Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

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Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

In patients allocated to this arm a CT guided core biopsy will be performed

If the patient is randomised to this arm, the lesion will be located via R-EBUS.

Each patient will have 3 cryo biopsies and 3 forceps biopsies. The order of the cryo biopsy and forcep biopsy will be randomly allocated at the time of initial randomisation.

CT guided biopsy will be performed by a trained interventional radiologist using core biopsy.

CT guided core biopsy

Cryo-biopsy will be performed via R-EBUS guidance. Cryo biopsy probe will be applied for 4 seconds for each biopsy and a minimum of 3 biopsies will be performed . Each patient will also have 3 forceps biopsies. The order of forceps biopsy or cryo biopsy will be randomly allocated.

Cryo-biopsy via Radial EBUS navigation

Samantha Herath, MBBS, MPhil, FRACP

Andrew Veale, FRACP

Samantha Herath, MBBS, FRACP

Obtaining a tissue sample to diagnose a PPL suspected of cancerous origin is of utmost importance. The current gold standard; Transthoracic CT guided needle biopsy approach with a success rate of \>90% comes at the expense of an increased side effect profile.

Given that most lung cancers originate in the bronchus, hence named "bronchogenic carcinoma", it would be rational to think that endobronchial route should provide the best route of sampling with the least amount of side effects. Radial EBUS has become popular during the last decade as an endobronchial modality in diagnosing PPL with minimal side effects. However, the yield is still not satisfactory in comparison to CT guided biopsy with only 73% success rate in a meta-analysis. There is also with wide variation in different centres.

Use of a new biopsy method called cryo-biopsy using the R-EBUS guide sheath may bridge the gap and increase the diagnostic yield of PPL.

Cryo biopsy had been proven to give larger sample sizes and reduced crush artefact compared to the conventional radial EBUS biopsies.

However, there have been no head to head trials comparing Cryo-probe biopsy vs. the gold standard: CT guided biopsy.

Cryo-biopsy has very favourable side effect profile without any pneumothorax occurrence. If the yield were to be non-inferior to CT guided biopsy this would certainly be the preferred choice of biopsy for PPL in the future.

Methodology All patients with a PPL requiring a diagnostic biopsy will be eligible for recruitment to the trial. The recruited patients will be randomly allocated to either CT guided core biopsy or radial EBUS guided cryobiopsy.

Study design Multi centre intervetional,randomised control trial.

Study population:

Patients diagnosed with a PPL that requires a biopsy.

If the patient is randomised to the cryo biopsy arm:

The procedure will be done under the usual guidelines and practice of the centre as for a flexible bronchoscopy procedure.

Once flexible bronchoscopy is introduced the pre-determined desired segment, the R-EBUS is inserted covered by the GS.

Once the R EBUS locates the lesion, the GS is left in situ and the USS probe is retracted.

The cryoprobe is then inserted through the GS to the desired location. Flexible Cryoprobe (outer diameter 1.9mm) will be applied for 4 seconds for each biopsy. The cryogen gas used will be Co2.

The probe will be retracted together with the GS and the bronchoscope en masse after each biopsy. A minimum of 1 and maximum of 3 samples will be taken.

A CXR is taken within 1 hour post procedure to access for pneumothorax. Adverse events during the procedure will be recorded. If a chest tube placement, other investigations due to side effects or overnight hospital stay were to be required; all costs will be calculated retrospectively. Minor bleeding will not be considered an additional cost as this occurs with routine bronchoscopy.

If the patient is randomised to the CT biopsy arm:

A CT guided core biopsy will be performed as per usual practice of that centre. 2-6 passes will be performed for each PPL.

A CXR 1hour post procedure will be performed to assess for pneumothorax or procedure related bleeding.

If a chest tube placement, other investigations due to side effects or overnight hospital stay were to be required all costs will be calculated retrospectively.

At the pathology:

All samples will be assessed for the size of the sample and the suitability for molecular testing. An independent pathologist will assess samples.

Economic analysis:

For both procedures: Both direct and indirect costs will be calculated. The main aim of cost analysis is to calculate the cost of side effect management in each arm to determine the most cost-effective method of sampling a PPL.

