Efficacy of Intraoperative CT Feedback of Wedge Resected Lung for the Assessment of Surgical Margin
Phase: NA
Conditions: Lung Cancer (Diagnosis)
Sponsor: University Health Network, Toronto

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Efficacy of intraoperative CT feedback of wedge resected lung for 
the assessment of surgical margin 
 
                                                       Protocol Version #2 
                                                  Date: 26APR2024 
 
Research Objectives 
Aim1: To assess how surgical outcomes are impacted by intraoperative CT 
feedback. 
Aim2: To assess the validity of the additional resections. 
 
Study Background 
Lung cancer is the most prevalent cancer and the leading cause of cancer 
death in Canada. In 2020, lung cancer resulted in the deaths of 21,200 
Canadians (1). The high mortality reflects both its high incidence and low 
survival. Although it is one of the most aggressive malignant tumors, as with 
many other types of cancer, patients can live cancer-free if the diagnosis is 
accurate and timely treatment is administered. Low-dose computed tomography 
(LDCT) scans can help find abnormal areas in the lungs that may be cancerous. 
Research has shown that scanning patients at higher risk of lung cancer using 
LDCT saved more lives compared to chest x-rays (2). In Canada, opportunistic 
screening is occurring in at least six provinces and implementation of organized 
programs is expected in the coming years (3). The increased prevalence of CT 
screening and advances in diagnostic technology, particularly the widespread 
use of thin-slice computed tomography, have enabled increased detection of 
early-stage small lung cancers (4). Early-stage lung cancer is often featured as 
a ground-glass opacity (GGO) associated with a pathological lepidic growth 
pattern that is considered to be related to a more favorable prognosis (5). 
Therefore, these GGO-dominant lung cancers could be optimal candidates for 
sublobar resections, which is to remove a section of a lobe of the lung that 
contains the lung cancer and a margin of healthy tissue around the cancer. This 
is an alternative to the conventional, more radical, pulmonary lobectomy (6, 7). 
Sublobar resection, including segmentectomy and wedge resection, is less 
invasive, sparing more healthy lung tissue and is associated with improved 
patient recovery. However, an increasing number of hazy lung tumors are also 
being detected, which are difficult to localize intra-operatively as they are 

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neither palpable, nor visible to the naked eye. To address the challenge of 
identifying small pulmonary nodules during surgery we have studied the 
accuracy of CT-guided insertion of microcoils prior to lung surgery (8). In 
addition, CT-guided microcoil localization was also associated with excellent 
recurrence-free survival for small lung tumors (9). The other challenge 
regarding sublobar resection is the possibility of locoregional cancer recurrence 
due to positive stump cytology and insufficient surgical margins which is defined 
as the amount of normal lung tissue excised around the tumor. These factors 
correlate with postoperative local recurrence but sometimes contradicted the 
results, in other words, positive stump cytology with negative surgical margin 
and vice versa (10). Therefore, keeping sufficient safety margins is important to 
ensure a complete resection. Currently, at least 15 mm distance or tumor size 
distance from the gross tumor is considered as a safe surgical margin in 
sublobar resections for prevention of local surgical recurrences in lung cancer 
(10, 11). Same can be said for metastatic lung tumors where margin length has 
been reported to be associated with the predicted probability of local recurrence 
(12, 13). 
If the surgical margin is insufficient, additional resection or postoperative 
radiation therapy may be required which can cause patients additional stress. 
To date, there is no established method for confirming whether sufficient 
surgical margin was obtained during surgery, only as a pathological specimen 
post operation. To address this intraoperative limitation of margin assessment, 
we evaluated a radiological evaluation for sublobar resection specimen using 
CT during surgery. This method was demonstrated to be feasible for the 
assessment of the surgical margin as described below. However, the previous 
study did not include any feedback of the results intraoperatively, which did not 
contribute to decision-making and treatment strategy. The ability to accurately 
evaluate surgical margins intraoperatively could reduce the risk of locoregional 
recurrence and eliminate the need for additional treatment after surgery. 
Moreover, optimal intraoperative feedback to surgeon could influence surgical 
decision making and contribute to the satisfactory outcome.  
 
 
Pre-clinical study 
1) Protocol establishment for lung specimen preparation 
Pre-clinical ex-vivo pig lung experiments assessed the feasibility of the image 

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acquisition and surgical margin measurement procedure by CT. A total 30 pig lung 
resected specimen were evaluated for the assessment. Resected lungs required 
re-inflation by injecting air to obtain the specimen CT image with sufficient quality 
for further analysis. After image acquisition, the lung specimen was instilled with 
10% formalin neutral buffer solution using a 25-gauge needle and then soaked in 
the solution for at least 24 h. Microscopic histological specimen analysis was 
possible after standard tissue processing including fixation, gross assessment, 
and staining. We concluded that the additional steps can be easily integrated into 
the existing work flow without compromising specimen integrity since all imaged 
specimens were adequate for subsequent histopathologic analysis. 
 
