Ignite Creation Date:
2024-05-06 @ 3:59 PM
Last Modification Date:
2024-10-26 @ 2:01 PM
Study NCT ID:
NCT04828850
Status:
UNKNOWN
Last Update Posted:
2022-03-22
First Post:
2021-03-26
Brief Title:
Preoperative Lymph Node Staging With EBUS-TBNA in Clinical N0 Non Small-cell Lung Cancer
Sponsor:
European Institute of Oncology
Organization:
European Institute of Oncology
Study Overview
Official Title:
Preoperative Lymph Node Staging by EBUS-TBNA in Clinical N0 Non Small-cell Lung Cancer
Status:
UNKNOWN
Status Verified Date:
2022-03
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The introduction of modern staging systems has increased the detection of small peripheral lung cancers at an early stage 1 Stage I non-small-cell lung cancers NSCLCs are confined to the lung without lymph node involvement and surgical resection is currently considered the standard therapeutic approach
Nodal staging is initially performed non-invasively with computer tomography CT and positron emission tomography PET scans followed by minimally invasive staging with endobronchial ultrasound-guided transbronchial needle aspiration EBUS-TBNA when CT andor PET are suggestive of mediastinal nodal involvement Lobectomy with radical lymphadenectomy is currently considered the treatment of choice for early-stage lung cancer
Several studies demonstrated that primary invasive non- small-cell lung carcinomas 20 cm were twice as likely to have nodal metastases as carcinomas 20 cm emphasizing that small lung cancers had less lymph node involvement and confirming a better survival In our pilot study 18 published in 2011 in the European Journal of Thoracic Surgery no nodal involvement was observed in any of the 62 patients with pulmonary nodule size less than 10 mm in 20 out of 120 patients 17 with nodule size 11-20 mm and in 9 out of 37 tumors 24 21-30 mm in size p 00007
These patients could be spared radical lymph node dissection if deemed not essential thereby reducing operative risks postoperative morbidity and surgery time A preoperative diagnostic determination to establish the size and correct staging of the tumor is mandatory for appropriate selection of candidates avoiding unnecessary surgery
Nodal staging is initially performed non-invasively with computer tomography CT and positron emission tomography PET scans followed by minimally invasive staging with endobronchial ultrasound-guided transbronchial needle aspiration EBUS-TBNA when CT andor PET are suggestive of mediastinal nodal involvement Lobectomy with radical lymphadenectomy is currently considered the treatment of choice for early-stage lung cancer
Several studies demonstrated that primary invasive non- small-cell lung carcinomas 20 cm were twice as likely to have nodal metastases as carcinomas 20 cm emphasizing that small lung cancers had less lymph node involvement and confirming a better survival In our pilot study 18 published in 2011 in the European Journal of Thoracic Surgery no nodal involvement was observed in any of the 62 patients with pulmonary nodule size less than 10 mm in 20 out of 120 patients 17 with nodule size 11-20 mm and in 9 out of 37 tumors 24 21-30 mm in size p 00007
These patients could be spared radical lymph node dissection if deemed not essential thereby reducing operative risks postoperative morbidity and surgery time A preoperative diagnostic determination to establish the size and correct staging of the tumor is mandatory for appropriate selection of candidates avoiding unnecessary surgery
Detailed Description:
BACKGROUND AND RATIONALE The introduction of modern staging systems such as computed tomography CT and positron emission tomographyCT PETCT with fluorodeoxyglucose FDG has increased the detection of small peripheral lung cancers at an early stage 1 Stage I non-small-cell lung cancers NSCLCs are confined to the lung without lymph node involvement and surgical resection is currently considered the standard therapeutic approach Lobectomy with radical lymphadenectomy is currently considered the treatment of choice for early-stage lung cancer irrespective of tumor size or its metabolic features on PET However the new TNM classification recently demonstrated that very small lung cancers may be less aggressive than others 2 suggesting a less aggressive surgical approach to reduce morbidity
According to the new TNM classification 8th edition the overall 5-year survival rate for pathological stage IA NSCLC was 85 ranging from 80 to 90 for T1a and T1c tumors respectively compared with 64 for stage IB tumors 2 Among patients with stage I cancer tumor size may affect outcome and drive survival as confirmed by different studies 7-12
