Feasibility Study on the Contribution of Guided Puncture With Echoendoscopy in Evaluation of Hypermetabolic Lymphadenopathy Mediastinum Lower, Rear and Middle, Detected in PET-CT to 18 FDG (PET)
Phase: NA
Conditions: Hypermetabolic Lymphadenopathy Mediastinum Lower, Posterior and Middle, Detected by PET-CT With 18F-FDG (PET)
Sponsor: Institut Bergonié

 
 
 
FEASIBILITY STUDY OF ENDOSCOPIC ULTRASOUND-GUIDED 
FINE-NEEDLE ASPIRATION (EUS-FNA) FOR THE ASSESSMENT 
OF HYPERMETABOLIC LYMPHADENOPATHIES IN THE LOWER, 
POSTERIOR AND MIDDLE MEDIASTINUM, DETECTED BY 
18FDG PET-CT  
 
APOGEE STUDY SUMMARY 
(Apport de la POnction Guidée sous ÉchoEndoscopie – Contribution of Endoscopic Ultrasound Guided 
Aspiration) 
 
Translation of version n°4 of 11/07/2016 
Including the substantial modification n°1 of 12/10/2012 
Including the substantial modification n°2 of 13/06/2013 
Including the substantial modification n°3 of 04/08/2014 
Including the substantial modification n°4 of 11/07/2016 
 
N° IDRCB: 2012-A00985-38 – n° IB: 2012-01 
NCT01892501 
 
Coordinator 
Prof Dominique BÉCHADE 
Department of Medical Oncology 
Medical Oncologist 
Institut Bergonié 
 
229, cours de l’Argonne – 33076 BORDEAUX Cedex 
 
Tel: 05.56.33.78.71 – Fax: 05.56.33.33.83 – Email: d.bechade@bordeaux.unicancer.fr 
 
Co-Coordinator 
Dr Anne-Laure CAZEAU 
Department of Nuclear Medicine 
Nuclear Medicine Specialist 
Institut Bergonié 
 
229, cours de l’Argonne – 33076 BORDEAUX Cedex 
 
Tel: 05.56.33.33.33 – Fax: 05.56.33.33.84 – Email: a.cazeau@bordeaux.unicancer.fr 
 
 
Clinical and Epidemiological Research Unit 
Prof Simone MATHOULIN-PELISSIER  
Institut Bergonié, Bordeaux 
Director 
 
Dr Stéphanie HOPPE 
Institut Bergonié, Bordeaux 
Epidemiologist 
 
Carine BELLERA 
Institut Bergonié, Bordeaux 
Biostatistician 
 
Caroline LALET 
Institut Bergonié, Bordeaux 
Clinical Research Assistant 
 
Clinical Trials Unit 
Barbara LORTAL 
Emilie TOULZA 
Institut Bergonié, Bordeaux 
Pharmacists 
 
Pathology Department  
Dr Isabelle SOUBEYRAN  
Institut Bergonié, Bordeaux 
Pathologist 
 
PROMOTOR 
INSTITUT BERGONIE 

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SUMMARY 
 
Study title 
Feasibility 
study 
of 
endoscopic 
ultrasound-guided 
fine-needle 
aspiration 
(EUS-FNA) 
for 
the 
assessment 
of 
hypermetabolic 
lymphadenopathies in the lower, posterior and middle mediastinum, 
detected by 18FDG PET-CT  
Promotor 
Institut Bergonié 
Coordinator 
Prof Dominique BÉCHADE 
Institut Bergonié 
Indication 
Mediastinal lymphadenopathies 
Methodology 
Single center study 
Number of patients 50 patients  
Study duration 
End of inclusions: 31/12/2017 
Follow-up duration: 1 year 
Study duration: 6 years 
Beginning of the study: 2nd semester 2012 
Objectives 
/ 
Endpoints 
Primary objective: 
To assess the performance in terms of sensitivity of EUS-FNA for the 
characterization of mediastinal lymphadenopathies, hypermetabolic on PET, for 
new cancers or relapse. 
 