2) Evaluation of CT margin measurement 
In order to simulate the surgical margin measurement by CT after sublobar lung 
resection, a pseudo lung nodule was created by injecting agar gel into the pig 
lung specimen. We confirmed that it was possible to measure the distance 
between the edge of pseudo tumor and cut surface. This CT based margin 
assessment measurement was then compared to the measurement carried out 
by pathology, which is the gold standard for assessing margin length. In all 
evaluated lungs (n=30), surgical margin measured by CT was 3.50 mm +/- 2.69 
mm greater than that measured by pathology. This discrepancy was possibly 
attributable to tissue shrinkage by formalin fixation during standard pathology 
process (14). Based on the result of this preclinical study, clinicians should keep 
in mind that margin length shortening would be expected by tissue processing. 
 
Clinical study 
1) Protocol 
The Previous clinical study was conducted to assess the feasibility of CT margin 
measurement (REB #22-5528). From October 2022 to March 2023, patients 
treated with sublobar resection (Segmentectomy or wedge resection) for clinical 
lung malignancies were introduced to the study by their treating surgeon. Of those, 
the patients who provided consent to the study after explanation by research 
coordinator were enrolled. Patients data including age, gender, CT findings 
(tumor diameter, location, distance between pleura to tumor), surgical data 
(surgical procedure, preoperative marking, operative time, blood loss), 
pathological diagnosis, margin data (CT margin, pathological margin) were 
collected.  

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CT margin was calculated as follows: i) resected lung specimen was inflated with 
25-gauge needle and an appropriately syringe, while monitoring to prevent 
alveolar wall destruction using a pressure transducer. ii) The specimen was 
placed on a CT scanner with adjustment of staple line perpendicular to CT axial 
line and scanned CT in Spatio-temporal targeting and amplification of radiation 
response (STTAAR) innovation center. iii) CT margin was defined as the distance 
between tumor and tumor side of the staple line, and measured. After the 
assessment, the specimen was delivered to the surgical pathology department, 
and standard pathological examination was performed. 
 
2) Results 
 54 patients were enrolled. In this study. In 4 patients (7.4%), poorly inflated 
specimen caused the tumor to be undetectable, which we subsequently excluded. 
Consequently, 92.6% of cases, 50 patients (52 specimens) were analyzed. 
Surgical margin measured by CT was significantly longer than pathological 
margin (11.74 ± 8.52 VS 10.08 ± 7.22, p = 0.033). 21% surgical margin length 
reduction was observed from CT to pathological assessment. Medial correlation 
was found between CT assessed margin and pathological margin (r = 0.7679). 
Margin assessment for resected lung is feasible and accessible way to identify 
tumor and surgical margin during surgery. Surgeons should be aware that CT 
assessed surgical margin will be longer than pathological margin.  
 
Sample size 
We aim to evaluate 80 cases over 2 years. We would like to include all 9 thoracic 
surgeons in our division to evaluate the impact to the surgical outcome “surgical 
margin” over the course of the study. As this is unlikely as not all surgeons will 
perform wedge resections, we will enroll consecutive patients regardless of who 
the attending surgeon is. 
 
 
Patient Groups 
Inclusion criteria: 
・Patients scheduled for lung wedge resection for primary lung cancer or 
metastatic lung tumor (included suspected lesions). 

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・18 years of age or older. 
 
Exclusion criteria: 
・Any patients with inability to give informed consent 
・Wedge resection for non-therapeutic purpose, e.g. diagnostic purpose. 
 
Study Plan and Methods 
 
This is a single center clinical trial. We will ask thoracic surgeons in our institution 
to work together for this research. A total of 80 patients scheduled for wedge 
resections for lung malignancies (including suspected patients) will be enrolled in 
this study. The attending surgeon will introduce the study to the patients and a 
research coordinator will then go through the consenting process, answer any 
questions and enroll the patient if they wish to participate within one month before 
surgery.  
 
