A Single-arm, Phase II Study of Thoracoscopic Lung Cancer Staging With the Use of Intraoperative Ultrasound at the Time of Definitive Resection
Phase: NA
Conditions: Lung Cancer
Sponsor: Joel Thompson, PhD

1 
 
Local Protocol #: 
Please insert your local protocol # for this study. 
 
TITLE:  
 A single-arm, Phase II study of thoracoscopic lung cancer staging with the use of 
Intraoperative Ultrasound at the time of definitive resection 
 
Coordinating Center: 
 
 
Markey Cancer Center 
University of Kentucky 
*Principal Investigator: 
Jeremiah T. Martin MB BCh 
 
740 South Limestone A301 
 
Lexington, KY 40536-0284 
 
Tel: 
859-323-6494 
 
Fax: 
859-257-4685 
 
Email: j.martin@uky.edu 
 
Co-Investigators: 
Angela Mahan, MD 
Timothy Mullett, MD 
740 South Limestone A301 
740 South Limestone A301  
Lexington, KY 40536-0284 
Lexington, KY 40536-0284 
Tel:    859-323-6494 
Tel:    859-323-6494 
Fax:    859-257-4685 
Fax:    859-257-4685 
Email: algill1@uky.edu 
Email: mullett@uky.edu 
 
Joseph Zwischenberger MD 
740 South Limestone A301 
Lexington, KY 40536-0284 
Tel  :859-323-6494 
Fax:  859-257-4685 
Email: joseph.zwischenberger@uky.edu 
 
 

NCI Protocol #: 
Version Date: 
 
2 
Statistician: 
 
Study Coordinator: 
 
Heidi L. Weiss, Ph.D. 
Name 
 
800 Rose Street, CC448 
Address 
 
Lexington, KY 40536 
Address 
 
859-323-0577 
Telephone 
 
 
Fax 
 
heidi.weiss@uky.edu 
e-mail address 
 
Responsible Research Nurse: 
Responsible Data Manager: 
 
Name 
Name 
 
Address 
Address 
 
Address 
Address 
 
Telephone 
Telephone 
 
Fax 
Fax 
 
e-mail address 
e-mail address 
 
 
 
Original Phase II Protocol / Version 1.1  / 11.7.2013 
 
 

NCI Protocol #: 
Version Date: 
 
3 
SCHEMA 
 
All patients undergoing video-assisted thoracoscopic (VATS) resection of lung cancer will 
receive standard therapy including lobectomy or sub-lobar resection and mediastinal lymph node 
dissection. After completion of the standard of care, intraoperative ultrasound will be used to 
evaluate lymph node stations for the presence of any missed lymph nodes with particular focus 
on lymph nodes which may appear pathologic on ultrasound evaluation. 
 
Additional lymph nodes which are found by ultrasound evaluation will be resected and sent with 
the standard specimen for evaluation of presence of tumor. 
 
Patients will receive standard-of-care treatment in the postoperative period, including adjuvant 
therapy as dictated by final pathologic stage. 
 
Data will be reviewed for rates of pathologic upstaging, and sensitivity and specificity of 
ultrasound as an additional diagnostic tool in the operating room will be evaluated. 
 
 

NCI Protocol #: 
Version Date: 
 
4 
 
 
Patients with NSCLC appropriate for 
VATS lung resection  
 
 
 
Successful surgical procedure including standard mediastinal lymph node dissection) 
 
 
 
 
Intraoperative U/S evaluates nodal stations  
for presence of additional and possibly pathologic nodes 
 
 
 
 
Resection of U/S identified nodes 
 
 
 
 
Pathologic evaluation of both standard resection and  U/S-guided resected nodes 
 
 
 

NCI Protocol #: 
Version Date: 
 
5 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives...................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Lung Cancer .............................................................................................................7 
2.2 
Lung Cancer Staging................................................................................................8 
2.3 
Surgical Therapy ......................................................................................................8 
2.4 
Intraoperative Ultrasound ........................................................................................9 
2.5 
BK Medical ApS Ultrasound transducer system .....................................................9 
2.6 
Rationale ................................................................................................................10 
3. 
PATIENT SELECTION ....................................................................................................11 
3.1 
Eligibility Criteria ..................................................................................................11 
3.2 
Exclusion Criteria ..................................................................................................11 
3.3 
Inclusion of Women and Minorities ......................................................................12 
4. 
REGISTRATION PROCEDURES ...................................................................................13 
4.1.1 Protocol Review and Monitoring Committee and Institutional Review 
Board Review.........................................................................................................13 
4.1.2 Enrollment Guidelines ...........................................................................................13 
4.1.3 Informed Consent...................................................................................................13 
4.1.4 Compliance with Laws and Regulations................................................................14 
5. 
TREATMENT PLAN ........................................................................................................16 
5.1 
Enrollment and Screening Process.........................................................................16 
5.2 
Surgery ...................................................................................................................16 
5.3 
Intraoperative Ultrasound Examination .................................................................19 

