Conditions: Stage I Endometrial Carcinoma Stage II Endometrial Carcinoma Stage III Endometrial Carcinoma Stage IV Endometrial Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 58
Healthy volunteers: no

Brief summary:
This clinical trial studies lymph node mapping in patients with newly diagnosed endometrial cancer undergoing surgery. Lymph node mapping may help in planning surgery to remove endometrial cancer and affected lymph nodes.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the detection rate, sensitivity, and negative predictive value of sentinel lymph node (SLN) biopsy in endometrial cancer patients.

SECONDARY OBJECTIVES:

I. To compare different surgical modalities (open procedures, minimally invasive procedures, and single-site technology) and different injectants (isosulfan blue and indocyanine green) for SLN biopsy.

II. To determine total operating room time (from the time the patient enters the room to the time the patient leaves the room) as well as console time (robotic)/operating time for minimally invasive procedures.

OUTLINE:

Patients undergo SLN mapping using isosulfan blue and/or indocyanine green solution injected directly into the cervix. Following SLN identification and biopsy, patients undergo hysterectomy, bilateral salpingo-oophorectomy, and/or complete pelvic lymphadenectomy. Patients expressing SLN positive for metastasis undergo para-aortic lymphadenectomy.

After completion of study treatment, patients are followed up at 2-4 weeks.

Arms:
arm 1: Patients undergo SLN mapping using isosulfan blue and/or indocyanine green solution injected directly into the cervix. Following SLN identification and biopsy, patients undergo hysterectomy, bilateral salpingo-oophorectomy, and/or complete pelvic lymphadenectomy. Patients expressing SLN positive for metastasis undergo para-aortic lymphadenectomy.

Interventions: intervention 1: lymph node mapping intervention 2: sentinel lymph node biopsy intervention 3: isosulfan blue intervention 4: indocyanine green solution intervention 5: therapeutic conventional surgery intervention 6: lymphadenectomy
Intervention descriptions: intervention 1: Undergo lymph node mapping using isosulfan blue and/or indocyanine green solution intervention 2: Undergo SLN biopsy intervention 3: Undergo lymph node mapping using isosulfan blue and/or indocyanine green solution intervention 4: Undergo lymph node mapping using isosulfan blue and/or indocyanine green solution intervention 5: Undergo hysterectomy, bilateral salpingo-oophorectomy and/or complete pelvic lymphadenectomy intervention 6: Undergo para-aortic lymphadenectomy

Protocol document:
Prot_SAP_000.pdf: 
 
Cleveland Clinic _ Sentinel Lymph Node Mapping for Endometrial Cancer  
Protocol Version 3: 8/2/13 
 
2 
 
STUDY NUMBER:  CASE 9813 
 
STUDY TITLE:   
Sentinel Lymph Node Mapping for Endometrial Cancer 
 
 
 
 
PRINCIPAL INVESTIGATOR: Chad Michener, MD 
The Cleveland Clinic  
9500 Euclid Avenue, Desk A81 
 
 
 
 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
216-444-6601 
michenc@ccf.org 
 
CO-INVESTIGATOR: 
 
Kimberly L Levinson, MD MPH 
The Cleveland Clinic  
9500 Euclid Avenue, Desk A81 
 
 
 
 
Cleveland, OH   44195 
216-444-4884  
 
 
 
levinsk@ccf.org 
 
CO- INVESTIGATOR:  
Peter G Rose, MD 
The Cleveland Clinic  
9500 Euclid Avenue, Desk A81 
 
 
 
 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
216-444-1712 
 
 
 
 
roseg@ccf.org  
 
CO- INVESTIGATOR:  
Mehdi Moslemi-Kebria, MD 
The Cleveland Clinic  
9500 Euclid Avenue, Desk A81 
 
 
 
 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
216-444-4884 
 
 
 
 
kebriam@ccf.org 
 
CO- INVESTIGATOR:  
Jason Knight, MD 
The Cleveland Clinic  
9500 Euclid Avenue, Desk A81 
 
 
 
 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
216-444-4884 
 
 
 
 
knightj@ccf.org 
 
 
CO- INVESTIGATOR:  
Robert DeBernardo, MD 
 
                                    The Cleveland Clinic  
                                                      9500 Euclid Ave. Desk A81 
 
 
 
 
Cleveland, OH  44195 
                                                       216-444-7645 
                                                       DEBERNR@ccf.org 


 
Cleveland Clinic _ Sentinel Lymph Node Mapping for Endometrial Cancer  
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STUDY COORDINATOR: 
Lynn Borzi, RN 
The Cleveland Clinic  
9500 Euclid Avenue, Desk A80 
 
 
 
 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
216-445-3158 
 
 
 
 
borzil@ccf.org 
 
 
STUDY COORDINATOR: 
Agnes Medrick, RN, BSN 
The Cleveland Clinic  
9500 Euclid Avenue, Desk A81 
 
 
 
 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
216-444-6343 
 
 
 
 
medrica@ccf.org 
 
STUDY COORDINATOR: 
Donna White, RN BSN 
The Cleveland Clinic  
9500 Euclid Avenue, Desk A81 
 
 
 
 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
216-444-3414 
 
 
 
 
whited11@ccf.org 
 
STATISTICIAN:  
 
Benjamin Nutter 
 
The Cleveland Clinic 
9500 Euclid Ave 
 
 
 
Cleveland, OH 44195  
 
 
 
216-445-1365 
 
 
 
 
nutterb@ccf.org 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
SCHEMA 
 
1.0  
INTRODUCTION  
 
1.1 
Endometrial Cancer and Treatment  
1.2  
Sentinel Lymph Node Biopsy 
1.3  
Sentinel Lymph Node Biopsy in Endometrial Cancer 
1.4 
Clinical Data –Techniques for Sentinel Lymph Node Biopsy in Endometrial Cancer 
1.4.1 Injection Site 
1.4.2 Detection Method 
1.4.3 An algorithm for Sentinel Lymph Node Biopsy 
1.4.4 Surgical Modality and Sentinel Lymph Node Biopsy 
1.5 
Rationale 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
 
3.0 
STUDY DESIGN 
3.1 
Study Design 
3.2 
Number of Subjects 
3.3 
Expected Duration of Subject Participation 
3.4.1 Duration of Therapy 
3.4.2 Duration of Follow-up 
 
4.0  
PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
 
5.0 
REGISTRATION  
5.1 
Registration 
 
6.0  
TREATMENT PLAN 
6.1 
Isosulfan Blue and Indocyanine Green 
6.2 
Intervention  
6.2 
Duration of Therapy 
6.3 
Duration of Follow Up 
 
7.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
7.1 
Adverse Events and Potential Risk List  
 
8.1.1 Name of Agent 
7.2 
Definitions 


 
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7.2.1  Adverse Events 
7.2.2  Significance of an Adverse Event 
7.2.3  Serious Adverse Events 
7.2.4  Expectedness 
7.2.5  Attribution 
7.3 
Reporting Procedures for All Adverse Events 
7.4 
Serious Adverse Event Reporting Procedures 
7.5 
Data Safety Toxicity Committee    
 
 
 
8.0       PHARMACEUTICAL INFORMATION  
 
8.1  
Isosulfan Blue 
 
8.2  
Indocyanine Green 
 
  9.0 
STUDY PARAMETERS AND CALENDAR 
 9.1  
Study Parameters 
 9.1.1 Screening Evaluation 
 9.1.2 Study Parameters 
 9.2  
Calendar 
 
 10.0 
MEASUREMENT OF EFFECT choose solid tumor or hematologic tumors 
 10.1 
Sentinel Node Biopsy Evaluation  
 10.1.1 Definitions 
 
 
 11.0 
DATA REPORTING/REGULATORY CONSIDERATIONS 
 11.1 
Data Reporting 
 11.2 
Regulatory Considerations  
 11.2.1 Written Informed Consent 
 11.2.2 Subject Data Protection 
 11.2.3 Retention of Records 
 11.2.4 Audits and Inspections 
 11.2.5 Data Safety and Monitoring Plan 
 