Secondary objectives: 
• 
Evaluate 
the 
negative 
predictive 
value 
of 
EUS-FNA 
for 
the 
characterization of mediastinal lymphadenopathies, hypermetabolic on 
PET, for new cancers or relapse. 
• 
Evaluate the impact of the combination of the two techniques on 
diagnostic and therapeutic management. This will be evaluated by: 
- 
the percentage of more invasive diagnostic procedures avoided 
(e.g. surgeries: mediastinoscopy, thoracoscopy) 
- 
the possible modification of the therapeutic strategy after 
endoscopic puncture, compared to the strategy that would have 
been envisaged after PET alone. 
• 
Evaluate the diagnostic performance of this method according to the 
stage of treatment (diagnosis, evaluation of the therapeutic response or 
suspicion of relapse), thoracic or extra-thoracic location and the 
pathological type of the tumor. 
• 
Compare tumor characteristics described on PET (size and intensity of 
lymphadenopathy fixation) in patients with a confirmed diagnosis of 
cancer and those with a diagnosis of benign pathology (using as 
reference EUS-FNA when it is positive and the follow-up at 1 year when it 
is negative), to define more efficient criteria for PET interpretation. 
Inclusion criteria 
1. Patients 
with 
a 
PET 
showing 
one 
or 
more 
hypermetabolic 
lymphadenopathies in the middle and/or lower and/or posterior 
mediastinum and requiring diagnostic certainty for therapeutic strategy 
decisions.  
2. PET scan performed for the following indications: 
• 
Pre-therapeutic assessment of thoracic or extra-thoracic neoplasms 
(patients without a history of cancer). 
• 
Evaluation of the response to cancer treatment. 
• 
Suspicion of relapse in patients with a personal history of thoracic or 
extra-thoracic neoplasms. 
3. PET with a positive result: 
• 
For lymphadenopathies with a small axis > 1cm: result greater than 
or equal to the hepatic background. 
• 
For lymphadenopathies with a small axis < 1cm: result strictly 
greater than the hepatic background noise. 
4. Patient with an indication for a surgical diagnostic procedure (whether it 
is feasible or not). 

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5. Lymphadenopathy(s) accessible to EUS-FNA via the esophagus, that is, 
allowing a technically feasible aspiration procedure from the esophagus 
(without recusing vascular structures). 
6. Age ≥ 18 years old. 
7. PET scan performed 6 weeks before endoscopy. 
8. Platelets ≥ 70,000 / mm3; TP ≥ 60%. 
9. Patient of childbearing age with negative pregnancy test and / or 
contraception. 
10. Signed informed consent. 
11. Patient affiliated to a social security scheme. 
 
Non-inclusion 
criteria 
1. General contraindication(s) to performing endoscopy. 
2. Unfavorable anesthetic assessment (precluding general anesthesia). 
3. Esophageal stenosis. 
4. Coagulation disorders. 
5. Pregnant or breastfeeding woman. 
6. Inability to undergo medical monitoring of the trial for geographic, social 
or psychological reasons. 
7. Adult patient under a legal protection measure or unable to express 
consent. 
Study procedure 
When a patient has a PET scan showing one or more hypermetabolic 
lymphadenopathies in the lower, middle or posterior mediastinum, his/her file is 
presented to a multidisciplinary consultation meeting MTM#1, to define the 
diagnostic strategy: strategy chosen to perform a surgical biopsy to obtain 
histological documentation of the mediastinal lymphadenopathy with obvious 
impact on the therapeutic choices. 
The patient is eligible to participate in the study if the indication for 
mediastinoscopy is made. 
The patient is then informed of the study and signs the informed consent if s/he 
agrees to participate. 
We differentiate 2 groups of patients depending on the feasibility of the surgical 
procedure: 
Group A: surgical biopsy is possible 
Group B: surgical biopsy cannot be performed (medical or anesthetic 
contraindications): at that time, definition of the therapeutic strategy that would 
have been decided in the absence of histological documentation: 
• Surgery from the outset 
• Chemotherapy or other cancer treatment 
• Non-cancer treatment / patient management for suspected benign pathology 
• No treatment. 
The EUS-FNA via the esophagus is then performed for the 2 groups of patients 
(within a maximum of 6 weeks after the PET scan), under general anesthesia and 
endoscopic control, with a disposable 19-gauge needle (EchoTip, Cook 
Endoscopy ) and with 3 needle passages per node. 
Pathology samples are taken: 3 tubes taken per lymph node (1 tube per needle 
passage), in most cases, only 1 lymph node will be taken: 
• 2 tubes for oncology analysis 
• 1 frozen tube for microbiological analysis (mainly tuberculosis) in the event of a 
negative oncology analysis and if there is evidence of a pathology 
The slides are then read by 2 different pathologists: routine reading by a 
pathologist from the Institut Bergonié then confirmatory reading by Dr I 
Soubeyran. 
Depending on the pathological results (5 to 6 days delay), the therapeutic 