Several studies demonstrated that primary invasive non- small-cell lung carcinomas 20 cm were twice as likely to have nodal metastases as carcinomas 20 cm emphasizing that small lung cancers had less lymph node involvement and confirming a better survival 11-15 Based on that Ishida et al and then Konaka et al have already demonstrated the absence of lymph node involvement in sub-centimeter lung cancers and the feasibility to omit lymph node dissection in those cases 1516 However Zhoua et al recommended systematic nodal dissection in the presence of sub-centimeter disease finding nodal metastases in 15 of NSCLC 1 cm but also including higher tumor stages such as stage II and III in their study without performing PET scan as part of the preoperative staging 17 In our pilot study 18 published in 2011 in the European Journal of Thoracic Surgery no nodal involvement was observed in any of the 62 patients with pulmonary nodule size less than 10 mm in 20 out of 120 patients 17 with nodule size 11-20 mm and in 9 out of 37 tumors 24 21-30 mm in size p 00007 All 55 patients with nodule SUV 20 and all 26 non-solid lesions were pN0 respectively p 00001 and p 003 So we adopted cut-offs of 10 mm for nodule diameter and 20 as peak SUV to distinguish patients with nodal involvement from those without
These patients could be spared radical lymph node dissection if deemed not essential thereby reducing operative risks postoperative morbidity and surgery time A preoperative diagnostic determination to establish the size and correct staging of the tumor is mandatory for appropriate selection of candidates avoiding unnecessary surgery
Data have demonstrated that positron emission tomography PET-FDG is a reliable tool versus CT in evaluating both solitary pulmonary nodules and lymph node involvement 3 Standard nodal staging is initially performed non-invasively with PET followed by minimally invasive staging with endobronchial ultrasound-guided transbronchial needle aspiration EBUS-TBNA when PET is suggestive of mediastinal nodal involvement In fact EBUS-TBNA is a minimally invasive procedure with a high yield for lymph node staging of lung cancer 4 EBUS-TBNA allows access to the paratracheal lymph node stations levels 2R 2L 4R 4L the subcarinal lymph node level 7 hilar interlobar and lobar lymph nodes levels 10 11 and 12 Previous studies including systematic reviews and meta-analyses and more recently Yasufuku et al have demonstrated a major impact of EBUS-TBNA on management of patients with non-small cell lung cancer NSCLC with a diagnostic yield comparable to mediastinoscopy 56 Annema et al have recently confirmed that the sensitivity of endosonography is similar to that of mediastinoscopy 85 vs 79 respectively and associated with a lower complication rate 1 vs 6 for mediastinoscopy so concluding that endosonography should be the first step for mediastinal nodal staging 19
In patients without evidence of mediastinal nodal metastasis on PET and CT the need for EBUS-TBNA becomes less clear The most recent American College of Chest Physicians ACCP evidence-based guidelines recommend minimally invasive mediastinal staging with a needle technique in patients with a central tumor or nodal hilar disease N1 on PETCT This is based on the increased prevalence of N2 disease in this group but this is a grade 1C recommendation that is based on low quality evidence In patients with peripheral tumors and no evidence of mediastinal or hilar nodal disease on PETCT invasive staging is not recommended
Concerns have been raised regarding these recommendations given that the prevalence of occult nodal metastasis in patients with N0 disease by PETCT appears to be higher than previously reported with recent studies showing values as high as 17-22 2021 EBUS-TBNA may provide an attractive option to increase staging accuracy However sensitivity of EBUS-TBNA in patients with clinical N0N1 disease on PETCT is unclear and largely based on retrospective studies 2223 The only prospective study published by Leong et al 24 demonstrated that a significant proportion of patients with N0N1 disease by PETCT had N2 disease 20 and EBUS-TBNA was able to identify a substantial fraction of these patients thus improving diagnostic accuracy compared with PETCT alone Sensitivity of EBUS-TBNA however appears lower compared with historical data from patients with larger volume mediastinal disease 5626
TRIAL OBJECTIVES
Hypotheses
In selected series the overall sensitivity of EBUS varies from 80-90 88 but for clinical N0N1 drops to 40-49
About 24 of patients with early stage lung cancer 2 cm and less than 5 cm T1bc and T2ab N0 PET- would be N whereas none of the T1a less or equal than 1 cm NSCLC would be upstaged considering the absence of N 19
From reference 19 pT size ALL pN 10 mm 62 0 0 11-20 mm 120 20 17 20 mm 37 9 24
7 OVERALL DESIGN AND PLAN OF TRIAL
71 Design of the study All patients clinical stage I and II will be undergone EBUS-TBNA for the staging of hilar and mediastinal lymph nodes
