DIVision of the Interlobar Fissure in Patients Who Do Not Respond to Endobronchial Lung Volume Reduction

DIVision of the Interlobar Fissure in Patients Who Do Not Respond to Endobronchial Lung Volume Reduction

Surgical division of fissure is hypothesized to be safe and feasible. However, there is no preparatory study to test this hypothesis. It is logically expected that morbidity from the procedure could be less than standard LVRS and in preparation to a side-to-side trial of fissure division versus standard LVRS, a safety and feasibility study is required to test this hypothesis and inform future trial design.

• Rationale

Lung volume reduction surgery (LVRS) and Endobronchial lung volume reduction (EBLVR) are both established treatment options for selected patients with symptomatic emphysema. In a randomized trial EBLVR was found to be non-inferior to LVRS in efficacy but uses fewer hospital resources.

Fissure completeness is however necessary for EBLVR to work and this is initially assessed on CT imaging and quantified by a software-based analysis called StratX. If anatomical completeness is less than 80% on StratX, EBLVR cannot be pursued, whereas if fissures are more than 80% complete, further functional assessment with a bronchoscopy and a balloon test called Chartis is required. The presence of a functionally incomplete fissure is called collateral ventilation and precludes EBLVR. If collateral ventilation is absent, EBVs can then be inserted in the target lung lobe.

The intended outcome of the procedure is the achievement of target lobar atelectasis (TLA), leading to reduced hyperinflation and improvement of the dyspnea.

When TLA is not achieved, current best practice is to obtain a CT to check for signs of EBV displacement or paravalvular leak. A further post-procedure StratX is also obtained to identify which valves or airways are affected. A revisional bronchoscopy is then performed to replace/reinsert valves or exclude other causes of malfunctioning such as mucus plugs or granulation tissue formation.

A proportion of patients (up to 20%) will however not show significant TLA despite optimisation or exclusion of EBV malfunctioning at revisional bronchoscopy. When this is the case, surgery in the form of LVRS is the only available treatment for this group of patients. Morbidity from this procedure though is significantly higher, requiring much longer recovery, hospitalization and use of healthcare resources.

The absence of TLA following EBLVR is commonly explained with the appearance of delayed /occult collateral ventilation through an anatomically incomplete fissure despite a favourable initial Chartis assessment..

We hypothesize that this limitation of EBLVR can be addressed by the elimination of collateral ventilation by surgical division of the incomplete interlobar fissure.

Partially complete fissures would also logically require a reduced extent of lung resection and a reduced number of stapled lines compared to LVRS; in addition, given the presence of the already implanted EBVs in the target lobe, this may potentially result in reduced postoperative air leak from resection of fragile lung tissue, hospital stay and complications.

Furthermore, this maneuver is already part of the repertoire of thoracic surgeons as it is required in most lung resection procedures (lobectomy, segmentectomy) for lung cancer.

Fissure division with endobronchial valves in-situ will also allow for intraoperative visual confirmation of target lobe collapse at the end of the procedure with increased chances of volume reduction benefit than can be assumed from EBLVR alone. Operative time may be less or equivalent to LVRS.

In this study, recruitment will be limited to non-responders EBLVR patients. Other causes for lack of response would be excluded prior to recruitment as per routine practice (CT analysis and revisional bronchoscopy). Based on current practice, an average of 3-5 patients per year per centre would be eligible. This safety and feasibility study is therefore designed to include at least 15 treated subjects from 4 UK centres over a period of 18 months. Or 18 months from each site opening to recruitment.

Data collected will inform further larger scale studies in LVR-naïve patients with proven incomplete fissures (concomitant EBV placement and fissure division) and a randomized controlled trial of surgical fissure division + EBV, against standard LVRS.

• Intervention

Thoracoscopic (video assisted or robotic assisted) surgical division of interlobar fissure. Under GA, the patients will be positioned in lateral decubitus. Single lung ventilation. Standard thoracoscopic approach as per individual surgeon preference or practice. Fissure identified and surgical division with mechanical stapler performed.

• Potential risk and benefits

The patients will have already undergone an extensive selection process for EBLVR and an unsuccessful initial EBLVR procedure without clinical benefit.