 
 12.0 
STATISTICAL CONSIDERATIONS 
 
 Appendix A: Inclusion and Exclusion Criteria form  
 
 
REFERENCES 
 


 
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1.0 
INTRODUCTION 
 
1.1 
Endometrial Cancer and Treatment 
  
The incidence of endometrial cancer in the United States in 2008 was 40,100, with 7,470 
deaths from this disease [1]. The majority of patients diagnosed with uterine cancer are 
diagnosed at an early stage (FIGO stage I), when surgical resection often leads to a good 
prognosis [2]. While hysterectomy and bilateral salpingo-oophorectomy are the standard of 
care for stage I tumors, the role for lymphadenectomy is still highly debated. This is due to 
the fact that there are significant risks associated with this procedure, including increased 
operative time and surgical complications, lymphedema, and lymphocyst formation [3]. 
Furthermore, evidence suggests that lymphadenectomy for stage I disease affords no 
improvement in overall or recurrence free survival [4]. Nonetheless, approximately 10% of 
women with stage I disease will have metastases to the pelvic lymph nodes, a finding which 
changes both the treatment recommendations and prognosis for the patient [5].  
For this reason, SLN sampling is a surgical procedure that has gained enthusiasm as a 
means of identifying those patients who should be upstaged. This technique has been shown 
to be more accurate than MRI or CT scan [6], but without the risks associated with complete 
lymphadenectomy [7]. 
In higher risk disease (both higher stage as well as for tumors with intermediate risk 
factors), the role of SLN biopsy also remains unclear. While lymphadenectomy remains the 
standard of care in this patient population, SLN biopsy may be useful in patients who either 
refuse lymphadenectomy or for those patients who are unable to undergo this procedure due 
to surgical risk factors. 
 
1.2 
Sentinel Lymph Node Biopsy 
 
The theory behind SLN biopsy is that the sentinel node is the first node in the lymphatic 
drainage pattern from a tumor; therefore, if this node is negative for metastasis, the remaining 
nodes should also be negative [8]. Techniques to identify the sentinel lymph node include 
injection of dye or radioisotope (most often into the tumor site), which then travels through 
the lymphatic system to the sentinel node. This node is then detected either by visualization 
(if dye is used) and/or by a gamma probe and specialized imaging (for radioisotope 
localization).  Once the sentinel node has been identified, the node is removed and sent to 
pathology to be examined for evidence of metastases. Pathologists are now using advanced 
techniques such as ultrastaging and immunohistochemistry to help reveal micrometastases 
[9,10].  If metastases are noted, then a complete lymphadenectomy is carried out. If no 
metastasis is evident in the sentinel node, then further dissection is not necessary [11]. While 
the literature suggests that there is a learning curve for surgeons utilizing this technique, after 
approximately 30 cases [12,13], SLN biopsy can be performed with good and reliable results 
[11]. 
This concept was first described by Cabanas in 1977 [14]. Subsequently, significant work 
was done in both melanoma [15] and breast cancers [8], where sentinel lymph node biopsy, 
rather than complete lymphadenectomy, has become accepted as routine practice [16]. The 
approval of this technique in these cancers is based on significant evidence showing that the 
correct sentinel node from a tumor could be determined with high sensitivity and low false 


 
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negative rate [11]. This means that there must be few cases in which the sentinel node is 
negative, while a positive node went unidentified.  
 
 
 
1.3  Sentinel Lymph Node Biopsy in Endometrial Cancer  
 
Burke et al. first introduced SLN biopsy for endometrial cancer in 1996[17]; however this 
technique has only more recently begun further evaluation as of the 21st century. Kang et al 
performed a recent meta-analysis in 2011, which identified the current body of evidence 
available. Through an extensive literature search, this manuscript identified 26 studies on 
sentinel lymph node biopsy in endometrial cancer (see Table 1) [18].  
 
Table 1. (from Kang et al.) [18] Meta-analysis of 26 studies 
 
Authors 
Year 
N 
Injection 
site 
Route of surgery 
Detection 
method 
Pathology 
Assessment 
Study 
Burke et al. 
1996 
15 
SM 
Laparotomy 
Dye only 
HE 
Unknown 
Gargiulo et al. 
2003 
11 
C 
Laparoscopy 
Both 
HE/IHC 
Unknown 
Pelosi et al. 
2003 
16 
C 
Laparoscopy 
Both  
HE/IHC 
Unknown 
Petynski et al. 
2003 
33 
SM/C 
N/S 
Both 
N/A 
Unknown 
Fersis et al 
2004 
10 
HS 
Laparotomy 
Isotope only 
HE 
Unknown 
Houb et al. 
2004 
25 
SM/C 
Laparoscopy 
Dye only 
HE 
Unknown 
Lelievre et al. 
2004 
12 
C 
Laparotomy/scopy 
Both 
HE/IHC 
Prospective 
Niikura et al. 
2004 
28 
HS 
Laparotomy 
Isotope only 
HE/IHC 
Unknown 
Gien et al. 
2005 
16 
HS 
Laparotomy 
Dye only 
HE 
Unknown 
Maccauro et al. 
2005 
26 
HS 
Laparotomy 
Both  
HE/IHC 
Unknown 
Dzvincuk et al. 
2006 
33 
C 
Laparotomy/scopy 
Isotope only 
N/A 
Prospective 
Altgassen et al. 
2007 
23 
SM 
Laparotomy 
Dye only 
HE/IHC 
Unknown 
Dealoye et al. 
2007 
60 
HS 
Laparotomy/scopy 
Both 
HE/IHC 
Unknown 
Frumovitz et al. 
2007 
18 
SM 
Laparotomy 
Both 
HE  
Prospective 
Li et al. 
2007 
20 
SM 
Laparotomy 
Dye only  
HE 
Unknown 
Lopes et al. 
2007 
40 
SM 
Laparotomy 
Dye only 
HE/IHC 
Unknown 
Ballester e al. 
2008 
46 
C 
Laparotomy/scopy 
Both  
HE/IHC 
Unknown 
Bats et al. 
2008 
43 
C 
Laparotomy/scopy 
Both 
HE/IHC 
Prospective 
Perrone et al. 
2008 
40 
HS, C 
Laparoscopy 
Isotope only 
HE/IHC 
Unknown 
Robova et al. 
2009 
91 
SM/H  
Laparotomy 
Both 
HE  
Prospective 
Vidal-Sicart et al. 
2009 
35 
N/A 
N/A 
Isotope only 
N/A 
Unknown 
Zenzola et al. 
2009 
14 
C 
Laparotomy 
Both 
N/A 
Unknown 
Feranec et al. 
2010 
21 
HS 
Laparotomy 
Both  
N/A 
Unknown 
Mais et al. 
2010 
34 
C 
Laparotomy/scopy 
Dye only 
HE/IHC 
Prospective 
Ballester et al. 
2011 
125 
C 
Laparotomy/scopy 
Both 
HE/IHC 
Prospective 
Khoury-Collado 
et al. 
2011 
266 
C, 
C/SM 
Laparotomy/scopy 
Dye only, 
both 
HE/IHC 
Prospective 
 
N/A = not available; SM = subserosal myometrium; C = cervix; HS = hysteroscopic; HE = 
hematoxylin-eosin staining; IHC = immunohistochemistry. 


 
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This meta-analysis reported a detection rate of 78% and a sensitivity of 93% for sentinel 
lymph node biopsy. From this study, assuming a 10% metastasis risk, a false negative rate of 
1% was calculated [18].  
Since the publication of this meta-analysis, there have been four additional prospective 
studies on SLN biopsy in endometrial cancer that these authors were able to identify. 
Examining the results from these 4 prospective trials, sensitivity of SLN biopsy is high, and 
negative predictive value (NPV) is also relatively high (Table 2.). 
 