NCI Protocol #: 
Version Date: 
 
6 
5.4 
Duration of Therapy ...............................................................................................19 
5.5 
Duration of Follow Up ...........................................................................................19 
5.6 
Criteria for Removal from Study ...........................................................................20 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................21 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................21 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................25 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................25 
10. 
STUDY CALENDAR .......................................................................................................26 
11. 
MEASUREMENT OF EFFECT........................................................................................27 
11.1 
Evaluation of intraoperative ultrasonography ........................................................27 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................27 
12.1 
Data Reporting .......................................................................................................27 
13. 
STATISTICAL CONSIDERATIONS...............................................................................28 
13.1 
Study Design/Endpoints.........................................................................................28 
13.2 
Sample Size/Accrual Rate ......................................................................................28 
13.3 
Stratification Factors ..............................................................................................29 
13.4 
Analysis of Primary and Secondary Endpoints .....................................................29 
13.5 
Interim Analyses ....................................................................................................29 
13.6 
Data Management ..................................................................................................29 
13.7 
For phase 2 protocols only: Reporting and Exclusions .........................................30 
REFERENCES ..............................................................................................................................31 
 
 
 

NCI Protocol #: 
Version Date: 
 
7 
1. OBJECTIVES 
 
Hypothesis: Intra-operative thoracoscopic ultrasound following standard video-assisted 
thoracoscopic (VATS) dissection will increase the rate of pathologically staged in N2 nodes in 
non-small cell lung cancer patients undergoing definitive surgical resection. (H0: upstaging rate 
of 2% vs H1: upstaging rate of 8%) 
 
1.1 
Primary Objectives 
 
To determine the rate of detection of occult pathologic N2 lymph nodes with the addition of 
intra-operative ultrasound to VATS. 
 
1.2 
Secondary Objectives 
 
 Evaluate surgical complication rate 
 Measure time to perform the evaluation and effects on overall operative time 
 Rate of detection of additional lymph nodes by ultrasound 
 Sensitivity of VATS ultrasound related to lymph nodes harvested after standard 
dissection: does ultrasonography reveal any additional pathologically positive lymph 
nodes over standard techniques. 
 
2. BACKGROUND 
 
 
2.1 
Lung Cancer 
Lung cancer is the leading cause of cancer deaths in the United States and worldwide. About 
228,190 new cases of lung cancer (both small cell and non-small cell) and about 159,480 deaths 
from lung cancer are predicted in the US for 2013.(1)  Non-small cell lung cancer (NSCLC) 
represents about 85% of all lung cancer and frequently has a dismal outcome. The 5-year 
survival rate for late-stage (stages III and IV) patients is less than 10%. Survival is directly 

NCI Protocol #: 
Version Date: 
 
8 
related to stage. As such, treatment of lung cancer is stage-based.(2) 
 
2.2 
Lung Cancer Staging 
The evaluation of N2 disease in NSCLC represents an important decision point. In patients who 
present with N2 positive disease based on imaging, and confirmed by tissue diagnosis, treatment 
is primarily systemic. A small subset of stage I-II patients, who have been evaluated prior to 
resection and are found at the time of surgery to have microscopic metastases to their N2 nodal 
stations, are upstaged to IIIA and receive postoperative systemic therapy. Although the incidence 
of pathologic upstaging is low (7.6% for standard thoracotomy with lobectomy), if these patients 
are not detected at the time of surgery they will be misclassified as stage I-II based on tumor size 
and may not receive any additional therapy after surgery. This will result in the increased risk of 
nodal and systemic recurrence, with impact on the stage-based survival.(3, 4) 
 
2.3 
Surgical Therapy 
Lung cancer surgery has been traditionally performed by open thoracotomy. The thoracotomy 
incision is associated with significant pain which places patients at risk for postoperative 
pulmonary complications, delays recovery, and can hinder compliance with adjuvant therapy 
regimens.(5) 
 
Advances in minimally invasive surgery have allowed for the safe performance of a 
thoracoscopic (VATS) lobectomy which is associated with vastly improved postoperative pain 
control. As such, patients have shorter lengths of stay, increased postoperative mobility with 
decreased rates of postoperative complications, and importantly have improved compliance with 
adjuvant therapy regimens.(5) 
 
Despite this, there has been slow adoption of VATS. Nationally, only 30% of lung cancer 
resections are performed using minimally invasive techniques. Critique of the technique has 
included difficulty with the learning curve, and the debate regarding lymph node yield and the 
oncologic equivalency continues. 
 