Obtaining a tissue sample to diagnose PPL suspected of cancerous origin is of utmost importance. Sampling of PPL can be done either through the chest wall (transthoracic) or through the airways that lead to the PPL (endobronchial).

The current gold slandered is Transthoracic Needle Aspiration (TTNA) approach is done by using CT guided biopsy with a success rate of \>90%. However, this success in diagnostic yield comes at the expense of increased side effect profile including a very high risk of pneumothorax (up to 30%). Half of these patients require chest drain insertion.

Given that most lung cancers originate in the bronchus, hence named "bronchogenic carcinoma", it would be rational to think that endobronchial route should provide the best way of sampling with least amount of side effects. However, the yield is still not satisfactory and has a wide confidence interval.

When diagnosing a PPL endobronchially, accurate visualisation of the lesion is the main issue. To overcome this issue various navigation methods have been used to accurately locate the PPL to improve the diagnostic yield.

The use of Radial Endo Bronchial USS (R-EBUS) is one such navigational modality. The conventional R-EBUS guided biopsies are carried out using cytology brushes and forceps biopsy. These methods had been extremely safe with \<1% pneumothorax rate however, the diagnostic yield in a meta-analysis of 14 studies is only 73%.

Use of a new biopsy method called cryo-biopsy may bridge the gap and increase the diagnostic yield of PPL.

Cryotherapy is the use of a compressed gas released at a high flow that rapidly expands and creates very low temperatures up to -89C. These very low temperatures then cause tissue to get stuck to the end of the cryo-probe. Due to the rapid cooling the microvasculature around the biopsy site go into vasospasm and reduces bleeding despite a large biopsy sample being acquired.

Cryotherapy has been used in the airway since 1968. The ability to use this method while the patient is using high flow oxygen as well as being a cheap equipment to use makes it very affordable and useful equipment in any interventional bronchoscopy unit. Most bronchoscopists will be trained and familiar with cryo biopsy technique.

The cryo-biopsies were compared against forceps biopsies in this study and demonstrated larger sample size and less crush artefact favouring cryo- biopsy use.

The most encouraging results published recently was looking at cryo-biopsy for PPL using R-EBUS guidance, which demonstrated a yield of 74% and the ability to obtain 3 times larger tissue biopsies when compared to traditional forceps biopsies. There were no pneumothorax in this cohort and only minor bleeding was recorded requiring bronchoscopy suction alone and no other intervention recorded.

However, there had been no head to head trials comparing Cryo-probe vs. the gold standard: CT-guided biopsy.

As cryo-biopsy has very favourable side effect profile without any pneumothorax occurrence if the yield were to be non-inferior this would certainly be the preferred choice of biopsy for PPL in the future.

With regards to cost analysis it has been shown that R-EBUS guided biopsy Vs. CT guided biopsy has similar cost profiles for the procedure alone. However the final cost of the procedure depends on the side effects experienced using each procedure, making CT guided biopsy the costlier of the 2 methods.

However, cryo-biopsy and CT guided biopsy had not been compared in an economic analysis before.

Methodology All patients with a PPL requiring a diagnosis will be eligible for the trial.

Prior to the procedure: (Either CT guided biopsy or cryo biopsy)

1. The size of the lesion will be recorded (volume assessment and maximum diameter on the axial scan) from the CT scan prior to procedure. .

If the patient is randomised to the cryo biopsy arm:

