluorodeoxy-D-glucose (FDG) positron emission tomography (PET)/CT are the initial steps followed by tissue sampling through mediastinoscopy and/or thoracotomy, which are invasive procedures. There is controversy regarding the possibility of omission of the invasive diagnostic procedures and solely relying on noninvasive presurgical staging CT and FDG PET/CT results. Eighty-three patients who had PET/CT, mediastinoscopy, and thoracotomy for NSCLC were analyzed. For all lymph nodes that may be sampled by mediastinoscopy, PET/CT sensitivity was 80%, specificity was 86%, positive predictive value was 47%, and negative predictive value (NPV) was 97%; and for those in this group whose clinical stage was T1/T2 M0, sensitivity was 100% and specificity was 84%. For lymph nodes accessible only at thoracotomy, sensitivity was 42% and specificity was 88%. FDG PET/CT is accurate in assessing stations 2R/L, 4R/L, and 7 nodes and has the potential to replace mediastinoscopy in the treatment algorithm of T1/T2 M0 disease. A negative PET/CT may potentially prevent the patient from invasive mediastinoscopy given its high NPV. However, a patient with positive PET/CT should undergo tissue biopsy with pathology confirmation.
Project description:BACKGROUND:The present study aims to assess the performance of 18F-FDG PET-CT on mediastinal staging of non-small cell lung cancer (NSCLC) in a location with endemic granulomatous infectious disease. METHODS:Diagnostic test study including patients aged 18?years or older with operable stage I-III NSCLC and indication for a mediastinal lymph node biopsy. All patients underwent a 18F-FDG PET-scan before invasive mediastinal staging, either through mediastinoscopy or thoracotomy, which was considered the gold-standard. Surgeons and pathologists were blinded for scan results. Primary endpoint was to evaluate sensitivity, specificity and positive and negative predictive values of PET-CT with images acquired in the 1st hour of the exam protocol, using predefined cutoffs of maximal SUV, on per-patient basis. RESULTS:Overall, 85 patients with operable NSCLC underwent PET-CT scan followed by invasive mediastinal staging. Mean age was 65?years, 49 patients were male and 68 were white. One patient presented with active tuberculosis and none had HIV infection. Using any SUV_max >?0 as qualitative criteria for positivity, sensitivity and specificity were 0.87 and 0.45, respectively. Nevertheless, even when the highest SUV cut-off was used (SUV_max ?5), specificity remained low (0.79), with an estimated positive predictive value of 54%. CONCLUSIONS:Our findings are in line with the most recent publications and guidelines, which recommend that PET-CT must not be solely used as a tool to mediastinal staging, even in a region with high burden of tuberculosis. TRIAL REGISTRATION:The LACOG 0114 study was registered at ClinicalTrials.gov , before study initiation, under identifier NCT02664792.
Project description:OBJECTIVES:Invasive mediastinal nodal staging is recommended before curative-intent resection in patients with non-small cell lung cancer deemed at risk for mediastinal lymph node involvement. We evaluated the use and survival effect of preoperative invasive mediastinal nodal staging in a population-based non-small cell lung cancer cohort. METHODS:We analyzed all curative-intent resections for non-small cell lung cancer from 2009 to 2018 in 11 hospitals in 4 contiguous Dartmouth Hospital Referral Regions, comparing patients who did not have invasive mediastinal nodal staging with those who did. RESULTS:Preoperative invasive nodal staging was used in 22% of 2916 patients, including mediastinoscopy only in 13%, minimally invasive procedures only in 6%, and both approaches in 3%. Sixty-three percent of patients at risk for nodal disease (tumor size ?3.0 cm/T2-T4; N1-N3 by computed tomography or positron-emission tomography-computerized tomography criterion) did not undergo invasive staging; among those who did not have invasive testing, 47% had at least 1 of the 3 clinical indications. Mediastinoscopy yielded a median of 3 lymph nodes and 2 nodal stations; 17% of mediastinoscopies and 31% of endobronchial ultrasound procedures yielded no lymph node material. Patients not invasively staged were more likely to have no nodes (6% vs 2%; P < .0001) and no mediastinal nodes (20% vs 11%; P < .0001) examined at surgery. Invasive staging was associated with significantly better survival (P = .0157). CONCLUSIONS:More than a decade after the 2001 American College of Surgeons Patient Care Evaluation report, preoperative invasive nodal staging remains underused and of variable quality, but was associated with survival benefit in high-risk patients.