NCI Protocol #: 
Version Date: 
 
9 
Small-volume randomized controlled trials performed by centers routinely employing the 
technique have failed to demonstrate issues from an oncologic standpoint. However, a large 
review of national data demonstrates a significant rate of upstaging of patients when a 
thoracotomy is performed as compared with VATS. A limitation of VATS, as in all minimally 
invasive surgery, is the inability to palpate the tissues and this may be a factor. This was also 
recently replicated in a national study published in Denmark this year.(3, 4, 6) 
 
2.4 
Intraoperative Ultrasound 
Intraoperative ultrasound is routinely used in laparoscopic cases and has added significant value 
in terms of ability of the surgeon to determine anatomic boundaries and assess for metastatic 
disease.(7-9) To date, this modality has seen limited utilization in VATS and in particular there 
are no reports of use of the technology being used to assess lymph nodes at the time of surgery. 
Given its ability to objectively assess tissue beyond simple visual inspection this should help to 
identify pathologic lymph nodes in these patients if indeed they are present.   
 
 
 
2.5 
BK Medical ApS Ultrasound transducer system 
 
BK Medical ApS, Peabody MA, manufactures an FDA-
approved ultrasound transducer/system for use during minimally 
invasive surgery. (8666-RF, 10-5MHz ultrasound transducer). 
This system is routinely used at the University of Kentucky in 
general surgery, hepatobiliary surgery, gynecologic oncology, 
and neurosurgery to assist the surgeon with intraoperative 
decision making.  
 
The system has not been used in thoracic applications at the 
University of Kentucky. The laparoscopic probe would be 
introduced into the chest at the time of VATS through the pre-

NCI Protocol #: 
Version Date: 
 
10 
existing incision to allow for an evaluation of lymph node stations after performing a standard 
lung cancer resection and lymph node dissection. 
 
http://www.bkmed.com/8666RF_en.htm 
 
 
2.6 
Rationale 
 
Standard approaches have been developed to lung cancer resections using VATS. This includes a 
standard sampling of lymph node stations to obtain an accurate pathologic staging. However 
evaluation of these nodes is limited by the reliance of the surgeon on conventional 2-dimensional 
video imaging of anatomy and does not allow for palpation of abnormal tissues. 
 
VATS lobectomy is associated with potentially missed N2 nodal disease during surgical 
resection of presumed early-stage lung cancer. Pathologic false negative evaluation will result in 
patients who are truly stage III being misclassified as stage I-II and as such missing the 
opportunity to benefit from adjuvant therapy. Recent review of national data demonstrates the 
occurrence of pathologic upstaging during standard thoracotomy in 7.6% of resections, 
compared with 2.3% of VATS cases. Limitations incurred by minimally invasive surgery may be 
responsible for this differential rate. 
 
Intraoperative ultrasound adds an additional dimension to the evaluation of lymph nodes and 
abnormal tissue. If there are additional lymph nodes present, which have not been resected by 
standard techniques, they should be detected by an intraoperative ultrasound scan. 
 
 
 
 
 

NCI Protocol #: 
Version Date: 
 
11 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have potentially resectable non-small cell lung cancer by VATS as 
determined by a multidisciplinary team review. This primary should not have undergone 
any neoadjuvant chemo- or radiation therapy. 
 
3.1.2 Age ≥18 years.   
 
3.1.3 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.4 Life expectancy of greater than 3 months 
 
3.1.5 Patients be able to undergo VATS resection as defined below: 
 
 
Preoperative FEV1 
 
≥  40% predicted 
 
OR 
 
Post-operative predicted FEV1 ≥ 0.8 l 
 
Hg  
 
≥ 8.0 
 
No evidence of coronary ischemia on stress evaluation   
 
 
3.1.6 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients with surgery for a prior ipslilateral lung cancer are excluded 
 
 

NCI Protocol #: 
Version Date: 
 
12 
3.2.2 Patients who are receiving any other investigational agents. 
 
3.2.3 Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
  
3.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
(Patients with HIV are not excluded from this study) 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. As such, no 
particular accrual targets are pre-defined with plans to accrue consecutive patients during the 
enrolment period. 
 
 
 
 

NCI Protocol #: 
Version Date: 
 
13 
4. REGISTRATION PROCEDURES 
 
4.1.1 Protocol Review and Monitoring Committee and Institutional Review Board Review 
 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by the Markey Cancer Center’s Protocol Review an 
Monitoring Committee and the University of Kentucky Institutional Review Board (IRB). A 
signed and dated statement that the protocol and informed consent have been approved by the 
IRB must be maintained in the Markey Cancer Center Clinical Research and Data Management 
Shared Resource Facility (MCC CRDM SRF) regulatory binder. Any amendments to the 
protocol, other than administrative ones, must be reviewed and approved by the study sponsor 
and the UK IRB.   
 
