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
TL;DR: It is hypothesized 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, and may be associated with lower morbidity and comparable survival.
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
).
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Samsung Medical Center1, Katholieke Universiteit Leuven2, Chungbuk National University3, University of Ioannina4, Tata Memorial Hospital5, National Taiwan University6, Peking Union Medical College7, Kidwai Memorial Institute of Oncology8, University of Malaya9, University of Amsterdam10, New Generation University College11, Gachon University12, University Hospital of Lausanne13
TL;DR: These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS).
64 citations
TL;DR: The rate of unforeseen N2 disease after negative endosonography findings was similar in patients undergoing immediate lung tumor resection to those undergoing confirmatory mediastinoscopy first, at the cost of 6.0% rate of complications by mediastinescopy.
28 citations
TL;DR: It was found that in LC patients with COPD, compared to those without it, fewer numbers of TLSs and B cells were detected, and those patients died significantly earlier, and these results have implications in the diagnosis and treatment options of lung tumors in patients with underlying respiratory diseases.
Abstract: Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B and T cells, and (2) associations of the immune biomarkers with the patients' 10-year overall survival (OS). TLSs (numbers and area), B [cluster of differentiation (CD) 20], and T (CD3), and GCs cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients. Ten-year OS was analyzed in the patients. Immune profile in tumors of LC-COPD versus LC: TLS numbers and areas significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC patients for B or T cells. Immune profile in tumors versus non-tumor specimens: TLS areas and B cells significantly increased, T cells significantly decreased in tumors of both LC and LC-COPD patients. Survival: in LC-COPD patients: greater area of TLSs and proportion of B cells were associated with longer survival rates. The immune tumor microenvironment differs in patients with underlying COPD and these different phenotypes may eventually impact the response to immunotherapy in patients with LC.
26 citations
Cites result from "MEDIASTinal staging of non-small ce..."
...Notwithstanding, in all surgical cases, intra-operative systematic hilar and mediastinal lymphadenectomy (at least, ipsilateral paratracheal, subcarinal, and ipsilateral pulmonary ligament) was performed as previously recommended [40,41]....
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TL;DR: This study demonstrated high variation in staging and treatment of patients with stage IIIA NSCLC among MDTs in different hospitals, and suggested that some variation may be unavoidable in these challenging patients and should strive for more uniformity.
15 citations
Cites background from "MEDIASTinal staging of non-small ce..."
...Elsewhere, discussions are ongoing regarding whether to omit mediastinoscopy.(25) Also, brain MRI was not requested when indicated by more than half of the MDTs,...
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TL;DR: Although adherence to the European NSCLC mediastinal staging guideline on initial use of endosonography was good, 30% of endOSonography procedures were performed insufficiently and unforeseen N2 rates following staging by endos onography with or without confirmatory mediastinoscopy were comparable.
15 citations
References
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TL;DR: The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.
Abstract: Growing demand for health care, rising costs, constrained resources, and evidence of variations in clinical practice have triggered interest in measuring and improving the quality of health care delivery. For a valuable quality assessment, relevant data on outcome must be obtained in a standardized and reproducible manner to allow comparison among different centers, between different therapies and within a center over time.1–3 Objective and reliable outcome data are increasingly requested by patients and payers (government or private insurance) to assess quality and costs of health care. Moreover, health policy makers point out that the availability of comparative data on individual hospital's and physician's performance represents a powerful market force, which may contribute to limit the costs of health care while improving quality.4
Conclusive assessments of surgical procedures remain limited by the lack of consensus on how to define complications and to stratify them by severity.1,5–8 In 1992, we proposed general principles to classify complications of surgery based on a therapy-oriented, 4-level severity grading.1 Subsequently, the severity grading was refined and applied to compare the results of laparoscopic versus open cholecystectomy9 and liver transplantation.10 This classification has also been used by others11–13 and was recently suggested to serve as the basis to assess the outcome of living related liver transplantation in the United States (J. Trotter, personal communication). However, the classification system has not yet been widely used in the surgical literature.