1. The bronchoscopist will plan the pathway to the PPL based on the CT scans. The sub segments from which the lesions could be biopsied will be pre-determined and documented. If available, virtual bronchoscopy will be used to confirm this navigational path to the lesion.
2. Maximum time allowed to locate the lesion via R-EBUS would be 20 mins.
3. The procedure will be done under the usual guidelines and practice of the centre as for a flexible bronchoscopy procedure. As this is a multi-centre trial centre variation on the usual practice of bronchoscopy may vary.
4. Some centres may use fluoroscopy, in addition, to localise the lesion. This is also acceptable in the protocol.
5. If an endobronchial lesion is found then the patient is excluded.
6. Once flexible bronchoscopy is introduced the pre-determined desired segment, the R-EBUS is inserted covered by the GS.
7. Once the R EBUS locates the lesion, the GS is left in situ and the USS probe is retracted.
8. The cryo probe is then inserted through the GS to the desired location. Flexible Cryo probe (outer diameter 1.9 mm) will be applied for 4 seconds for each biopsy.
9. The probe will be retracted together with the GS and the bronchoscope en masse after each biopsy.
10. A minimum of 1 and maximum of 3 samples will be taken.
11. A CXR is taken within 1-hour post procedure to access for pneumothorax.
12. Adverse events during the procedure will be recorded as: Minor bleeding (requiring cold saline or adrenalin), moderate bleeding (requiring a bronchial blocker or APC) and a large bleed (requiring blood transfusion, FFP, cardiothoracic support) etc.
13. If a chest tube placement, other investigations due to side effects or overnight hospital stay were to be required all costs will be calculated retrospectively. Minor bleeding will not be considered an additional cost as this occurs with routine bronchoscopy.

If the patient is randomised to the CT biopsy arm:

1. The interventional radiologist will decide on the best position for the patient to stay during the procedure.
2. A core biopsy will be performed as per usual practice of that centre. In CMDHB all CT guided biopsies are performed as core biopsies.
3. The patient will have 2-6 biopsies from the PPL.
4. Patient lies on the side of the biopsy for 1 hour post procedure. Post procedure monitoring will be performed as per usual practice.
5. A CXR 1 hour post procedure will be performed to assess for pneumothorax or procedure related bleeding.
6. If a chest tube placement, other investigations due to side effects or overnight hospital stay were to be required all costs will be calculated retrospectively.

At the pathology:

All samples will be assessed for area of specimen to assess the size. The ability to perform molecular typing will be documented.

An independent pathologist will assess samples

Economic analysis:

For both procedures: Both direct costs (From the hospital records) and indirect cost (by administering a patient questionnaire) will be recorded.

The main aim of cost analysis is to calculate the cost of side effect management in each arm to determine the most cost effective method of sampling a PPL.

Comparing Diagnostic Yield Between R-EBUS Guided Cryo Biopsy Vs. CT Guided Biopsy for PPL

Randomised Controlled Trial Comparing the Diagnostic Yield of Radial Endo-Bronchial Ultra-Sound (R-EBUS) Guided Cryo-biopsy Vs. CT-guided Transthoracic Biopsy in Patients With Parenchymal Lung Lesion, Suspected of Lung Cancer (CT-CROP)

This outcome measures the efficacy of CT guided biopsy (The current Gold standard) against the new biopsy method called cryo-biopsy which has better safety profile from previous pilot studies.

The CT guided biopsy has good efficacy rates but a high risk of pneumothorax (up to 30%) and pulmonary haemorrhage (4-27%), which requires further management adding to the cost of the intervention. The cryobiopsy method had been proven in pilot studies to have a better safety profile with \<1% pneumothorax risk. Hence comparing the side effect profile and if cryo biopsy is far safer alternative would make this the first option for the patient.

Cryo biopsy gives a larger sample size and hypothesized to give a better molecular analysis for EGFR mutation and ALK mutation analysis

Middlemore Hospital, New Zealand

Respiratory Physician, Intervetional bronchoscopist

Multiple Pulmonary Nodules

blood sample (2 tubes of 7.5 mL of blood = 15 mL) during the preoperative check-up on the day of the ultrasound-bronchoscopy in order to compare the sensitivity of the analysis of free circulating DNA present in the supernatant of pulmonary nodules less than 20 mm samples taken under ultrasound-bronchoscopy to that present in the plasma

Patients will be taken from an additional blood sample (2 tubes of 7.5 mL of blood = 15 mL) during the preoperative check-up on the day of the ultrasound-bronchoscopy in order to compare the sensitivity of the analysis of free circulating DNA present in the supernatant of pulmonary nodules less than 20 mm samples taken under ultrasound-bronchoscopy to that present in the plasma.

Blood samples

Valentin HELUAIN, MD

Sandra BERNARD, PM

Valentin HELUAIN

Lung cancer screening is based on low dose CT scan (LDCT), a highly sensitive but poorly specific tool.