4.1.2 Enrollment Guidelines 
 
Eligible patients will be identified by the principal investigator and co-investigators of this study. 
Potentially eligible patients will be screened in the University of Kentucky Markey Cancer 
Center clinics by the investigators, study personnel, and the Principle Investigator (PI). Upon 
obtaining proper consent, patients will be enrolled into the study.   
 
 
4.1.3 Informed Consent 
 
The goal of the informed consent process is to provide people with sufficient information so they 
can make informed choices about whether to begin or continue participation in clinical research.  
The process involves a dynamic and continuing exchange of information between the research 
team and the participant throughout the research experience.  It includes discussion of the study's 
purpose, research procedures, risks and potential benefits, and the voluntary nature of 
participation. 

NCI Protocol #: 
Version Date: 
 
14 
The informed consent document provides a summary of the clinical study and the individual's 
rights as a research participant.  The document acts as a starting point for the necessary exchange 
of information between the investigator and potential research participant.  Also, research 
participants and their families may use the consent document as an information resource and 
reference throughout participation in the trial.  The informed consent document is often 
considered the foundation of the informed consent process; it does not, however, represent the 
entirety of the process.  Nor is the informed consent document a risk-management tool for the 
investigator and/or institution. 
 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained.  The informed consent form is considered to be part of the protocol, 
and must be submitted by the investigator with the protocol at the time of IRB review. 
 
4.1.4 Compliance with Laws and Regulations 
 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, any applicable local health authority, and Institutional Review Board 

NCI Protocol #: 
Version Date: 
 
15 
(IRB) requirements.  The PI or designee will be responsible for obtaining continuing and not less 
than annual IRB re-approval throughout the duration of the study.  Copies of the Investigator’s 
annual report to the IRB and copies of the IRB continuance of approval must maintained by the 
MCC CRDM SRF.  The PI or designee is also responsible for notifying the Data and Safety 
Monitoring Committee of the MCCC and the UK IRB of any significant adverse events that are 
serious and/or unexpected, as per SOP’s of those entities. DSMC will review adverse events of 
this IIT as per its SOP. 
 
 
 
 

NCI Protocol #: 
Version Date: 
 
16 
5. TREATMENT PLAN 
 
5.1 
Enrollment and Screening Process  
 
Prior to any study-required tests, subjects must first provide written informed consent to 
participate in this study.  All lab tests and radiographic studies should be completed prior to 
surgery.  Preoperative evaluation will include: 
 Complete history, physical examination, and evaluation of Zubrod Performance Status. 
 Multidisciplinary review of case presentation: Either Pathological (biopsy) or 
cytologically proven non-small cell lung cancer, or patients suspected of having early 
stage NSCLC are enrolled.  
 CT with contrast or PET/CT (preferred)of chest and upper abdomen to include the liver 
and adrenals  
 Baseline brain MRI or CT scan.  
 Bone scan, only if the patient has bone pain and/or and elevated alkaline phosphatase > 
1.5 x ULN. 
 Pulmonary function tests - including FEV1  
 CBC; serum chemistry tests to include creatinine, and electrolytes. 
 
5.2 
Surgery 
 
Surgery will occur on an inpatient basis.   
 
Intraoperative monitoring will consist of standard intravenous access, arterial line and EKG 
monitoring. 
 
Lung isolation will be performed under general anesthesia in standard manner with the use of 
dual lumen endotracheal intubation or bronchial blocker at the discretion of the cardiothoracic 
anesthesiologist. 
 

NCI Protocol #: 
Version Date: 
 
17 
The chest will be accessed using standard thoracoscopic (VATS) techniques. The operating 
surgeon will assess resectability, and perform the definitive operation. In the case of those 
patients who have a suspicion of, but do not have a diagnosis of cancer prior to surgery, a wedge 
resection or intraoperative core biopsy will be performed with pathology confirming the presence 
of NSCLC with frozen section. 
 
The resection will include the standard mediastinal lymph node dissection as routinely performed 
by the operating surgeon. At a minimum, these stations will include: 
1) Right Upper/Middle Lobe – R4, 7 
2) Right Lower Lobe – 7, R8/9 
3) Left Upper Lobe – 5, 7 
4) Left Lower Lobe – 7, L8/9 
 
 

NCI Protocol #: 
Version Date: 
 
18 
 
(Figure 1, IASLC mediastinal lymph node map)(10) 
 
 
At the conclusion of the thoracoscopic lung cancer resection, the BK 8666-RF ultrasound 
transducer will be introduced through the existing operating ports and used to evaluate all lymph 
node stations evaluable from the ipsilateral thorax. Additional lymph nodes identified in the 
defined stations above will be resected, and imaging characteristics noted. Image-capture will be 

NCI Protocol #: 
Version Date: 
 
19 
used to document the appearance of lymph nodes which are identified for resection to allow for 
clinico-pathologic correlation. 
 