Project description:Surgery is the most important curative treatment modality for patients with early-stage non-small cell lung cancer (NSCLC). We examined the pattern of surgical resection for NSCLC in a high incidence and mortality region of the United States over a 10-year period (2004-2013) in the context of a regional surgical quality improvement initiative. We abstracted patient-level data on all resections at 11 hospitals in 4 contiguous Dartmouth Hospital Referral Regions in North Mississippi, East Arkansas, and West Tennessee. Surgical quality measures focused on intraoperative practice, with emphasis on pathologic nodal staging. We used descriptive statistics and trend analyses to assess changes in practice over time. To measure the effect of an ongoing regional quality improvement intervention with a lymph node specimen collection kit, we used period effect analysis to compare trends between the preintervention and postintervention periods. Of 2566 patients, 18% had no preoperative biopsy, only 15% had a preoperative invasive staging test, and 11% underwent mediastinoscopy. The rate of resections with no mediastinal lymph nodes examined decreased from 48%-32% (P < 0.0001), whereas the rate of resections examining 3 or more mediastinal stations increased from 5%-49% (P < 0.0001). There was a significant period effect in the increase in the number of N1, mediastinal, and total lymph nodes examined (all P < 0.0001). A quality improvement intervention including a lymph node specimen collection kit shows early signs of having a significant positive effect on pathologic nodal examination in this population-based cohort. However, gaps in surgical quality remain.
Project description:INTRODUCTION:The emergence of endobronchial ultrasound (EBUS) changed the approach to staging lung cancer. As a new method being incorporated, the use of EBUS may lead to a shift in clinical and costs outcomes. OBJECTIVE:The aim of this systematic review is to gather information to better understand the economic impact of implementing EBUS. METHODS:This review is reported according to the PRISMA statement and registered on PROSPERO (CRD42019107901). Search keywords were elaborated considering descriptors of terms related to the disease (lung cancer / mediastinal staging of lung cancer) and the technologies of interest (EBUS and mediastinoscopy) combined with a specific economic filter. The literature search was performed in MEDLINE, EMBASE, LILACS, Cochrane Library of Trials, Web of Science, Scopus and National Health System Economic Evaluation Database (NHS EED) of the Center for Reviews and Dissemination (CRD). Screening, selection of articles, data extraction and quality assessment were carried out by two reviewers. RESULTS:Seven hundred and seventy publications were identified through the database searches. Eight articles were included in this review. All publications are full economic evaluation studies, one cost-effectiveness, three cost-utility, and four cost-minimization analyses. The costs of strategies using EBUS-TBNA were lower than the ones using mediastinoscopy in all studies analyzed. Two of the best quality scored studies demonstrate that the mediastinoscopy strategy is dominated by the EBUS-TBNA strategy. CONCLUSION:Information gathered in the eight studies of this systematic review suggest that EBUS is cost-effective compared to mediastinoscopy for mediastinal staging of lung cancer.
Project description:Nodal staging of non-small-cell lung cancer (NSCLC) is crucial in evaluation of prognosis and determination of therapeutic strategy. This study aimed to determine the negative predictive value (NPV) of combined positron emission tomography and computed tomography (PET-CT) in patients with stage I (T1-2N0) NSCLC and to investigate the possible risk factors for occult nodal disease.Studies investigating the performance of PET in conjunction with CT in the nodal staging of stage I NSCLC were identified in the MEDLINE database. The initiative of standards for reporting of diagnostic accuracy (STARD) was used to ensure study quality. Pathologic assessments through mediastinoscopy or thoracotomy were required as the reference standard for evaluation of PET-CT accuracy. Stata-based meta-analysis was applied to calculate the individual and pooled NPVs.Ten studies with a total of 1122 patients with stage I (T1-2N0) NSCLC were eligible for analysis. The NPVs of combined PET and CT for mediastinal metastases were 0.94 in T1 disease and 0.89 in T2 disease. Including both T1 disease and T2 disease, the NPVs were 0.93 for mediastinal metastases and 0.87 for overall nodal metastases. Adenocarcinoma histology type (risk ratio [RR], 2.72) and high fluorine-18 (18F) fluorodeoxyglucose (FDG) uptake in the primary lesion were associated with greater risk of occult nodal metastases.Although overall occult nodal metastases in clinical stage T1-2N0 NSCLC is not infrequent, combined PET and CT provide a favorable NPV for mediastinal metastases in T1N0 NSCLC, suggesting a low yield from routine invasive staging procedures for this subgroup of patients.
Project description:BACKGROUND:Endosonography with needle aspiration (EBUS/EUS-NA) is recommended as the first choice for mediastinal nodal assessment in non-small cell lung cancer (NSCLC). It is important to maintain adequate negative predictive value of the procedure to avoid unnecessary additional surgical staging, but there are few studies on the influence of operator-related factors including competency on false negative results. This study aims to compare the false negative rate of individual operators and whether it changes according to accumulation of experience. METHODS:This is a retrospective study of NSCLC patients who were N0/N1 by EBUS/EUS-NA and confirmed by pathologic staging upon mediastinal lymph node dissection (n?=?705). Patients were divided into a false negative group (finally confirmed as pN2/N3) and a true negative group (pN0/N1). False negative rates of six operators and whether these changed according to accumulated experience were analyzed. RESULTS:There were 111 (15.7%) false negative cases. False negative rates among six operators ranged from 8.3 to 21.4%; however, there were no statistical differences before and after adjustment for patient characteristics and procedure-related factors (P?=?0.346 and P?=?0.494, respectively). In addition, false negative rates did not change as each operator accumulated experience (P for trend?=?0.632). CONCLUSIONS:Our data suggest that there would be no difference in false negative rates regardless of which operator performs the procedure assuming that the operators have completed a certain period of observation and have performed procedures under the guidance of an expert.