Table 2. Results from recent prospective studies 
 
 
Author 
Year 
Type 
Pts 
Detection 
Inj 
Procedure 
Detection Sens 
NPV 
How 
2012 
Prospective 
100 
Isotope 
C 
Robotic 
92% 
89% 
99% 
Solima 
2012 
Prospectve 
59 
Isotope 
H 
Ex-lap or LSC 
95% 
90% 
98% 
Buda 
2012 
Prospective 
25 
Isotope/ISB 
C 
Ex-lap or LSC 
91% 
100% 
Unk 
Ballester 
2011 
Prospective 
125 
Isotope/ISB 
C 
Ex-lap or LSC 
89% 
84% 
97% 
 
While the evidence that exists is encouraging, it is important to recognize that we are 
still in the early stages of analysis of SLN biopsy in endometrial cancer. The number of 
patients studied thus far does not yet allow us to get an accurate sense of the true false-
negative rate [3], and large, prospective, randomized controlled trials will be necessary to 
validate these findings. 
 
1.4  
Clinical Data-Techniques for Sentinel Lymph Node biopsy in Endometrial 
Cancer 
 
While SLN biopsy appears to be a promising development in the treatment of 
endometrial cancer, several details regarding the techniques utilized must also be clarified. 
Two areas that remain controversial are the ideal site of injection, and the detection method 
utilized (dye versus isotope versus both isotope and dye, versus new techniques using ICG). 
To date, the studies that have been done have utilized a variety of these techniques, and it 
remains unclear which provide the most optimal results (Table 1). 
 
1.4.1  Injection Site 
 
Anatomically, the lymphatic drainage from the uterus is complex, with the lower uterine 
segment draining to the pelvic lymph nodes, and the upper segment draining to the para-
aortic nodes. For this reason, injection site for SLN biopsy in endometrial cancer has been 
brought into question. Three sites of injection have been explored and reported: 1. uterine 
subserosa (7 studies with detection rates ranging from  0-92%), 2. cervix (7 studies [with or 
without additional injection into the myometrium] with detection rates ranging from 83-
100%), and 3. endometrium, via hysteroscopy (5 studies with detection rates from 0-100%) 
[3]. While all 3 sites have shown high detection rates, there are several advantages to 
performing the injection into the cervix.  
Although cervical and endometrial lymphatic spread patterns are different, deep injection 
into the cervix has demonstrated that the proper areas of drainage are reached [3], with good 


 
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penetration to the uterine vessels, parametria, lower uterine segment, and to the cornua [19], 
Accordingly, a recent meta-analysis showed that peri-cervical injection was associated with a 
statistically significant increase in detection rate of sentinel node when compared with other 
sites [18]. Additionally, injection into the cervix is technically advantageous as this is the 
easiest site to reach pre-operatively [3]. The trend in the literature is also toward cervical 
injection, with the 4 most recent prospective studies utilizing this technique (see Table 1). 
 
1.4.2  Detection Method 
 
Blue dye alone, radioisotope alone, or combinations of both detection methods have all 
been utilized in the literature (see Table 1), and while the optimal strategy remains unknown, 
each technique has advantages and disadvantages. The major disadvantages of isotope 
injection are that it must be performed on either the day before or the morning of surgery. 
Furthermore, this must be done in the nuclear medicine department, and it therefore requires 
extensive logistical coordination and preparation in order to optimize results [20]. This 
technique can therefore be technically challenging as well as costly. The injection of dye is 
much simpler, as it is injected immediately prior to surgery, and additional dye can be 
injected if needed [19]. It is additionally less costly. While allergic reactions to dye are rare 
(<1%) and often mild, severe allergic reactions have been reported [19]. 
The evidence for the optimal technique is inconsistent, with some evidence suggesting 
that the detection rates are equivalent and some suggesting that the combination of isotope 
and blue dye injection is superior [7]. However, due to the logistical challenges and cost 
associated with isotope injection, the cost-benefit of adding this technique is unclear. 
Furthermore, evidence from gynecologic oncology literature suggests a similar learning 
curve for SLN biopsy, with approximately 30 cases as the plateau point [10].  Some evidence 
suggests that experience of the surgeon rather than detection method is the more critical 
factor in the detection rate [18].  
 
New detection methods and techniques are also currently being investigated, such as 
the use of fluorescing dye. While further studies are needed to compare these methods to 
conventional blue dye and isotopes, studies that have utilized ICG in other sites are very 
promising. ICG is a tricarbocyanine dye that fluoresces in the near infrared spectrum when 
illuminated with 806nm light. The fluorescent light is then captured with a special video 
camera device that allows the ICG to be displayed in the visible light spectrum. ICG is highly 
water-soluble and rapidly binds to plasma proteins, qualities that make it useful for 
assessment of blood flow [21]. Therefore, it has been used surgically to assess patency of 
grafts in vascular surgery [22], coronary artery bypass grafting [21], transplant surgery and 
plastic surgery procedures that require flap reconstruction [23]. Because ICG binds to 
albumin and therefore has a propensity for lymphatic tissue, in the early 2000’s, it was first 
hypothesized that ICG might be a useful injectant for sentinel node identification. In 2005, 
Kitai et al investigated the use of ICG for SLN biopsy in breast cancer and were the first to 
propose that the use of ICG could improve both detection rate and negative predictive value 
of SLN biopsy in breast cancer [24]. This technique has become more popular, particularly 
for SLN biopsy in breast cancer [25] and melanoma, and recent data suggests that the 
lymphatic drainage pattern of ICG is identical to that of radioisotope [26]. There are only 2 
studies that have utilized ICG for sentinel node detection in endometrial cancer. The first 
study found that ICG was superior to isosulfan blue for SLN detection and that by using a 


 
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combination of ICG and isosulfan blue, a 100% detection rate could be achieved [27]. The 
other study was a feasibility study for sentinel lymph node biopsy utilizing robotics in both 
endometrial and cervical cancer patients. This study showed a comparable detection rate to 
isotope and blue dye in a small sample [28]. 
 
1.4.3 An Algorithm for Sentinel Lymph Node Biopsy 
 
In a recent report by Barlin et al., the use of a sentinel lymph node mapping algorithm for 
endometrial cancer was introduced. These authors propose that by following this algorithm, 
the false-negative rate for SLN biopsy can be minimized. This algorithm is as follows: 
evaluation of the peritoneum and serosa via washings, evaluation of the retroperitoneal 
lymph nodes via mapping for the SLN and removal of any suspicious node. If there is no 
mapping to a hemi-pelvis, a complete pelvic lymphadenectomy should be performed on that 
side. Para-aortic lymphadenectomy should be performed at the discretion of the surgeon 
(please see Figure 1). Utilizing this algorithm may help to further diminish the false-negative 
rate of SLN biopsy, even in more high risk stage I endometrial cancers [29].  
 
Figure 1. (From Barlin et al. [29])  Surgical algorithm for endometrial cancer 
 
 
1.4.4 Surgical Modality and Sentinel Lymph Node Biopsy 
 
To our knowledge, thus far, sentinel lymph node biopsy procedures have been performed 
by laparotomy, conventional laparoscopy, and conventional robotics. Evidence suggests that 
minimally invasive techniques, including laparoscopy and robotics, should now be the 
standard of care for endometrial cancer [30], however, at times, open procedures may also be 


 
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necessary. Single-port laparoscopy is also now being utilized for endometrial cancer cases 
[31], yet, to our knowledge, there are no reports of single-port technology utilized for 
sentinel lymph node biopsy. While there is still limited prospective data on the benefits of 
single-port techniques, the available data suggests that outcomes for single-port laparoscopy 
are similar to those of conventional laparoscopy, with the added benefit of improved 
cosmesis and decreased pain [32].  
The most recent advance in single-port technology is the single-port robot, which is now 
FDA-approved for gynecologic cases [33]. Robotic technology has provided improved 
optics, improved range of motion, and a shorter learning curve when compared to 
conventional laparoscopy [34]. A recent study by Escobar et al. compared LESS surgery to 
conventional LSC and robotic surgery for endometrial cancer and found no difference in 
outcomes [35]. In a recent study by Rossi et al, the robot was utilized to perform SLN biopsy 
in both endometrial and cervical cancers. The findings in this study suggest that robotics 
might have additional advantages specific for SLN biopsy procedure. This study showed a 
relatively short operating room time (186 min from patient entry into the room until exiting 
the room), as well as the ability to utilize new and integrated technologies (a fluorescence 
imager) [28]. These advantages will also translate to single-port robotics as technology 
develops [31].  
 