All patients will be undergoing robotic RATS or videothoracoscopic VATS lobectomy plus radical lymph node dissection following the Society of Thoracic Surgery STS guideline All lymph nodes previously sampled with EBUS-TBNA will be compared with those harvested during surgery
Statistical analysis Observed Surgery pN- pN Predicted EBUS Negative TN FN UPSTAGING FNTPtotal patients Positive FP TP SENSITIVITY is defined as the ration of TP TPFN A sample size of 12 upstaged patients will achieve 80 power to detect a difference of sensitivity 384 assuming that the sensitivity under the null hypothesis is 49 results of the meta-analysis by Leong et al 2018 22 and that the actual sensitivity is 88 956 in the study by Guarize et al 2018 25 using a two-sided binomial test
N Upstaging EBUS Upstaging Surgery Sensitivity Leong 2017 Meta-analysis 15 6- 24 na 49 Naur 2017 167 6 10167 1012115 43 1021 Ong 2015 220 8 18220 2727100 367 Shingyoji 2014 113 6 7113 176 20113 35 720 Vial 2018 75 8 675 20 1575 40 615
Assuming that the proportion of patients with pathological pN upstaging is 24 a total sample of 50 patients will be necessary to be enrolled in the study
This hypothesis will be rejected if 2 or more FN are observed among the 12 upstaged patients
ETHICAL CONSIDERATIONS
Patient protection The responsible investigator will ensure that this study is conducted in agreement with the Declaration of Helsinki
The protocol will be approved by the Local Ethics Committee
Subject identification A sequential identification number will be automatically attributed to each subjectpatient registered in the trial This number will identify the subjectpatient and must be included on all case report forms
Informed consent The investigator must provide to each subjectpatient both oral and written information about the Trial and must ensure that the subject is fully informed about the aims of the trial procedures potential risks any discomforts and expected benefits
The subjectpatient must agree that hisher data will be processed and stored in an anonymous form for evaluation of this trial and any later overviews and that his her data may also be transferred in an anonymous form to third parties
It must be emphasized that participation is voluntary and that the subject has the right to withdraw from the Trial at any time without prejudice
A physician must obtain the subjects voluntary personally signed and dated Informed Consent prior to any Trial - related procedure
DATA SUBMISSION We will conduct the trial according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICH Good Clinical Practice GCP guidelines
Case report forms Data will be collected as for trial specific case report forms
Signing and submitting forms All forms should be signed by the Principal Investigator or designee
Data management Data collected in this trial will be sent to the Data Management Office of the European Institute of Oncology The Data Management Center will process the data and will generate queries and forms requests The statistician will perform the data analysis
Authorization log The Principal Investigator PI should identify the other members of the Clinical Trial Team who are supervised by the PI and approved to provide information in case report form CRF queries etc
SubjectPatient identification log As per GCP subjectspatients have the right to confidentiality Therefore no subjectpatients names should be used in CRFs or any other documentation transmitted to the data management Item that are used to identify a subjectpatient include initials of subjectspatients name date of birth registration number
ADMINISTRATION RESPONSABILITIES The Chairmen of the study will be responsible for writing the protocol reviewing all case report forms and documenting their review on evaluation forms the contents of the reports and for publishing the study results They will also generally be responsible for answering all clinical questions concerning eligibility treatment and the evaluation of the subjectspatients
PROPERTY OF DATA AND PUBLICATION POLICY Property of data is of European Institute of Oncology The main results of the clinical trial will be published in a peer-reviewed scientific journal The final publication will be written by the Study Chairman or by one or more co-investigators of the study
All publications abstracts or presentations including data related to the present trial will be submitted for review to the Chair of the study prior to submission
Trials results will not be released before data maturity has been reached for the primary endpoint of the trial
According to the new TNM classification 8th edition the overall 5-year survival rate for pathological stage IA NSCLC was 85 ranging from 80 to 90 for T1a and T1c tumors respectively compared with 64 for stage IB tumors 2 Among patients with stage I cancer tumor size may affect outcome and drive survival as confirmed by different studies 7-12