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strategy for the mediastinal lymph nodes is defined during a second MTM 
(MTM#2), making it possible to assess the impact of carrying out the EUS-FNA: 
• Surgery from the outset 
• Chemotherapy or other cancer treatment 
• Non-cancer treatment / patient management for suspected benign pathology 
• No treatment 
• Choice of another surgical diagnostic procedure (non-contributive result) 
Patients will be followed up for 12 months. Clinical and radiological data obtained 
during standard patient management will be collected. 
For patients who have had a negative biopsy, follow-up will consist of performing 
a thoraco-abdomino-pelvic scan  at 6 and 12 months. 
 Study design 
 
 
 
        
Evaluation criteria 
The primary endpoint is the performance of EUS-FNA after detection of 
lymphadenopathy by PET (index test). The performance will be evaluated by 
sensitivity. In the majority of cases, only one lymphadenopathy will be removed 
and diagnostic accuracy will be estimated per patient and not per lesion. 
• The reference technique (Gold standard) is follow-up for 12 months. In 
particular, we consider that there are: 
Diagnosis of malignancy: 
• 
if the management and the clinical and radiological follow-up 
established following EUS-FNA indicate the presence of a neoplastic 

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pathology, or 
• 
if the thoraco-abdomino-pelvic scans carried out at 6 and 12 months 
after the EUS-FNA indicate the presence of progressive neoplastic 
pathology. In case of doubt and if the doctor taking care of the 
patient deems it necessary, additional examinations may be carried 
out to confirm this diagnosis. 
Absence of malignancy: if the thoraco-abdomino-pelvic scans carried out 
6 and 12 months after the EUS-FNA indicate the absence of 
progressive neoplastic pathology. In case of doubt and if the doctor 
taking care of the patient deems it necessary, additional 
examinations may be carried out to confirm this diagnosis. 
• The technique evaluated is EUS-FNA. In particular, we consider that there is: 
• 
Diagnosis of malignancy: if the histology carried out on the material 
taken by the endoscopic puncture shows a malignant tumor. 
• 
Absence of malignancy: if the histology carried out on the material 
taken by the endoscopic puncture shows a benign pathology (benign 
tumor, sarcoidosis). 
• 
Atypical, suspect or non-contributory result, diagnosis of malignancy 
/ benignity impossible. 
• The sensitivity corresponds to the rate of subjects with a diagnosis of 
malignancy (without taking into account atypical / suspect or non-contributory 
results) according to the EUS-FNA results (index test) among all the subjects 
considered to be suffering from a neoplastic pathology according to the reference 
test. 
Secondary endpoints are: 
• The negative predictive value of EUS-FNA will be evaluated. It corresponds 
to the rate of subjects with a diagnosis of benign pathology according to the 
reference test among all the subjects for whom EUS-FNA reveals a benign 
pathology (without taking into account atypical / suspect or non-contributory 
results). 
 
Impact on care will be evaluated in 2 ways based on (i) clinical utility and (ii) 
concordance between the MTM1/ MTM2 therapeutic strategies. 
 
The clinical utility of endoscopic ultrasound puncture (Groups A and B) 
• 
The puncture will be considered to have clinical utility, if it makes it 
possible to avoid more invasive diagnostic procedures (mediastinoscopy 
or thoracoscopy for patients in group A) or if it allows the patient to 
benefit from an appropriate treatment (result of the malignant biopsy) or 
to avoid receiving an unjustified treatment (result of the benign biopsy): 
case of patients well classified in malignant / benign by the EUS-FNA. 
• 
The EUS-FNA will be considered to have no clinical utility if the result of is 
invalidated by the reference examination, or if the result of the puncture 
does not allow a diagnosis to be made. 
 
