CT-controlled advanced navigation techniques for transbronchial pulmonary lesion access; evaluation of augmented fluoroscopy bronchoscopic navigation based diagnostic yield.

Rationale: Lung cancer is one of the leading most frequent types of cancer and
is the most lethal malignancy in the Netherlands. Mortality is high due to its
advanced stage disease at diagnosis. To improve survival current guidelines are
moving towards CT-screening of the high risk population (U.S. Preventive
Services Task Force, 2014). In the American National Lung Screening Trial
(NLST), a 20% decrease mortality was found. Herein, 39.1% of the participants
of the NLST were found to have at least one peripheral pulmonary lesion (PPL)
of more than 4mm in diameter, and of those, 72.1% underwent additional
diagnostics procedures (The National Lung Screening Trial Research Team, 2011).
These CT-scans thus detect numerous nodules and rapidly increase the demand for
minimal invasive accurate and safe diagnostic and therapeutic procedures.
The historically available and current first diagnostic procedure in the
work-up of PPLs is fluoroscopy guided Trans Bronchial Biopsy (TBB) despite its
low pooled yield of 31.1% (Gould et al., 2013). Several new modalities have
recently become available in specialized centers. These endobronchial
modalities include endobronchial ultrasound radial mini-probe guided biopsy
(rEBUS), ultrathin bronchoscopy (UB), virtual navigation bronchoscopy (VNB),
and electromagnetic navigation bronchoscopy (EMN). A meta-analysis by Wang et
al. (2012) showed that the individual diagnostic yield of these techniques
ranged from 67% to 73.2%, and an overall pooled diagnostic yield was
approximately 70% (Wang Memoli, Nietert, & Silvestri, 2012). Although this
offers a big improvement in performance when compared to the conventional TBB,
a diagnostic yield of approximately 70% still demands further improvement given
the clinical need.
When the above transbronchial techniques do not provide an unambiguous outcome,
an additional and more invasive diagnostic work-up remains indicated. To
exclude the possibility of missing malignancies, trans thoracic needle
aspiration is first indicated (TTNA; pooled sensitivity 90%, specificity
96-98%, false positive rate 22% (Rivera, Mehta, & Wahidi, 2013)). If deemed
inaccessible, surgical biopsy may be alternatively indicated depending on
patient risk of malignancy. With a reported pneumothorax rate of 25% in the
Radboudumc and UMC Groningen combined, TTNA complication rates are high when
compared with endobronchial techniques (1.5%) (Wang Memoli et al., 2012;
Wiener, Schwartz, Woloshin, & Gilbert Welch, 2011). Surgical biopsy is an even
more invasive modality, and a 4.2% 90-day mortality has been reported (British
Thoracic Society Pulmonary Nodule Guideline Development Group, 2015).
Once a diagnosis has been made, surgical excision of a pulmonary nodule by VATS
or thoracotomy can be used to perform either wedge resection, segmentectomy or
lobectomy. Morbidity rates following VATS and thoracotomy have been reported to
range from 0-9.6% (British Thoracic Society Pulmonary Nodule Guideline
Development Group, 2015).
Ideally, a transbronchial approach having high diagnostic accuracy would
overcome the need of this sequential increasingly invasive diagnostic and
consecutive treatment approach. Newer pilot studies now show that combining
multiple new endobronchial modalities might provide a solution in preventing
more invasive additional diagnostic staging, reporting diagnostic yields
exceeding 80% (Eberhardt, Anantham, Ernst, Feller-Kopman, & Herth, 2007;
Lamprecht et al., 2012; Loo, Halligan, Port, & Hoda, 2014). When an accurate
and certain transbronchial diagnosis by combining multiple techniques can
indeed be provided, a next step would be to enable immediate transbronchial
treatment.

Diagnostic yield and navigation accuracy of a combination of commercially
available endobronchial navigation and imaging techniques will be evaluated in
patients with peripheral pulmonary lesions. Cost-effectiveness and safety will
be modelled on basis of collected study performance. The aim of this study is
to determine diagnostic yield, navigation accuracy, safety, and, to collect
data for developing diagnostic algorithms to further cost-effectively increase
yield, reduce complication rate and determine technical needs of future
technological platforms that are not only able to diagnose, but also
simultaneously treat.

In this adaptive clinical trial we will investigate the diagnostic yield of a
combination of commercially available imaging and navigation techniques for
reaching peripheral lung lesions. The two investigated techniques will herein
be the rEBUS imaging modality combined with augmented fluoroscopy based virtual
bronchoscopy navigation. Confirmation of reaching the lung lesion will be by
means of CT (fluoroscopic) imaging. Rapid On-Site Evaluation (ROSE) of
cytopathology will be used for obtaing a per-procedural outcome on tissue
biopsy representativeness. The study will replace the current conventional
standard TBB procedure (fluoroscopy and rEBUS guided bronchoscopy) in the
endoscopy suite. Consecutive patients will be included on the the department of
radiology (needed to monitor patient safety and CT availability). All data will
be prospectively collected. In case tissue biopsy is found to be malignant or
benign, it will be termed representative. In case tissue biopsy is found to be
non-representative (=blood, anatomical lung tissue, unreachable), conventional
follow-up of CT guided TTNA, follow-up monitoring and/or surgical biopsy will
serve as golden standard for obtaining tissue diagnosis. For verification of
reaching the target lesion, another study parameter of interest, (cb)CT imaging
will be performed for verification that instruments are within the nodule
(per-procedurally available).