1.5.  
Rationale 
 
By performing sentinel lymph node biopsy for endometrial cancer, we may be able to 
further minimize the risks of lymph node evaluation, while continuing to obtain critical 
prognostic information for patients. In this study, we examine detection rates, false negative 
rates, and negative predictive value of SLN biopsy for endometrial cancer in order to further 
add to the body of evidence on SLN biopsy for endometrial cancer. 
 
 
 


 
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2.0  
OBJECTIVES 
 
2.1  
Primary Objective  
 
To determine the detection rate, sensitivity, and negative predictive value of SLN biopsy in 
endometrial cancer patients. 
 
2.2 
Secondary Objective(s) 
 
To compare different surgical modalities (open procedures, minimally invasive procedures, 
and single-site technology) and different injectants (isosulfan blue and indocyanine green) 
for SLN biopsy. 
 
To determine total operating room time (from the time the patient enters the room to the time 
the patient leaves the room) as well as console time (robotic)/ operating time for minimally 
invasive procedures.  
 
 


 
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3.0  
STUDY DESIGN 
 
3.1  
Study design  
 
This is a prospective cohort analysis. Consecutive, eligible, consenting patients will be 
enrolled into the study, and data will be collected on their operative procedure and pathology.  
 
3.2  
Number of Subjects 
 
For this study, a sample size of 200 patients will initially be included. This sample size 
was calculated using the Raosoft sample size calculator online (available at 
http://www.raosoft.com/samplesize.html). A 5% margin of error was used, with a 95% 
confidence interval, a population size of 20,000 (as suggested), and a 15% response 
distribution. This 15% response distribution was chosen based on 2 large randomized trials 
that showed that the rates of positive pelvic lymph nodes in patients with presumed stage I-II 
disease were 9% and 13% respectively [36, 37]. In order to ensure an adequate sample size a 
15% difference was utilized for this calculation. 
 
3.3 
Expected Duration of Subject Participation  
 
 
Participation in this study will begin at the time of the patient’s initial evaluation and will 
last through the time of their post-operative visit (approximately 6 weeks after surgery) 
 
3.4.1   Duration of Therapy 
 
There will only be one point of intervention, which will be on the day of the patient’s 
surgery. 
 
3.4.2 Duration of Follow Up 
 
Patients will be followed only until the time of their first post-operative visit.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
 
 
 


 
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4.0 
PATIENT SELECTION 
 
The form below has also been included as Appendix A: 
 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study.  Use the checklist to confirm a patient’s eligibility.  The 
checklist must be completed for each patient and must be signed and dated by the treating 
physician.   
 
Patient’s Name _____________________________________________________________ 
 
Medical Record # ___________________________________________________________ 
 
Research Nurse /  
Study Coordinator Signature: _________________________________ Date _________ 
 
Treating Physician [Print] ____________________________________________________ 
 
Treating Physician Signature:  ________________________________ Date __________ 
 
4.1 
Inclusion Criteria 
 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
 4.1.1 Women must have newly diagnosed histologically or cytologically confirmed 
Endometrial Cancer. 
 
 4.1.2 
Women should have received no prior therapy for their disease  
 
4.1.3 
Women who are planning to undergo hysterectomy, bilateral salpingo-
oophorectomy, and pelvic lymphadenectomy for the management of their endometrial cancer 
 
4.1.4 Women must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a patient from study enrollment. 
 
4.2.1 Women who are receiving any other investigational agents. 
 
4.2.2  Women with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to isosulfan blue or indocyanine green or other agents used 
in this study. 
 


 
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4.2.3 Women with hypersensitivity to phenylmethane compounds, or a history of allergic 
reaction to iodides 
 
4.2.4 
Patients with 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.  
 
4.2.5 Women with a history of prior LEEP or Cone procedures performed on their cervix 
 
4.2.6 Women with a history of lymphedema, lymphoma, or lymphatic hyperplasia 
(Castleman disease) 
 
4.2.7  Women with a history of a prior malignancy 
 
4.2.8 Women may also be excluded at the discretion of their surgeon if he or she feels that 
the patient is not an appropriate candidate. 
 
4.3 
Inclusion of Women and Minorities   
 
Members of all races and ethnic groups are eligible for this trial. 
 


 
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5.0 
REGISTRATION  
 
5.1  
Registration  
 
All subjects who have been consented are to be entered into the RedCap Database. There will 
be no further registration that is necessary for this study.  


 
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6.0  
TREATMENT PLAN 
 
6.1 
Isosulfan Blue and Indocyanine Green 
 
Isosulfan blue (Lymphazurin)1% is an aqueous solution that is available in the operating 
rooms at Cleveland Clinic Main campus and Fairview and Hillcrest campuses. It is supplied 
as a 5ml single dose vial, 1% aqueous solution in a phosphate buffer, and it is manufactured 
as a sterile and pyrogen-free product. No special storage or preparation is needed for this dye 
as it is stored at room temperature. Adverse effects only include hypersensitivity reactions, 
which occur in approximately 2% of patients. Blue discoloration of the skin may occur. No 
drug interactions are known [38]. 
Indocyanine Green is a water-soluble, tricarbocyanine dye that is comes prepared in a 
sterile solution containing 25mg of indocyanine green and 5% sodium iodide. No special 
storage is necessary for this dye. It is dissolved using sterile water and titrated to the 
appropriate concentration desired. For the purposes of this study, a 500µg dose will be 
prepared. A 25mg vial of ICG will first be reconstituted in 10cc of saline. Once dissolved,1cc 
of this ICG solution will be added to1.5cc of additional saline. This new solution will 
therefore contain 2.5mg of ICG in 2.5cc of saline (or 500 µg/0.5 cc). Adverse effects of ICG 
include anaphylactic or urticarial reactions in patients with a history of iodine allergy and 
these patients are therefore excluded from this study. The ICG is available in the operating 
rooms at both the Cleveland Clinic Main campus and Hillcrest and Fairview campuses.  
 
6.2 
Intervention  
 
Treatment must be administered only on an inpatient basis.  
 
Patients who consent to participate in this study will be scheduled for their procedure in 
the normal fashion. Procedures will not be delayed for the purpose of the study. All 
procedures will be performed via the surgical modality determined by the surgeon.  
On the day of surgery, after the patient has been placed under general anesthesia in the 
operating room, she will be placed in the dorsal lithotomy position, and she will undergo a 
routine examination under anesthesia. The patient will be prepped and draped in the usual 
sterile fashion. 
Depending upon the surgical modality utilized, access the intra-abdominal cavity will be 
obtained (either via laparotomy or minimally invasive techniques). Subsequently, attention 
will be turned to the cervix, where a spinal needle will be used to inject 2ml of isosulfan blue 
directly into the cervix (1 ml at the 3 o’clock position and 1 ml at the 9 o’clock position) and/ 
or ICG with 0.5 ml of ICG will be injected at both the 3 o’clock and 9 o’clock positions on 
the cervix. Following injection, the SLN will be identified and removed in a manner 
consistent with the algorithm proposed by Barlin et al (see Figure 1.), with sentinel lymph 
nodes removed from each hemi-pelvis [29]. After all mapped nodes are removed, they will 
be sent for pathologic examination via frozen section. Results of this analysis will be 
delivered to the surgeon via telephone call into the operating room. Subsequently, 
hysterectomy, bilateral salpingo-oophorectomy and a complete pelvic lymphadenectomy will 
be performed. All specimens removed will be sent to pathology. Para-aortic 
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back positive for metastasis. Otherwise, para-aortic lymphadenectomy will be performed at 
the discretion of the surgeon. 
If, at any time, the surgeon determines that the above protocol is inappropriate, the 
procedure will be varied in the best interest of the patient. 
 