 
Reported adverse events and potential risks are described in Section 7.  Appropriate therapy 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
 
5.3 
Intraoperative Ultrasound Examination 
 
Intraoperative ultrasound will be performed at the completion of the standard lung cancer 
resection with mediastinal lymph node dissection. This evaluation will be performed by a 
different surgeon from the primary surgeon (either JM or AM) performing the operation to 
minimize operator variability with the ultrasound system and help control for bias. Additional 
lymph nodes identified will be resected and sent for pathologic evaluation. It is anticipated that 
this additional evaluation and treatment should take no more than 30 minutes and as such a time 
limit of 30 minutes from introduction of the ultrasound probe into the surgical field will be set. 
 
5.4 
Duration of Therapy 
 
Treatment will occur at the time of surgery and subjects will be followed for 30-days post 
operatively or until resolution of all study related adverse events < grade 2.   
 
5.5 
Duration of Follow Up 
 
Patients will be followed for 30 days after their operation or until resolution of all greater than 
grade 2 adverse events that are possibly, probably or definitely related to study intervention as 

NCI Protocol #: 
Version Date: 
 
20 
determined by the treating physician.  Patients removed from study for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event to < grade 2. 
 
5.6 
Criteria for Removal from Study 
 
The possibility exists that a patient who has been screened and enrolled for the study, was taken 
to the operating room without a definitive diagnosis. At the time of surgery, if a diagnosis of 
non-malignancy, or tumor other than NSCLC is rendered, then the patient will be removed from 
the study. 
 
 
 
 

NCI Protocol #: 
Version Date: 
 
21 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 N/A 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via AdEERS) in addition to routine 
reporting. 
 
7.1 
Expected Toxicities 
 
Ultrasound represents a non-invasive, atraumatic method of evaluation of tissues. The 
performance of the exam itself should not incur adverse events. The following adverse 
conditions may be related directly or indirectly to the use of ultrasound in this setting: 
- 
Injury during introduction/operation of the ultrasound probe 
The ultrasound transducer is a firm object, used in contact-evaluation. It is unlikely, but 
possible, that traumatic injury to any intrathoracic structure may occur during conduct of 
an examination. 
- 
Injury to recurrent laryngeal nerve 
Extensive dissection in the paratracheal region, where level 2 and 4 nodes are located, 
may result in injury to the recurrent laryngeal nerve. This would manifest as 
postoperative hoarseness. 
- 
Chylothorax / Lymphatic leak 
Lymph leak may occur during a more extensive lymph node dissection 
- 
Extended operating time 
Ultrasonographic screening will add additional time to the operation that would otherwise 
be completed. Additional time under general anesthetic is associated with increased risks 
due to infection. As such, additional time for this procedure will not exceed 30 minutes 
and postoperative complications will be monitored as defined above. 

NCI Protocol #: 
Version Date: 
 
22 
 
 
7.2 
Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 

NCI Protocol #: 
Version Date: 
 
23 
7.3.1 For MCC Investigator-Initiated Trials (IITs), investigators must report to the Overall PI 
any serious adverse event (SAE) on the local institutional SAE form. This applies to the 
following categories: 
 Grade 2 (moderate) and 3 (severe) Events – Only events that are 
Unexpected and Possibly, Probably or Definitely Related / Associated with 
the Intervention. 
 ALL Grade 4 (life threatening or disabling) Events – Unless expected 
AND specifically listed in protocol as not requiring reporting. 
 ALL Grade 5 (fatal) Events regardless of study phase or attribution 
 
Note: If subject is in Long Term Follow Up, death is reported at continuing review.  
 
7.3.2 The following table outlines the required forms and reporting structure for this clinical 
trial. 
 
Study type 
Expedited reporting to 
MCC 
Expedited 
reporting to 
External Agency 
Non-
expedited 
AE 
Form 
IRB 
IIT where MCC 
investigator 
holds the IDE or 
IND 
 
Grade 2 and 3 – 
Unexpected AE 
PLUS Possibly, 
Probably or 
Definitely Related  
 
ALL Grade 4 
Unless expected 
AND listed in 
protocol as not 
requiring 
reporting. 
 