Not applicable, In this diagnostic study a new combination of currently
commercially available techniques is evaluated. See the research protocol for
more details.

The burden and risks associated with participation are considered lower or
equal to the combined burden and risks associated to the current daily practice
since essentially the same procedures are performed when current clinical
standards are followed. rEBUS and virtual navigation bronchoscopy (VBN) based
techniques such as AFBN have been studied in clinical studies for several
years. rEBUS has herein had a formal recommendation of use for peripheral
pulmonary lesion diagnosis in recent guidelines (Rivera et al., 2013). VBN is
furthermore suggested also to be used in combination with available technology
when sampling nodules, with a pooled yield approximately equal to that of EMN
and rEBUS when used as individual modality (Gould et al., 2013; Rivera et al.,
2013).

In patients who would conventionally receive TBB (fluoroscopy and rEBUS
guided), the following advantages apply:
- An increase in diagnostic yield, without increasing the complication risks as
compared to the currently used TBB procedure. The pooled diagnostic yield of
newer individual modalities is approximately 70% when compared to the
approximate 30% yield of the conventional TBB procedure (Gould et al., 2013;
Wang Memoli et al., 2012). Combining modalities has been reported to increase
yield further. Complication risks of TBB and these newer diagnostic modalities
are both 1.5%, mainly attributable to pneumothoraxes (Wang Memoli et al.,
2012).
- The two conventionally temporally separate procedures (TBB & consecutive TTNA
if no adequate sample is obtained) are combined into one session in this study
when technically possible, as technology for immediate TTNA conversion is
available in the study setting. The total patient burden by having to undergo
two temporally separate procedures with additional approximately 2-3 weeks
waiting time (at current at the Radboudumc) as in the conventional work-up is
thus reduced into a single session.
- The necessity of cross-over to CT-guided TTNA is lower, as there is an
expected increased yield by transbronchial diagnosis through the here studied
combination of techniques (Gould et al., 2013; Wang Memoli et al., 2012). The
pooled risk of pneumothorax requiring chest tube drainage by TTNA was found 25%
in the Radboudumc and UMC Groningen combined, and in 10% of cases hemorrhages
occurred [unpublished data, submitted to RSNA 2017]. Again, complication risks
of TBB and these newer diagnostic modalities are both ~1.5%, mainly
attributable to pneumothoraxes (Wang Memoli et al., 2012). The total risk of
complications for the majority of patients included in this study is thus
lower.

In patients who would conventionally receive TBB (fluoroscopy and rEBUS
guided), the following potential burden and risks apply:
- Radiation exposure in the study procedure is higher when compared with the
conventional TBB procedure due to the use of CT for navigation calibration and
positioning confirmation, and, CT fluoroscopic guidance and positioning
confirmation as opposed to C-arm fluoroscopy guidance and confirmation alone in
conventional TBB. The added radiation exposure is based upon the need of a
navigation system calibration low dose CT (2.4 mSv) and in elective cases where
fluoroscopy does not provide sufficient detail, a target lesion confirmation
low dose CT (2.4mSv) at the end of the procedure. Because of a study procedure
yield increase, conventionally often needed additional procedures due to a lack
of diagnostic yield, such as CT guided TTNA and/or surgical biopsy, may be
prevented (whereas CT guided TTNA requires multiple low dose CT scans as well).
The majority of subjects is >50 years old, and if these study techniques are
able to diagnose with high accuracy, yield increase importance in terms of life
expectancy greatly outweighs additional radiation exposure risk.
- When participating in this study, all patients will be deeply sedated. In our
current local protocol, all patients indicated for fluoroscopy guided TBB are
planned for procedural sedation with propofol sedation. The sedation level at
current for this procedure is mild in approximately 60% of the cases and deep
in 40% in the remaining group following the standard operating procedure. With
deeper sedation, a laryngeal mask or endotracheal tube is used to allow a safe
ventilation and optimal means for monitoring of the patient. For this reason we
will use deep sedation for all patients in this study, improving imaging
quality and also allowing for TTNA in breath-hold when a conversion is
indicated. Side effects of using a mask are mild pain of the throat and
hoarseness in rare cases. Side effects of the deeper sedation are equal as in
the conventional work-up, yet chances upon these side effects are higher
because of increased procedure duration and deeper sedation.Side effects of the
deeper sedation include sleep apnea and muscle dystonia.
- Due to the additional navigation techniques, catheter manipulation time and
potential need for additional TTNA the procedure taking place in the
interventional radiology in this study setting, the added procedure time is
approximately 30 minutes (the current standard of care average procedure time
is 75 minutes; approximately 45 minutes for bronchoscopy and 30 minutes for
TTNA).

The subgroup of patients initially (conventionally) referred for upfront
surgical biopsy may benefit significantly when participating in this study.
When a diagnosis can be obtained using this study protocol, a thoracoscopic or
open surgical procedure may be prevented or simplified. Currently, when a
diagnosis cannot be obtained preceding to the surgical procedure, a CT guided
marker and onsite pathology are needed, and, the risk of conversion from VATS
to open surgery is higher.

The procedures will take place in an environment optimally suited for finding
and treating complications. Subjects will not receive any compensation for
study participation other than the here above mentioned benefits.