We will enroll 80 patients in 2 years for this study. Prior to first surgery, every 
surgeon will be asked to complete a questionnaire 1 to investigate the 
background of surgeon. At each surgery, we ask for questionnaire 2 orally before 
and after resection to assess the contribution of feedback to margin results. Once 
the wedge resection is performed, the resected specimen will be brought to 7th 
floor in STTARR innovation center in Princess Margaret Cancer Research Tower 
(PMCRT). Resected lung specimen will be inflated with 25-gauge needle and 
appropriately sized syringe. The air injection pressure as well as the total inflation 
pressure will be continuously monitored to prevent alveolar wall destruction using 
a pressure transducer. For the precise surgical margin measurement, the staple 
line is adjusted perpendicular to CT axial line. Surgical margin will be measured 
and its image will be captured. Surgical margin is defined as the distance from 
tumor to the tumor side of staple line (not including the width of staple line). The 
data (included CT image and CT surgical margin) will be numbered and exclude 
individual information (only include study number and date). The data will be 
transferred from CT scan to our laptop using universal serial bus (USB), then 
shared with surgeons by tablet in operating room through online storage service 

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such as OneDrive or directly with laptop or USB. These processes are expected 
to take about up to 20 minutes. Surgeons will wait and refer to these results, and 
make a decision if additional resection should be made. The lung specimen will 
be delivered to the pathological laboratory and routine pathologic work up will be 
proceeded per standard care, including fixation, gross assessment, and selection 
of clinically relevant tissue blocks for sectioning, staining, and microscopic 
assessment. Within several days after surgery, we will send the CT measured 
margin length and reconstructed 3D image of the resected specimen to the 
attending surgeon, and ask them to complete the rest of questionnaire 2. This is 
to evaluate the usefulness of the CT image feedback and the surgeon’s 
satisfaction for each case. 
Additionally, once the pathological result for each patient is revealed, surgeons 
will receive the results of the margin length comparison (CT based margin and 
pathological margin). After the total course of surgery, we will ask each surgeon 
individually for questionnaire 3 after feedback of the individual result of this study 
to assess the satisfaction by intraoperative feedback. 
 
 
Benefits 
Intraoperative feedback of surgical margin measured by CT correlates to 
pathological margin length, and could help make a decision for additional 
resection. Patients with a confirmed sufficient margin could have better local 
cancer control.  
 
Risks 
Additional resection could induce complication such as air leakage.  
 
Extra time commitment for patients 
The entire intraoperative feedback process takes about up to 20 minutes, further 
increasing the operation time.  
 
Outcome Measures 
The primary outcome of the study will include (1) the contribution of intraoperative 
feedback to treatment decision, and its validity, and (2) assessing how 
intraoperative feedback affects surgical margins over the course. The secondary 
outcome will be the assessment of surgeons’ satisfaction with intraoperative 

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feedback.  
 
Statistics 
A linear mixed model will be performed to analyze the difference of the process 
between expected and actual margin over the course. Pearson’s correlation 
analysis will be performed to analyze the correlation between the parameters 
measured on CT and on pathological analysis. Limits of agreement analysis will 
be performed per the Bland-Altman method to evaluate agreement between 
preoperative expectation for surgical margin and actual margin. ROC curves will 
be used to assess the CT margin to predict short pathological margin. GraphPad 
Prism8 (GraphPad Software, La Jolla, CA, USA) and R (for linear mixed model) 
will be used for statistical analysis. All p-values will be based on a two-sided 
hypothesis, with p-values < 0.05 indicating statistical significance. 
 
Data Collection and Monitoring 
The following data will be collected prospectively using source documents and a 
database specially constructed for the purpose. Data will be collected 
prospectively on all patients. Due to the low risk and influence for the patients 
involved in this study, a DSMB is not required. 
(1) Patients’ background (age, gender, body weight, body mass index, history, 
smoking habit, preoperative diagnosis) 
(2) Preoperative CT information (tumor location, tumor size, CT appearance, 
Consolidation tumor ratio, distance between tumor and pleura) 
(3) Surgical information (surgery date, attending surgeon’s study number, 
operative procedure, operative duration, preoperative marking, intraoperative CT 
image acquisition time, tumor size in intraoperative CT, margin length in 
intraoperative CT, additional resection, procedure change, intraoperative 
findings) 
(4) Pathological results (pathological diagnosis, tumor size, tumor spread through 
air space, pathological margin length) 
(5) Others (postoperative complication, length of stay) 
(6) Questionnaire results including surgeons’ study number (see questionnaire 
section) 
 
Access to Source Data/Documents 
Access to the study data will be permitted for study investigators, coordinators, 

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and UHN REB. 
 
Consent 
All patients will receive both verbal and written information about the study and 
will be asked to give informed consent using study-specific consent forms. Nine 
thoracic surgeons in the division of thoracic surgery in Toronto General Hospital 
has received the explanation of this study and accepted to participate in this study 
in the previous conference. We will ask them to provide written consent for this 
study prior to the study.   
 
 
Data Handling and Record Keeping 
All data will be de-identified. Each subject will be given a study number with data 
stored securely in a locked cabinet. As described in the consent form, we will 
maintain a list for each patient, study number for the specimen, corresponding 
CT scan identification and questionnaire. This list will be kept by the study 
investigator in a secure place, separate from the study file for up to 10 years. We 
will follow storage, transport and destruction of confidential information policy. 
 
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