ALL Grade 5 
(fatal) Events 
FDA: 
Suspected AE that 
is serious and 
Unanticipated (not 
listed in IB or 
consent) 
OnCore  and 
DSMC 
reporting 
only 
Mandatory 
Medwatch 3500a 
for Serious and 
unanticipated 
 
OnCore for all 
others 
Yes if it meets 
the IRB 
reporting 
requirements: 
Unanticipated 
Problem and/or 
Serious AE 
(use IRB AE 
reporting form 
for all 
correspondence 
with IRB) 
 
 
 
 
 

NCI Protocol #: 
Version Date: 
 
24 
7.3.3 MCC Expedited Reporting Guidelines for MCC IITs 
 
Investigators within MCC will report SAEs directly to the MCC DSMC per the MCC 
DSMC SOP and the University of Kentucky IRB reporting policy.  
 
 
 
 
Attribution 
MCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event. 
 
 
 
7.4 
Expedited Reporting to External Agencies 
 
The Overall PI will comply with the policies of all external funding agencies and the UK IRB 
regarding expedited reporting, as per the UK IRB’s SOP: 
http://www.research.uky.edu/ori/SOPs_Policies/C4-0150-
Mandated_Reporting_to_External_Agencies_SOP.pdf. 
 
7.4.1  Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.   
 
7.4.2 Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to the UK Office of Risk Management any participant 
safety reports or sentinel events that require reporting according to institutional policy.  

NCI Protocol #: 
Version Date: 
 
25 
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
OnCore case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
8. PHARMACEUTICAL INFORMATION 
N/A 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
N/A 
 
 
 

NCI Protocol #: 
Version Date: 
 
26 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  Scans 
and x-rays must be completed <4 weeks prior to surgery.  Routine postoperative evaluation 
includes a first postop visit at 2 weeks post discharge, and a 30 day (post-surgery) follow-up visit 
to complete the study follow-up period. 
 
 
Pre- 
Study 
Admission 
2 week post discharge 
30 day post surgery 
Off Studyc 
Ultrasound / Surgery 
 
A 
 
 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Physical exam 
X 
X 
 
X 
Vital signs 
X 
X 
 
X 
Height 
X 
 
 
 
Weight 
X 
X 
 
X 
Performance status 
X 
X 
 
X 
CBC w/diff, plts 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
EKG (as indicated) 
X 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
Tumor measurements 
X 
 
Radiologic evaluation 
X 
 
S: 
[Ultrasouond/Surgery]: 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
c: 
Off-study evaluation.   
 
 
 

NCI Protocol #: 
Version Date: 
 
27 
11. MEASUREMENT OF EFFECT 
 
11.1 
Evaluation of intraoperative ultrasonography 
 
For the purposes of this study, patients will be evaluated at the time of surgery for potentially 
occult pathologic involvement of N2 nodes. Evaluation will be undertaken for determination of 
sensitivity, specificity and false positive rate for lymph nodes evaluated by VATS ultrasound. 
Intraoperative evaluation will determine the appearance of standard mediastinal lymph node 
stations as defined in section 5.2. Appearance of lymph nodes found during imaging will be 
documented, and additional nodes sampled will be labeled as such to determine whether or not 
ultrasound allowed the detection of additional pathologic nodes and therefore contributed to 
upstaging. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
This study will require data submission and reporting via the OnCore Database, which is 
the official database of the Markey Cancer Center Clinical Research and Data 
Management Shared Resource Facility (CRDM SRF).  Instructions for submitting data is 
listed in Study-Specific Data Management Plans created by CRDM SRF staff. 
 
12.1.2 Responsibility for Data Submission 
 
Study staff are responsible for submitting study data and/or data forms to OnCore as per 

NCI Protocol #: 
Version Date: 
 
28 
the Markey Cancer Center CRDM SRF SOP’s.  This trial will be monitored by the MCC 
Data and Safety Monitoring Committee (DSMC) on a schedule determined by the 
Protocol Review and Monitoring Committee at the initial PRMC review.  THE CRDM 
SRF staff is responsible for compiling and submitting data for all participants and for 
providing the data to the Principal Investigator for review.   
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a single-arm, two-stage, Phase II trial of intraoperative ultrasound in thoracoscopic 
surgery (VATS) with the primary goal of testing the upstaging rate of patients with presumed 
clinically N2 negative disease, to N2 positive disease. Secondary study endpoints include 
complication rate (see Section 1.2 above), length of surgical time, lymph nodes detected by 
ultrasound and estimation of sensitivity, specificity and false positive rate for lymph nodes 
evaluated by VATS ultrasound.  
     