The data that will be collected falls into three categories: demographic variables, 
procedural variables, SLN variables. The demographic variables will be collected at the time 
of the patient’s initial clinic visit. These variables will include: age, race, number of prior 
abdominal surgeries, and medical comorbidities.  
The procedural and SLN variables will be collected at the time of the procedure. The 
procedural variables that will be collected will include: surgical modality, total operating 
room time, console time (robotic)/SILS operating time, time from cervical injection to SLN 
inspection/detection, estimated blood loss, intra-operative complications, conversion to 
laparotomy (for MIS) (Figure 2.) 
 
Figure 2. Data Collection Sheet: Procedural Variables 
 
Patient ID 
Surgical 
modality 
Total OR 
time 
Console/ SILS 
operating time 
Injection – SLN 
detection 
EBL 
Complications 
Conversion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The console time/ operating time (for MIS procedures) will be documented from the 
time that the sentinel lymph node dissection begins and include the SLN biopsy, the 
hysterectomy, bilateral salpingo-oophorectomy, and complete lymph node dissection. All 
procedural variables collected will be documented at the time of surgery by either the 
Gynecologic Oncology fellow or the attending surgeon. Pathologic variables will include: the 
number of SLN detected on each hemipelvis (both by isosulfan blue and by ICG), location of 
mapped SLNs, number of positive lymph nodes (both SLN and in full lymphadenectomy), 
total number of pelvic lymph nodes dissected, total number of para-aortic lymph nodes 
dissected, histologic subtype, depth of myometrial invasion, grade, tumor size, 
lymphovascular space invasion, final stage of disease.  
 
Reported adverse events and potential risks of Isosulfan Blue and Indocyanine Green are 
described in Section 7.0.  
 
6.3  
Duration of Therapy 
 
There will only be one point of intervention, which will be on the day of the patient’s 
surgery. 
 
6.4 
Duration of Follow Up 
 
Patients will be followed only until the time of their first post-operative visit.  
 


 
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The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 


 
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7.0 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
The following is a list of AEs (Section 7.1) and the reporting requirements associated with 
observed AEs (Sections 7.3 and 7.4).  
 
The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will 
be recorded and reported immediately. 
 
7.1 
Adverse Events and Potential Risks  
  
7.1.1 Isosulfan Blue (Lymphazurin) 1% 
• hypersensitivity reactions - approximately 2% of patients 
• blue discoloration of the skin  
• No drug interactions are known [38]. 
 
7.1.2 Indocyanine Green  
• anaphylactic or urticarial reactions in patients with a history of iodine allergy  
 
7.2 
Definitions  
 
7.2.1 
Adverse Events   
 
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research or 
any underlying disease, disorder, or condition of the subject. In general, adverse events that 
are at least partially the result of (a) or (b) would be considered related to the research, 
whereas adverse events solely related to (c) or (d) would be considered unrelated to the 
research.  
 


 
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External adverse events are adverse events experienced by subjects enrolled in multicenter 
clinical trials at sites other than the site(s) over which the Institutional Review Board has 
jurisdiction.  
Internal adverse events are adverse events experienced by subjects enrolled at the site(s) 
under the IRB’s jurisdiction for either multicenter or single-center research projects.  
 
7.2.2 The significance of an adverse event is used to describe the patient/event outcome or 
action criteria associated with events that pose a threat to a patient’s life or functioning (i.e., 
moderate, severe or life threatening).  Based on the National Cancer Institute Guidelines for 
the Cancer Therapy Evaluation Program, severity can be defined by the following grades of 
events: 
 
 
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance) 
 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; non-
invasive intervention; transfusion; elective interventional radiological procedure; therapeutic 
endoscopy or operation). 
 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional radiological 
procedure; therapeutic endoscopy or operation). 
 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life-
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis; life–threatening physiologic consequences; need for intensive care or 
emergent invasive procedure; emergent interventional radiological procedure, therapeutic 
endoscopy or operation). 
 
Grades 5 are fatal adverse event resulting in death.     
 
7.2.3   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes:  
• Results in death.  
• Is a life-threatening adverse experience.  The term life-threatening in the definition 
of serious refers to an adverse event in which the subject was at risk of death at the 
time of the event.  It does not refer to an adverse event which hypothetically might 
have caused death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Any adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
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o The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a serious 
adverse event dependant on clinical judgment.  In addition where local regulatory 
authorities specifically require a more stringent definition, the local regulation takes 
precedent.  
• Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
• Is a congenital anomaly/birth defect.  
• Is an important medical event.  Important medical events that may not result death, 
be life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood disease or disorders, or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
7.2.4 Expectedness 
Adverse Events can be Expected or Unexpected. 
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
7.2.5 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
 
 


 
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7.3  
Reporting Procedures for All Adverse Events 
 
All participating investigators will assess the occurrence of AEs throughout the subject’s 
participation in the study.  Subjects will be followed for toxicity for 30 days after treatment has 
been discontinued or until death, whichever occurs first.  The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study treatment 
or participation is not the cause.   
 
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the subject which occur after the subject has signed the informed consent are fully 
recorded in the subject’s case report form, subject’s medical records, and/or any other 
institutional requirement. Source documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.   
 
The investigator will provide the following for all adverse events: 
• Description of the event 
• Date of onset and resolution 
• Grade of toxicity  
• Attribution of relatedness to the investigational agent 
• Action taken as a result of the event 
• Outcome of event 
 
In this study, descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 available at http://ctep.cancer.gov will be utilized for 
AE reporting.  
 
Investigative sites will report adverse events to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. 
 
7.4  
Serious Adverse Event Reporting Procedures 
 
Serious adverse events that occur beginning with the signing of the informed consent form, 
during treatment, or within 30 days of the last dose of treatment must be reported to The 
Cleveland Clinic Principal Investigator. 
 
Investigative sites will report serious adverse events to their respective IRB according to the 
local IRB’s policies and procedures in reporting serious adverse events. 
 
 
7.5  
Data Safety Toxicity Committee 
 


 
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It is the Case Comprehensive Cancer Center’s Principal Investigator’s responsibility to ensure 
that ALL serious adverse events are reported to the Case Comprehensive Cancer Center’s Data 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
Sponsor or other Regulatory body.  
 
 
 
 
 
 
 
 
 


 
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8.0  
PHARMACEUTICAL INFORMATION    
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8.0.    
 
 
8.1  
Lymphazurin 
 
Chemical Name:      
N-[4- [[4-(diethylamino)phenyl] (2,5-disulfophenyl) 
methylene]-2,5- cyclohexadien-1-ylidene]-N-
ethylethanaminium hydroxide 
 
 
Other Names:         
Isosulfan Blue 
 
 
Mode of Action:      
binds to serum proteins and is picked up by lymphatic vessesls 
 
Metabolism:    
10% is excreted unchanged in the urine in 24 hrs 
 
Product description:   
a sterile aqueous solution for subcutaneous administration. The 
solution contains no preservative.  
 
Solution preparation:  
Phosphate buffer in sterile, pyrogen free water is added in 
sufficient quantity to yield a final pH of 6.8-7.4. Each ml of 
solution contains 10mg Isosulfan blue, 6.6 mg sodium 
monohydrogen phosphate and 2.7mg potassium dihydrogen 
phosphate. 
 
 
Storage requirements:   
none 
 
Route of administration:  cervical 
 
Drug Procurement: Isosulfan Blue must be obtained from commercial sources.   
 
8.2  
Indocyanine Gree 
 
Chemical Name:      
sodium 4-[2-[(1E,3E,5E,7Z)-7-[1,1-dimethyl-3-(4-
sulfonatobutyl)benzo[e]indol-2-ylidene]hepta-1,3,5-trienyl]-1,1-
dimethylbenzo[e]indol-3-ium-3-yl]butane-1-sulfonate 
 
 
Other Names:         
Cardiogreen, Foxgreen, IC-Green 
 
 
Classification: 
Cyanine Dye 
 
Mode of Action:      
Peak spectral absorption at about 800 nm and therefore visible in 
the near infrared spectrum. Requires special camera device to 
visualize. Binds tightly to plasma proteins and therefore has a 
propensity for lymphatic tissue 


 
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Metabolism:    
removed by the liver and bile 
 
Product description:   
 A fluorescent dye used in medicine as an indicator substance 
 
Solution preparation:  
available in a powder form and reconstituted in sterile water 
 
 
Storage requirements:   
none 
 
Route of administration:  cervical 
 
Drug Procurement: indocyanine green must be obtained from commercial sources.   
 


