Clinical trial NCT02395939: Comparing Diagnostic Yield Between R-EBUS Guided Cryo Biopsy Vs. CT Guided Biopsy for PPL
Official title: 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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Lung Cancer
Keywords: Cryobiopsy
Radial EBUS
Guide Sheath
Peripheral pulmonary lesions
Lead sponsor: Middlemore Hospital, New Zealand
Sponsor class: OTHER
First posted: 2015-03-24
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* All patients aged \>18 years with a peripheral pulmonary lesion, suspected of lung cancer, requiring a biopsy
* The lesion will be included irrespective of the relationship to the bronchus or ground glass appearance.

Exclusion Criteria:

1. Patients with mediastinal adenopathy amenable to liner EBUS should have this procedure first and enrolled only if it fails to derive a diagnosis.
2. Endobronchial tumour on flexible bronchoscopy
3. Platelet count\>150
4. International Normalised Ratio \>=1.5
5. Haemoglobin\>100
6. Neutrophils \>1.0
7. Glomerular Filtration Rate\>30
8. Liver Function Test\< 2 times upper limit of normal
9. Unable to give consent/intellectually impaired

Primary outcomes:
measure: Diagnostic yield of cryo biopsy Vs. CT guided biopsy as measured by final histological diagnosis
timeFrame: 2 years
Secondary outcomes:
measure: Safety profile as measured by the rate of pneumothorax and bleeding
timeFrame: 2 years
measure: Ability to sub type and molecular type the biopsy sample over and above the conventional radial EBUS samples
timeFrame: 2 years
Other outcomes:
measure: Cost analysis between cryo biopsy and CT guided biopsy for PPL
timeFrame: 2 years
Locations:
city: Auckland,
country: New Zealand
facility: Middlemore Hospital,
Study officials:
affiliation: Middlemore Hospital, New Zealand
name: Samantha Herath, MBBS, FRACP
role: PRINCIPAL_INVESTIGATOR
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