  
13.2 
Sample Size/Accrual Rate 
 
A Simon’s two-stage optimum design is employed to test the null hypothesis that upstaging rate 
is equal to 2% versus an alternative equal to 8% (11).  A sample of 34 patients will be enrolled in 
the first stage.  The trial will be terminated if none of the first 34 patients were upstaged; 
otherwise, an additional 36 patients will be enrolled in the second stage (for a total of 70 
patients).  If the intervention is actually not effective at detecting N2 pathologic nodes, there is a 
0.049 probability of concluding that it is (alpha error rate of 5%) while if it effective, there is a 
0.198 probability of concluding that it is (for 80% power).  Based on the hypothesized upstaging 
rate above, if the total number of upstaged patients detected is less than equal to 3, then the 
intervention will be rejected.  

NCI Protocol #: 
Version Date: 
 
29 
 
In order to account for at most a 10% drop-out rate, a total of 78 patients will be enrolled into the 
trial.  The projected accrual rate is 30 – 40 patients per year (about 3 per month).  We expect to 
accrue patients into the study within 2 years.  
  
13.3 
Stratification Factors 
Not Applicable for this trial 
 
 
13.4 
Analysis of Primary and Secondary Endpoints 
 
Estimate of upstaging rate will be calculated along with exact 95% binomial confidence interval.  
The estimate will be adjusted given the two-stage nature of the study design.  Descriptive 
statistics including median, inter-quartile range, etc. will be calculated to summarize length of 
surgical time and number of lymph nodes detected. False positive rate, sensitivity and specificity 
of ultrasound evaluation of additional lymph nodes regarding upstaging compared with 
pathology evaluation will be calculated.  All patients who received study intervention will be 
included in safety analysis including estimation of overall complication rate and rates for each 
complication event mentioned  in section 7.0 above  using frequencies and proportions (See 
section 13.7.1 below).  
 
13.5 
Interim Analyses  
As indicated in sections 13.1 and 13.2 above, an interim analysis of upstaging rate will be 
performed after 34 patients have been accrued into the study based on a Simon’s two-stage 
optimum design.  
 
13.6 
Data Management 
The study statistician and staff from the Biostatistics Shared Resource Facility (BSRF) of the 
Markey Cancer Center will work closely with the study PI and the Clinical Research and Data 
Management (CRDM SRF) at Markey in the development of eCRFs for the study.  Specifically, 

NCI Protocol #: 
Version Date: 
 
30 
the statisticians will attend several meetings including the Protocol Initiation Meeting (PIM) to 
address all statistical considerations for this protocol including incorporation of interim 
monitoring plans to assess upstaging rate, appropriate and accurate collection of primary and 
secondary study endpoints and inclusion of valid values and range checks for data fields.  The 
OnCore clinical trial management system, managed by Markey’s CRDM SRF, will be the 
primary database repository of clinical data from all patients enrolled into this trial.  Data will be 
accessed by the study statistical on a regularly-scheduled basis to perform statistical 
programming for conduct of data quality control, data management, generation of interim reports 
and statistical analysis.  The BSRF has developed an automated mechanism for generating the 
interim trigger for assessment of upstaging rates as indicated in section 13.2 and 13.5 above.  In 
collaboration with the study team, procedures will be developed for timelines for data quality 
control, resolution of data queries, interim reporting and final data analysis,  
 
13.7 
For phase 2 protocols only: Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity/Safety 
All enrolled patients will be included in the safety analysis. Specifically, the following safety 
parameters will be evaluated: Any occurrence of injury related to VATS ultrasound, incidence of 
hoarseness attributable to recurrent laryngeal nerve injury, incidence of chylothorax. In addition, 
any evaluation which has not been completed within 30 minutes will be noted as a safety issue 
due to prolonging operative time. Incidence tables will be generated to summarize incidence of 
patients reporting at least one episode of each specific adverse event and incidence of serious 
adverse events. The total number of episodes for each event reported (Frequency Table), the 
severity and attribution to study intervention of each episode reported (Severity Table and 
Attribution Table) will also be displayed. Listings of adverse events by patients will include the 
time to onset, the duration of each event, the severity of each event, and the relationship of the 
event to study intervention, whether it was a serious event, and whether it caused withdrawal. 
Toxicities will be graded according to Common Toxicity Criteria (CTCAE) v4.0.   
  