 
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9.0  
STUDY PARAMETERS AND CALENDAR  
 
9.1 
Study Parameters 
 
9.1.1 Screening Evaluation   
 
Screening evaluations for inclusion and exclusion criteria will be used to determine the 
eligibility of each subject for the study. All evaluations must be completed < 30 days prior to 
administration of protocol therapy.  
 
9.1.2 Study Period 
 
The study begins at the time of pre-operative evaluation and ends at the time of the post-
operative visit.  
 
9.2 
Calendar 
 
  
Screening evaluation will be conducted within 1 day prior to administration of protocol 
therapy.  
 


 
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10.0  MEASUREMENT OF EFFECT   
 
10.1 
Sentinel Node Biopsy Evaluation 
 
For the purposes of this study, the success of sentinel node biopsy will be evaluated by the 
detection rate of the sentinel lymph node for each patient, the sensitivity of the sentinel node 
to determine the true lymph node status (metastatic disease or not), and the false negative 
rate. Definitions for these are below.  The comparator for these values will be the detection 
rate, sensitivity, and false negative rate for breast and vulvar cancers, in which sentinel 
lymph node biopsy is standard practice. In 2005, the American Society of Clinical Oncology 
stated that for breast cancer, sentinel lymph node detection rate should reach 85% with a 
false negative rate ≤ 5% [39]. In the most recent randomized trials examining sentinel lymph 
node biopsy in breast cancer, detection rates ranged from 93-97%. The false negative rates in 
the SNAC, ALMANAC, and NSABP B-32 trials ranged from 4.7% (ALMANAC) to 9.8% 
(NSABP B-32) [40, 41, 42]. In vulvar cancer, where sentinel lymph node biopsy has also 
become more widely accepted, studies similarly report detection rates ranging from 93-98% 
while false negative rates are approximately 7.7 -8.3% [43,44]. 
 
10.1.1   Definitions 
 
Sensitivity, false negative and false negative rate will be limited to those patients in whom a 
sentinel node is detected.  
 
False negative = a sentinel node that is identified and determined to be negative, however, 
upon complete lymphadenectomy, a different lymph node is found to be positive 
 
Sensitivity = the number of patients with a positive SLN over those patients with a positive 
SLN plus those patients with a false negative lymph node 
 
False negative rate = 1-sensitivity or the number of patients with a false negative SLN over 
the number of patients with a positive SLN plus those with a false negative lymph node 


 
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Our definition 
Other definition 
FN 
H 
F+H 
FN Rate 
H/D+H 
F+H/D+F+H 
Sensitivity 
D/D+H 
D/D+F+H 
NPV 
I/E 
- 
 
 
 
 


 
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11.0 
RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
11.1 
Data Reporting  
 
The RedCap Database will be utilized for data collection for both accrual entry and trial data 
management.  RedCap is a Data Management System housed on secure servers maintained at 
The Cleveland Clini.  Access to data through RedCap is restricted by user accounts and 
assigned roles.  Once logged into the RedCap system with a user ID and password, RedCap 
defines roles for each user which limits access to appropriate data.  
 
RedCap is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification.  
 
11.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws.  
11.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures.  
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility.  Subjects must also be notified that they are free to discontinue 
from the study at any time.  The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 
11.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow the 
sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 
information that includes all hospital records relevant to the study, including subjects’ medical 
history. 
 
11.2.3  Retention of records 
 
The Principal Investigator supervises the retention of all documentation of adverse events, case 
report forms, source documents, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with national and international regulations and 


 
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the institution in which the study will be conducted, or for the period specified by the sponsor, 
whichever is longer. No records will be destroyed until the Principal Investigator confirms 
destruction is permitted.  
 
11.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits 
or inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.   
11.2.5 Data Safety and Monitoring Plan 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI regulations.  


 
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12.0     STATISTICAL CONSIDERATIONS 
 
Numerical values will be summarized by mean and standard deviation when the data 
have an approximately normal distribution; otherwise they will be summarized by median 
and interquartile range.  Normality will be evaluated through visual inspection of histograms,  
boxplots, and normal QQ plots.  Analyses specific to each aim are listed below.  Secondary 
multivariable analysis may included logistic regression using metastasis as the dependent 
variable with type of dy utilized, surgical modality, surgeon, tumor stage, grade and presence 
of lymphovascular space invasion as independent variables.  Significance will be determined 
by a p-value less than or equal to 0.05 unless otherwise stated.   
 
Specific Aim 1: 
Sensitivity, specificity, and negative predictive value of SLN biopsy for detecting 
metastasis will be estimated and appropriate 95% confidence intervals for each value will be 
provided. 
Specific Aim 2: 
Sensitivity, specificity, and negative predictive value of SLN biopsy for detecting 
metastasis will be compared between surgical modalities using pairwise comparisons for 
each surgical modality.  Comparisons will be perfomed using two sample tests of proportions 
based on a normal approximation.  Since three such pairwise comparisons are required, 
significance will be determined by a Bonferonni adjusted significance level of 0.05 / 3 = 
0.17. 
Specific Aim 3: 
Sensitivity, specificity, and negative predictive value of SLN biopsy for detecting 
metastasis will be compared between injectants utilized using a two sample test of 
proportions based on a normal approximation. 
Specific Aim 4: 
Total operating room time will be estimated as a mean with 95% confidence interval if 
the data have an approximately normal distribution.  Otherwise, the median and a 
bootstrapped 95% confidence interval for the median will be reported.  Similar summaries 
will be provided for the console time (robotic)/ operating time. 
 
 


 
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Appendix A: 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study.  Use the checklist to confirm a patient’s eligibility.  The 
checklist must be completed for each patient and must be signed and dated by the treating 
physician.   
 
Patient’s Name _____________________________________________________________ 
 
Medical Record # ___________________________________________________________ 
 
Research Nurse /  
Study Coordinator Signature: _________________________________ Date _________ 
 
Treating Physician [Print] ____________________________________________________ 
 
Treating Physician Signature:  ________________________________ Date __________ 
 
 
Inclusion Criteria 
 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
 
Women must have newly diagnosed histologically or cytologically confirmed 
Endometrial Cancer. 
 
 
Women should have received no prior therapy for their disease  
 
 
Women who are planning to undergo hysterectomy, bilateral salpingo-
oophorectomy, and possible pelvic lymphadenectomy for the management of their 
endometrial cancer 
 
 
Women must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
 
Exclusion Criteria 
 
The presence of any of the following will exclude a patient from study enrollment. 
 
 
Women who are receiving any other investigational agents. 
 
 
Women with a history of allergic reactions attributed to compounds of similar chemical 
or biologic composition to isosulfan blue or indocyanine green or other agents used in this 
study. 
 


 
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Women with hypersensitivity to phenylmethane compounds, or a history of allergic 
reaction to iodides 
 
 
Patients with 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.  
 
 
Women with a history of prior LEEP or Cone procedures performed on their cervix 
 
 
Women with a history of lymphedema, lymphoma, or lymphatic hyperplasia 
(Castleman disease) 
 
 
Women with a history of a prior malignancy 
 
 
Women may also be excluded at the discretion of their surgeon if he or she feels that 
the patient is not an appropriate candidate. 
 