The strength of the previous classification relied on the principle of grading complications based on the therapy used to treat the complication. This approach allows identification of most complications and prevents down-rating of major negative outcomes. This is particularly important in retrospective analyses. However, we felt that modifications were necessary, particularly in grading life-threatening complications and long-term disability due to a complication. We also felt that the duration of the hospital stay can no longer be used as a criterion to grade complications. Although definitions of negative outcomes rely to a large extend on subjective “value” appraisals, the grading system must be tested in a large cohort of patients. Finally, a classification is useful only if widely accepted and applied throughout different countries and surgical cultures. Such a validation was not done with the previous classification.
Therefore, the aim of the current study was 3-fold: first, to propose an improved classification of surgical complications based on our experience gained with the previous classification1; second, to test this classification in a large cohort of patients who underwent general surgery; and third, to assess the reproducibility and acceptability of the classification through an international survey.
23,435 citations
"MEDIASTinal staging of non-small ce..." refers background in this paper
...Major morbidity is defined as the proportion of patients having morbidity of grade III-IV (Clavien-Dindo classification) or recurrent laryngeal nerve injury, which is a specific serious adverse event associated with mediastinoscopy [22]....
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TL;DR: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden, while for many cancers, Denmark is closing the survival gap with the other Nordic countries.
2,756 citations
"MEDIASTinal staging of non-small ce..." refers background in this paper
...In the Netherlands 9175 new non-small cell lung cancer (NSCLC) patients were diagnosed in 2017 [1, 2]....
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VU University Amsterdam1, University of La Rioja2, Radboud University Nijmegen Medical Centre3, University of Cologne4, Erasmus University Rotterdam5, King's College London6, Memorial Sloan Kettering Cancer Center7, Vanderbilt University Medical Center8, Beth Israel Deaconess Medical Center9, University of Iowa10, Bosch11, Medical University of Vienna12
TL;DR: Both the previous and these new guidelines specifically aim to achieve standardised uptake value harmonisation in multicentre settings.
Abstract: The purpose of these guidelines is to assist physicians in recommending, performing, interpreting and reporting the results of FDG PET/CT for oncological imaging of adult patients. PET is a quantitative imaging technique and therefore requires a common quality control (QC)/quality assurance (QA) procedure to maintain the accuracy and precision of quantitation. Repeatability and reproducibility are two essential requirements for any quantitative measurement and/or imaging biomarker. Repeatability relates to the uncertainty in obtaining the same result in the same patient when he or she is examined more than once on the same system. However, imaging biomarkers should also have adequate reproducibility, i.e. the ability to yield the same result in the same patient when that patient is examined on different systems and at different imaging sites. Adequate repeatability and reproducibility are essential for the clinical management of patients and the use of FDG PET/CT within multicentre trials. A common standardised imaging procedure will help promote the appropriate use of FDG PET/CT imaging and increase the value of publications and, therefore, their contribution to evidence-based medicine. Moreover, consistency in numerical values between platforms and institutes that acquire the data will potentially enhance the role of semiquantitative and quantitative image interpretation. Precision and accuracy are additionally important as FDG PET/CT is used to evaluate tumour response as well as for diagnosis, prognosis and staging. Therefore both the previous and these new guidelines specifically aim to achieve standardised uptake value harmonisation in multicentre settings.
2,029 citations
"MEDIASTinal staging of non-small ce..." refers methods in this paper
...All participating centres should adhere to the European Association of Nuclear Medicine procedure guidelines of FDG-PET/CT for tumour imaging to guarantee high quality of performing, interpreting and reporting FDGPET/CT-scan [21]....
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TL;DR: To achieve uniformity and to promote future analyses of a planned prospective international database, the International Association for the Study of Lung Cancer proposes a new lymph node map which reconciles differences among currently used maps, and provides precise anatomic definitions for all lymph node stations.
976 citations
"MEDIASTinal staging of non-small ce..." refers background in this paper
...mediastinal zone (according to the international association for the study of lung cancer (IASLC) node map) [16, 19]....
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TL;DR: In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiother- apy, and radiotherapy should be considered the preferred locoregional treatment for these patients.
Abstract: Background : Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy. Methods : Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum- based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan–Meier analyses from time of randomization. Results : Induction chemotherapy resulted in a response rate of 61% (95% confidence interval [CI] = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response; 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%; one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups. Conclusion : In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiother- apy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.
585 citations