Having already excluded at revisional bronchoscopy (pre-enrollment in the trial) any malfunctioning or malpositioning of the valves, at the conclusion of the procedure, the intended outcome (target lobar collapse) has a very high probability of being achieved and can be directly visualized and confirmed during thoracoscopy. This may lead up to a 40% improvement in lung function and exercise ability with a consequent durable improvement in quality of life. Further hospital admissions may also be reduced.

We would logically expect morbidity and hospital stay to be less than LVRS, with shorter recovery time and increased chances of achieving the intended outcome. However to demonstrate this, a side-to-side trial of fissure division against standard LVRS would be required. This present study will build the foundations and help inform the design of said trial.

In this study, as the objective is to demonstrate the safety and feasibility of the trial procedure, we want to see and expect to see that morbidity is at least in line with, or less than what expected with standard LVRS, which would be the only other option available for this group of patients.

With standard LVRS, 30-day mortality risk would be up to 3-4%. The most common expected morbidity is protracted air leak requiring drainage with a hospital stay of up to 14 days. Other risks include severe chest infection/exacerbation leading most commonly to type 2 respiratory failure, acute and chronic chest pain, cardiovascular morbidity (DVT-PE, MI, stroke, arrhythmia, heart failure) as well as all other common generic risks related to surgery/general anaesthesia. Risk of conversion to thoracotomy is negligible.

Standard perioperative care will be used.

Currently, in the eligible patient population, the alternatives will therefore be to do nothing and accept ongoing poor condition, or standard LVRS with potential for greater air leak, hospital stay and higher risk of drain-related complications i.e. pain/infection. Rather than a novel procedure, the proposed trial procedure would be an alternative, lesser procedure for patients, utilizing a surgical approach (division of anatomical fissure) that is already in the standard and essential repertoire of thoracic surgeons, being performed by each surgeon in at least 50-100 anatomical lung resection per year.

• Study Hypothesis

The study hypothesis states that it is safe to perform minimally invasive interlobar fissure division in patients who have not responded to prior EBLVR due to occult collateral ventilation. We also hypothesize that it is feasible to recruit the intended number of patients and that complete fissure division, which is the prerequisite to obtain the required target lobe collapse, can be achieved in >90% of the cases. Furthermore, this study will permit future conduct of a prospective randomized comparison of this technique with conventional LVRS.

Inclusion criteria

1. Age < or equal 75 years

2. Stable COPD with less than or equal to 10mg prednisolone daily

3. Nonsmoking for 3 months prior to screening and willing to not smoke during the study duration

4. Willing and able to complete protocol required study follow-up assessments and procedures

5. Fit for thoracoscopy under general anaesthesia (surgical and anaesthetic assessment)

6. Recent (< 18 months) endobronchial lung volume reduction (EBLVR) and lack of response defined by:

   1. Persistent symptomatic dyspnoea (mMRC >2) which in the patient's view is no better than baseline
   2. Absence of target lobar collapse with any residual aeration apparent on imaging
   3. Persistence of (6a) and (6b) following post procedure StratX CT analysis and revisional bronchoscopy.

Exclusion criteria

1. Fissure completeness <90% on pre EBLVR StratX (i.e less than 10% of fissure to be divided)
2. Chartis positive for collateral ventilation or not performed/not satisfactory at initial EBLVR
3. Quantitative perfusion of target lobe >25% of total on SPECT assessment.
4. Previous lung surgery or pleurodesis on the target side for LVR.
5. Clinically significant bronchiectasis -greater than 4 tablespoons mucus per day.
6. More than 3 COPD exacerbation episodes in the last year.
7. Evidence of hypercapnia (pCO2 >7KPa) - ABG to be performed on admission for index procedure
8. Clear evidence of pulmonary hypertension (systolic pulmonary arterial pressure >45mmHg) or evidence or right ventricular dysfunction as determined by a recent echocardiogram (<12mo)
9. Left ventricular ejection fraction (LVEF) less than 40% as determined by a recent echocardiogram (<12mo)
10. Myocardial infarction within 6 months of screening.
11. Unable to safely discontinue anticoagulants or platelet activity inhibitors for 7 days.