Agreement between MTM1 / MTM2 therapeutic strategies 
In all patients, the agreement between the therapeutic strategies taken 
before and after the results of the EUS-FNA will be assessed. 
• 
Therapeutic strategy for the mediastinal lymph nodes described at 
inclusion envisaged in MTM 1 
o 
Surgery from the outset 
o 
Chemotherapy or other cancer treatment 
o 
Non-cancer management in the event of a suspected benign 
pathology 
o 
No treatment 
• 
Therapeutic strategy for the mediastinal lymph nodes described at 
inclusion envisaged in MTM2 
o 
Surgery from the outset 
o 
Chemotherapy or other cancer treatment 
o 
Non-cancer management in case of benign pathology 
o 
Other surgical diagnostic procedure 

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o 
No treatment 
• 
Agreement between the 2 strategies considered: for any discrepancy 
between the 2 strategies considered before the endoscopic puncture and 
after, the puncture will be considered to have had an impact on the 
treatment. 
• 
Side effects 
In all cases, the side effects associated with performing the EUS-FNA will be 
collected and classified according to the Clavien-Dindo classification of surgical 
complications [Clavien P et al. Ann Surg 2009; 250: 187-96]. 
Number 
of 
inclusions 
necessary 
This project is an exploratory pilot study, the main objective of which is to 
evaluate the performance of EUS-FNA via the esophagus, carried out after a PET 
scan showing hypermetabolic lymphadenopathy. Again, the main judgment 
criterion is sensitivity. 
Due to the small amount of data available in the literature concerning the 
sensitivity and specificity of this examination, we did not calculate a number of 
patients necessary, but determined the number of patients taking into account 
the feasibility and recruitment criteria possible at Institut Bergonié as well as 
acceptable precision of the estimations. 
For 50 patients, we estimated that the precision of the sensitivity and specificity 
estimate would be 12% for an expected sensitivity of 95% (95% confidence 
interval: [89%; 100%]) [Kalade AV et al. Intern Med J. 2008 - sensitivity and 
specificity of EUS-FNA coupled with PET Scan, but for histology data, whereas in 
our project we will have cytology data]. 
Statistical analysis  
Patient characteristics at inclusion 
The patients included will be described according to the following 
characteristics: 
• 
Compliance with eligibility criteria 
• 
Epidemiological characteristics 
The diagnosed mediastinal lymphadenopathy will be described: 
• 
On PET scan: injected dose, fixation time, location, size of the 
minor axis (mm), fixation grade (0 to 4), SUV max mediastinal 
vascular background, SUV max hepatic background, SUV max 
lymph nodes, SUV max tumor, N / T ratio, N / Liver ratio. 
• 
Endoscopic ultrasound: number of lymph nodes, location, shape, 
size, echogenicity, characteristics of the boundaries. 
• 
Quality of samples obtained by EUS-FNA. 
• 
Pathological characteristics: malignant tumor, benign tumor or 
sarcoidosis, atypical or suspect, non-contributory. 
Definitions of the study populations 
• 
Eligible population 
• 
All patients meeting the eligibility criteria. Patient eligibility will be 
established by the steering committee on a case-by-case basis. 
• 
Eligible and assessable population for the main criterion 
All the patients included in the study, for whom 1) the eligibility criteria 
are met, 2) the results of the endoscopic guided puncture are 
contributory. 
Analysis of judgment criteria 
• 
The characteristics of the patients at inclusion will be described 
from the eligible population 
• 
The main and secondary criteria will be described on the basis of 
the eligible and assessable population 
• 
Subgroup analyses, in particular by type of cancer, may be 

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considered, but only on an exploratory basis. 
• 
Quantitative variables will be described using descriptive statistics 
(range, quartile and median). 
• 
Qualitative variables will be described on the basis of the 
proportions and presented with their 95% confidence interval.