Several studies demonstrated that primary invasive non- small-cell lung carcinomas 20 cm were twice as likely to have nodal metastases as carcinomas 20 cm emphasizing that small lung cancers had less lymph node involvement and confirming a better survival 11-15 Based on that Ishida et al and then Konaka et al have already demonstrated the absence of lymph node involvement in sub-centimeter lung cancers and the feasibility to omit lymph node dissection in those cases 1516 However Zhoua et al recommended systematic nodal dissection in the presence of sub-centimeter disease finding nodal metastases in 15 of NSCLC 1 cm but also including higher tumor stages such as stage II and III in their study without performing PET scan as part of the preoperative staging 17 In our pilot study 18 published in 2011 in the European Journal of Thoracic Surgery no nodal involvement was observed in any of the 62 patients with pulmonary nodule size less than 10 mm in 20 out of 120 patients 17 with nodule size 11-20 mm and in 9 out of 37 tumors 24 21-30 mm in size p 00007 All 55 patients with nodule SUV 20 and all 26 non-solid lesions were pN0 respectively p 00001 and p 003 So we adopted cut-offs of 10 mm for nodule diameter and 20 as peak SUV to distinguish patients with nodal involvement from those without
These patients could be spared radical lymph node dissection if deemed not essential thereby reducing operative risks postoperative morbidity and surgery time A preoperative diagnostic determination to establish the size and correct staging of the tumor is mandatory for appropriate selection of candidates avoiding unnecessary surgery
Data have demonstrated that positron emission tomography PET-FDG is a reliable tool versus CT in evaluating both solitary pulmonary nodules and lymph node involvement 3 Standard nodal staging is initially performed non-invasively with PET followed by minimally invasive staging with endobronchial ultrasound-guided transbronchial needle aspiration EBUS-TBNA when PET is suggestive of mediastinal nodal involvement In fact EBUS-TBNA is a minimally invasive procedure with a high yield for lymph node staging of lung cancer 4 EBUS-TBNA allows access to the paratracheal lymph node stations levels 2R 2L 4R 4L the subcarinal lymph node level 7 hilar interlobar and lobar lymph nodes levels 10 11 and 12 Previous studies including systematic reviews and meta-analyses and more recently Yasufuku et al have demonstrated a major impact of EBUS-TBNA on management of patients with non-small cell lung cancer NSCLC with a diagnostic yield comparable to mediastinoscopy 56 Annema et al have recently confirmed that the sensitivity of endosonography is similar to that of mediastinoscopy 85 vs 79 respectively and associated with a lower complication rate 1 vs 6 for mediastinoscopy so concluding that endosonography should be the first step for mediastinal nodal staging 19
In patients without evidence of mediastinal nodal metastasis on PET and CT the need for EBUS-TBNA becomes less clear The most recent American College of Chest Physicians ACCP evidence-based guidelines recommend minimally invasive mediastinal staging with a needle technique in patients with a central tumor or nodal hilar disease N1 on PETCT This is based on the increased prevalence of N2 disease in this group but this is a grade 1C recommendation that is based on low quality evidence In patients with peripheral tumors and no evidence of mediastinal or hilar nodal disease on PETCT invasive staging is not recommended
Concerns have been raised regarding these recommendations given that the prevalence of occult nodal metastasis in patients with N0 disease by PETCT appears to be higher than previously reported with recent studies showing values as high as 17-22 2021 EBUS-TBNA may provide an attractive option to increase staging accuracy However sensitivity of EBUS-TBNA in patients with clinical N0N1 disease on PETCT is unclear and largely based on retrospective studies 2223 The only prospective study published by Leong et al 24 demonstrated that a significant proportion of patients with N0N1 disease by PETCT had N2 disease 20 and EBUS-TBNA was able to identify a substantial fraction of these patients thus improving diagnostic accuracy compared with PETCT alone Sensitivity of EBUS-TBNA however appears lower compared with historical data from patients with larger volume mediastinal disease 5626
TRIAL OBJECTIVES
Hypotheses
In selected series the overall sensitivity of EBUS varies from 80-90 88 but for clinical N0N1 drops to 40-49
About 24 of patients with early stage lung cancer 2 cm and less than 5 cm T1bc and T2ab N0 PET- would be N whereas none of the T1a less or equal than 1 cm NSCLC would be upstaged considering the absence of N 19
From reference 19 pT size ALL pN 10 mm 62 0 0 11-20 mm 120 20 17 20 mm 37 9 24