 
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REFERENCES 
[1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71-96.  
[2] Creasman WT, Odicino F, Maisonneuve P et al. Carcinoma of the corpus uteri. J Epidemiol 
Biostat 2001; 6: 47-86. 
[3] Khoury-Collado F., Abu-Rustum NR. Lymphatic mapping in endometrial cancer: a literature 
review of current techniques and results. Int J Gynecol Cancer (2008); 16: 1163-68. 
[4] ASTEC study group, Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of 
systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomized 
study. Lancet 2009; 373 (9658): 125-36.  
[5] Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical 
pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. 
Cancer 1987; 60 (suppl): 2035–41. 
[6] Selman TJ, Mann CH, Zamora J, Khan KS. A systematic review of tests for lymph node 
status in primary endometrial cancer. BMC Womens Health 2008; 8: 8.  
[7] Abu-Rustum NR, Khoury-Collado F, Pandit-Taskar N, Soslow RA, Dao F, Sonoda Y, Levine 
DA, Brown CL, Chi DS, Barakat RR, Gemignani ML. Sentinel lymph node mapping for grade 1 
endometrial cancer: Is it the answer to the surgical staging dilemma? Gynecologic Oncology 
(2009) 113: 163-69. 
[8] Veronesi U, Paganelli G Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection 
in breast cancer with clinically negative lymph-nodes. Lancet 1997; 349: 1864-67.  
[9] Mocellin S, Hoon DS, Pilati P, et al. Sentinel lymph node molecular ultrastaging in patients 
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1588-1595.  
[10] Ballester M, Dubernard G, Lecuru F, Heitz d, Mathevet P, Marret H, Querleu D, Folfier F, 
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[11] Cochran AJ, Roberts AA, Saida T. The place of lymphatic mapping and sentinel node 
biopsy in oncology. Int J Clin Oncol 2003; 8(3): 139-50. 
[12] Hill AD, Tran KN, Akhurst T, et al. Lessons learned from 500 cases of lymphatic mapping 
for breast cancer. Ann Surg 1999; 229: 528-535. 
[13] Tafra L (2001) The learning curve and sentinel node biopsy. Am J Surg 182:347–350 
[14] Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977; 39: 456-66. 
[15] Morton DL, Wen DR, Wong JH et al. Technical details of intraoperative lymphatic mapping 
for early stage melanoma. Arch Surg 1992; 127: 392-399. 
[16] Perrone AM, Casadio P, Formelli G, Levorato M, Ghi T, Costa S, Meriggiola MC, Pelusi G. 
Cervical and hysteroscopic injection for identification of sentinel lymph node in endometrial 
cancer. Gynecologic Oncology (2008) 111: 62-67. 
[17] Burke TW, Levenback C, Tomos C, Morris M, Wharton JT, Gershenson DM. 
Intraabdominal lymphatic mapping to direct selective pelvic and paraaortic lymphadenectomy in 
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[18] Kang S, Yoo HJ, Hwang JH, Lim MC, Seo SS Park SY. Sentinel lymph node biopsy in 
endometrial cancer: Meta-analysis of 26 studies. Gynecol Oncol 2011; 123: 522-27. 
[19] Abu-Rustum N, Khoury-Collado F, Gemignani ML. Techniques of sentinel lymph node 
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[20] Zivanovic O, Khoury-Collado F, Abu-Rustum NR, Gemignani ML. Sentinel Lymph Node 
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[21] Reuthebuch, Haussler A, Genoni M, Tavakoli et al. Novadaq SPY: Intraoperative Quality 
Assessment in Off-Pump Coronary Artery Bypass Grafting. CHEST 2004; 125: 418-424.  
[22] Yamamoto M, Orihashi K, Nishimori H, Wariishi S, et al. Indocyanine green angiography 
for intra-operative assessment in vascular surgery. Eur J Vasc Endovasc Surg. 2012 Apr; 43(4): 
426-32. 
[23] Lui DZ, Mathes DW, Zenn MR, Neligan PC. The application of indocyanine green 
fluorescence angiography in plastic surgery. J Reconstr Microsurg. 2011 Jul; 27(6): 355-64. 
[24] Kitai T, Inomoto T, Miwa M, Shikayama T. Fluorescence navigation with indocyanine 
green for detecting sentinel lymph nodes in breast cancer. Breast Cancer 2005; 12: 211– 215. 
[25] Wishart GC, Loh SW, Jones L, Benson JR. A feasibility study (ICG-10) or indocyanine 
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[26] Brouwer OR, Buckle T, Vermeeren L, Klop WM, Balm AJ, et al. Comparing the hybrid 
fluorescent-radioactive tracer indocyanine green-99m Tc-nanocolloid with 99m Tc-nanocolloid 
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Delair DF, Barakat RR, Abu-Rustum NR. The importance of applying a sentinel lymph node 
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for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study 
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standard laparoscopy, and robotic patients with endometrial cancer. Ann Surg Oncol 2012; 
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R, Torri V, Amoroso M, Croce C, Mangioni C. Systematic pelvic lymphadenectomy vs. no 
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ICF_001.pdf: 
Protocol Version #3: 02August2013 
Consent version: 13August2015 
Page 1 of 7 
CONSENT FOR CANCER RESEARCH  
Project Title: Sentinel Lymph Node Mapping for Endometrial Cancer  
Principal Investigator: Chad Michener, MD, Cleveland Clinic  
216-445-0226 
Sponsor: None 
Cancer research studies are coordinated by physicians and scientists from Cleveland 
Clinic, University Hospitals and Case Western Reserve University (CWRU) through the 
NIH National Cancer Institute (NCI) designated Case Comprehensive Cancer Center 
(Case CCC).  The goal of this collaboration is to enhance cancer treatment and 
research in Northeast Ohio.  This study is being offered at Cleveland Clinic. 
1.  Introduction 
We are asking you to participate in a research study. The purpose of this document is to 
summarize your discussion with the research team and provide you with written 
information to help you decide whether you want to participate in research.  Your 
decision is completely voluntary.  
Your treating doctor may also be an investigator on this research study. If so, your 
doctor will have an interest in both your welfare and in the research study. You are not 
required to take part in this research study offered by your doctor. You may ask for a 
second opinion from another doctor who is not linked to this study. If you choose not to 
be in this study, the quality of your regular medical care will not be affected.  
Please ask any questions you may have about the study or this consent form before 
signing it. Please take your time to make your decision. You will be given a copy of this 
form to keep. 
2.  Purpose 
Why Are You Being Asked To Take Part In This Research?  
You are being asked to participate in this research study because you will be having 
surgery for your endometrial (uterine) cancer that includes removing some of your pelvic 
lymph nodes (pelvic lymphadenectomy). 
Why Is This Study Being Done? 
The purpose of this study is to investigate the usefulness of sentinel lymph node 
biopsy for endometrial cancer.  
CCF IRB #: 13-662
Approval Date: 6/21/2016
Expiration Date: 6/20/2017


Protocol Version #3: 02August2013 
Consent version: 13August2015 
Page 2 of 7 
Lymph nodes are small glands which help to fight infection. Cancer cells can 
sometimes spread to lymph nodes. During cancer surgery some of your lymph nodes 
will be removed to see if the cancer has spread to them. In this study researchers will 
be using a procedure called a sentinel lymph node biopsy which will help to find the 
sentinel lymph node, the first lymph node that cancer would usually spread to.  
During your surgery while you are asleep (under anesthesia) doctors will use a small 
needle to inject a dye into your pelvic area. The dye will then travel to the sentinel 
lymph node. The doctor will then remove that lymph node and send it to the 
pathologist for examination. The doctors will then complete your surgery as planned 
and explained to you before surgery.  
Researchers will use the information they receive from your surgery and pathology 
reports to help determine the usefulness of sentinel lymph node biopsy for 
endometrial cancer.  
How Many People Will Take Part In The Study? 
    Approximately 200 people will take part in this study. About 100 patients will be                              
enrolled at Cleveland Clinic. 
3.  Study Procedures 
You will have 3 routine visits for this study. All of these visits will be done even if you 
are not entered into the study. There are not any additional tests, visits, or 
examinations that are required specifically for this study. The table below explains 
what will happen at your visits.  
Visit
Intervention
What procedures/tests that will be 
done at this visit? 
Visit 1
Within one 
month before 
surgery 
Pre-operative evaluation 
x Routine pre-operative labs 
x Routine pre-operative 
examination 
x Sign consent 
Visit 2
Operation 
x Cancer procedure with sentinel 
lymph node biopsies 
CCF IRB #: 13-662
Approval Date: 6/21/2016
Expiration Date: 6/20/2017