Complementary specific approaches are thus strongly needed, among which cell-free DNA (cfDNA) genotyping has been proven highly specific but of low sensitivity (25 to 50% for stage I diseases) due to inconstant tumor shed. Tumor biopsy is thus often required and radial endobronchial ultrasound (rEBUS) bronchoscopy is a minimally invasive approach (\<3% complications) but of limited sensitivity in cases of nodules \< 20 mm.

The investigators hypothesized that methylation analysis on cfDNA floating in supernatant derived from rEBUS specimens could improve rEBUS sensitivity

Tumor biopsy is often required to characterize indeterminate nodules. Radial endobronchial ultrasound (rEBUS) bronchoscopy is often used due to a low rate of complications but its sensitivity is limited for small nodules.

The investigators hypothesized that methylation analysis on cfDNA floating in supernatant derived from rEBUS specimens could improve rEBUS sensitivity.

The primary outcome of this pilot, diagnostic validation, monocentric study is the sensitivity of targeted (9 genes panel) methylation analysis on supernatant cfDNA to detect a malignant nodule.

Secondary outcomes include the comparison of supernatant to pathology and plasma cfDNA methylation analysis.

Specificity, negative predictive value (NPV), positive predictive value (PPV) of targeted (9 genes panel) methylation analysis on supernatant cfDNA to detect a malignant nodule will be analyzed.

60 patients planned for a rEBUS bronchoscopy for one, two or three \< 20 mm nodule, without mediastinal or extra thoracic lesions (cT1N0M0) will be included.

The day of the rEBUS bronchoscopy, 2 7.5 mL blood samples are collected. rEBUS samples' supernatant, usually discarded, is saved.

Cell free DNA is extracted from these biological specimens at the Laboratory of Oncological Medical Biology (LBMO) in Toulouse University Cancer Institute and tested for methylation (targeted analysis on 9 genes).

The patients will be followed for one year to obtain a final diagnosis and correlate it with tissue, nodule supernatant and plasma methylation analyses.

Molecular Analysis of Endoscopic Cytology Samples Supernatant in Pulmonary Nodules

Molecular Analysis of Endoscopic Cytology Samples Supernatant in Pulmonary Nodules (Cancer Or Benign Endoscopy) (KOBE)

Promoter methylation rates of the 9 targeted genes in the free circulating DNA of the endoscopic samples supernatant is obtained by quantitative Polymerase Chain Reaction (PCR) of bisulfite-treated DNA fragments from the cytological samples supernatant after DNA concentration and separation by size at the Centre of Cancer Research of Toulouse (CRCT).

These analyses will be performed blinded to the clinical data and the histopathology result of the lung nodule.

Methylation profiles of free circulating DNA from plasma obtained after centrifugation of blood samples will be obtained by the same method as described for analysis of cytopunction's supernatant methylation profile.

These analyses will be performed blinded to the clinical data and the histopathology result of the lung nodule.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparing Diagnostic Yield Between R-EBUS Guided Cryo Biopsy Vs. CT Guided Biopsy for PPL	NCT02395939	Lung Cancer	CT guided core ... Cryo-biopsy via...	18 Years -	Middlemore Hospital, New Zealand
Comparing Diagnostic Yield Between R-EBUS Guided Cryo Biopsy Vs. CT Guided Biopsy for PPL	NCT02395939	Lung Cancer	CT guided core ... Cryo-biopsy via...	18 Years -	Middlemore Hospital, New Zealand
Molecular Analysis of Endoscopic Cytology Samples Supernatant in Pulmonary Nodules	NCT05306912	Lung Cancer Lung; Node	Blood samples	18 Years -	University Hospital, Toulouse
Comparing Diagnostic Yield Between R-EBUS Guided Cryo Biopsy Vs. CT Guided Biopsy for PPL	NCT02395939	Lung Cancer	CT guided core ... Cryo-biopsy via...	18 Years -	Middlemore Hospital, New Zealand

Spots Global Cancer Trial Database for radial ebus

Every month we try and update this database with for radial ebus cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for radial ebus

Every month we try and update this database with for radial ebus cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for radial ebus cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.