7 OVERALL DESIGN AND PLAN OF TRIAL
71 Design of the study All patients clinical stage I and II will be undergone EBUS-TBNA for the staging of hilar and mediastinal lymph nodes
All patients will be undergoing robotic RATS or videothoracoscopic VATS lobectomy plus radical lymph node dissection following the Society of Thoracic Surgery STS guideline All lymph nodes previously sampled with EBUS-TBNA will be compared with those harvested during surgery
Statistical analysis Observed Surgery pN- pN Predicted EBUS Negative TN FN UPSTAGING FNTPtotal patients Positive FP TP SENSITIVITY is defined as the ration of TP TPFN A sample size of 12 upstaged patients will achieve 80 power to detect a difference of sensitivity 384 assuming that the sensitivity under the null hypothesis is 49 results of the meta-analysis by Leong et al 2018 22 and that the actual sensitivity is 88 956 in the study by Guarize et al 2018 25 using a two-sided binomial test
N Upstaging EBUS Upstaging Surgery Sensitivity Leong 2017 Meta-analysis 15 6- 24 na 49 Naur 2017 167 6 10167 1012115 43 1021 Ong 2015 220 8 18220 2727100 367 Shingyoji 2014 113 6 7113 176 20113 35 720 Vial 2018 75 8 675 20 1575 40 615
Assuming that the proportion of patients with pathological pN upstaging is 24 a total sample of 50 patients will be necessary to be enrolled in the study
This hypothesis will be rejected if 2 or more FN are observed among the 12 upstaged patients
ETHICAL CONSIDERATIONS
Patient protection The responsible investigator will ensure that this study is conducted in agreement with the Declaration of Helsinki
The protocol will be approved by the Local Ethics Committee
Subject identification A sequential identification number will be automatically attributed to each subjectpatient registered in the trial This number will identify the subjectpatient and must be included on all case report forms
Informed consent The investigator must provide to each subjectpatient both oral and written information about the Trial and must ensure that the subject is fully informed about the aims of the trial procedures potential risks any discomforts and expected benefits
The subjectpatient must agree that hisher data will be processed and stored in an anonymous form for evaluation of this trial and any later overviews and that his her data may also be transferred in an anonymous form to third parties
It must be emphasized that participation is voluntary and that the subject has the right to withdraw from the Trial at any time without prejudice
A physician must obtain the subjects voluntary personally signed and dated Informed Consent prior to any Trial - related procedure
DATA SUBMISSION We will conduct the trial according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICH Good Clinical Practice GCP guidelines
Case report forms Data will be collected as for trial specific case report forms
Signing and submitting forms All forms should be signed by the Principal Investigator or designee
Data management Data collected in this trial will be sent to the Data Management Office of the European Institute of Oncology The Data Management Center will process the data and will generate queries and forms requests The statistician will perform the data analysis
Authorization log The Principal Investigator PI should identify the other members of the Clinical Trial Team who are supervised by the PI and approved to provide information in case report form CRF queries etc
SubjectPatient identification log As per GCP subjectspatients have the right to confidentiality Therefore no subjectpatients names should be used in CRFs or any other documentation transmitted to the data management Item that are used to identify a subjectpatient include initials of subjectspatients name date of birth registration number
ADMINISTRATION RESPONSABILITIES The Chairmen of the study will be responsible for writing the protocol reviewing all case report forms and documenting their review on evaluation forms the contents of the reports and for publishing the study results They will also generally be responsible for answering all clinical questions concerning eligibility treatment and the evaluation of the subjectspatients
PROPERTY OF DATA AND PUBLICATION POLICY Property of data is of European Institute of Oncology The main results of the clinical trial will be published in a peer-reviewed scientific journal The final publication will be written by the Study Chairman or by one or more co-investigators of the study
All publications abstracts or presentations including data related to the present trial will be submitted for review to the Chair of the study prior to submission
Trials results will not be released before data maturity has been reached for the primary endpoint of the trial
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None