Protocol Version #3: 02August2013 
Consent version: 13August2015 
Page 3 of 7 
Visit 3
2-4 weeks 
after surgery
Post-operative evaluation
x Routine post-operative 
examination 
Your participation in the study will end after your post operative evaluation (visit 3).  
4.  Risks
The surgery you are having is not part of the study. Your doctor(s) will explain the 
risks and benefits of your surgery and you will sign a separate permission form for 
that.  
The main risk to this study is that you may have some additional lymph nodes 
removed if you participate in the study. This study requires a pelvic lymph node 
dissection. If you were not participating in this study, your doctor may or may not 
decide to perform a pelvic lymph node dissection. By removing these lymph nodes, 
we will be able to tell you whether or not they have cancer in them. However, there is 
a small risk of lymphedema (approximately 5-10%), which causes swelling of the legs 
post-operatively. 
The only other additional risk to the study is the very low risk of a sensitivity reaction 
to one of the dyes used to identify a sentinel lymph node. A sensitivity reaction may 
include shortness of breath, wheezing, a fast heart rate and low blood pressure. If 
this kind of reaction occurs during surgery you will be given medicine to help with 
these symptoms. There is less than a 2% risk of this type of reaction. 
5.  Benefits
    There is no guarantee that you will personally benefit by participating in this research 
    study.  Your participation in this study may provide information that may help other  
    people who have a similar medical problem in the future.  
6.  Alternatives to Participation
The alternative to participation in this study is to receive the standard surgical 
treatment for your disease, or to receive no treatment at all. 
7.  Costs and Compensation
There are no additional costs to you for participation in this research study.  The cost 
for routine tests and services that would normally be performed even if you don’t 
participate in the study will be billed to you or your insurance provider.  
You will not be paid for participating in this study.  
CCF IRB #: 13-662
Approval Date: 6/21/2016
Expiration Date: 6/20/2017


Protocol Version #3: 02August2013 
Consent version: 13August2015 
Page 4 of 7 
8.  Research-Related Injury 
It is important that you tell your study doctor or nurse if you feel that you have been 
injured because of taking part in this study.   
If injury occurs as a result of your involvement in this research, medical treatment is 
available from Cleveland Clinic and another medical facility but you/your medical 
insurance will be responsible for the cost of this treatment.  A research injury is an 
injury that happens as a result of taking part in this research study.  If you are injured 
by a medical treatment or procedure that you would have received even if you 
weren’t in the study, that is not considered a “research injury”. There are no plans for 
payment of medical expenses or other payments, including lost wages, for any 
research-related injury.  To help avoid injury, it is very important to follow all study 
directions. 
You will get medical treatment if you are injured as a result of taking part in this study.  
You and/or your health plan will be charged for this treatment.   The study will not pay 
for medical treatment.   
Further information about research-related injuries is available by contacting the 
Cleveland Clinic Institutional Review Board at (216) 444-2924.  
9.  Privacy and Confidentiality
If you volunteer to participate in this research, your protected health information (PHI) 
that identifies you will be used or disclosed to Chad Michener, MD or Kimberly 
Levinson, MD, the research staff at Cleveland Clinic and to Case Western Reserve 
University for administration. 
The PHI that we may use or disclose (release) for this research may include your 
name, address, phone number, date of birth, Social Security number, information 
from your medical record, lab tests, or certain information relating to your health or 
condition.. 
Some of the tests and procedures done solely for this research study may also be 
placed in your medical record so other doctors know you are in this study.  Upon 
completion of the study, you may have access to the research information that is 
contained in your medical record.   
In addition to the investigators and research staff listed above, your PHI may be 
looked at by other groups involved with the study such as the Cleveland Clinic 
Institutional Review Board, the Case Comprehensive Cancer Center Protocol Review 
CCF IRB #: 13-662
Approval Date: 6/21/2016
Expiration Date: 6/20/2017


Protocol Version #3: 02August2013 
Consent version: 13August2015 
Page 5 of 7 
and Monitoring Committee.  Your PHI may also be used by and/or disclosed 
(released) to: 
x The Food and Drug Administration;
x The Department of Health and Human Services; 
Once your personal health information is released it may be re-disclosed and no 
longer protected by privacy laws. 
Your research information may be used and disclosed indefinitely, but you may stop 
these uses and disclosures at any time by writing to Chad Michener, MD or 
Kimberly Levinson, MD, Cleveland Clinic at 9500 Euclid Ave., A-81, Cleveland, 
Ohio 44195, (216) 445-0226. 
Your participation in the research will stop, but any information previously recorded 
about you cannot be removed from the records and will continue to be used as part of 
this research.  Also, information already disclosed outside the Cleveland Clinic 
cannot be retrieved.  This will not affect your rights to treatment or benefits outside 
the research study.    
The Cleveland Clinic will not use your information collected in this study for another 
research purpose without your written permission; unless the Cleveland Clinic 
Institutional Review Board (IRB) assures your privacy and confidentiality is protected.  
The IRB is a committee whose job it is to protect the safety and welfare of research 
subjects. 
By signing this informed consent form, you are agreeing to the use of your research 
and medical record information.  If you choose not to sign this consent form, you will 
not be able to participate in this research study.  This Authorization does not have an 
expiration date. 
10.  Voluntary Participation 
Your participation in this research study is voluntary.  Choosing not to participate will 
not alter your usual health care or involve any penalty or loss of benefits to which you 
are otherwise entitled.  If you decide to join the study, you may withdraw at any time 
and for any reason without penalty or loss of benefits.  If information generated from 
this study is published or presented, your identity will not be revealed.   
If new information becomes available that may affect the risks or benefits associated 
with this study or your willingness to participate in it, you will be notified so that you 
can decide whether or not to continue participating.   
CCF IRB #: 13-662
Approval Date: 6/21/2016
Expiration Date: 6/20/2017


Protocol Version #3: 02August2013 
Consent version: 13August2015 
Page 6 of 7 
11.  Questions About the Research
If you have any questions, you can ask the Principal Investigators and/or research 
staff by writing or calling: Chad Michener, MD or Kimberly Levinson, MD, 
Cleveland Clinic, 9500 Euclid Ave., Desk A-81, Cleveland, Ohio 44195, 216-445-
0226.
Emergency and After-hours Contact Information
Main campus patients should contact the page operator at (216) 444-2200 or toll free 
at (800) 223-2273, and ask for the oncologist (cancer doctor) that is on call. 
If you are a Cleveland Clinic-Fairview participant, please call (216) 476-7540. 
If you are a Cleveland Clinic-Hillcrest participant, please call (440) 312-5560. 
If you have questions about your rights as a research subject, you may contact the 
Institutional Review Board (IRB) at Cleveland Clinic IRB 216-444-2924. 
Where Can I Get More Information?
You may call the National Cancer Institute’s Cancer Information Services at: 
 
1-800-4-CANCER (1-800-422-6237)  
You may also visit the NCI website at http://cancer.gov 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo 
You will get a copy of this form.  If you want more information about this study, ask 
your study doctor.   
US National Institutes of Health (NIH) Clinical Trial Database
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web 
site at any time. 
12.  Signature 
Signing below indicates that you have been informed about the research study in 
which you voluntarily agree to participate; that you have asked any questions about 
the study that you may have; and that the information given to you has permitted you 
to make a fully informed and free decision about your participation in the study.  By 
signing this consent form, you do not waive any legal rights, and the investigator(s) or 
CCF IRB #: 13-662
Approval Date: 6/21/2016
Expiration Date: 6/20/2017


Protocol Version #3: 02August2013 
Consent version: 13August2015 
Page 7 of 7 
sponsor(s) are not relieved of any liability they may have.  A copy of this consent form 
will be provided to you. 
Signature of Participant  
 
Date  
   Printed Name of Participant 
I have discussed the information contained in this document with the participant and it is 
my opinion that the participant understands the risks, benefits, alternatives and 
procedures involved with this research study. 
Signature of Person Obtaining Consent 
Date  
 
 
Printed Name of Person Obtaining Consent 
CCF IRB #: 13-662
Approval Date: 6/21/2016
Expiration Date: 6/20/2017