 

NCI Protocol #: 
Version Date: 
 
31 
 
REFERENCES 
 
1. 
Lung Cancer Statistics. 2013 [cited 2013 5/22/13]; Available from: 
http://www.cancer.org/cancer/lungcancer-non-smallcell/overviewguide/lung-cancer-non-small-
cell-overview-key-statistics. 
2. 
Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest. 
2009;136(1):260-71. Epub 2009/07/09. 
3. 
D'Amico TA, Niland J, Mamet R, Zornosa C, Dexter EU, Onaitis MW. Efficacy of 
mediastinal lymph node dissection during lobectomy for lung cancer by thoracoscopy and 
thoracotomy. The Annals of thoracic surgery. 2011;92(1):226-31; discussion 31-2. Epub 
2011/07/02. 
4. 
Licht PB, Jorgensen OD, Ladegaard L, Jakobsen E. A National Study of Nodal 
Upstaging After Thoracoscopic Versus Open Lobectomy for Clinical Stage I Lung Cancer. The 
Annals of thoracic surgery. 2013. Epub 2013/05/21. 
5. 
Puri V, Meyers BF. Video-assisted thoracoscopic surgery lobectomy for lung cancer. 
Surgical oncology clinics of North America. 2013;22(1):27-38, v. Epub 2012/11/20. 
6. 
D'Amico TA. Long-term outcomes of thoracoscopic lobectomy. Thoracic surgery 
clinics. 2008;18(3):259-62. Epub 2008/10/04. 
7. 
Hariharan D, Constantinides V, Kocher HM, Tekkis PP. The role of laparoscopy and 
laparoscopic ultrasound in the preoperative staging of patients with resectable colorectal liver 
metastases: a meta-analysis. American journal of surgery. 2012;204(1):84-92. Epub 2012/01/17. 
8. 
Hottenrott C. Endoscopic and laparoscopic ultrasonography used to predict tumor 
staging and improve therapeutic decisions for upper gastrointestinal tract cancer. Surgical 
endoscopy. 2012;26(1):280-1. Epub 2011/07/27. 
9. 
Soliman HO, Gad ZS, Mahmoud AM, Farahat AM, Abdelrazek NM, Gareer WY. 
Laparoscopy with laparoscopic ultrasound for pretreatment staging of hepatic focal lesions: a 
prospective study. Journal of the Egyptian National Cancer Institute. 2011;23(4):141-5. Epub 
2012/07/11. 
10. 
Wynants J, Stroobants S, Dooms C, Vansteenkiste J. Staging of lung cancer. 

NCI Protocol #: 
Version Date: 
 
32 
Radiologic clinics of North America. 2007;45(4):609-25, v. Epub 2007/08/21.  
11. 
Simon R.  Optimal two-stage designs for Phase II clinical trials.  Controlled Clinical 
Trials, 10:1- 10, 1989. 
 

NCI Protocol #: 
Version Date: 
 
33 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 

NCI Protocol #: 
Version Date: 
 
34 
APPENDIX B CASE RECORD FORM  

A single-arm, Phase II study of thoracoscopic lung cancer staging with the use of Intraoperative Ultrasound at the time of 
definitive resection 
 
1. Preoperative 
a. 
Name / MRN __________________ 
b. Age  ________ 
c. 
Gender  M / F 
d. ECOG status ____ 
e. 
Physiologic parameters 
i. ECHO: Ejection Fraction (EF) ___ 
% 
f. 
PFTs 
i. FEV1 (% predicted) ____ % 
ii. DLCO if done   ____ % 
g. Clinical Stage: 
i. CT data –  nodule size ___ mm 
ii. PET data  
– nodule size / nodes _____  
iii. Brain MRI – done, positive / 
negative _____ 
iv. Discussed at Multi-Disciplinary 
conference Y/N – outcome 
h. Planned resection: 
i. Lobectomy / Wedge / Other 
ii. Surgeon : _______________ 
iii. Surgeon for Ultrasound: 
_______________ 
 
 
 
 
 
2. Intraoperative 
a. 
Surgeon : ___________ 
b. Operative time (exclusive of ultrasound time) : ______ 
c. 
Blood loss: ______ ml 
d. Surgical approach : __________ 
e. 
Surgeon comments about the case : ____________ 
 
 
3. Intraoperative Ultrasound 
a. 
Sonographer: ___________ 
b. Ultrasound time: ______________ 
c. 
Lymph node stations examined  
i. Paratracheal ___ 
ii. Subcarinal ___ 
iii. Prevascular ___ 
iv. Infrahilar ___ 
d. Ultrasound findings 
i. Number of suspicious nodes identified : ______ 
ii. Number of nodes retrieved : ______ 
iii. Maximal size of additional lymph node by ultrasound criteria: ______ 
 
4. Postoperative, inpatient 
a. 
Length of stay : ______d 
b. Chest tube duration : ______ d 
c. 
Chest tube daily drainage (daily) 
i. ___ ___ ___ ___ ___  
d. Need for any additional procedures : ______ 
e. 
Surgeon comments on postoperative stay: ______ 
 
5. Postoperative, followup 
a. 
Final pathologic staging : ______ 
T, N, M 
b. Was N staging affected by the Ultrasound screening? : ______ 
c. 
Postoperative comments, concerns, complications. : ______ 
_________________________________________________ 
_________________________________________________